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Dramatic Progress in Fight against Advanced Melanoma

Oral Oncolytics Abandoned by 1 of 10 Patients with Cancer

“This is truly a time for celebration for our patients”

High out-of-pocket cost the main culprits

By Neil Canavan

By Audrey Andrews Schuchter, MD, Professor of Medicine and Chief, Hematology Oncology, Department of Medicine, Abramson Cancer Center, Philadelphia. “Over the years we’ve had only 2 drugs approved for this, and both have pretty limited activity in advanced patients.” Yet, in the course of 20 minutes, the results reported for 2 clinical trials with 2 new drugs with Continued on page 8

Significant Advances in Lung Cancer Highlighted at AACR Novel biomarkers, diagnostic test, and therapeutic targets

By Caroline Helwick Orlando, FL—Lung cancer studies made news at the 2011 American Association of Cancer Research annual meeting. Research groups identified potential new therapeutic targets; developed a biomarker panel to detect lung cancer in nonsmokers and, possibly, in early-stage mesothelioma; and outlined the potential to reduce the risk for lung cancer in former smokers.

Biomarkers in the Blood A panel of biomarkers may soon identify the presence of lung cancer in blood samples. When used in conjunction with spiral computed tomography scans, which are not very specific for lung cancer diagnoses, the assay could help triage patients for further assessment.

Continued on page 28

AVBCC Conference | March 29-30 | Philadelphia

Chicago, IL—One of every 10 patients with cancer abandons new prescriptions for oral oncolytics, according to a study presented at the American Society of Clinical Oncology 2011 annual meeting and concurrently published in the Journal of Oncology Practice (Streeter SB, et al. 2011; 7:46-51).

Although the 10% prescription aban-

donment rate is in line with that of some other specialty drugs, it is higher than rates for chronic conditions, such as hypertension and depression. And, more distressing, the study results show that the rate climbs to approximately 25% among patients whose out-of-pocket (OOP) costs exceed $500.

Lee Schwartzberg, MD, Medical Continued on page 22

Exemestane Reduces First Invasive Breast Cancer by 65% New option for primary prevention in women at risk

By Susana Wright Chicago, IL—Exemestane (Aromasin) appears to be a good alternative to tamoxifen (Nolvadex) for prevention of breast cancer in postmenopausal women, according to results of the randomized, placebo-controlled MAP.3 trial reported at ASCO 2011.

Exemestane reduced the risk of a first invasive breast cancer by 65% in healthy postmenopausal women with risk factors for breast cancer, and also reduced the risk of known breast cancer precursor lesions, including ductal carcinoma in situ, lobular carcinoma in situ, atypical ductal hyperplasia, and atypical lobular hyperplasia, which would suggest further reductions in invasive cancers as time goes by.

Exemestane did not increase the

Photo courtesy SABCS/Todd Buchanan 2010

Chicago, IL—Oncologists do not engage in hyperbole. It is not in their nature. If the word “unprecedented” is used to describe a clinical outcome, it’s because something truly remarkable has occurred; such is the case in the reporting of 2 investigations of advanced melanoma at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) for the drugs vemurafenib (PLX4032) and ipilimumab (Yervoy).

“You have to understand the landscape of what our patients with advanced melanoma has looked like,” said melanoma expert Lynn M.

Paul Goss, MD, PhD incidence of any serious side effects compared with placebo, including second malignancies, or treatment-related deaths.

Exemestane is currently indicated for the adjuvant treatment of postContinued on page 14

INSIDE FDA UPDATES

First thyroid cancer drug

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VALUE PROPOSITIONS

Patients embrace extra testing for targeted therapies . . . . . . . . . . . . . . 6 MEETING COVERAGE

Full Coverage of the First Annual Conference of the Association for Value-Based Cancer Care Coming in July ©2011 Engage Healthcare Communications, LLC

ASCO annual meeting . . . . . . . . . . . . . 8 AACR annual meeting . . . . . . . . . . . 28 ISPOR annual international meeting . . . . . . . . . . . . . . . . . . . . . . . . . . 35

AMCP annual meeting

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VBCC PERSPECTIVE

The challenge of value-based care in oncology . . . . . . . . . . . . . . . . . 20 HEALTH POLICY

ACOs: implications for oncologists . . . . . . . . . . . . . . . . . . . . . . . 21 Real-life data: savings with 21-gene test . . . . . . . . . . . . . . . . . . . . . 30

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VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 12:52 PM Page 3

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 brett@engagehc.com Lara Reiman lara@engagehc.com 732-992-1892 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Senior Production Manager Robyn Jacobs Quality Control Director Barbara Marino 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 and reprint information please contact: circulation@valuebasedcare.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 PERMISSIONS DEPARTMENT. Fax: 732-992-1881.

Address all editorial queries to: editor@valuebasedcare.com Telephone: 732-992-1889 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 7 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved.

Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher.

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

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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VBCC PERSPECTIVES

NCCN CONFERENCE

The Challenge of Value-Based Care in Oncology: Improving Clinical Outcomes More….

Hepatitis B a Risk with Chemotherapy More….

AMCP ANNUAL MEETING ASCO ANNUAL MEETING ASCO Presidents: Patients, Pathways, and Progress Patients–Oncologists Discussion on Treatment Costs Personalized Medicine Comes of Age More….

Will Generic Docetaxel Lower Total Medical Costs with Taxane Therapy?

Comparing 4 Leading Regimens for NSCLC More….

ACCC NATIONAL MEETING Oncology 2021: Cost, FDA, and Cancer Care More….

AACR ANNUAL MEETING Metabolic Syndrome a High Risk for Liver Cancer Investigational Regimen Improves Survival in CRC

ISPOR INTERNATIONAL MEETING National Survey Reveals Disparities in Mammography OOP Expenditures More….

HOPA ANNUAL MEETING Pharmacist Reviews Cancer Drugs in the Pipeline

HEALTH POLICY Humana’s Real-World Data Confirm CostSavings with the 21-Gene Recurrence Assay 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

Section Editor

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY

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

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

Ira Klein, MD, MBA Aetna Hartford, CT

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

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

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

Naimish Pandya, MD University of Maryland Baltimore, MD

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

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

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT David Hom, MBA Solucia Farmington, CT

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Foley Hoag Washington, DC Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

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FDA UPDATES Vandetanib First Drug Indicated for Medullary Thyroid Cancer The US Food and Drug Administration (FDA) approved the orphan drug vandetanib (trade name pending; AstraZeneca), a tyrosine kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease.

Vandetanib is the first and only FDAapproved treatment for this rare cancer.

“Vandetanib’s approval underscores the FDA’s commitment to approving treatments for patients with rare and difficult-to-treat diseases,” said Richard Pazdur, MD, Director of the Office of Oncology Drug Products at the FDA. The recommended dose is 300 mg administered orally once daily. For patients with moderate renal impairment or severe impairment, the starting dose should be 200 mg.

Medullary thyroid cancer can occur spontaneously or present as part of a genetic syndrome. Its estimated incidence in the United States in 2010 was 1300 to 2200 cases, representing 3% to 5% of all cases of thyroid cancer.

The approval was based on an international, multicenter, randomized, double-blind trial involving 331 patients with unresectable locally advanced or metastatic medullary thyroid carcinoma.

The median progression-free survival (PFS) rate was 22.6 months with vandetanib versus 16.4 months with placebo. Overall, 15% of the patients had died, and overall survival (OS) did not differ between the 2 groups.

The most common grade 3 or 4 adverse events (≥5%) were diarrhea/ colitis, hypertension and hypertensive crisis, QT prolongation, fatigue, and rash. Five patients who received vandetanib died from respiratory failure, respiratory arrest, aspiration pneumonia, cardiac failure with arrhythmia, or sepsis; 2 additional patients died after data were collected.

Vandetanib is associated with serious adverse effects and was approved with a risk evaluation and mitigation strategy program. (April 6, 2011)

production of cytochrome P450 17A1 (CYP17A1), a hormone that stimulates cancer-cell growth.

The FDA accelerated abiraterone’s approval ahead of it’s scheduled June 20, 2011, regulatory date.

The recommended dosage for abiraterone is 1000 mg orally once daily in combination with prednisone 5 mg orally twice daily.

In a phase 3 clinical study, 1195 patients with late-stage castrationresistant prostate cancer who had previously received docetaxel chemotherapy were randomized to abiraterone 1000 mg/day with prednisone 5 mg twice daily or a placebo twice daily with prednisone. Among patients who received abiraterone, median OS, the primary end point, was 14.8 months

compared with 10.9 months in patients given placebo.

The most common adverse effects with abiraterone were joint swelling or discomfort, hypokalemia, muscle discomfort, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. (April 28, 2011)

FDA Accelerates Abiraterone Approval for Advanced Prostate Cancer Expedited through the FDA’s priority review program, abiraterone acetate (Zytiga; Centocor Ortho Biotech) in combination with prednisone received approval for the treatment of metastatic castration-resistant prostate cancer in patients who have previously undergone chemotherapy with docetaxel. Abiraterone targets the

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FDA UPDATES New Indication for Everolimus for Neuroendocrine Pancreatic Cancer The FDA approved a new indication for everolimus (Afinitor; Novartis) for the treatment of metastasized or unresectable locally advanced progressive neuroendocrine tumors of pancreatic origin, a rare pancreatic cancer that progresses slowly.

Fewer than 1000 new cases are diagnosed annually in the United States.

“Patients with this cancer have few effective treatment options,” said Dr Pazdur. “Afinitor has demonstrated the ability to slow the growth and spread of neuroendocrine tumors of the pancreas.”

The recommended dosage for everolimus is 10 mg orally daily. Severe or

intolerable adverse events may necessitate a temporary reduction of the dosage to 5 mg daily or a dose interruption.

The median PFS was 11 months with everolimus versus 4.6 months among those who received placebo.

The most common grade 3 or 4 adverse events (≥5%) were stomatitis and diarrhea.

ADVERTISEMENT

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

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

1

2

4 3 5 Years post-chemotherapy

6

7

8

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.

© 2010 Amgen. All rights reserved.

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06-10

Everolimus is already indicated for the treatment of advanced renal-cell carcinoma that fails to respond to treatment with sunitinib (Sutent) or sorafenib (Nexavar) and for unresectable subependymal giant-cell astrocytoma associated with tuberous sclerosis. (May 5, 2011)

Sunitinib Second New Drug for Pancreatic Neuroendocrine Tumors Sunitinib (Sutent; Pfizer) is the second new option for the treatment of metastasized or unresectable locally advanced progressive pancreatic neuroendocrine cancerous tumors. The “FDA believes it is important to provide cancer patients with as many treatment options as possible,” Dr Pazdur said. “The agency is committed to working with companies to bring innovative new therapies to the market and encourages companies to continue exploring additional uses for approved products.”

The recommended dose for sunitinib is 37.5 mg/day orally. A dose interruption or reduction to 25 mg daily may be necessary when adverse events are severe or intolerable.

The efficacy and safety of sunitinib were established in a single study of 171 patients with metastatic or unresectable locally advanced disease. The median PFS was 10.2 months with sunitinib compared with 5.4 months with placebo. The most common grade 3 or 4 adverse events (≥5%) were neutropenia, hypertension, palmar-plantar erythrodysesthesia syndrome, and leukopenia.

Sunitinib has previously been approved for the treatment of metastatic renal-cell carcinoma and gastrointestinal stromal tumor. (May 20, 2011)

New Formulation of Levoleucovorin Approved A new, ready-to-use (RTU) injectable formulation of the folate analog levoleucovorin (Fusilev; Spectrum Pharmaceuticals) received FDA approval.

Like the previously approved lyophilized formulation, the RTU formulation is indicated for rescue after high-dose methotrexate therapy in the treatment of osteosarcoma.

Levoleucovorin is also indicated for reducing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists.

Levoleucovorin is available in vials as freeze-dried powder and in singleuse vials containing 17.5-mL and 25-mL sterile solution. When administered as rescue therapy, the recommended dosage is 7.5 mg every 6 hours for 10 doses. (April 29, 2001) ■

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VALUE PROPOSITIONS Patients Value Additional Tests for Experimental Cancer Therapies

Florida Cancer Network Adds Web-Based Treatment Tool to Address Quality, Cost Issues

A survey of 61 patients with cancer suggests that many patients are willing to undergo extra tests to participate in clinical trials that will give them access to experimental cancer treatments that may offer improved outcomes and potentially increased survival options.

The team of researchers from the Mayo Clinic, Scottsdale Healthcare, AZ, and the Translational Genomics Research Institute in Phoenix suggests that these results may help increase support for personal medicine research that is focused on targeted therapies that require specific testing to identify a subset of patient populations with a particular genetic makeup that would benefit from these treatments.

“This is the first study of its kind where patients themselves were asked what tests and medical imaging studies they would be willing to undergo while participating in clinical studies for their cancer. Patients also were asked how invasive they perceived such tests and studies,” said lead author Raoul Tibes, MD, PhD, a hematologist/oncologist at the Mayo Clinic Cancer Center. Patients appear to be willing to ignore the extra burden of even invasive testing in the hope of receiving advanced experimental therapies that are often not available outside of clinical trials. The study is scheduled to appear in July in Cancer.

“This is important information, because it tells us that we can design clinical studies that ask patients to give extra tumor biopsies. But we need to carefully judge how many biopsies we request and what molecular tests we do with the tumor sample,” said coauthor Mitesh J. Borad, MD, Associate Director of Phase I Drug Development, Mayo Clinic, AZ.

The Florida Comprehensive Care Network (FCCN), a statewide network of medical and radiation oncologists providing comprehensive, evidence-based care to patients with cancer, has signed an agreement with ITA Partners that allows FCCN to use ITA’s oncology decision-support platform (called eviti) across its network of oncologists.

Using a web-based platform will provide FCCN’s oncologists evidencebased treatment options for each patient, in real-time, at the point of prescribing.

This “is an ideal platform for our business model. Our physicians are committed to providing treatment that has been demonstrated to be effective. eviti gives them access to all evidence-based options at the point of care, allowing them to more efficiently make informed and effective treatment plan decisions that align with the patient’s insurance plan language,” said Craig Deligdish, MD, Chief Medical Officer, FCCN and VBCC board member.

“Our common goal of appropriate, cost-effective treatment for every patient makes the ITA-FCCN partnership valuable to patients, providers, and payers. eviti will help break down information barriers, assuring that each patient is prescribed evidence-based care,” said Eduardo Beruff, ITA President and Chief Executive Officer. eviti is the first independent, fully integrated solution that addresses not only the quality but also the cost concerns of patients with cancer, oncologists, and payers in any treatment setting.

Researchers Discover 2 Molecules Involved in Cancer Metastasis Researchers from Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, identified 2 regulatory molecules that enable a tumor, which originally is usually not deadly, to metastasize. This discovery could eventually help develop new therapies for the prevention of metastasis by inactivating these molecules.

The 2 molecules, p190RhoGEF and p190RhoGAP, “regulate the activity of RhoC, an enzyme that plays a crucial role during tumor metastasis and that has been identified as a biomarker for invasive breast cancer,” according to a press release from the university (April 7, 2011).

Small but Positive Reductions in Some Cancer Death Rates A new report published in March in the Journal of the National Cancer Institute (2011;103:714-736) shows slow but consistent reductions in some cancer types in men and women between 2003 and 2007, the most recent years for which data are available.

Reductions in men include –2.5% in lung/bronchus cancer; –3.3% in prostate cancer; –3.2% in colon/rectal cancer; and –0.9% in leukemia.

In women, reductions were –0.9% in lung/bronchus cancer; –2.2% in breast cancer; –3.2% in colon/rectal cancer; and –1.7% in ovarian cancer.

Pancreatic cancer increased in both sexes.

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Oncologist Calls for Shorter Time to Approval of High-Value Targeted Cancer Drugs New understanding of the mechanism of cancer as genetic and molecular cancer–causing lesions has enabled the development of targeted therapies that are producing excellent results in early clinical trials. This new understanding of the mechanism of cancer and the resultant development of superior therapies should shorten the time to drug approval by the US Food and Drug Administration (FDA), said Bruce A. Chabner, MD, Professor of Medicine, Harvard Medical School, and Director of Clinical Research, Massachusetts General Hospital Cancer Center, Boston, in a recent perspective in the New England Journal of Medicine (2011;364:1087-1090).

Recent phase 1 clinical trials of many targeted cancer drugs have produced excellent results and merit a change in the FDA requirement for long and costly randomized phase 3 trials. “When striking clinical results have been demonstrated in a sizable, readily identifiable patient population in phase 1, the journey to drug approval should not be prolonged,” Dr Chabner stated.

He cited the recent results of 2 new phase 1 trials (of patients who have not responded to standard therapies) with 2 agents—PLX4032, which produced an 81% response rate in 38 patients with melanoma with BRAF mutation, and crizotinib, with a 57% response rate in 82 patients with non–small-cell lung cancer EML4-ALK fusion. In both cases, the disease control rate for ≥8 weeks exceeded 90%, with little toxicity. Such results, he argues, require reconsideration of the prolonged and expensive process, especially for conditions with limited effective therapies. The value of these highly targeted therapies warrants an accelerated process.

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FROM THE LITERATURE Beta-Blocker Therapy for ≥1 Year Reduces Mortality in Malignant Melanoma The association between beta-blocker therapy and the overall risk for cancer has not been well investigated. One earlier study suggested that betablockers may reduce the risk for prostate cancer, and preclinical trial findings indicate that beta-blockers inhibit tumor growth and metastasis in melanoma.

New results have demonstrated for the first time that taking beta-blockers for ≥1 year is associated with improved outcomes in thick malignant melanoma (De Giorgi V, et al. Arch Intern Med. 2011;171:779-781).

Researchers prospectively reviewed clinical records from 1993 through 2009 of all patients with histologically confirmed malignant melanoma (Breslow thickness >1 mm). Patients who used beta-blockers for ≥1 year were considered to have undergone treatment.

Of 121 patients with a thick melanoma, 30 had been receiving beta-blocker therapy for ≥1 year. After a median follow-up of 2.5 years, tumor progression occurred in 3.3% of patients taking beta-blockers and in 34.1% of those not taking the drugs. A Cox model indicated a 36% risk reduction for every 1 year of beta-blocker use. No deaths occurred in patients taking beta-blockers compared with 24 deaths in those not taking beta-blockers.

Beta-blocker therapy for >1 year significantly reduced the risk for death from thick melanoma.

The prevalence of basal-like breast cancer was greater in younger African American women than in white, but this cancer does not seem to be inherently more aggressive in this population. The authors noted that disparities in access to care, rather than racial eth-

nicity, could affect poor outcomes in these women.

Mortality was greatest in all women with HER2-positive/ERnegative subtype. Mortality was higher in African American women than in white women, but race was

significant only among women with the luminal A subtype. In women with basal-like breast cancer, mortality was higher in white women than in African American women and was greatest in postmenopausal white women.

Continued on page 50

Racial Disparities in Breast Cancer Linked to Access to Care, Not Biology Breast cancer among younger African American women is often the more aggressive basal-like subtype, which has been suggested as one of the reasons that long-term outcomes have been worse in that population than in white women.

Recent findings, however, show that African American women have worse outcomes regardless of the type of breast cancer they have, suggesting that other reasons, including access to care, is a main reason for their poor clinical outcomes (O’Brien KM, et al.

Clin Cancer Res. 2010;16:6100-6110).

This study involved 518 African American women and 631 white women who had breast cancer (classified as either luminal A, luminal B, basal-like, or HER2-positive/ER-negative) that was diagnosed between 1993 and 2001. They were followed up for a median of 9 years and were case matched to National Death Index– recorded deaths through 2006.

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With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology offers health plans and oncology practices a comprehensive solution that enhances the quality and consistency of patient care. With evidence-based medicine as the foundation of the program, we further help patients by providing direct, personalized support and education between office visits as well as advance care planning regarding future treatment and care preferences. Through this patient-centric approach, we help health plans and oncology practices collaborate by aligning incentives to drive better patient outcomes as well as encourage the efficient use of healthcare resources. After all, isn’t cancer a disease we should manage together?

To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.

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ASCO ANNUAL MEETING

Dramatic Progress in Fight against Advanced... entirely different mechanisms of action strongly suggest that the lives of thousands of patients are about to change.

“With ipilimumab approved just weeks ago [on March 25, 2011] and vemurafenib very likely to be approved soon on the basis of the randomized phase 3 trial presented here today, it is really unprecedented to have 2 new types of therapeutic approaches with such high level of activity become available at the same time,” Dr Schuchter said. And that activity can be profound.

“When patients with the BRAF mutation are treated with vemurafenib [the mutation required for the activity of the drug], within 72 hours their symptoms can improve—this level of activity in patients who are seriously ill is remarkable.” Further, the drug is very well tolerated, incurring few of the side effects expected with the use of chemotherapy. “This is truly a time for celebration for our patients,” she pointed out.

The successful results for both new drugs were published in the New England Journal of Medicine (Chapman PB, et al. 2011 Jun 5 [Epub ahead of print]) on the day of the ASCO presentations.

Vemurafenib Vemurafenib, an oral drug, is a targeted therapy that inhibits the activity of the BRAF genetic mutation, an aberration that exists in up to 60% of patients with melanoma. “This pathway is one of the primary ways a cell begins to proliferate when it receives an appropriate signal,” explained study investigator Paul B. Chapman, MD, of Memorial Sloan-Kettering Cancer Center, New York. Normally the pathway is inactive, but with the BRAF mutation the pathway is constitutively active. “It’s like having a switch broken in the on position.” Vemurafenib was designed to bypass that switch, thereby interrupting the signaling pathway and resulting in melanoma (and only melanoma) cell death.

In this phase 3, randomized, openlabel trial, vemurafenib was compared with dacarbazine (administered by injection) in 675 previously untreated patients with late-stage melanoma identified as having the BRAF mutation. After beginning treatment, patients’ responses to therapy were assessed at 6 and 12 weeks and then every 9 weeks thereafter.

Positive results for the vemurafenibreceiving cohort were seen almost immediately. “It is unprecedented to report a trial this early,” said Dr

8

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Chapman. “Yes, our median follow-up time is still only 3 months, yet, the survival curves separated very early.”

Although not enough time had passed to calculate a median overall survival

“It is really unprecedented to have 2 new types of therapeutic approaches with such high level of activity.”

—Lynn M. Schuchter, MD (OS), the estimated 6-month survival rate for patients taking vemurafenib was 84% versus only 64% in those treated with dacarbazine. “That’s a 63% decrease in risk of death, a huge difference,” he said.

Large differences in progression-free survival (PFS) were also seen (median of 5.3 months for vemurafenib vs 1.6 months for dacarbazine), with a 74% decrease in disease progression risk for the former. The general response rate was 48.4% for vemurafenib and 5.5% for dacarbazine. All treatment benefits were gained with only minimal side effects.

“It is unprecedented to report a trial this early. Yes, our median follow-up time is still only 3 months, yet, the survival curves separated very early.”

—Paul B. Chapman, MD “This is the first single agent that as a monotherapy improves the proportion of therapeutic response, progression-free survival, and overall survival as compared with a chemotherapy treatment,” concluded Dr Chapman.

“This is a foundation that our field can build on to develop even more effective treatment by using melanoma drug combinations.”

Ipilimumab The second study in advanced

VALUE-BASED CANCER CARE

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June 2011

Continued from cover

melanoma reported at the meeting included a new combination of dacarbazine and ipilimumab. Ipilimumab is a human monoclonal antibody that interacts with the activated T-cells of the immune system, causing the T-cells to persist in their attack on diseased tissue rather than have that activity be naturally attenuated over time. “This allows for a much more robust T-cell activation and proliferation,” said lead investigator Jedd D. Wolchok, MD, Medical Oncologist at Memorial SloanKettering Cancer Center.

Ipilimumab had previously demonstrated activity in melanoma in a study presented at last year’s ASCO meeting; however, patients in that trial had already received standard

treatment were allowed to continue in the study for the maintenance phase, where they received either ipilimumab or placebo.

At a median follow-up of 3 years, the OS results showed superiority for the active-drug combination: 47.3% of patients were alive at 1 year with the ipilimumab/dacarbazine combination versus 36.3% of patients with dacarbazine alone; median times of survival were 11.2 months versus 9.1 months, respectively.

“This equated to a 28% reduction in the risk of death for the combination,” said Dr Wolchok. An improvement in PFS was also observed; the median duration of response was 19.3 months with ipilimumab versus 8.1 months

The use of vemurafenib plus ipilimumab “equated to a 28% reduction in the risk of death for the combination.”

—Jedd D. Wolchok, MD treatment before administration of ipilimumab. “This was the first drug ever to improve overall survival in previously treated patients,” said Dr Wolchok, who reported that based on those results, the current study was initiated to give ipilimumab to patients as front-line therapy, just after their late-stage melanoma diagnosis.

In this randomized, blinded investigation, 502 patients with late-stage melanoma were randomized in a 1:1 fashion to a combination of ipilimumab/dacarbazine or to dacarbazine/ placebo, administered every 3 weeks.

After 4 treatment cycles, all patients who were showing response to either

with dacarbazine alone. “This sustained response is very characteristic of ipilimumab as an immunotherapy.”

Of note, serious side effects were more frequent with ipilimumab and were related to the immune response (ie, inflammatory in nature). However, these effects were typically resolved with dose de-escalation or with the use of corticosteroids.

“This is the second randomized study to show a survival advantage for the use of ipilimumab,” concluded Dr Wolchok. “We look forward to combining ipilimumab with other active agents, perhaps vemurafenib, in the near future.” ■

Amrubicin Outperforms Topotecan as Second-Line Therapy for SmallCell Lung Cancer

By Susana Wright Chicago, IL—Results of the phase 3 ACT-1 trial suggest that amrubicin (Calsed) may have some advantages over topotecan (Hycamtin) as secondline treatment for small-cell lung cancer (SCLC). Both drugs achieved similar overall survival (OS) as second-line treatment, but amrubicin improved response rates, improved progressionfree survival (PFS), and improved control of lung cancer–associated symptoms, whereas topotecan worsened those symptoms.

Subgroup analysis suggested that amrubicin achieved a modest im-

provement in OS compared with topotecan in patients who were refractory at baseline.

Lead investigator Robert M. Jotte, MD, hematologist/oncologist at the Rocky Mountain Cancer Center, US Oncology, Denver, presented these at ASCO 2011. “Topotecan is too difficult to use and is not a good option for our patients,” he said.

SCLC has a dismal prognosis, with a 5-year survival of approximately 6%, and there is a pressing need for more effective treatments, Dr Jotte said. The Continued on page 9

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ASCO ANNUAL MEETING

Evidence Base Lacking for Almost 1 of 5 Metastatic Colon Cancer Regimens Costs to payers are in the millions of dollars

By Audrey Andrews Chicago, IL—Treatment regimens that are not based on evidence and therefore not included in treatment guidelines are used “with some frequency” in patients with metastatic colon cancer, according to academic investigators who teamed up with UnitedHealth Group to examine claims data. They presented their findings at ASCO 2011.

The average patient with a diagnosis of metastatic colon cancer had a 19% chance of receiving a regimen not backed by evidence. In the case of bevacizumab alone, this amounted to $1.3 million in costs for UnitedHealthcare.

Jonas A. de Souza, MD, a hematologist/oncologist at the University of Chicago Medical Center, examined the use of various regimens that include panitumumab (Vectibix), cetuximab (Erbitux), bevacizumab (Avastin), oxaliplatin (Eloxatin), capecitabine

(Xeloda), and irinotecan (Camptosar) for metastatic colon cancer. Since the early 2000s, he said, the newer agents have “strikingly improved the treatment of colon cancer; however, they have increased the price of treatment.”

Median survival has increased from approximately 18 months in the early 2000s to more than 25 months today.

The availability of cetuximab, bevacizumab, and panitumumab is largely responsible for this improvement.

One of 7 patients with cancer now spends >20% of household income on healthcare and insurance and often must choose less-effective treatments.

“Not uncommonly we see patients referred to us having received substandard care,” he said.

Given the growing number of drugs used for this type of cancer, it is a “given” that some percentage of treatments will not be based on evidence, which has clinical and cost implica-

Amrubicin Outperforms... Continued from page 8 study goal was to see if topotecan and amrubicin could improve the outcomes with SCLC. Topotecan is approved in the United States and in Europe as second-line treatment for SCLC; amrubicin, a potent topoisomerase II inhibitor, is approved in Japan for SCLC and nonSCLC. A total of 637 patients were randomized in a 2:1 ratio to intravenous (IV) amrubicin 40 mg/m2 on days 1 to 3 or IV topotecan 1.5 mg/m2 on days 1 to 5, with growth factors given in the last third of the trial. Both arms received a median of 4 cycles of chemotherapy.

More patients received full-dose chemotherapy in the amrubicin arm.

More than 75% of patients receiving amrubicin did not require dose reductions versus 55.3% of those treated with topotecan.

Median OS was 7.5 months in the amrubicin arm versus 7.8 months in the topotecan arm. However, a hazard ratio (HR) of 0.880 suggested that amrubicin achieved some improvement over topotecan after 6 months, Dr Jotte noted.

Amrubicin appears to have a modest advantage in patients with refractory disease (median OS 6.2 months vs 5.7 months, respectively) but not in OS-sensitive patients. Dr Jotte noted that the HR of 0.766 for refractory

VOL. 2

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disease suggested that amrubicin improved survival after 6 months in this subgroup.

Overall response rates significantly favored amrubicin over topotecan (31.1% vs 16.9%, respectively), as did time to PFS (4.1 months vs 3.5 months, respectively).

Patients taking amrubicin had better control of SCLC symptoms, including improved appetite, cough, and dyspnea; these symptoms worsened in patients taking topotecan. Both agents caused fatigue, which was approximately 3 times greater with topotecan.

More infections occurred with topotecan than amrubicin, but fewer transfusions were needed with topotecan than with amrubicin (31.8% vs 52.8%, respectively).

More cases of anemia, neutropenia, and thrombocytopenia were reported in the topotecan arm. Approximately 11% of patients in both arms died with treatment. Despite concern about cardiotoxicity with amrubicin, no difference in left-ventricular ejection fraction was found between the 2 arms with cumulative dosing.

Steven Vogel, MD, a community oncologist in New York City, said that in his practice, his choice to treat with amrubicin depends on cost, since other options are available for second-line therapy. ■

“Our findings support the development of clinical pathways and new payment methods that limit the use of non–evidence-based regimens and that promote high-value care.”

—Jonas A. de Souza, MD tions for payers, patients, and society.

“It is important to identify low-value care,” Dr de Souza maintained.

“Our hypothesis was that non–evidence-based regimens for metastatic colon cancer are both commonly prescribed and reimbursed,” he said.

3 Regimens Singled Out The primary objective was to estimate the utilization of 3 regimens addressed in the National Comprehensive Cancer Network guidelines as not recommended in patients with metastatic colon cancer: • Single-agent capecitabine as a salvage therapy after failure on a fluoropyramidine-containing regimen (ie, 5-fluorouracil, capecitabine) • Bevacizumab combined with a second-line regimen after progression on a bevacizumab-containing firstline regimen (ie, continuation of bevacizumab after progression) • Panitumumab after clinical failure on cetuximab or cetuximab after failure on panitumumab (ie, sequential use of an epidermal growth factor receptor [EGFR] inhibitor).

The UnitedHealthcare claims database represents >26 million members and 700,000 physicians. The analysis included 7642 patients with incident colon cancer diagnosed between January 2007 and July 2010. Of these patients, 1041 (14%) received ≥1 agent used only in the metastatic setting.

Of 864 patients using bevacizumab, 90 received the drug beyond progression. This included patients receiving bevacizumab/oxaliplatin who progressed and went on to use bevacizumab plus irinotecan or vice versa.

Of 121 patients receiving capecitabine, 49 received single-agent capecitabine after having used it in combination with standard regimens. For the EGFR inhibitors, 144 patients received cetux-

imab and 38 received panitumumab; 6 patients received panitumumab after progressing on cetuximab.

In total, non–evidence-based regimens constituted 10% of bevacizumabbased treatments, 40% of capecitabinebased treatments, and 16% of EGFR-based treatments. The average patient had a 13% chance of receiving a regimen for metastatic colon cancer that was not evidence-based.

A sensitivity analysis based on treatment and the original diagnosis identified 917 patients, and 600 patients were identified based on the drug regimen only. “We considered these true cases of metastatic colon cancer,” he said. Examination of this group showed that 139 (19%) patients had received ≥1 treatment regimens not based on evidence.

What Did This Cost Payers?

The cost of inappropriate prescribing of antineoplastic agents was considerable. Bevacizumab was used non–evidence-based in 636 claims, meaning that for a 70-kg man receiving 5 mg/kg at a cost of $5.96/mg (average sales price January 2011), UnitedHealthcare paid out $1,326,696, Dr de Souza said.

Capecitabine was non–evidencebased in 218 claims, resulting in $621,463 in reimbursements. Panitumumab had 19 unsupported claims, resulting in $69,665.

Dr de Souza acknowledged that this was a retrospective analysis of administrative data, and no data on clinical outcomes were available.

Patient demographic information was limited, and investigators made assumptions regarding the diagnosis of metastatic colon cancer. They did, however, take into consideration that some patients may have been switched to unsupported regimens based on toxicity with standard treatment. If this occurred within 90 days, they were not counted in the analysis; the analysis included only those patients switching to unsupported regimens beyond 90 days of the initial therapy.

Dr de Souza speculated that physicians may prescribe regimens that are not backed by evidence because they have no knowledge of their lack of benefit, they have financial incentives for doing so, or they simply lack alternatives for these very ill patients.

“Our findings support the development of clinical pathways and new payment methods that limit the use of non–evidence-based regimens and that promote high-value care,” Dr de Souza concluded. ■

www.ValueBasedCancerCare.com

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Now Approved

YERVOY

â&#x201E;˘

(ipilimumab)

INDICATION YERVOY is indicated for the treatment of unresectable or metastatic melanoma.

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 immunemediated 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.

Important Safety Information continued on adjacent page.

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:02 PM Page 11

IMPORTANT INFORMATION ImportantSAFETY Safety Information Recommended Dose Modifications:

Immune-mediated Endocrinopathies:

Withhold dose for moderate immune-mediated adverse reactions until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day.

Permanently discontinue YERVOY for any of the following: t 1FSTJTUFOU NPEFSBUF BEWFSTF SFBDUJPOT PS JOBCJMJUZ UP SFEVDF corticosteroid dose to 7.5 mg prednisone or equivalent per day. t 'BJMVSF UP DPNQMFUF GVMM USFBUNFOU DPVSTF XJUIJO XFFLT GSPN administration of first dose. t 4FWFSF PS MJGF UISFBUFOJOH BEWFSTF SFBDUJPOT

t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF to life-threatening immune-mediated endocrinopathies (requiring IPTQJUBMJ[BUJPO VSHFOU NFEJDBM JOUFSWFOUJPO PS JOUFSGFSJOH XJUI BDUJWJUJFT of daily living; Grade 3-4) occurred in 9 (1.8%). â&#x20AC;&#x201C; All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. o PG UIF QBUJFOUT XFSF IPTQJUBMJ[FE GPS TFWFSF FOEPDSJOPQBUIJFT t .PEFSBUF FOEPDSJOPQBUIZ SFRVJSJOH IPSNPOF SFQMBDFNFOU PS NFEJDBM intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1Â case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. t .FEJBO UJNF UP POTFU PG NPEFSBUF UP TFWFSF JNNVOF NFEJBUFE endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. t .POJUPS QBUJFOUT GPS DMJOJDBM TJHOT BOE TZNQUPNT PG IZQPQIZTJUJT adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. â&#x20AC;&#x201C; 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. â&#x20AC;&#x201C; Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. â&#x20AC;&#x201C; Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. â&#x20AC;&#x201C; In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland.

Immune-mediated Enterocolitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF threatening or fatal (diarrhea of â&#x2030;Ľ7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred JO BOE NPEFSBUF EJBSSIFB XJUI VQ UP TUPPMT BCPWF CBTFMJOF abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients. t "DSPTT BMM :&370: USFBUFE QBUJFOUT O

EFWFMPQFE intestinal perforation, 4 (0.8%) died as a result of complications, and

XFSF IPTQJUBMJ[FE GPS TFWFSF FOUFSPDPMJUJT t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG FOUFSPDPMJUJT TVDI BT diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). â&#x20AC;&#x201C; In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms.

Immune-mediated Hepatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF MJGF threatening, or fatal hepatotoxicity (AST or ALT elevations >5X the upper limit of normal (ULN) or total bilirubin elevations >3X the ULN; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%), with fatal hepatic failure in 0.2% and IPTQJUBMJ[BUJPO JO t BEEJUJPOBM :&370: USFBUFE QBUJFOUT FYQFSJFODFE NPEFSBUF IFQBUPUPYJDJUZ NBOJGFTUFE CZ -'5 BCOPSNBMJUJFT "45 PS "-5 FMFWBUJPOT >2.5X but â&#x2030;¤5X the ULN or total bilirubin elevation >1.5X but â&#x2030;¤3X the ULN; Grade 2). t .POJUPS -'5T IFQBUJD USBOTBNJOBTF BOE CJMJSVCJO MFWFMT BOE BTTFTT patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. â&#x20AC;&#x201C; In patients with hepatotoxicity, rule out infectious or malignant DBVTFT BOE JODSFBTF GSFRVFODZ PG -'5 NPOJUPSJOH VOUJM SFTPMVUJPO

Immune-mediated Dermatitis: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT TFWFSF life-threatening or fatal immune-mediated dermatitis (e.g., StevensJohnson 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%) patients. â&#x20AC;&#x201C; 1 (0.2%) patient died as a result of toxic epidermal necrolysis. o BEEJUJPOBM QBUJFOU SFRVJSFE IPTQJUBMJ[BUJPO GPS TFWFSF EFSNBUJUJT t 5IFSF XFSF :&370: USFBUFE QBUJFOUT XJUI NPEFSBUF (SBEF

dermatitis. t .POJUPS QBUJFOUT GPS TJHOT BOE TZNQUPNT PG EFSNBUJUJT TVDI BT SBTI and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated.

Immune-mediated Neuropathies: t In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-BarrĂŠ syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN PG :&370: NZBTUIFOJB HSBWJT and additional cases of Guillain-BarrĂŠ syndrome have been reported. t .POJUPS GPS TZNQUPNT PG NPUPS PS TFOTPSZ OFVSPQBUIZ TVDI BT unilateral or bilateral weakness, sensory alterations, or paresthesia.

Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t *O UIF QJWPUBM 1IBTF TUVEZ JO :&370: USFBUFE QBUJFOUT DMJOJDBMMZ significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. t "DSPTT UIF DMJOJDBM EFWFMPQNFOU QSPHSBN GPS :&370: JNNVOF mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis.

Pregnancy & Nursing: t :&370: JT DMBTTJGJFE BT QSFHOBODZ DBUFHPSZ $ 5IFSF BSF OP BEFRVBUF 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. t )VNBO *H( JT LOPXO UP DSPTT UIF QMBDFOUBM CBSSJFS BOE :&370: JT BO IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus. t *U JT OPU LOPXO XIFUIFS :&370: JT TFDSFUFE JO IVNBO NJML #FDBVTF 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.

Common Adverse Reactions: t The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%).

1MFBTF TFF #SJFG 4VNNBSZ PG 'VMM 1SFTDSJCJOH *OGPSNBUJPO JODMVEJOH Boxed WARNING regarding immune-mediated adverse reactions, on following pages.

For additional information, please visit Š2011 Bristol-Myers Squibb, Princeton, NJ 08543 731US11AB08003 YERVOY is a trademark of Bristol-Myers Squibb. All rights reserved.

03/11

Printed in USA

www.YERVOY.com/hcp

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:03 PM Page 12

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.

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).

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.

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.

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

Immune-mediated Dermatitis 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 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].

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:05 PM Page 13

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

a

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

41

7

34

5

31

3

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.

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

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 There is no information on overdosage with YERVOY. 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

a

Including fatal outcome.

Including intestinal perforation. c Underlying etiology not established. b

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.

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

1281558A2

IP-B0001A-03-11

Issued: March 2011

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:06 PM Page 14

ASCO ANNUAL MEETING

Patients, Pathways, and Progress the Focus of ASCO Presidents

By Neil Canavan Chicago, IL—Addressing the many attendees at the American Society of Clinical Oncology (ASCO) annual meeting, outgoing President George Sledge Jr, MD, of Indiana University Simon Cancer Center, said, “I think I could write the history of our specialty by looking at the history of our annual meeting. Some of the milestones I recall from past meetings in just the last decade include imatinib for [gastrointestinal stromal tumors], arguably one of the most, if not the most, dramatically effective antineoplastic treatments to date; adjuvant treatment of breast cancer with the targeted agent trastuzumab; and last year’s crizotinib, also an exquisitely targeted agent, for lung cancer. These are the great moments of our profession.” The data to be presented at this year’s meeting promise to be no less exciting, he said. And indeed, they did not disappoint.

The theme chosen for ASCO 2011 was “Patients, Pathways, and Progress.” “Patients always come first,” said Dr Sledge. “They are our primary focus and our inspiration as physician/scientists.”

The term “pathways” in this context has multiple meanings: molecular pathways dominating invasion, growth, and metastasis of tumors; pathways patients follow during the course of their care; and clinical

“Progress follows from our mastery of those pathways and from our commitment to research and clinical excellence.”

—George Sledge Jr, MD

research pathways that new treatments traverse on their way to the clinic. “Progress follows from our mastery of those pathways and from our commitment to research and clinical excellence,” Dr Sledge noted.

Incoming ASCO president Michael Link, MD, the Lydia J. Lee Professor in Pediatric Cancer at Stanford University School of Medicine and a member of the medical staff of the Lucile Salter Packard Children’s Hospital at Stanford, is no less enthusiastic about the work ahead.

Given that the vast majority of cancer research presented at ASCO addresses adult onset of disease, Dr Link is quick to describe the advantages he will bring to ASCO as a pediatric oncologist.

Exemestane Reduces First Invasive... menopausal women with estrogenreceptor–positive early breast cancer.

It is not indicated for the prevention of breast cancer.

Although tamoxifen is approved by the US Food and Drug Administration (FDA) for prevention of breast cancer, only approximately 4% of eligible women actually take this drug, said lead author Paul Goss, MD, PhD, Harvard Medical School and Massachusetts General Hospital. Tamoxifen carries serious but relatively rare risks of venous thromboembolism and endometrial cancer. In contrast, exemestane is not FDA approved for the prevention of breast cancer. The drug is about to go off patent, and it is not clear whether its manufacturer will file for the prevention indication.

“It is extraordinary that we can reduce the incidence of breast cancer by 65%. That is a massive benefit. In our opinion, exemestane represents a new option for consideration of breast cancer prevention for postmenopausal women who meet the criteria of the MAP.3 trial. This study provides a rationale for wider implementation of preventive use of

14

I

exemestane,” Dr Goss stated.

Between 2004 and 2010, MAP.3 enrolled 4560 postmenopausal women aged ≥37 years (median age, 62 years) with at least 1 risk factor for breast cancer (age ≥60 years, Gail score >1.66%, previous atypical ductal hyperplasia, and atypical lobular

“It is extraordinary that we can reduce the incidence of breast cancer by 65%.

In our opinion, exemestane represents a new option for consideration of breast cancer prevention for postmenopausal women who meet the criteria of the MAP.3 trial.”

—Paul Goss, MD, PhD hyperplasia). At baseline, median Gail score was 2.3% and average body mass index (BMI) was 28 kg/m2.

Approximately 50% of the partici-

VALUE-BASED CANCER CARE

I

June 2011

“It’s clear that many of the advances in oncology were pioneered in pediatrics,” he said. Although pediatric oncology is a relatively small area in cancer care, pediatrics has been on the leading edge of cancer care for quite some time. “The multidisciplinary approach to the patient with cancer was pioneered in pediatrics; many of the issues of survivorship, and awareness of late effects of treatment have come from pediatrics and from long-term follow-up of our cured patients.” ■

Continued from cover

pants were aged >50 years, 40% had a Gail score >1.66%, and 11% had a history of intraepithelial neoplasia.

During the 3-year follow-up, 11 cases of breast cancer were diagnosed in the exemestane arm compared with 32 in the placebo arm. Exemestane significantly reduced the incidence of estrogen-receptor–positive tumors—7 in the exemestane arm versus 27 in the placebo arm—and in HER2-negative tumors (10 and 26, respectively).

The superiority of exemestane to placebo was evident across all risk groups, including Gail score, age, BMI, prior lobular carcinoma in situ, and prior ductal carcinoma in situ.

Side effects that were higher with exemestane compared with placebo included hot flashes, fatigue, insomnia, gastrointestinal effects, and arthritis. Hot flashes occurred in 40% of women treated with exemestane and 32% of those in the placebo groups.

The incidence of bone fracture, osteoporosis, cardiovascular events, and other malignancies was similar in both arms.

“The elephant in the kitchen [in women at risk for breast cancer] is

at a glance ➤ Exemestane reduced the risk for a first invasive breast cancer by 65% in healthy postmenopausal women who are at risk for breast cancer ➤ It also reduced the risk for known breast cancer precursor lesions ➤ Exemestane did not increase the incidence of any serious side effects ➤ Unlike tamoxifen, exemestane is currently not indicated for breast cancer prevention ➤ These new results indicate that this drug is a viable alternative option for women at risk for breast cancer prophylactic mastectomy. Exemestane is now another treatment option for these women,” said Andrew Seidman, MD, Memorial Sloan-Kettering Cancer Center, NY, who chaired the press conference where these data were presented. ■

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ASCO ANNUAL MEETING

Patients’ Comfort Level with Discussions on Treatment Costs Exceeds that of Oncologists

By Neil Canavan Chicago, IL—Results of a recent survey presented at ASCO 2011 show that patients with cancer were far more willing to participate in conversations about their cancer treatment costs than their physicians.

“We were actually surprised by these results,” said Andrea Bullock, MD, Beth Israel Deaconess Medical Center, Boston, MA. “We thought they would be resistant in the same way that oncologists are known to be, but for different reasons.” Past studies have shown that oncologists are reluctant to address this sensitive topic; in 2 large, published surveys, >80% of oncologists reported being uncomfortable discussing costs with patients.

“Our study shows that in looking at patients’ perceptions, the majority of them are willing to talk.” Other studies have suggested that physician-patient communications regarding costs may facilitate a decrease in overall spending, minimizing patient and societal financial burden.

In this survey, a 31-item questionnaire measured cancer patients’ discussion preferences regarding the cost of cancer care, including questions such as:

• I would like my doctor to talk with me about my out-of-pocket (OOP) costs when he/she recommends a cancer test or treatment • I would prefer to discuss the cost of my cancer care with someone other than my doctor • My doctor should consider the country’s healthcare costs as he/she makes medical decisions.

Results showed that 68% of survey respondents would prefer to have out-of-pocket expenses discussed before treatment, with a majority expressing the desire to have that conversation with their treating physicians.

Results showed that of the 256 survey respondents, 68% would prefer to have OOP expenses discussed before treatment, with a majority wishing to have that conversation with their treating physicians.

However, 55% of respondents said that healthcare costs in the country at large or the particular patient’s OOP expenses should not influence treatment decision-making. Patients receiving active chemotherapy were less likely to discuss costs.

“We came up with the questions shortly after the [ASCO] Task Force guidelines were published in 2009, which recommended that oncologists begin these conversations,” said Dr Bullock; “frankly, we thought that patients may be resistant to talking about cost out of fear that if it was discussed it may affect how aggressively they are treated.”

Nevertheless, 32% prefer to discuss financial matters with someone other than their physician. Dr Bullock speculates that this is because of the limited time patients have with their physicians, which makes them prefer to focus on issues of care. “That’s the greatest limitation from their perspective, that they are not comfortable enough doing it, they don’t have the knowledge.”

Larger institutions may want to bring advisors on board for these conversations, Dr Bullock suggests,

at a glance ➤ Previous studies report that 80% of oncologists are uncomfortable discussing treatment cost with patients ➤ A new survey shows that 68% of patients with cancer would like to discuss out-ofpocket costs with their treating physician before initiating treatment ➤ 32% of patients preferred to discuss financial issues with someone other than their treating physician ➤ In 2009, ASCO Task Force guidelines recommended that oncologists begin such conversations with their patients acknowledging that community practices likely do not have the resources for such a position. However, with the costs for cancer care estimated at $124 billion for 2010, it is clearly time to start talking. ■

The Big Cost Drivers in End-of-Life Cancer Care Are Not the Drugs Chicago, IL—The rising costs of healthcare in the United States are often blamed on the cost of drugs, especially in oncology. A study reported at the meeting on end-of-life cancer care suggests that the biggest part of the bill may come from inpatient hospitalization, not from drugs.

April Teitelbaum, MD, Senior Medical Director at Innovus, Eden Prairie, MN, presented results of a retrospective analysis of claims (N = 28,530) at end of life from a major health plan. Median patient age was 61.5 years, and the most common tumors were lung (18%), breast (12%), and colorectal (9%). Claims data were analyzed for the last 6 months of care before death.

Cancer-related costs increased from a mean of $7835 in the 6 months before death to >$25,000 in the last month of life. These escalating costs were inversely related to the use of curative or palliative therapeutics, but they were directly influenced by an increase in inpatient hospitalizations (Table).

For the entire 6-month period, the

VOL. 2

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mean total cancer-related cost was $74,212; outpatient care accounted for $30,254 (41%) of the cost versus $40,702 (55%) for inpatient care (hospice care accounted for $3256). Of total outpatient costs, $10,710 (34%) was attributed to pharmacotherapy —chemotherapy or biologics; drug therapy accounted for 13.9% of total inpatient plus outpatient end-of-life care costs.

“If you look at the last month before death, total costs jump from just under $8000 to over $25,000— and most of that figure is inpatient care.”

—April Teitelbaum, MD “With the economic climate today, and so many advances in healthcare, it’s very important to take a look at what the costs at the end of life are,”

Table Cancer-Related Costs in the 6 Months before Death Mean Mean outpatient Mean outpatient Month before Mean total inpatient Mean hospice service cost, chemotherapy cost, $ (%) death cost, $ cost, $ (%) cost, $ (%) $ (%) 6th

7834

1785 (23)

28 (0)

3849 (49)

2172 (28)

5th

9230

3269 (35)

61 (1)

3751 (41)

2149 (23)

4th

10,051

4087 (41)

95 (1)

3762 (37)

2107 (21)

3rd

10,362

4646 (45)

173 (2)

3692 (35)

1852 (18)

2nd

11,469

6356 (55)

435 (4)

3242 (28)

1437 (13)

Last

25,261

20,559 (81)

2464 (10)

1632 (6)

606 (3)

said Dr Teitelbaum. “If you look at the last month before death, total costs jump from just under $8000 to over $25,000—and most of that figure is inpatient care.”

The challenge is how to communicate these facts to patients. “It’s important to have these discussions with the patients,” said Dr Teitelbaum, “to have them understand that palliation does not mean hospice.”

She advised that a conversation about costs and the potential health benefits, including advanced directives, should occur early rather than late and does not mean abandoning the patient.

“At the very last minute when you’re facing a patient in the intensive care unit, and there’s no advanced directive, and you don’t know what the patient wants, then you have no choice,” and costs can go through the roof.—NC ■

www.ValueBasedCancerCare.com

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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

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:09 PM Page 16

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:11 PM Page 17

If You Define Value as an Overall Survival Advantage:

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

MEDIAN OS NOT REACHED FOR VcMP

90

% 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

3

6

9

12

15

18

21

24

27

30

33

36

39

42

45

48

51

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_June_11_2_Follow ASCO Tabloid 6/17/11 1:12 PM Page 18

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.

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ASCO ANNUAL MEETING

Assay Aids Patient Selection for Temozolomide in Glioblastoma

By Audrey Andrews Chicago, IL—A prognostic marker that can be identified with a commercial test can identify patients with newly diagnosed glioblastoma who would benefit from life-prolonging temozolomide treatment, according to Mark R. Gilbert, MD, Professor, Department of Neuro-oncology, at the Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston. Dr Gilbert presented data from a new study at a late-breaking session at ASCO 2011.

“There is a pressing need for molecular tests that assist in the identification and monitoring of the most effective treatment for each cancer patient.

This is especially true with cancer therapeutics that rely on inducing DNA damage in the tumor,” said Dr Gilbert, lead investigator.

MGMT (O6-methylguanine-DNA methyl transferase) is a key DNA repair enzyme produced by the MGMT gene. When the MGMT gene is methylated, no MGMT is produced. The more MGMT present in the tumor, the more active the DNA repair, which lessens the efficacy of therapies that work by inducing DNA damage.

“The MGMT gene test (MDxHealth) was confirmed in the RTOG 0525 clinical trial to define prognosis for patients with newly diagnosed glioblastoma.

Ongoing clinical trials have incorporated this now-validated prognostic marker,” he said.

“There is a pressing need for molecular tests that assist in the identification and monitoring of the most effective treatment for each cancer patient….This study confirmed the prognostic significance of MGMT methylation in glioblastoma.”

—Mark R. Gilbert, MD Two studies demonstrated the benefit of the test. One study (LBA2000) described the development of the MGMT gene test and the consolidation of biomarkers into risk groups.

These risk profiles created in the training set were applied to samples from 763 patients in RTOG 0525 (a comparison of dosing schedules of temozolomide), which gave external validation to the test.

The application of the molecular risk

classification to RTOG 0525 samples selected patients with significantly (P <.001) improved survival, and it improved on current means of prediction by revealing an additional distinct risk group.

RTOG 0525 was a phase 3 trial that compared standard adjuvant temozolomide with a dose-dense schedule in newly diagnosed glioblastoma patients. Patients were randomized to receive either standard treatment (temozolomide on days 1-4 every 28 days) or the dose-dense regimen (temozolomide on days 1-21 every 28 days) for up to 12 cycles. Clinical outcomes were evaluated according to (1) prognostic recursive partitioning (based on age, performance status, extent of pretreatment surgery, neurologic function, mental status), (2) MGMT status (methylated, unmethylated, indeterminate), and (3) radiation therapy treatment.

The MGMT gene test was able to identify the patients with glioblastoma who benefited most from the treatment. Patients whose tumors demonstrated MGMT methylation had a median survival time of 21.2 months versus 14 months without methylation (P <.001) and longer progression-free survival (8.7 months vs 5.7 months; P <.001). Treatment arm and radiation technique did not predict survival.

at a glance ➤ The more MGMT present in the tumor, the more active the DNA repair, which lessens the efficacy of therapies that work by inducing DNA damage ➤ The new study confirmed the prognostic significance of MGMT methylation in glioblastoma ➤ The results of this study suggest that treatment decisions based on the molecular characteristics of the tumor are not only feasible but make a clinical difference “This study confirmed the prognostic significance of MGMT methylation in glioblastoma,” Dr Gilbert said.

The results suggested that treatment decisions based on the molecular characteristics of the tumor are not only feasible but make a clinical difference.

MGMT testing is now being provided for numerous phase 2 and phase 3 trials, including the phase 3 CENTRIC trial, in which only MGMT-methylated patients will receive the investigational integrin inhibitor cilengitide added to current chemotherapy for glioblastoma. ■

Maintenance Therapy with PARP Inhibitor Delays Ovarian Cancer Progression Chicago, IL—The oral poly ADP-ribose polymerase (PARP) inhibitor olaparib given as maintenance therapy delayed the time to tumor progression in patients with relapsed ovarian cancer, according to findings from an international study reported at ASCO 2011.

Jonathan Ledermann, MD, of University College London, United Kingdom, who presented the results, announced, “Olaparib significantly prolonged progression-free survival by nearly 4 months on average compared with placebo. This shows proof of principle for the concept of maintenance therapy in ovarian cancer using a PARP inhibitor.” The overall survival analysis is not yet mature.

Olaparib targets DNA repair weakness in tumors by inhibiting base excision repair through a defect known as homologous repair deficiency. The drug has already proved effective in patients with the BRCA gene mutations, which are often seen in patients

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with ovarian cancer, Dr Ledermann noted.

This phase 2 randomized, placebocontrolled study investigated the use of olaparib as maintenance therapy in

placebo arm; median progression-free survival rates were 8.4 months and 4.8 months, respectively, which translated to a very significant 65% risk reduced for disease progression.

“Olaparib significantly prolonged progression-free survival by nearly 4 months on average compared with placebo. This shows proof of principle for the concept of maintenance therapy in ovarian cancer using a PARP inhibitor.”

—Jonathan Ledermann, MD

patients with relapsed serous ovarian cancer who had responded to at least 2 previous platinum regimens (ie, were platinum-sensitive). Patients were randomized to oral olaparib 400 mg twice daily (N = 136) or placebo (N = 129).

Disease progression occurred in 44% of the olaparib arm versus 72% of the

“Our progression-free survival difference was very impressive and better than we anticipated,” Dr Ledermann commented. At the time of analysis, 50% of the patients treated with olaparib versus 16% of those receiving placebo were still being treated.

Olaparib was well tolerated and tox-

icities were consistent with those seen in previous studies, although there was a significant increase in nausea, fatigue, and vomiting with the active drug. Further studies will help determine the drug’s role in the routine treatment of ovarian cancer, he added.

Mark G. Kris, MD, Chair of ASCO’s Cancer Communications Committee, commented at a press briefing that the study is “important for 2 reasons.”

• “First, the study fulfills a previously unmet need for women fighting ovarian cancer, that is, it lengthens the time that the disease is controlled after successful initial treatment. This translates usually into normal or near-normal quality of life. The study showed that olaparib can actually help do this,” he said.

• Second, he added, the study shows the potential for targeted therapy to be effective based on exploiting a particular defect in the cancer cells’ ability to repair themselves.—AA ■

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VBCC PERSPECTIVE

The Challenge of Value-Based Care in Oncology: Improving Clinical Outcomes Interview with Matthew Mitchell, PharmD, MBA, Manager, Pharmacy Services, SelectHealth, Salt Lake City, UT

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he focus on value in patient care has taken a prominent place in any discussion related to improving care delivery, but no agreement exists on what that “value” is. In this interview, Value-Based Cancer Care asked Dr Mitchell to elaborate on the way his plan, SelectHealth, approaches this critical issue in cancer care and the potential implications to payers and providers.

costs, on a per-patient per-month or per-year basis. However, we have yet to see reports that show better clinical outcomes.

This means that the true challenge is the measurement itself—how are outcomes measured? What are the specific components that should go into the clinical or the quality measures? This is not easy to define.

Q: From your payer’s vantage point, what does value-based oncology care mean to you?

Dr Mitchell: When discussing valuebased care in oncology, the first question we must ask is—how do we define “value”? We can discuss valuebased care for any disease, be it diabetes and the use of a branded medication in the pharmacy benefit, or oncology, in which the care model would vary all the way to the recently publicized accountable care organization that would involve a bundled or a capitated rate for cancer treatments.

Once we agree on what we mean by value-based care, we also have to define the challenges—be they logistics or clinical in nature.

Q: Can you describe some of these challenges?

Dr Mitchell: The main challenge of value-based cancer care for payers and for providers is the application of quality measures. There is a big push today to use pathways and guidelines in the entire oncology arena, from the National Comprehensive Cancer Network all the way down to the local, facility-specific doctor who is following pathways. Putting these pathways into place is a challenge: some organizations measure their pathway compliance and some do not, but very few centers measure the clinical efficacy of the pathway they use.

I have yet to see a study that shows improved clinical outcomes based on pathway use. There are some studies, or white papers, on reduced costs with the use of pathways, but none shows improved clinical outcomes.

US Oncology is likely the biggest model we currently have in terms of published results on pathway use: they measured pathway performance of their doctors within their facilities, showing that the clinical outcomes were similar to not following pathways, but patients who continued to be treated by a pathway had reduced

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I have yet to see a study that shows improved clinical outcomes based on pathway use. There are some studies…on reduced costs with the use of pathways, but none shows improved clinical outcomes.

Q: How does SelectHealth address the need to improve clinical measures in oncology?

Dr Mitchell: We have recently embarked on a pilot program to address this very issue of how to measure clinical outcomes based on pathway use. Being a regional plan gives Select Health the opportunity to build relationships with local oncologists, with their key opinion leaders or their organization heads. The first step toward improving clinical outcomes is building and maintaining relationships with oncologists, relationships that are based on trust and that allow us to discuss clinical outcomes—what the clinical offices are currently measuring—and then enable us to build objectives that coincide with the clinicians’ and payers’ goals, to align our goals.

This year we are implementing goals around 4 areas in cancer care, trying to measure those areas based on performance of pathway use. These 4 measure areas are:

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1. Adjunct therapy for colorectal cancer, and the 3 following areas in supportive care 2. Erythropoiesis-stimulating agents (ESAs)—red blood cell stimulators 3. Colony-stimulating factor (CSF) drugs—white blood cell stimulators 4. Antiemetics.

But that necessitates building a way to measure these, which is not an easy task. To do this we are using both pharmacy and medical claims: based on these claims we are trying to assess whether a treatment fits the pathway criteria. This is often complicated because of laboratory values, staging, diagnosis, previous therapy and concurrent therapy, as well as other items reflected in the claims.

One example is a patient who received a growth white cell stimulator (often used in patients with cancer to fight infection), but based on the patient’s white cell count, that treatment may not seem appropriate.

However, the patient may have a reason that would qualify him/her for that treatment, yet this information is not going to be found within the claims. We need measures to verify that what the clinics are doing is appropriate, which is what SelectHealth is doing with our pilot program. Figuring out the measuring components is one of the biggest challenges.

Q: Is this pilot program unique to SelectHealth?

Dr Mitchell: Several other plans are working on similar initiatives.

One of the most publicized is the Michigan Blue Cross Blue Shield (Michigan Blues) health plan, which is using the P4 Healthcare Oncology tool. The P4 Healthcare is a company that puts together pathways for providers and payers (the 4 “Ps” stand for physicians, patients, pharmaceutical companies, and payers).

Payers that are using the P4 tool are reimbursing based on providers’ compliance with the P4 pathways, which are agreed on by academic centers and community oncologist groups; Michigan Blues have agreed on their payment plan in oncology based on those P4 rates.

This regional payer trend is now spreading to national payers that are also buying oncology pathways to structure their reimbursement. According to a press release issued in March 2011 in Specialty Pharmacy News

(vol 8, no 3; http://aislicenses. com/NSPN/fetchPdf.php?folder= SPN_pdf&name=spn0311), Aetna is the first national plan to sign a deal with P4 Healthcare for cancer management. This recent move by a large national payer such as Aetna signals a new trend of national plans signing up with the main pathway providers (P4 Healthcare or US Oncology) to structure their reimbursement plans for cancer care. This trend is likely to continue and grow. This is one of the reasons that the large purchasing groups, such as AmerisourceBergen or McKesson have purchased these pathway-driven companies.

Q: Does this growing trend suggest that pathway use is the road to achieving value in cancer care?

Dr Mitchell: This remains to be seen. Using oncology pathways appears to help reduce the costs of cancer care but to date it has not been shown as a way to achieve value, if we accept the definition of value as including enhanced clinical outcomes.

Indeed, it is difficult to define valuebased care in any area, and particularly in cancer care. How do you define the value of a life? It is also hard to measure performance clinic to clinic, cancer site to cancer site, or physician to physician (eg, some physicians get more difficult patients). It is truly hard to define value in cancer.

A true model of accountable care, however, may be the direction toward value-based cancer care—an accountable care model where providers are paid a certain amount to take care of a patient with a certain cancer stage and a certain type of cancer, and the decisions are based on the patient’s true needs; this may be, for example, not ordering every test that may or may not help, and only doing things that are directed to care, including the use of cost-effective therapy.

Q: What are some of the quality and cost implications for payers?

Dr Mitchell: The first concern for payers in cancer care is—how many lines of therapy should a health plan cover? There is a point of diminishing returns. If you try the first line of therapy for a specific cancer, you get the best outcome. If you have to try a second line, you’ll get a lesser outcome. If you try a third line of therapy, you’ll get a lesser outcome, and so forth. The Continued on next page

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HEALTH POLICY

Accountable Care Organizations: Implications for Oncologists

By Rhonda Greenapple, MSPH, President and Founder, Reimbursement Intelligence, Madison, NJ

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he journey for healthcare costsavings is a never-ending process. One of the newest healthcare delivery models, which is mandated for Medicare beneficiaries in the healthcare reform law, is the accountable care organization (ACO).

This new model requires ACOs to focus on primary care, but it has implications for oncologists as well.

Oncologists Can Join, Not Start, an ACO An ACO is a network of providers that agrees to manage all of the healthcare needs for a defined population in a specific period—at least 5000 primary care Medicare patients for at least 3 years. In effect, an ACO is an integrated system that attempts to eliminate fragmented care for Medicare beneficiaries and coordinate their entire care—prevention, diagnosis and treatment, and the continuing management of chronic diseases, as well as aftercare.

The ACO requires providers to manage all the health needs of their covered populations. The cost-saving is expected to come from eliminating unnecessary or redundant procedures, sharing clinical information among providers, and meeting quality targets that allow providers to keep a portion of the savings. Providers will be paid more for keeping their Medicare patients healthy and out of the hospital.

Under this new model, providers must collect and report utilization and cost data to the Centers for Medicare and Medicaid Servcies and for their ACO population, as well as on meas-

ures of quality of care and population health. A provider may be required to meet minimum quality standards to continue to participate in an ACO. The law allows any number of organizations to form an ACO, including physician group practices, practice networks, hospitals, hospital–physician systems, and other groups.

Oncologists, like other specialists, cannot take the lead in launching and managing an ACO, but they can join as many ACOs as they wish.

“The potential savings in clinical oncology will be driven by the design of incentive structures. The more oncologists are allowed to provide cost-effective care, the more likely they will be to participate.”

—Alan Lieber Few Quality Measures for Cancer Care Of the 65 proposed quality measures outlined in the ACO law, only the preventive measures of screening for colon cancer and mammography relate specifically to cancer care. Patrick Cobb, MD, Chairman of Community Oncology Alliance (COA) and the COA Policy Committee, and Ted Okon, Executive Director of COA, outlined the challenges for oncologists in a recent article on OncologyStat.com.

The Challenge of Value-Based...

Continued from page 20 point of diminishing returns is after the second line of therapy.

The second issue is, if drug A and drug B have very similar outcomes, but drug A is much less expensive, then the ability to use drug A for the majority of the time and cover A for the majority of the time is a big issue.

From a payer’s standpoint, it may have to be done by adjusting the reimbursement away from the way reimbursement is traditionally done.

For example, using an average selling price (ASP)-type reimbursement, which is a percentage-plus reimbursement, where drug A costs $100 and drug B is $1000, if you reimburse

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ASP plus 20% for each, the physician is likely going to use drug B, to get the 20% of $1000 instead of 20% of $100. If we can find a few of these “big therapies” with similar clinical outcomes, then we will reimburse much higher for a generic drug and still save costs.

Finally, no payer wants to end up in the news for saying they denied care because they did not value 4 months of life or 2 weeks of life. In pancreatic cancer, there is a drug approved based on 2 weeks of survival benefit. Is this value? In cancer, 4 months is actually a fairly decent amount of time. These are major challenges for payers. ■

According to Dr Cobb and Mr Okon, “An oncology provider participating in an ACO will be under enormous pressure to simply control or reduce costs.

Supporters argue that ACOs are different from HMOs, in part because they are not just about cost-savings—quality measures must be satisfied.

However, there are no quality measures for cancer treatment. Furthermore, although there is a nod to quality, no one should kid themselves—ACOs are really all about saving money.”1 They cite the following hypothetical example: “What happens when a new $93,000 prostate vaccine or $120,000 melanoma drug becomes available? These expensive new therapies will threaten to break the ACO bank, putting the pressure squarely on the oncologist to either keep the patient’s best interest or that of the ACO as highest priority. Few oncologists will want to be placed in that position.”1 Overlook Medical Center in Summit, NJ (part of Atlantic Health), is in the process of creating 2 ACOs. In a phone interview in May 2011, Overlook’s president, Alan Lieber, pointed out, “The potential savings in clinical oncology will be driven by the design of incentive structures. The more oncologists are allowed to provide cost-effective care, the more likely they will be to participate.”

at a glance ➤ ACOs are now mandated by the healthcare reform law for Medicare beneficiaries ➤ Oncologists cannot start an ACO, which is focused on primary care, but they can join such a program, and will likely be affected by it ➤ Of the 65 proposed quality measures outlined in the ACO law, only colon cancer screening and mammography relate to cancer care ➤ The potential savings in oncology will likely be driven by the incentive structure ➤ The burning question, according to Dr Cobb and Mr Okon, “is ‘who’ oncologists are accounted to—payers…or their patients”

“Oncologists, like other specialists, cannot take the lead in launching and managing an ACO, but they can join as many ACOs as they wish.”

Cost versus Quality in Oncology An ACO management will have to address the delivery, measurement, and cost of quality of cancer care. The issue of quality versus cost may result in clinical dilemmas between primary care physicians and oncologists. For example, for a cost-conscious primary care physician, the high cost of cancer surgery could function as a disincentive to refer a patient to a surgeon. The physician could instead suggest a less expensive course of chemotherapy.

Dr Cobb and Mr Okon summarized it best; “The burning question is ‘who’ oncologists are accountable to—payers (in finding cost-savings), or their patients (in providing quality cancer care)? Certainly, at a time when cancer incidence and treatment costs are both increasing, oncologists bear some responsibility for controlling costs. The strategies for doing so include providing care, for example, that minimizes emergency room visits and hospitalizations and using evidence-based guidelines to control treatment costs, when possible. However, first and foremost, oncologists are accountable to their patients in providing the highest quality cancer care.”1 The jury on ACOs will be out for a long time. ACOs must prove that they enhance overall healthcare quality, while also reducing costs. As for oncologists, they must become familiar with ACO rules and regulations to determine the best way they can contribute in such a model. ■ Reference 1. Cobb P, Okon T. Just ‘who’ is the oncologist accountable to in an accountable care organization?

September 7, 2010. www.oncologystat.com/view points/cancer-policy-forum/Just_Who_Is_the_ Oncologist_Accountable_to_in_an_Accountable_Care _Organization.html. Accessed May 31, 2011.

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ASCO ANNUAL MEETING

Personalized Medicine Comes of Age at ASCO 2011

By Neil Canavan Chicago, IL—Personalized medicine was the subject of the first press conference held at ASCO 2011 and the topic of one of the scientific sessions.

Large-Scale Evidence for Benefits of Targeted Therapies Apostolia M. Tsimberidou, MD, PhD, Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, M. D. Anderson Cancer Center, Houston, headed a phase 1 clinical trial based on the hypothesis that tumor molecular analysis and use of targeted therapies to counteract the effects of specific mutations would improve patient outcomes.

In this exploratory, nonrandomized study, 1114 patients underwent molecular analysis; of these, 460 patients were identified with between 1 and 4 known oncogenic mutations, including KRAS (19%), BRAF (19%), and PIK3CA (10%). These patients were then matched to available and/or investigatory targeted therapies, and treatment outcomes were compared

with nontargeted therapy (ie, standard of care) controls.

Among patients with 1 aberration, the results were striking—the overall response rate was 27% in the targeted therapy group versus 5% in the standard of care group (P <.01). The treatment superiority was evident by an increased disease stabilization and time to treatment failure (TTF).

“We have demonstrated on a large scale that this personalized medicine approach is associated with improved clinical outcomes.”

—Apostolia M. Tsimberidou, MD, PhD

“There was a median increase of 3 months in TTF, which was also associated with median increased survival of 13.4 versus 9 months,” said Dr Tsimberidou. “We have demonstrated

on a large scale that this personalized medicine approach is associated with improved clinical outcomes.”

Striking Activity with Crizotinib Results from an ongoing, open-label, phase 1 study further highlights the progress made with personalized medicine. The study drug was crizotinib, which targets the pathway of the anaplastic lymphoma kinase (ALK) gene mutation, a key oncogenic driver in non–small-cell lung cancer (NSCLC).

“ALK rearrangements in lung cancer were first described in 2007 and occur in between 3% and 5% of all NSCLC cases,” said D. Ross Camidge, MD, PhD, Associate Professor, Division of Medical Oncology, University of Colorado, Denver.

The first human study of crizotinib was launched in 2006, but after the discovery of the ALK-NSCLC connection, the study was amended to screen for patients who were positive for ALK mutations. Dr Camidge presented results from 116 patients with ALKpositive NSCLC who were treated

Oral Oncolytics Abandoned by 1 of 10 Patients...

Director at the West Clinic, Memphis, TN, who participated in the study, presented the data.

“Our key finding is that 10% of patients who are prescribed their first oral oncolytic never even pick up the drug,” Dr Schwartzberg told ValueBased Cancer Care. “They don’t have the opportunity to get benefit from their treatment. Also, one quarter delay getting their prescription, sometimes as much as 90 days. Here are patients with advanced cancer who need therapy now, and they are not getting it.”

The study was based on an analysis conducted by Avalere Health using pharmacy claims from 2007 to 2009.

Abandonment rate was calculated for the initial claim, in which abandonment was defined as reversal of an adjudicated pharmacy claim without a subsequent paid claim for any oncolytic (oral or intravenous) within the ensuing 90 days.

Regression analysis included patient demographics, plan type, drug type, cost-sharing, and concurrent prescription activity.

The following oral drugs were analyzed: capecitabine (Xeloda), imatinib (Gleevec), sorafenib (Nexavar), sunitinib (Sutent), lenalidomide (Revlimid), erlotinib (Tarceva), temozolomide (Temodar), and lapatinib (Tykerb)—all primarily prescribed for advanced disease.

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“Our key finding is that 10% of patients who are prescribed their first oral oncolytic never even pick up the drug.”

—Lee Schwartzberg, MD High Cost-Sharing, Multiple Drugs Patients were primarily abandoning their cancer drugs because of 2 key factors: high cost-sharing and higher prescription activity. Claims with costsharing >$500 were 4 times more likely to be abandoned than claims with costsharing of ≤$100.

Although 73% of patients with new oncolytic prescriptions had a cost-sharing ≤$100, 16% of patients had OOP costs >$500.

The abandonment rate increased as OOP costs increased. Claims with costsharing >$500 had the highest—25%— abandonment rate compared with 6% for claims with OOP costs of ≤$100 (odds ratio [OR] 4.46; P <.001).

“Our study shows that many cancer patients are abandoning the medicine

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they need,” said Lauren Barnes, Vice President of Avalere Health. “With 45.5% of Medicare patients in our sample facing cost-sharing >$500 for their first anticancer drug, this is a Medicare quality issue of the first order.”

Many newer cancer drugs are oral agents that are usually self-administered without medical supervision.

Although it is more convenient for patients, there may be trade-offs in terms of adherence and monitoring of side effects.

Patients were also more likely to abandon oral oncolytics if they had to

at a glance ➤ New data show that 10% of patients with cancer abandon their new oral oncolytics ➤ The abandonment rate climbs to approximately 25% among patients whose OOP costs exceed $500 compared with 6% for those with OOP ≤$100 ➤ Patients were more likely to abandon oral oncolytics if they took multiple medications, if they were enrolled in Medicare (16%) versus a commercial health plan (9%), and if their income level was low

with crizotinib 250 mg twice daily in 28-day cycles.

At a median follow-up of 11 months, the overall response rate was an impressive 61% in this heavily pretreated patient population. The responses were rapid (median 8 weeks), and the preliminary median progression-free survival period was 10 months.

“The striking activity of crizotinib in ALK-positive lung cancer was apparent very early in clinical development,” said Dr Camidge. “This demonstrates that robust efficacy signals may be revealed, even within small cohorts where the population is molecularly uniform.”

Treatment-related adverse events were mild, mainly gastrointestinal, manifested early, and diminished as treatment continued.

Phase 3 clinical trials have been initiated, and given the robust nature of these results, the drug manufacturer is seeking accelerated approval from the US Food and Drug Administration in conjunction with these trials. ■

take multiple medications. Abandonment rate in patients with ≥5 claims for noncancer medications in the previous month was 12% compared with 9% for patients with no claims in the previous month (OR 1.50; P <.001).

Medicare coverage and lower income were also related to higher rates of abandonment when each was compared individually. Patients with an annual income <$40,000 had an abandonment rate of 11%, decreasing to 10% for incomes between $40,000 and $75,000, and to 9% when income exceeded $75,000. Abandonment rates for Medicare claims were 16% versus 9% for those with commercial insurance.

The investigators suggest that the likelihood for abandonment of newly prescribed oral oncolytics increases for patients with drug benefit designs with higher cost-sharing. Payers may need to consider these factors when designing a pharmacy benefit design for patients with cancer.

“The bottom line is that patients should have access to the most clinically appropriate care for their condition,” Dr Schwartzberg said. “We should not be creating obstacles to care for those who need it the most. This also tells me that physicians are not asking patients if they are taking their drugs. We just assume they are.” ■

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AVBCC is the fastest growing national specialty organization dedicated to improving the care of cancer patients and their quality of life.

The organization was established to provide a network for payers and oncology healthcare professionals to interact and network in order to promote optimal care for patients and their families.

2011 REGIONAL MEETINGS September 24 Chicago, IL

October 1 San Francisco, CA

November 19 Tampa, FL

2012 NATIONAL MEETING March 29-31, Houston, TX

Register online at

www.AVBCConline.org Sponsorship Opportunities Available Past Sponsors:

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KNOW YOUR PATIENTS’ HISTOLOGY AND BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer.

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.

ALIMTA is available in 100 mg and 500 mg vials.

Important Safety Information for Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

Warnings and Precautions Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities.

Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash.

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia).

Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

PM70198

0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED. ALIMTA® is a registered trademark of Eli Lilly and Company.

Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities.

Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min.

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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ALIMTAÂŽ (pemetrexed for injection) Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration.

Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother.

Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

Dose adjustments may be necessary in patients with hepatic insufficiency.

Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information.

Abbreviated Adverse Reactions (% incidence)â&#x20AC;&#x201D; 1st-line NSCLC The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1).

Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6).

For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page.

PM_HCP_ISI_NSCLC1_04052011

insideALIMTA.com

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ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information.

1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin.

See cisplatin package insert for more information.

2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle.

2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)].

Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)].

Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery.

Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities 75% of previous dose (pemetrexed and Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. cisplatin).

Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin).

Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. 50% of previous dose (pemetrexed and cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding.

If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2.

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.

Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation.

5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials.

Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone.

5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)].

5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reactionb (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.

In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin.

Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.

Gastrointestinal — colitis General Disorders and Administration Site Conditions — edema

ALIMTA® (pemetrexed for injection)

ALIMTA® (pemetrexed for injection)

a

NCI Common Toxicity Criteria (CTC).

Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3.

Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose b

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Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.

Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal.

7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration.

If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].

Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults.

8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population.

8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3)].

Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)].

8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-to-treat population.

8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others.

For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population.

10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. ®

ALIMTA (pemetrexed for injection)

PV 5209 AMP

In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days.

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay).

Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling.

Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)].

17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear.

17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)].

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

Literature revised March 17, 2011

Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 2004, 2011, Eli Lilly and Company. All rights reserved.

PM_HCP_BS_NSCLC1_04052011 PV 5209 AMP ®

ALIMTA (pemetrexed for injection)

PRINTED IN USA PV 5209 AMP

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:29 PM Page 28

AACR ANNUAL MEETING

Significant Advances in Lung Cancer...

The 6-biomarker panel was developed from 4 independent studies in smokers. All stages of lung cancer and histologic cell types were distinguishable in the assay. In the current study, the investigators applied the markers to 600 specimens from a nonsmoking population who developed cancer and a healthy control cohort.

“In recent years, more attention has focused on this never-smoker population of lung cancer cases,” said principal investigator Charlie Birse, PhD, Celera Corporation (which is developing the test). “The proportion of lung cancer cases among never-smokers is projected to increase in the coming years, as smoking prevention and cessation programs are introduced.”

An independent validation study among 40 patients with lung cancer who had never smoked confirmed the utility of the test in all cancer stages and all major histologic cell types.

“The markers showed a strong performance in the never-smoker study,” Dr Birse said, “with…a sensitivity of 85% and specificity of 83%.”

The test’s performance suggests it would best be used as a complement to imaging for detecting lung cancer in smokers and nonsmokers, he said.

New Test Detects AsbestosRelated Cancer A novel biomarker test appears very accurate in detecting proteins secreted from tumors caused by exposure to asbestos. The test may therefore be able to identify early-stage malignant mesothelioma, an aggressive pulmonary cancer with increasing incidence. Mesothelioma is usually fatal, because it is typically found in an advanced disease stage.

Harvey I. Pass, MD, of New York University Cancer Institute, and colleagues used the SomaLogic aptamer proteomics platform to examine 170 blood samples from 90 patients diagnosed with mesothelioma and 80 persons exposed to asbestos; they found 19 significant biomarkers for mesothelioma and combined these into the Multiplex SOMAmer Assay, which can measure 1000 proteins simultaneously from a small blood sample.

According to Dr Pass, the platform combines the best qualities of an immunoassay and can find and quantify low-abundance proteins secreted by tumor cells. Data on its clinical benefit are not yet available.

New Therapeutic Target A new gene mutation associated with squamous-cell lung cancer may lead to new targeted treatments for this

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histologic type of cancer, according to Matthew Meyerson, MD, PhD, of Dana-Farber Cancer Institute, Boston.

Several mutations in lung cancer have led to targeted approaches that are now in clinical trials; however, these are largely in adenocarcinoma.

“There are very few known targets for the treatment of squamous-cell lung cancer, and no approved targeted therapies,” Dr Meyerson said at a press briefing at the meeting.

He and his colleagues recently discovered that mutations in the DDR2 gene are present in about 4% of all cases of squamous-cell carcinoma of the lung and are associated with sensitivity to the tyrosine kinase inhibitor dasatinib (Sprycel).

Continued from cover

“About half of all smokers have stopped smoking in the United States, and about half of all cases of lung cancer are in former smokers,” he said.

“What can we do for these former smokers?”

“About half of all smokers have stopped smoking in the United States, and about half of all cases of lung cancer are in former smokers.”

—Paul A. Bunn Jr, MD

“The proportion of lung cancer cases among neversmokers is projected to increase in the coming years….The markers showed a strong performance… [with] a sensitivity of 85% and specificity of 83%.”

—Charlie Birse, PhD In cell lines harboring the DDR2 mutations, cell growth is inhibited by dasatinib, and animal models with the mutation are also sensitive to dasatinib. In addition, 1 patient with squamous-cell lung cancer and DDR2 mutations had a radiographic response to dasatinib, Dr Meyerson reported.

These data add to the growing list of targets being identified in lung cancer, for which new targeted agents may prove effective.

Chemoprevention with Oral Iloprost Oral iloprost (Ventavis), an analog of prostacyclin, showed promise as a chemopreventive agent for lung cancer, according to studies done at the Translational Genomics Research Institute in Phoenix, AZ. The drug significantly improved endobronchial dysplasia in former smokers, as judged by improvements in the average bronchial histologic score (based on the World Health Organization classification of premalignant lesions) and in the dysplasia index score, reported Paul A. Bunn Jr, MD, Executive Director of the International Association for the Study of Lung Cancer and Professor of Lung Cancer Research, University of Colorado Cancer Center, Denver.

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Iloprost is currently indicated for the treatment of primary pulmonary hypertension. The hypothesis was that if prostacyclin could be stimulated, or if patients were given a prostacyclin analog such as iloprost, lung cancer might be prevented, Dr Bunn said.

The phase 2 trial involved 152 individuals who were current or former smokers exposed to ≥20 pack-years of cigarettes and who had at least mild cytologic atypia on sputum cytology

and no history of cancer. Biopsies were performed on all areas that appeared abnormal on bronchoscopy.

Participants were then randomized to oral iloprost or placebo for 6 months. A second bronchoscopy was conducted, and biopsies of all previously sampled areas were repeated and conducted on new suspicious areas as well.

Within the whole cohort, 74% had at least 1 biopsy showing mild dysplasia or worse on the initial bronchoscopy.

Lesions were scored from 1 (normal) to 7 (carcinoma in situ). At baseline, as expected, current smokers had worse bronchial histology than former smokers, who had less atypia in the bronchial epithelium.

Former smokers given iloprost showed a significant improvement in the average of all biopsy scores: • Average scores improved from 3.3 at baseline to 2.1 at 6 months (–1.2 change) • Worst biopsy scores improved from 4.6 to 3.1 (–1.5 change) • Dysplasia index improved from 43% to 19.6% (–23.6% change).

“The histologic improvements in iloprost-treated former smokers were larger in magnitude than the difference between current and former smokers,” Dr Bunn reported. ■

Metabolic Syndrome a High Risk for Liver Cancer Orlando, FL—New results presented at the meeting suggest that the metabolic syndrome, which is strongly associated with diabetes and heart disease (and is characterized by elevated fasting glucose levels, central adiposity, dyslipoproteinemia, and hypertension), appears to also be strongly linked to the development of liver cancer.

Katherine McGlynn, PhD, of the National Cancer Institute (NCI), and colleagues used the Surveillance, Epidemiology, and End Results (SEER) program database to identify all Americans aged ≥65 years who were diagnosed with hepatocellular carcinoma or intrahepatic cholangiocarcinoma between 1993 and 2005.

They found 3649 cases of hepatocellular carcinoma and 743 cases of intrahepatic cholangiocarcinoma, and matched all of them with 195,953 patients without cancer.

Analysis showed that the metabolic syndrome was significantly more common among persons with liver cancer.

After adjusting for demographic fea-

“Over one third of the population is thought to have metabolic syndrome, and certain racial and ethnic minorities have a rate as high as 45%.”

—Katherine McGlynn, PhD tures and other risk factors, the metabolic syndrome remained significantly associated with increased risk for cancer—more than doubling the risk for hepatocellular carcinoma and raising the risk for intrahepatic cholangiocarcinoma by 56%.

Dr McGlynn noted the importance of finding this connection. “Over one third of the population is thought to have metabolic syndrome,” she said, “and certain racial and ethnic minorities have a rate as high as 45%.”

More research on this finding and its practical implications is needed.—CH ■

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AACR ANNUAL MEETING

Link of Heavy Drinking, Genetic Variant, and Gastric Cancer Confirmed

By Caroline Helwick Orlando, FL—Heavy beer drinkers who have a genetic variant related to alcohol metabolism are at significantly increased risk of developing gastric cancer, researchers said at the 2011 American Association for Cancer Research meeting.

Heavy beer drinking raised the gastric cancer risk regardless of the presence of the genetic variant, but not as significantly as in the presence of the variant, reported Eric Duell, PhD, Senior Epidemiologist in the Cancer Epidemiology Research Program at the Catalan Institute of Oncology in Barcelona, Spain.

The variant, known as rs1230025, is part of the alcohol dehydrogenase gene cluster (ADH1) that produces an enzyme that breaks down alcohol.

The investigators postulated that this variant might predispose heavy beer drinkers to an increased risk for gastric cancer.

Alcohol use has long been suspected to be a contributing factor for gastric cancer, but numerous studies have yielded mixed results. This is the first time an association has been found

among beer drinking, genetic variants, and gastric cancer.

“When we looked at these 2 factors together—heavy beer drinking and having 2 copies of the variant— people had more than a 700% increased risk of gastric cancer.”

—Eric Duell, PhD

“This is a classic gene-environment interaction,” Dr Duell suggested.

“Having both of these risks—heavy beer consumption and rs1230025— appears to be worse in terms of gastric cancer risk than having just one or neither.”

The researchers analyzed alcohol consumption and gastric cancer risk in more than 521,000 persons (aged 35-70 years) participating in the European Prospective Investigation into Cancer

and Nutrition (EPIC) study from 1992 through 1998.

In a case-control substudy of 365 gastric cancer cases and 1284 controls within EPIC, 2 single-nucleotide polymorphisms (SNPs) in the gene cluster ADH1 showed significant association with gastric cancer risk—rs283411 and rs1230025. One of these, rs1230025, interacted with beer consumption to

at a glance ➤ Heavy beer drinkers who have a genetic variant related to alcohol metabolism are at an increased risk for gastric cancer ➤ The risk for gastric cancer with any alcohol consumption is 25% compared with 75% in beer drinkers ➤ Heavy beer drinkers who have 2 copies of the variant have a 700% increased risk of gastric cancer

further increase the risk, Dr Duell said.

Compared with low ethanol consumption at baseline (0.1-4.9 g/day), heavy total alcohol (≥60 g/day) and beer consumption (≥30 g/day) were significantly associated with increased risk for gastric cancer. The overall increased risk with alcohol was 65%, and 75% with beer drinking. One 12-ounce beer contains approximately 13 g of pure ethanol/alcohol.

“When we looked at these 2 factors together—heavy beer drinking and having 2 copies of the variant—people had more than a 700% increased risk of gastric cancer,” Dr Duell said at a press briefing. “The results need to be replicated in other populations, as this is the first study to show a relationship between this SNP and gastric cancer risk.”

The exact mechanism for how alcohol may cause gastric cancer is not known, although the metabolite of alcohol, acetaldehyde, is a toxic and carcinogenic compound. Nitrosamines, which are found in beer, are a known animal carcinogen, Dr Duell pointed out. ■

Chemo-Immunotherapy Regimen Boosts Survival in CRC Superior results led to early termination of study Orlando, FL—A regimen that combines immunotherapy with chemotherapy doubled the overall survival (OS) time in patients with advanced colorectal cancer (CRC) over a standard chemotherapy regimen alone and improved progression-free survival (PFS), reported Pierpaolo Correale, MD, PhD, of Siena University School of Medicine, Italy.

The immunotherapy involved the combination of recombinant interleukin (IL)-2 and growth factors, an approach that is very experimental in CRC management. Patients with CRC are usually treated with chemotherapy that includes various combinations of fluorouracil or capecitabine (Xeloda), leucovorin, irinotecan (Camptosar), and oxaliplatin (Eloxatin; FOLFIRI or FOLFOX).

Recently, patients have also been routinely treated with bevacizumab (Avastin), cetuximab (Erbitux), or panitumumab (Vectibix); however, this study was initiated in 2005, before these monoclonal antibodies were used.

“These combinations have been suc-

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cessful in inducing tumor regression, retarding disease progression, and increasing overall survival,” said Dr Correale. However, the average PFS and OS “are still no more than 8 to 10 months and 20 to 22 months, respectively,” he noted.

He and his colleagues added gemcitabine to FOLFOX followed by granulocyte-macrophage colony-stimulat-

at a glance ➤ A regimen that combines chemotherapy and recombinant IL-2 with growth factors doubled the OS and improved PFS over standard chemotherapy alone in patients with advanced CRC ➤ These superior results led to an early termination of the study, which began before monoclonal antibodies were routinely used ➤ These results suggest the importance of using the patient’s immune system in colon cancer

ing factor and low-dose aldesleukin (Proleukin; IL-2; GOLFIG) to boost the immune system. They randomized 130 patients to GOLFIG or to FOLFOX for 12 cycles, followed by a regimen of maintenance therapy.

“These combinations have been successful in inducing tumor regression, retarding disease progression, and increasing overall survival.”

—Pierpaolo Correale, MD, PhD

The study was halted early because of the superior results seen with GOLFIG in the planned interim analysis, Dr Correale said.

Patients who received GOLFIG had a 16.5-month PFS compared with 7.5 months for those receiving FOLFOX—a 9-month improvement over standard treatment. The chemoimmunotherapy regimen was associ-

ated with an overall response rate of 63.1% compared with 33.8% with FOLFOX. Although OS was not a principal outcome, the 30-month median survival in the GOLFIG arm represented a >60% reduction in risk.

Adverse events were slightly more common in the GOLFIG arm, and 16% receiving the immunotherapy had fever related to IL-2, as well as self-limiting signs of autoimmunity. “These patients showed the best outcome, a finding that suggests the real involvement of the immune system in conditioning patients’ outcomes,” Dr Correale suggested.

Coinvestigator Piersandro Tagliaferri, MD, commented, “We believe these results confirm the importance of using the patient’s immune system to treat colon cancer.”

Because biologics have been shown to improve outcomes compared with chemotherapy alone, the GOLFIG regimen would best be compared with regimens containing monoclonal antibodies, the investigators acknowledged.—CH ■

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HEALTH POLICY

Humana’s Real-World Data Confirm Cost-Savings with the 21-Gene Recurrence Score Assay

By Caroline Helwick

A

new analysis of the Humana database shows that the 21gene recurrence score (RS) molecular assay (OncotypeDX; Genomic Health) leads to targeted management of early-stage breast cancer and reduces payer’s costs (Hornberger J, et al. J Oncol Pract. 2011;7[3s]: e38s-e45s).

“We found that the tests save money, and women have improved health, because they do not get chemotherapy that they don’t need,” John Hornberger, MD, MS, President and Chief Executive Officer of Cedar Associates, Menlo Park, CA, and Adjunct Clinical Professor, Stanford University, told ValueBased Cancer Care.

Adjuvant chemotherapy in earlystage breast cancer is guided by an assessment of the individual patient’s risk for recurrence. The American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend the 21-gene RS as a clinically valid tool for improving risk assessment for chemotherapy. A meta-analysis of decision-impact studies showed that the RS reduces the overall utilization of chemotherapy by 27% (Lo SS, et al. J Clin Oncol.

2010;28:1671-1676).

Previous health economic studies were based on the hypothesized use of adjuvant chemotherapy, showing the

A21-gene RS improved breast cancer outcomes and saved costs. This is the first study to rely on real-life data reflecting actual practice, said Dr Hornberger; this will help resolve the questions of the assay’s validity in actual practice.

analysis) was interested in showing its cost-effectiveness and in confirming the clinical benefits in real-life practice.

Genomic Health “gets pushback all the time, which is true for any manufacturer of a drug or device today,” Dr Hornberger said in the interview.

“We found that the [21-gene RS molecular gene] tests save money, and women have improved health, because they do not get chemotherapy that they don’t need.”

—John Hornberger, MD, MS

“Policymakers are keenly interested in learning how the assay affects outcomes and costs…after some period of experience with the assay,” said Dr Hornberger. “We incorporated the utility reported in the meta-analysis with real-world costs associated with adjuvant chemotherapy treatment as obtained from Humana to evaluate the cost-effectiveness of the 21-gene RS.” Payer’s Coverage Decision Validated Coinvestigator Louis Hochheiser, MD, Medical Director at Humana, was interested in validating Humana’s decision in 2006 to cover the assay.

Genomic Health (which funded the study but had no involvement in the

“They are all being asked, ‘Why should we pay for this?” He emphasized the importance of validating the clinical utility of all molecular assays (which were introduced in 2005), as well as this test.

The current study looked exclusively at the utilization of the test in 925 women who were lymph node–negative, estrogen receptor–positive; this study validated cost benefits for this patient population. There is a growing body of studies exploring whether the RS test should be used in other populations, Dr Hornberger added. “The analysis showed that the use of the RS does make a difference in how physicians treat patients. A lot of decisions were changed as a result of the test.”

Cancer Drug Use and Costs Sharply Rising Medco 2011 Drug Trends

T

here is no end in sight to the rising cost of fighting cancer, according to Medco’s 2011 Drug Trend Report (www.drugtrendreport. com/2011-report), which forecasted the cost of cancer drugs will grow 34% to 42% over the next 3 years.

Medco predicts that at this accelerated rate, oncology drugs will likely rise to the second- or third-largest trenddriving category by 2015, following only diabetes and central nervous system medications, according to the report, which tracks drug utilization and spending.

The aging population, enhanced cancer detection, and prolonged survivorship translate into a 30% increase in the number of persons living with cancer by 2020. These trends have heightened demand for oncology spe-

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cialty drugs, and the use of targeted therapies has increased by nearly 7%, according to the report.

“New cancer drugs reaching the market are expected to double during the next several years. Continued innovation…can help ensure the right person is getting the right drug at the proper dose and reduce waste.”

—Glen Stettin, MD

“New cancer drugs reaching the market are expected to double during

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See also “Oral oncolytics abandoned by 1 of 10 patients,” page 1 the next several years,” said Glen Stettin, MD, Medco’s Chief Medical Officer. “Continued innovation, including companion diagnostic or pharmacogenomic testing, can help ensure the right person is getting the right drug at the proper dose and reduce waste.

Due to the high cost and extended time patients may need treatment, the use of these latest design management tools is paramount,” he said.

“The emergence of biosimilar drugs will help mitigate some of the costs of specialty drugs, when they start to reach the marketplace in or around 2013,” Dr Stettin added. “We are already working with employers and other health plan providers to prepare for these fast-approaching future trends.”—CH ■

at a glance ➤ The 21-gene RS molecular assay improves health outcomes for women with early-stage breast cancer ➤ Real-life data from Humana show the RS assay reduced chemotherapy utilization by 27% ➤ This reduction in chemotherapy saved $1885 per patient ➤ Its impact on treatment decisions can save an average of $1160 per test ➤ Reduced overall supportive care as a result of the test translated to an immediate savings of $2568 per patient ➤ Cost-effectiveness analyses showed an 81% probability that it would save costs for health plans

Interventions Reduced, Costs Saved, Outcomes Improved Of the 925 women, 255 (27%) received adjuvant chemotherapy; 10% of women classified as low risk by the assay received adjuvant chemotherapy compared with 36% of those at intermediate risk and 72% of those at high risk.

Humana spent $3,784,200 for the 952 assays, with projected net savings of $1,104,320, or an average of $1160 per test, as a result of the test’s impact on treatment decisions.

The immediate per-patient savings were $1885 for a reduction in chemotherapy, $2568 for less supportive care, and –$472 for side-effect management.

In addition, the assay saved $199 per woman by preventing distant recurrence.

A separate analysis accounted for a 3% risk of chemotherapy-induced second primary tumors, which increased the net savings to $1,503,423. The estimated net savings for Humana with the RS was >$1 million during the test period. (Costs saved from reduced laboratory work-up and treatment-related outpatient visits were not included in the analysis.)

All risk categories gained qualityadjusted life-years. Cost-effectiveness acceptability curves showed an 81% probability that the 21-gene RS would be cost-saving to a health plan. ■

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For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:34 PM Page 32

reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information.

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].

INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information].

WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below.

Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.

In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information].

Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment.

Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy.

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.

Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma.

Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma.

Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm3 <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

0

10.2

0

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:35 PM Page 33

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks.

Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis.

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

12

0

0

4

0

0

19

2

0

14

<1

0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

18

0

0

12

0

0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.

Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.

Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma.

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology.

Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis.

0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

TM

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 2:19 PM Page 34

HEALTH POLICY

ASCO Calls for Open Discussions and Individualized Care for Patients with Advanced Cancer A new paradigm offers value to patients and to society

By Dalia Buffery

F

rank discussions with patients about their advanced cancer are challenging for physicians and their patients; however, avoiding such interactions is not a viable option, according to the American Society of Clinical Oncology (ASCO).

Building on its previous statements on end-of-life care and palliative care, ASCO has issued a new statement to oncologists, calling on them to recognize the value of an evidence-based individualized approach to cancer care for patients with advanced disease (Peppercorn JM, et al. J Clin Oncol. 2011; 29:755-760).

Unlike personalized medicine, which is based on the patient’s unique biologic characteristics, in the context of advanced disease that is often incurable (with increasing exceptions thanks to recently approved therapies for latestage cancer) ASCO is now urging oncologists to accept the need to properly inform patients with cancer about their prognosis, treatment challenges, and associated risks, and to institute a treatment plan that considers the clinical evidence, current guidelines for advanced disease, and the individual patient’s preferences that are based on well-informed parameters.

The authors highlight the need to change the paradigm of care for advanced cancer and overcome current barriers to individualized care at latestage disease, by tailoring care to the unique needs and preferences of the patient throughout the continuum of

care, including in metastasized disease.

Quality of life (QOL) is always the primary consideration in cancer care, according to this statement. Explaining available therapeutic options and risks to patients based on the evidence and discussing the patient’s prognosis are inherently part of quality of care in oncology.

ASCO is urging oncologists to accept the need to properly inform patients with cancer about their prognosis, treatment challenges, and associated risks, and to institute a treatment plan that considers the clinical evidence, current guidelines for advanced disease, and the individual patient’s preferences that are based on well-informed parameters.

The statement outlines the following 6 major aspects of individualized care for patients with advanced cancer.

Oncologists are advised to: 1. Ensure that patients are well informed about their prognosis and

treatment options and have opportunities to express their preferences and concerns regarding treatment options and supportive care 2. Offer anticancer therapy when the evidence supports a meaningful clinical benefit 3. Develop a treatment plan when advanced cancer is diagnosed that outlines the goals of therapy and prioritizes and enhances the patient’s QOL throughout the course of illness, including late-stage disease 4. When discussing interventions, explain the nature of the potential response, any potential associated adverse events and risks, total direct costs to the patient, and impact on QOL 5. When appropriate, offer such patients the opportunity to participate in clinical trials or other research that may improve their outcome or that of future patients 6. Minimize the physical and emotional burden during treatment by encouraging patients to switch to symptom-directed palliative care when cancer-directed options have been exhausted.

Oncologists must become aware of when stopping disease-directed therapy is appropriate, based on current guidelines. The statement outlines specific strategies to enhance provider education, with the goal of achieving individualized care for patients with advanced cancer, through various provider initiatives.

These initiatives should include patient and family education, insurance reimbursement reform, and support for research that is designed to help oncologists to overcome their resistance to communication with their patients with cancer.

These initiatives are intended to increase oncologists’ awareness of the need to establish an open dialogue with their patients and provide an individualized treatment plan for patients and for their families.

The current system of reimbursement incentivizes disease-targeted therapies even at the end of life rather than encouraging direct conversations with patients to establish their preferences when all therapeutic options have failed. This new approach to the management of patients with advanced cancer has value for patients as well as for society.

Although this evidence- and guidelines-based approach has recently been politicized with the unfortunate “death panels” epithet, ASCO believes that it is time to overcome such barriers and embrace the need to provide appropriate quality of care for patients with advanced cancer.

“We need to move toward developing a treatment plan that is consistent with evidence-based options (including disease-directed and palliative care) and the patient’s informed preferences for how we pursue and balance these options throughout the course of illness,” the authors say. ■

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VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:37 PM Page 35

ISPOR INTERNATIONAL MEETING

New, Real-World Data for Rituximab Use in NHL Raise Cost-Effectiveness Issues Investigators point to potential impact on formulary decisions

By Rosemary Frei Baltimore, MD—Using real-world administrative data to examine the costeffectiveness of rituximab (Rituxan), a Canadian team found that the 2-year absolute survival benefit is lower than the overall survival uncovered in other studies, and that the 5-year incremental cost is higher, according to the new data presented at the 2011 International Society for Pharmacoeconomics and Outcomes Research’s annual meeting.

“After we’ve gone over the data, and they’ve been published in a peerreviewed journal, we’ll be sharing the results with decision makers here, saying, ‘This is evidence in the real world of what you’re paying, and what you’re getting in return,’” said co–lead investigator Jeffrey Hoch, PhD, Director, Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto. “This may inform changes in drug formulary policy,” he noted.

Dr Hoch, with researchers from Cancer Care Ontario and 12 other researchers, received a grant from the Ontario Ministry of Health Drug Innovation Fund. This was the first study in Canada to incorporate recently developed statistical methods for analyzing costs and cost-effectiveness of a cancer treatment.

Analyzing data from the New Drug Funding program in Ontario—which pays for expensive intravenous cancer drugs—identified 2825 patients who received rituximab for diffuse, large Bcell lymphoma, the most common form of non-Hodgkin lymphoma (NHL).

Historically, the most common treatment for NHL was CHOP (Cytoxan [cyclophosphamide], hydroxydaunorubicin, Oncovin [vincristine], prednisone/prednisolone]. However, in 2001 the New Drug Funding program began paying for the addition of rituximab to CHOP (R-CHOP), initially for older patients (aged 60->80 years) and later (in mid-2004) adding younger patients aged <60 years.

The investigators compared data from patients treated with R-CHOP between 2001 and 2007 and patients treated with CHOP between 1997 and 2004.

To control for significant differences in the 2 sets of patients—for example, the patients receiving CHOP were significantly younger and had much less morbidity—they “hard-matched” the 2 cohorts on age for a total of 1131 in each group. This entailed matching

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each patient treated with CHOP with a patient treated with R-CHOP of exactly the same age. Patients were also paired by the likelihood of receiving rituximab. The 2 cohorts were similar in both characteristics and treatment choice.

The results showed that 3-year overall survival was 10% higher with RCHOP than with CHOP and 8% higher at 5 years. In addition, the 2-year absolute survival benefit with the addition of rituximab was 8%.

Although this is an added total survival, it is lower than the absolute survival benefit shown in 2 previous studies—the European GELA (Groupe d’Etudes des Lymphomes de l’Adulte) trial and an observational study conducted in British Columbia.

Using these real-world data, a cost analysis was done after adjusting for incomplete data (because of insufficiently long follow-up time) and dis-

Overall survival at 3 years was 10% higher at 3 years with R-CHOP than with CHOP and 8% higher at 5 years. counting the costs by 3% (because of cost differences in different years).

As can be expected, the adjusted 3year costs were significantly (P >.011) higher for R-CHOP than for CHOP— $77,000 versus $62,000, respectively.

The 5-year costs were approximately $87,000 and $70,000, respectively.

In addition, the incremental costs for adding rituximab to the CHOP regimen was approximately $15,000 at 3 years and $16,700 at 5 years. These figures are higher than in premarketing models studied by an American group and in postmarketing simulations in British Columbia. Moreover, the costeffectiveness ratios for R-CHOP were near $100,000 at 3 years and near $50,000 at 5 years.

The team attributes these differences from previous studies to the methodology applied in this study and the use of “real-world data in a real-world setting,” co–lead investigator Murray Krahn, MD, of Cancer Care Ontario, told Value-Based Cancer Care. ■

First National Survey Uncovers OOP Disparities in Mammography Expenditures

T

he first national study of average out-of-pocket (OOP) and overall mammography expenditures indicates that in 2007 and 2008, women living in the midwestern United States had an OOP expenditure that was nearly double those living in the Northeast or the West, at $47, $24, and $25, respectively, based on data presented at the 2011 International Society for Pharmacoeconomics and Outcomes Research’s annual meeting.

Women using office-based facilities had far higher OOP expenditures than those receiving mammograms at outpatient hospitals ($35 vs $28, respectively). However, overall mammography costs were higher at the outpatient hospitals ($310 vs $243, respectively).

The good news is that the average OOP mammography cost for all women was only $32.90, with average total mammography expenditures of $266.49. “This study highlights where disparities and variations exist among OOP and total expenditures for mammography, but also informs women what they can expect to pay OOP,” said principal investigator Traci LeMasters, BS, MA, research assistant, School of Pharmacy, West Virginia University, Morgantown.

“However, these are just averages for these subgroups from this particular data set.…And this also is not representative of all women aged 18 to 64,

because we included women with only 1 mammogram in a year,” she added.

The investigators analyzed 20072008 data from a nationally representative survey known as the Medical Expenditure Panel Survey, conducted by the Agency for Healthcare Research and Quality.

Data in the current analysis included 2020 women who received only 1 mammogram in 2007 or in 2008; of these women, 80% were white, 85.1% were not poor, and 86.8% had private insurance.

at a glance ➤ Women living in the midwestern United States had a nearly double OOP expenditure than those living in the Northeast or the West ➤ Among women with insurance, those with private insurance paid the highest OOP amount and the largest proportion of total mammography expenditures ➤ Women who were uninsured had the greatest OOP spending and paid the highest proportion of the total mammography cost

Not surprising, women who were uninsured had the greatest OOP expenditures ($60) of any of the women and paid the highest proportion of the total mammography cost (31%). In addition, OOP costs varied by region and by facility type.

Among women with insurance, those with private insurance paid $33 OOP—the highest amount and the largest proportion of total mammography expenditures (14%). Those with Medicaid coverage paid the lowest OOP, which was also the smallest proportion of total mammography costs.

Ms LeMasters is now analyzing survey data collected from women attending Bonnie’s Bus, a mobile mammography program. The bus crisscrosses West Virginia, with medical professionals on board providing mammography services to women in areas where low rates of mammography utilization and high rates of latestage breast cancer have been historically observed. Although it does not provide free mammograms, 38.6% and 34.2% of the mammograms received by women from Bonnie’s Bus in 2009 and 2010, respectively, were paid for by the West Virginia Breast and Cervical Cancer Screening Program.

Such services help remove the disparities highlighted in the study, observed Ms LeMasters.—RF ■

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NCCN ANNUAL CONFERENCE

Recommendations for Optimal Myeloid Growth Factors Use

By Audrey Andrews Hollywood, FL—The evidence for the use of myeloid growth factors in patients at high risk for febrile neutropenia (FN) is solid, Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, NC, told attendees at the 2011 National Comprehensive Cancer Network (NCCN) annual meeting.

Myeloid growth factors are the primary means of preventing chemotherapy-induced neutropenia. This often leads to FN, which can be fatal in 10% of patients, according to a database of more than 40,000 individuals. Some clinicians have recently expressed concern, however, that myeloid growth factor use is associated with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

As chairman of the NCCN’s Myeloid Growth Factors Panel, Dr Crawford reassured attendees that the benefits substantially outweigh any risks associated with the granulocyte colony-stimulating factors (G-CSFs) filgrastim (Neupogen) and pegfilgrastim (Neulasta).

The newer agent, pegfilgrastim, has a unique neutrophil-regulated clearance and, because of high sustained serum levels, is longer lasting, but its clinical efficacy appears to be similar to that of filgrastim’s.

The clinical outcomes for the single dose of pegfilgrastim and the daily dose of filgrastim were comparable in a 2007 meta-analysis, but the impact of

pegfilgrastim on overall survival and disease-free survival has been apparent in all major prognostic subgroups studied to date, Dr Crawford said.

Sargramostim (Leukine) is another myeloid growth factor option; however, because of its greater toxicity, it has a category 2B recommendation in the

NCCN guidelines.

The only major change to the 2011 clinical guidelines in this regard is the inclusion of a discussion of MDS/AML risk associated with the use of G-CSF.

prophylaxis should be initiated soon after the first chemotherapy and continued in subsequent treatments in any patient with a ≥20% risk for developing FN. “Our window for starting [G-CSF] prophylaxis is not big. We should start 24 to 72 hours after chemotherapy is completed,” he said. When administration is delayed, the duration of grade 4 neutropenia may be longer, and the risk of FN greater, Dr Crawford added. “The data suggest that what we do in the very first cycle of treatment makes a big difference.”

Some clinicians also try to lower FN risk by reducing the dose of chemotherapy, but this approach is not advisable, because it diminishes the survival benefit obtained from fulldose chemotherapy.

Prophylactic antibiotics can add to the protective benefit of G-CSF in selected settings, but they should not be used instead of them. To avoid the risk of antibiotic resistance,“The routine application of prophylactic antibiotics should be limited to high-risk inpatients with hematologic malignancies and stem-cell transplantation,” he said.

Timing of Growth Factor Use In a 2008 study conducted by Dr Crawford’s group, FN developed during the first 3 cycles in 11% of patients.

Because most FN events occur during the first cycle of chemotherapy, G-CSF

Despite MDS/AML Risk, Mortality Greatly Reduced The risk for MDS/AML with G-CSF prophylaxis was elevated by a recent meta-analysis (Lyman GH, et al. J Clin Oncol. 2010;28:2914-2924), regardless

“Our window for starting [G-CSF] prophylaxis is not big. We should start 24 to 72 hours after chemotherapy is completed….There clearly is an overall net benefit of G-CSF.” —Jeffrey Crawford, MD

of tumor type or treatment regimen; however, all-cause mortality was significantly lower among patients who received G-CSF therapy.

“There was an increase in MDS and leukemia, but the all-cause mortality analysis showed a significant reduction in risk. Leukemia risk was 0.005%, but the survival benefit was 5%. This amounts to an almost 10-fold difference in probabilities,” he said. “There clearly is an overall net benefit of G-CSF.” Who Should Receive Prophylaxis?

Primary G-CSF prophylaxis should be determined by the chemotherapy regimen, according to the NCCN guidelines, along with patient risk factors (Lyman GH, et al. Cancer. 2011;117: 1917-1927) and treatment intent (curative vs palliative). Clinicians should then determine whether the patient’s risk is high (>20%), intermediate (10%20%), or low (<10%).

High-risk patients, whose risk is elevated 5-fold over low-risk patients, should receive a G-CSF, regardless of treatment intent; low-risk patients should not receive them; and intermediate-risk patients should be considered for treatment based on risk factors, Dr Crawford said.

In addition to the type of chemotherapy, other risk factors include type of malignancy, age, previous treatment, preexisting conditions, performance status, and other factors. ■

Hepatitis B a Risk with Chemotherapy Hollywood, FL—Patients receiving chemotherapy are at risk for reactivation of the hepatitis B virus (HBV), which can result in negative outcomes, including death from liver failure.

According to Emmy Ludwig, MD, of Memorial Sloan-Kettering Cancer Center (MSKCC), New York, one third of the world has been exposed to HBV, “making it an enormous problem.”

HBV reactivation, however, can be prevented with effective antiviral prophylaxis; Dr Ludwig presented the current recommendations at the meeting.

HBV reactivation typically occurs as a result of immunosuppressive therapies in cancer, autoimmune disease, and organ transplantation. The risk does not end when chemotherapy is completed but persists for at least 6 months, and possibly longer in patients undergoing stem-cell transplantation and in those receiving rituximab (Rituxan). The risk for liver failure from HBV reactivation has

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been linked to the use of rituximab— precipitating a black box warning for these patients.

Antiviral prophylaxis can prevent chemotherapy-related HBV reactivation.

“If I had hepatitis B and was getting chemotherapy, I would put myself on an antiviral.”

—Emmy Ludwig, MD Lamivudine (Epivir) was used in many earlier studies and is effective; however, most patients will develop resistance to it after 5 years.

Newer agents, such as entecavir (Baraclude) are very effective, have less propensity for resistance, and are

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less likely to have drug interactions.

Entecavir, therefore, is the preferred antiviral at MSKCC, she said.

In March 2009, MSKCC initiated HBV screening of all new patients receiving immunosuppressive therapy. Among 4065 patients screened between May 2009 and September 2010, almost 10% tested positive for either the HBsAg or the hepatitis B core antibody (HBcAb). All of these patients were treated with antiviral prophylaxis, and none experienced HBV reactivation.

The evidence of potential benefit has led a number of medical groups to endorse HBV screening for patients receiving immunosuppressive therapy, including the American, European, and Asian-Pacific Associations for the Study of Liver Diseases; the Infectious Diseases Society of America; the American Gastroenterology Association; the American College of Rheumatology; and the Centers for Disease

Control and Prevention.

The National Comprehensive Cancer Care (NCCN) suggests that antiviral therapy “be strongly considered in patients with acute HBV infection undergoing hematopoietic stem-cell transplant or other intensive immunosuppression,” although this is based on limited data. In its guidelines for non-Hodgkin lymphoma, the NCCN recommends HBsAg and HBcAb screening for all patients receiving rituximab.

But such recommendations are not universal—most notably, routine screening is not recommended by the American Society of Clinical Oncology (ASCO). ASCO deems the evidence to be insufficient to determine the risks versus benefits with routine screening.

Nevertheless, Dr Ludwig recommends universal screening. “If I had hepatitis B and was getting chemotherapy, I would put myself on an antiviral,” she said.—AA ■

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Oncogenic BRAF: A new potential therapeutic target EGFR

1,2

EGFR

RAS

BRAF MEK

ERK

The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2: ~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6 In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com To contact your account manager for more information on BRAF visit: genentechmm.com References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell. 2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers.

Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer.

2006;119:1858-1862.

Demonstrating the Value of Innovation Š2011 Genentech, Inc., So. San Francisco, CA MCM0000269700 02/11

A Member of the Roche Group

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AMCP ANNUAL MEETING

Will Generic Docetaxel Lower Total Medical Costs with Taxane Chemotherapy for Metastatic Breast Cancer?

By Brett Kaplan Minneapolis, MN—With the March 2011 approval of generic docetaxel by the US Food and Drug Administration, payers and clinicians will likely want to consider the potential cost impact of a second generic taxane for the management of metastatic breast cancer, considering that the taxanes, including paclitaxel (Taxol), docetaxel (Taxotere), and albumin-bound paclitaxel (Abraxane), are the mainstay of metastatic breast cancer therapy.

In a poster presentation at the 2011 Academy of Managed Care Pharmacy meeting, Rex W. Force, PharmD, Professor and Director of Research, Family Medicine and Pharmacy Practice, Idaho State University, and Partner, improveRX, in Pocatello, ID, and colleagues, observed that docetaxel would have to be discounted by as much as 95% to generate significantly lower total medical costs compared with the use of albuminbound paclitaxel.

In addition, their analysis showed that the use of docetaxel therapy was associated with the highest utilization and cost of colony-stimulating factors

(CSFs) that are often used during taxane chemotherapy.

This cost analysis of paid medical claims from a payer included >350,000

discounted analysis for docetaxel showed an adjusted per-patient permonth cost of $4665 for docetaxel, $4537 for albumin-bound paclitaxel,

“Despite higher acquisition cost for albumin-bound paclitaxel compared with docetaxel, total medical costs will likely remain similar between the drugs once generic docetaxel becomes available.”

—Rex W. Force, PharmD

patients who had been treated for cancer between May 2006 and April 2009.

Of these, 4503 women were identified with metastatic breast cancer who received either docetaxel (N = 2599), generic paclitaxel (N = 1643), or albumin-bound paclitaxel (N = 261).

The team did an initial cost comparison for the 3 taxanes, followed by a discounted analysis for generic docetaxel. The initial analysis before the

and $3784 for generic paclitaxel.

In the discounted analysis, the total medical cost associated with docetaxel became significantly lower (at $3698) than the cost with albumin-bound paclitaxel only after the branded price of docetaxel was discounted by 95%.

The 3 drugs “differ in their efficacy, side effect profile, notably neutropenia, and ease of administration,” according to Dr Force and colleagues.

The study findings show that CSF utilization and cost were significantly reduced with generic paclitaxel or with albumin-bound paclitaxel: 76% of the women receiving docetaxel used CSF agents compared with only 50% of those receiving generic paclitaxel and 37% of those receiving albuminbound paclitaxel. The total cost of CSF use was also significantly (P <.05) reduced with generic paclitaxel (–$9232) and albumin-bound paclitaxel (–$12,100) compared with docetaxel.

In explaining the dramatic discount that was necessary to reach significant savings with docetaxel over albuminbound paclitaxel, Dr Force and colleagues said that the “result may be affected by wide confidence intervals around the price of both drugs.” They also suggested that “despite higher acquisition cost for albumin-bound paclitaxel compared with docetaxel, total medical costs will likely remain similar between the drugs once generic docetaxel becomes available.”

In 2010, the estimated cost of breast cancer therapy was $16.5 billion in the United States. ■

Comparing Total Medical Costs of 4 Leading Regimens for Non–Small-Cell Lung Cancer Minneapolis, MN—The cost of treating patients with advanced non– small-cell lung cancer (NSCLC) varies considerably according to the chemotherapy regimen used, including ancillary therapies. A new cost analysis of total medical costs for patients with advanced NSCLC receiving 1 of the 4 leading chemotherapy regimens shows that a regimen of carboplatin (Paraplatin) plus paclitaxel (Taxol) has the lowest total medical cost, whereas the regimen of carboplatin, paclitaxel, and bevacizumab (Avastin) carries the highest medical costs.

NSCLC, the most common form of lung cancer and the most common new form of cancer, was diagnosed in 225,000 Americans in 2010, leading to almost 160,000 deaths. Lung cancer results in more deaths each year than leukemia and breast, prostate, and colon cancers combined.

Platin-based chemotherapy has been the mainstay of therapy for advanced NSCLC. In this new analy-

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sis, which was presented at the meeting, a team of pharmacists led by Rex W. Force, PharmD, Professor and Director of Research, Family Medicine and Pharmacy Practice, Idaho State University, and Partner, improveRX, in Pocatello, ID, compared the total medical costs associated with the 4 most common platin-based chemotherapy regimens for advanced NSCLC.

Lung cancer results in more deaths each year than leukemia and breast, prostate, and colon cancers combined; in 2010, it led to almost 160,000 deaths in the United States.

Using medical claims from 2 large data sets, the researchers enrolled all patients who had received 1 of the leading 4 platin-based regimens used for treatment of advanced NSCLC.

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Per-patient per-month (PPPM) medical costs were compared for each regimen, along with the costs for ancillary medications, including colony-stimulating factor (CSF) agents, erythropoiesis-stimulating agents (ESAs), and antiemetic drugs.

A total of 5124 patients who were receiving 1 of the designated 4 regimens were included in the analysis.

The median overall survival was 9.4 months for the carboplatin/docetaxel regimen (N = 638); 10.0 months for both the carboplatin/paclitaxel (N = 2935) and carboplatin/gemcitabine regimens (N = 493); and 11.3 months for the carboplatin/ paclitaxel/bevacizumab regimen (N = 391).

Adjusted median PPPM medical cost and adjusted cost per median survival time were: • Carboplatin/paclitaxel, $6818 and $68,180 • Carboplatin/gemcitabine, $7350 and $73,500 • Carboplatin/docetaxel, $7869 and $73,968

• Carboplatin/paclitaxel/bevacizumab, $12,795 and $144,583 Utilization of ancillary medication associated with all regimens varied considerably. Compared with patients who received the carboplatin/paclitaxel regimen, those who received the carboplatin/paclitaxel/bevacizumab regimen had the highest CSF costs ($6971), almost double that of the CSF cost for those receiving carboplatin/ docetaxel ($3803).

Patients who received the carboplatin/gemcitabine regimen had higher total costs associated with the use of ESA ($3406) than those receiving carboplatin/paclitaxel, as did those who received the carboplatin/docetaxel regimen ($1101); the latter, however, had the lowest costs associated with antiemetic use (–$492 vs the cost for patients receiving the carboplatin/ paclitaxel regimen).

“These results indicate opportunities exist for health plans to manage costs related to NSCLC,” the investigators pointed out.—BK ■

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AMCP ANNUAL MEETING

Economic Impact of Erlotinib Maintenance Therapy in the Treatment of Non–Small-Cell Lung Cancer

By Brett Kaplan Minneapolis, MN—Erlotinib is a human epidermal growth factor receptor inhibitor administered as maintenance therapy in the treatment of locally advanced or metastatic non– small-cell lung cancer (NSCLC) that has not progressed after 4 cycles of platinum-based first-line therapy.

Data from the Sequential Tarceva in Unresectable NSCLC (SATURN) study, first reported in 2009, suggest that erlotinib (Tarceva) can improve overall survival and progression-free survival in some patients undergoing chemotherapy for advanced NSCLC. Using a budgetary assessment model based on a hypothetical health plan population of 500,000 enrollees, a team of investigators from the University of Washington, Seattle, and Genentech, San Francisco, analyzed the economic impact of adding erlotinib maintenance therapy to a multistep chemotherapy regimen for

advanced NSCLC. The results were presented in a poster session at the 2011 Academy of Managed Care Pharmacy annual meeting.

Josh J. Carlson, MPH, PhD, and colleagues analyzed data from the SATURN study, the Surveillance, Epidemiology and End Results (SEER) Medicare study, and US census and market research data to estimate the expected annual cost of therapy for eligible patients with NSCLC, according to the following criteria: the 1-year incidence of patients with stage IIIb/IV NSCLC that is appropriate to receive maintenance therapy; the proportion of eligible patients expected to receive first-, second-, or third-line and maintenance therapy; the per-patient cost of medication and drug administration; and treatment of drug-related adverse events.

Among this hypothetical plan population, 133 members would be under-

Cost-Effectiveness of Dalteparin and Enoxaparin for Preventing Venous Thromboembolism in Patients with Cancer Minneapolis, MN—Patients with cancer receiving anticancer therapy are at risk for recurrent venous thromboembolism (VTE). Prophylactic treatment against such an adverse event is often done with a low-molecular-weight heparin, such as dalteparin (Fragmin), or enoxaparin (Lovenox, Clexane). In previous research, dalteparin was more effective than oral anticoagulants in preventing recurrent VTE. Results from the new retrospective study called CLOT, using real-world data, show that dalteparin may be more cost-effective than enoxaparin for the prevention of recurrent VTE in patients with cancer.

Using commercial claims data, researchers from Global Health Economics & Outcomes Research, Summit, NJ, identified 12,053 patients with cancer who had a previous VTE event, including deep-vein thrombosis or pulmonary embolism.

A total of 396 patients received dalteparin and 11,657 patients received

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enoxaparin between January 2004 and December 2008.

The rate of recurrent VTE was significantly (P = .001) lower with dalteparin (2.8%) than enoxaparin (3.7%), whereas the rate of major bleeding did not differ significantly.

The total annual costs associated with VTE were $19,589, which, when multiplied by the rates of recurrent VTE and major bleeding, translated to a total per-patient cost of $589 for those taking dalteparin versus $754 for those taking enoxaparin. This analysis suggests that dalteparin is more costeffective than enoxaparin for VTE prevention in patients with cancer.

The investigators noted that the treatment duration did not mirror that in the 6-month study. “It would appear that patients are initially treated with newer, even more effective, yet more expensive, treatments followed by older, less effective and considerably cheaper treatments,” they observed.—BK ■

going treatment for advanced NSCLC, of which 11 would be receiving firstline treatment for squamous, or beva-

“Adding maintenance therapy with erlotinib to a health plan formulary has a small budgetary impact.”

—Josh J. Carlson, MPH, PhD

cizumab (Avastin)-ineligible nonsquamous, disease that does not progress after 4 cycles of platinum-based chemotherapy. Among the 11 members eligible for erlotinib, 4 would receive maintenance therapy.

The total health plan costs with erlotinib as a treatment option totaled to $318,066, with a change in total

cost of $62,279, or $0.0104 per member per month.

Dr Carlson explained the increase as “primarily driven by the addition of erlotinib maintenance therapy and the subsequent increased use of secondand third-line agents that have higher costs than erlotinib.”

He added that the model did not address recurrent NSCLC or efficacy beyond its immediate impact on expenditures, nor did it consider other maintenance therapy options in the base-case analysis. Nevertheless, he concluded, “adding maintenance therapy with erlotinib to a health plan formulary has a small budgetary impact.”

The budget impact of erlotinib in patients with NSCLC “is a tool that can be used by healthcare plans to assess the budgetary impact of covering erlotinib as a maintenance therapy,” Dr Carlson and his colleagues observed. ■

Chemotherapy-Induced Peripheral Neuropathy and Healthcare Costs in Patients with Metastatic Breast Cancer Minneapolis, MN—Chemotherapyinduced peripheral neuropathy (CIPN) is a common adverse effect associated with several chemotherapeutic agents, especially taxanes, platinum compounds, epothilones, and vinca alkaloids. Although CIPN is common, its incidence and effects on overall healthcare patterns and costs are not well documented.

At a poster presentation at the meeting, Stacy DaCosta Byfield, PhD, MPH, of innovus, Eden Prairie, MN, and colleagues analyzed the healthcare costs of CIPN for patients with metastatic breast cancer.

Claims data were for women receiving chemotherapy for metastatic breast cancer for the first time for at least 6 continuous months between July 2004 and July 2009.

Among 1821 women whose claims were examined, 3.8% (n = 70) had evidence of CIPN during the first chemotherapy episode versus 97.2% (n = 1751) who did not. Those who had CIPN had significantly more chemotherapy cycles (7.41) than

those who did not (5.67), and had a significantly longer chemotherapy episode (225 days vs 170 days, respectively).

All-cause healthcare costs were significantly higher among patients with CIPN ($100,293) than for those who did not have CIPN ($59,124). Patients with CIPN were also more likely to undergo certain procedures, such as nerve conduction and occupational therapy, receive anticonvulsants and antidepressants for controlling the disorder, and switch their regimen from the index chemotherapy. The incidence of drug discontinuation or dosing modification did not differ between the 2 groups, however.

Dr Byfield and colleagues noted that the claims data used in this study did not address certain relevant clinical and disease-specific details that could have affected the study’s outcome, such as each patient’s history of peripheral neuropathy, planned chemotherapy regimen, and reasons for any changes to the planned regimen.—BK ■

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In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

80

60

1.9

4.9

months

months

Placebo 40

Afinitor 20

0

2

4

6

8

10

12

14

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2 â&#x20AC; BSC=best supportive care.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Please see Important Safety Information on right side of page.

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

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Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances.

Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy.

Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor.

Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer.

Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment.

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor.

Fetal harm can occur if Afinitor is administered to a pregnant woman.

The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%).

The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet.

2008;372:449-456.

2.5mg 5mg 10mg

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis

Printed in U.S.A.

10/10

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AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information.

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label:

1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].

4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

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

5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily.

For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.

5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].

Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)].

5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)].

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)].

5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.

AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)].

5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.

Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

• Infections [see Warnings and Precautions (5.2)].

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo.

The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

97

52

13

93

23

5

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

0 0 0 0

Infections and Infestationsb

37

7

3

18

1

0

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 Pneumonitisc 14 4

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

0 0 0

1

0

14

<1

0

<1 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

0

7

0

0

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

60

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:49 PM Page 43

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2.

Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

25

<1

<1

7

0

0

21 3

1 <1

0 <1

4 2

0 0

0 0

a

Hematology Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.

Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).

8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information].

No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information].

8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively.

• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)].

Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).

[See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture.

Keep this and all drugs out of the reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.

AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.

Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

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ACCC ANNUAL NATIONAL MEETING

Oncology 2021: Cost, FDA, and Cancer Care

By Daniel Denvir Washington, DC—Oncology and healthcare are undergoing rapid changes. One thing that does not seem to be changing soon is the long-term prognosis of exploding costs.

The extent to which the US Food and Drug Administration (FDA) and the Centers for Medicare & Medicaid Services (CMS) will consider cost in making decisions concerning drug approval and reimbursement was the subject of a lively debate at the 2011 Association of Community Cancer Centers annual meeting.

Drug Costs and the FDA Scott Gottlieb, MD, a practicing physician and fellow at the American Enterprise Institute, previously Deputy Commissioner of the FDA, foresees an increasing preoccupation with cost at the FDA, however indirectly. “I don’t think that there will be anything in a regulatory process that will explicitly consider cost,” Dr Gottlieb said, pointing out that European regulators are addressing cost questions much more aggressively.

However, “I think there is a sentiment in the agency that because these drugs are so high-priced and the returns so lucrative in many cases, that it justifies the requests that the agency makes for higher and higher data requirements,” he said, adding that there is an explicit consideration of cost by the advisory committees in their dealing with manufacturers.

Thomas A. Gustafson, PhD, a Senior Policy Advisor at Arnold & Porter, LLP, does not think the FDA will shift its focus to cost control, although he acknowledges that the FDA “gets it that things are expensive” and “wants to make sure that on those decisions particularly they’re doing it right.”

Dr Gustafson was previously with the US Department of Health and Human Services and Deputy Director at the Center for Medicare Management, the predecessor to CMS. Patients Should Share in the Cost Burden Daniel H. Johnson Jr, MD, a fellow at the Heritage Foundation’s Center for Health Policy Studies, and Clinical Professor of Radiology, Tulane University, New Orleans, called for patients to share in the cost of healthcare as a way to encourage responsible use of the system and push down costs.

“What we have is a system that insulates the people from the cost, including cancer patients,” said Dr Johnson.

Some providers in the audience

44

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own clinical reasoning in what it pays for,” giving them authority “to pay for the least costly alternative option,” said Dr Gottlieb.

From left: Scott Gottlieb, Thomas A. Gustafson, Daniel H. Johnson Jr, and moderator Clifford Goodman, PhD

questioned the impact such a move would have on the poor. One physician stated that many of his patients had little money left after paying for the gas to drive to his clinic. Dr Johnson suggested that positive incentives, or rewards for prudent use of healthcare, could also play a role in curbing costs.

New Experiments in Bending the Cost Curve The healthcare reform law encourages the creation of new delivery systems as a key way to control costs.

According to Dr Johnson, accountable care organizations (ACOs), which hold a group of providers responsible for a patient’s care continuum, are a good idea. But he cautioned ACOs should not be the only option. “The good idea could become a trap, if that’s the only way care is delivered,” he acknowledged.

“The good idea could become a trap, if that’s the only way care is delivered. The medical home should not be a prison.”

—Daniel H. Johnson Jr, MD

Similarly, in the medical home, it would be helpful to have someone coordinating overall patient care and reducing the current fragmentation.

But, Dr Johnson cautions, “the medical home should not be a prison.”

The jury is still out on ACOs and

VALUE-BASED CANCER CARE

I

June 2011

other new delivery systems. For Dr Johnson, the existence of competing alternative models is crucial to figuring out what works: driving costs down and pushing quality up.

Referring to the healthcare reform

Impact of Cost-Containment Efforts on Oncology The panelists were also worried that the pressure to contain costs could alter the current system of regulating the use and reimbursement of medications for off-label indications in oncology.

In oncology, compendia regulate the reimbursement of off-label drugs and are a crucial site for innovation. Dr Gottlieb called the compendia an “optimum model.”

“I don’t think anything that the government comes up with is going to be more expert than that [compendia],” he said. “The threat in the longer term is that the agencies, as they need to control their own budgets, are going to want to get control over the off-label use of oncology

“The threat in the longer term is that the agencies, as they need to control their own budgets, are going to want to get control over the offlabel use of oncology products. And I see CMS starting to try to distance themselves from the compendia process.”

—Scott Gottlieb, MD bill, Dr Gottlieb said that integrated delivery systems are not laboratories for innovation, because “the things in the bill trying to address the Medicare cost issue mostly deal with trying to change around market power.”

The Independent Payment Advisory Board (IPAB) is another central costcontrol component of the new healthcare law—and a major concern to some in the oncology community. The IPAB must cap the rate of growth in Medicare spending to growth in the consumer price index. If Congress rejects an IPAB proposal, it must come up with a way to achieve equivalent savings.

Dr Gottlieb thinks it is unlikely that CMS will directly inject itself into clinical decision-making. Instead, it is likely to rely on price controls. “They’re not going to make individual coverage decisions,” he said, predicting that CMS will cut reimbursement rates, and possibly import Medicaid or Veterans Affairs drug schedules.

The establishment of an IPAB will also allow CMS to “embed more of its

products. And I see CMS starting to try to distance themselves from the compendia process.”

Dr Gustafson cautioned everybody, “In a nutshell, we’re running out of money, and that ought to scare us all.”

The only solutions are to reduce benefits, raise taxes, or make medicine more efficient, the panelists suggested.

Everyone seems to be pinning their hopes on that last option. ■

Look for Our Special Issue in July with Full Coverage of the First Annual Conference of the Association for Value-Based Cancer Care VOL. 2

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NO. 3

VBCC_June_11_2_Follow ASCO Tabloid 6/17/11 1:54 PM Page 45

COMMENTARY

No, You Can’t Keep Your Health Insurance A new study by McKinsey suggests that as many as 78 million Americans could lose employer health coverage

By Grace-Marie Turner, President, Galen Institute, and coauthor, Why ObamaCare Is Wrong for America

O

bamaCare will lead to a dramatic decline in employer-provided health insurance—with as many as 78 million Americans forced to find other sources of coverage.

This disturbing finding is based on my calculations from a survey by McKinsey & Company. The survey, published this week in the McKinsey Quarterly, found that up to 50% of employers say they will definitely or probably pursue alternatives to their current health-insurance plan in the years after the Patient Protection and Affordable Care Act takes effect in 2014. An estimated 156 million nonelderly Americans get their coverage at work, according to the Employee Benefit Research Institute.

Before the health law passed, the Congressional Budget Office estimated that only 9 million to 10 million people, or about 7% of employees who currently get health insurance at work, would switch to government-subsidized insurance. But the McKinsey Reprinted from the Wall Street Journal, June 8, 2011. Copyright © 2011 Dow Jones & Co. All rights reserved.

survey of 1300 employers across industries, geographies, and employer sizes found “that reform will provoke a much greater response” and concludes that the health overhaul law will lead to a “radical restructuring” of job-based health coverage.

Another McKinsey analyst, Alissa Meade, told a meeting of health-insurance executives last November that “something in the range of 80 million to 100 million individuals are going to change coverage categories in the 2 years” after the insurance mandates take effect in 2014.

Many employees who will need to seek another source of coverage will take advantage of the health-insurance

subsidies for families making as much as $88,000 a year. This will drive up the cost of ObamaCare.

In a study last year, Douglas HoltzEakin, a former director of the Congressional Budget Office, estimated that an additional 35 million workers would be moved out of employer plans and into subsidized coverage, and that this would add about $1 trillion to the total cost of the president’s health law over the next decade. McKinsey’s survey implies that the cost to taxpayers could be significantly more.

The McKinsey study, “How US health care reform will affect employee benefits,” predicts that employers will either drop coverage altogether, offer defined contributions for insurance, or offer coverage only to certain employees. The study concludes that 30% of employers overall will definitely or probably stop offering health insurance to their workers. However, among employers with a high awareness of the health-reform law, this proportion increases to more than 50%.

The employer incentives to alter or cease coverage under the health reform law are strong. According to

the study, at least 30% of employers would gain economically from dropping coverage, even if they completely compensated employees for the change through other benefit offerings or higher salaries. That’s because they no longer would be tethered to healthinsurance costs that consistently rise faster than inflation.

Employers should think twice if they believe the fine for not offering coverage will stay unchanged at $2000 per worker. “If many companies drop health insurance coverage, the government could increase the employer penalty or raise taxes,” according to the new study, authored by McKinsey consultants Shubham Singhal, Jeris Stueland, and Drew Ungerman.

The case for repeal of ObamaCare grows stronger every year. The massive shift of health costs to taxpayers thanks to the disruption of employersponsored health insurance will add further to the burgeoning federal budget deficit. Congress can and must develop policies that allow the marketplace to evolve and not be forced into ObamaCare’s regulatory straitjacket. ■

ACCC ANNUAL NATIONAL MEETING

Integrating a Wellness Perspective into Survivorship Care Washington, DC—Improved treatment, more effective screening, and an aging population have fueled the rapid growth of cancer survivors— approximately 12 million today in the United States, up from just 3 million in 1971. Since even before the Institute of Medicine’s pivotal 2005 report “From Cancer Patient to Cancer Survivor: Lost in Transition,” there has been a growing recognition of the need to treat cancer survivors across the continuum of care.

“Survivorship begins at the moment of diagnosis and lasts for a lifetime,” Frances Zandstra, RN, MBA, OCN, Director of the Cancer Survivorship Program at M. D. Anderson Cancer Center, Houston, told attendees at a session on survivorship care.

Survivors, of course, require surveillance screening, but they also benefit from care targeting everything from psychosocial issues and sexual health to monitoring for comorbidities and exercise and nutrition counseling.

The broader contours of survivorship are often “lost in transition,” when oncologists hand patients off to pri-

VOL. 2

NO. 3

mary care physicians. Cancer survivorship programs leverage multidisciplinary teams and electronic communication tools to reduce these obstacles.

“We’d give them the cake and say, ‘Congratulations, you’ve finished treatment,’ and then they would go to the parking lot and just collapse,” said Denice Economou, RN, MN, CNS, AOCN, Project Director for Survivorship Education for Quality Cancer Care at City of Hope National Medical Center, Duarte, CA. “They didn’t know what they were supposed to do next; they were scared.”

Now our idea is to try to keep surviving patients in the loop “and make a difference in that posttreatment phase.”

Communication is key. “How do we help our community physicians take care of survivors in the community?”

Ms Zandstra asked. “You get the call: ‘My doctor won’t give me a shingles vaccine because he’s afraid it’s going to stimulate my immune system and my cancer may come back.’ How do we help to educate and partner with them to take care of these survivors in

the community?”

Patients with cancer undergo a battery of treatments, and the specifics can be hard to remember, especially after the passage of time.

Breast cancer comprises a large number of patients with a variety of diagnoses, and it can be hard to define when the treatment stage ends.

“Survivorship begins at the moment of diagnosis and lasts for a lifetime.”

—Frances Zandstra, RN, MBA, OCN

Becky Ball, RN-BC, BSN, Clinical Services Manager at the Sanford Cancer Center in Sioux Falls, SD, said that the degree of patient organization still makes patients with breast cancer an attractive option for instituting a program. “It’s a difficult one to get going for a lot of reasons. But one of the benefits is that you have a patient population that really wants that serv-

ice, so they’re willing to participate and give you input into that program development.”

The basic components of survivorship care are standard, although the specific treatment needs vary by disease and disease severity. For patients with breast cancer, at M. D. Anderson they sort survivors into low- and highrisk tiers.

Providers are a good resource for dealing with cancer survival, according to Ms Ball. “Those first-line caregivers tend to have a better feel” for patient needs.

Aligning the needs of patients with payers’ approaches, however, can be a challenge. Ms Ball notes that it remains a challenge to know what aspects of survivorship programs payers will reimburse for.

She advocates that a wellness perspective be integrated throughout the entire survivorship process, because cancer should never be treated in isolation. Sanford has an American Cancer Society navigator on campus that runs support groups, which can be a big part of survivorship care.—DD ■

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GENITOURINARY CANCERS SYMPOSIUM

Harvard-Led Team Finds Small but Significant Increased Risk of CHF with Sunitinib

By Debra Wood, RN Orlando, FL—A comprehensive report demonstrates a small, but significant, increased risk of left ventricular decline and congestive heart failure (CHF) in patients taking sunitinib to treat renal and other cancers, and the researchers are recommending screening to detect cardiac problems before patients become symptomatic.

“Sunitinib has not been used as long as Avastin [bevacizumab], but we are finding the risk similar, and that could impact how practices monitor patients during treatment,” said Christopher J. Richards, a medical student at Harvard Medical School and the Dana-Farber Cancer Institute Kidney Cancer Center in Boston, at the 2011 Genitourinary Cancers Symposium, sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and

the Society of Urologic Oncology.

Mr Richards and colleagues performed a meta-analysis of 12 published phase 2 and 3 clinical trials to determine the risk of developing serious CHF in 5497 patients with renal-cell carcinoma and other cancers who were treated with the multitargeted receptor tyrosine kinase inhibitor sunitinib (Sutent).

Compared with patients receiving placebo, the relative risk of developing all-grade CHF in sunitinib-treated patients was 1.81, and the risk of highgrade CHF was 3.17.

Underreporting of low-grade CHF probably has occurred in the clinical trials, Mr Richards said, because it is an asymptomatic condition detected on screening. He added that he hoped this study would raise investigators’ awareness of the cardiac risks associated with the drug and include screen-

“Catch it early, because there is significant mortality associated with heart failure, even with low-grade CHF. If the patient with asymptomatic CHF has screening, adjusting the dose [of sunitinib] and changing other medications is something you can easily act upon.”

—Christopher J. Richards ing as part of the protocol.

“Catch it early, because there is significant mortality associated with heart failure, even with low-grade CHF,” Mr Richards said. “If the

Partial Nephrectomy Preferred over Radical Procedure for Small Renal Masses Reduced cost, improved clinical outcomes Orlando, FL—Guidelines for the management of stage I renal masses include partial and radical nephrectomy, but results of a new study presented at the 2011 Genitourinary Cancers Symposium suggest that partial nephrectomy is less costly and leads to fewer adverse health outcomes associated with kidney disease.

“Partial nephrectomy is cheaper and has better health outcomes; therefore, it is a better choice,” said Steven L. Chang, MD, MS, urology surgeon at Brigham and Women’s Hospital and instructor at Harvard Medical School.

Dr Chang and colleagues quantified, in general, the long-term economic and clinical costs of postoperative chronic kidney disease (CKD) after

Full Coverage of the First Annual Conference of the Association for Value-Based Cancer Care Coming in July

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“Partial nephrectomy is cheaper and has better health outcomes; therefore, it is a better choice.”

—Steven L. Chang, MD, MS

radical and partial nephrectomy, using a Markov model. The researchers based the findings on a 65-year-old man with normal renal function before treatment. They then evaluated cost, quality of life, and transition probabilities based on published literature, Medicare data, and expert opinions.

The associated costs over the patient’s lifetime were approximately $200,000 for radical nephrectomy compared with approximately $150,000 for

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partial nephrectomy. Patients receiving the partial surgery also would experience a better quality of life.

“Chronic kidney disease, stage 3, 4, and 5, has a 2-fold higher medical cost,” Dr Chang said. “With comorbidities, the cost gets multiplied.”

Dr Chang added that in many instances, physicians may not see the outcome of kidney disease, because it may occur after they stop following the patient, as many as 5 or 10 years after the initial surgery. He advised physicians to discuss with patients the long-term consequences before proceeding with surgery.

Over a lifetime, the research team found little cost difference between open and laparoscopic approaches.

However, CKD led to a substantial cost increase and a decrease in health outcomes, regardless of the surgical method.

“The impact is higher on younger patients,” Dr Chang said. “In a 45year-old male, physicians should think twice before doing a radical nephrectomy. The chance of a major impact is higher than with an 85-year-old.”

Even in those cases where surgeons perform a partial nephrectomy, patients still often experience issues associated with kidney disease, Dr Chang

patient with asymptomatic CHF has screening, adjusting the dose [of sunitinib] and changing other medications is something you can easily act upon.” ■

at a glance ➤ Although the guidelines for stage I renal masses include partial and radical nephrectomy, new data indicate several advantages with the partial procedure ➤ Associated costs over the patient’s lifetime are approximately $200,000 with radical nephrectomy versus $150,000 for partial nephrectomy ➤ Quality of life and overall health outcomes are also better with partial rather than radical nephrectomy ➤ The impact is greater in younger patients; those aged <45 years should likely not undergo radical nephrectomy.

This is less relevant for elderly patients said. He suggested performing a percutaneous biopsy to verify the lesion is malignant before proceeding with either a partial or radical nephrectomy, because new-onset postoperative CKD has a substantial economic and clinical affect on long-term outcomes.

“If at all possible, physicians should do a partial nephrectomy,” Dr Chang said. “It’s cheaper and has better health outcomes. It’s a better choice.”—DW ■

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GASTROINTESTINAL CANCERS SYMPOSIUM

Optimal Screening Method for Colorectal Cancer Still Debated rate of referral for colonoscopy, and the evaluation of extracolonic findings,” Dr Lieberman said. “Because of uncertainty about the benefit and risk of extraintestinal evaluations, the US Preventive Services Task Force has not endorsed CTC for screening.”

Questions of cost-effectiveness linger, and screening rates are subpar

By Caroline Helwick San Francisco, CA—Colorectal cancer is preventable but remains the secondleading cause of cancer death, because of persistently low screening rates. At the 2011 Gastrointestinal Cancers Symposium, colorectal cancer screening experts debated the relative merits of 2 modalities competing for patients and reimbursement dollars, both claiming to be cost-effective.

Computed Tomographic Colonography for Screening Two- and 3-dimensional computed tomographic colonography (CTC), also known as virtual colonoscopy, holds advantages over conventional optical colonoscopy (OC) for population screening, according to Perry J. Pickhardt, MD, of the University of Wisconsin School of Medicine and Public Health, Madison. However, politics and “turf issues” unrelated to medical evidence have delayed widespread acceptance and third-party coverage, he claims.

The most current versions of CTC can detect 90% of polyps ≥10 mm, which includes most early cancers.

According to Dr Pickhardt, CTC offers the following benefits compared with traditional colonoscopy: • Less invasive, with little or no risk • No need for sedation, pain medication, or recovery time • Allows for extracolonic evaluation (finding abdominal aortic aneurysms, other cancers) • Increases overall screening adherence • More cost-effective, because it reserves invasive colonoscopy for treatment (polypectomy).

Nearly all studies focusing on the cost-effectiveness of CTC for screening have shown it is more cost-effective than not screening. “CTC compares favorably with colonoscopy when appropriate input assumptions (ie, real values) are applied,” Dr Pickhardt said. Unlike OC, CTC does not pick up the diminutive (≤5 mm) lesions that pose little to no threat and are overtreated.

“Ignoring isolated diminutive lesions at CTC screening has been identified as a drawback by some, but I believe this approach results in a significant cost benefit, without any real penalty in terms of clinical efficacy,” he said. “If we sent every diminutive lesion we detected to colonoscopy, the

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cost would be exorbitant, but with a focus on large lesions, there’s a good chance that CTC screening can even be cost-saving.”

In a model Dr Pickhardt developed, an endoscopist would need to find 2353 diminutive lesions to identify 1 cancer among them, compared with 297 small lesions (6-9 mm) and just 11 large lesions (≥10 mm). The respective incremental cost ratios were $464, $59, and – $151 per person screened, respectively.

offered OC. Under this scenario, most decision models show that CTC would be more costly than other screening programs, he said.

He also expressed concerns that small polyps may be identified but never referred for further evaluation

by OC, and that flat polyps, which are not easily detected by CTC, will frequently be missed. The need for a second bowel preparation in patients referred to OC is also problematic, and

Colonoscopy Not Perfect Either “Clouds over colonoscopy” still keep it from being the near-perfect screening modality, Dr Lieberman added. These include the occurrence of interval cancers (ie, those found soon after screening) and low utilization rate, potential for harm, and screening quality in some centers.

Interval cancers—those that appear 3 to 5 years after colonoscopy and polypectomy—are observed in 0.3% to 0.9% of patients. “If colonoscopy were a perfect screening test, we would not expect to see this rate,” he noted.

These may be new, fast-growing lesions or a result of incomplete removal of neoplastic polyps. Of even greater concern, these lesions might have been missed during colonoscopy, which occurs for >10% of polyps >1 cm, Dr Lieberman said. “Missed lesions are the elephant in the endoscopy suite, and it raises questions about the efficacy of colonoscopy.”

Dr Lieberman stressed the importance of a complete examination— navigating the entire colon—that results in greater cancer detection.

“We need to do a better job of documenting quality and improving colonoscopy, which is a good test, although not perfect.” ■

“If we sent every diminutive lesion we detected to colonoscopy, the cost would be exorbitant, but with a focus on large lesions, there’s a good chance that CTC screening can even be cost-saving.”

—Perry J. Pickhardt, MD

Dr Pickhardt and colleagues compared CTC with OC for the detection of advanced neoplasia in a parallel community screening program of more than 3000 patients per arm (Kim DH, et al. N Engl J Med. 2007;357:14031412). Of the CTC-screened patients, 8% then had OC for further evaluation. Although more adenomatous polyps were removed in the OC arm, slightly more advanced cancers were found with CTC, and 3 times more cancers were detected. Furthermore, no serious complications occurred with CTC compared with 7 with OC. Based on meta-analyses, Dr Pickhardt calculates a sensitivity of 96.1% with CTC and 94.7% with OC for cancer detection; CTC also detects more proximal (right-sided) lesions, which can often be missed. Although concerns have been raised that CTC misses flat (sessile) polyps, “in our experience these are encountered at both conventional and virtual colonoscopy screening at a much lower frequency than polypoid lesions and tend to be less aggressive,” he said.

Unresolved Issues But David Lieberman, MD, of Oregon Health and Science University, Portland, expressed concerns about CTC, including the “threshold for referral to colonoscopy.”

Current guidelines recommend that all patients with polyps ≥6 mm (up to 25% of screened populations) be

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although same-day procedures would circumvent this, few institutions offer this, Dr Lieberman said.

Frequent extracolonic findings on CTC also trigger additional workups, usually for inconsequential reasons. The appropriate interval for screening with CTC also has not been determined.

“CTC provides an excellent structural exam alternative to colonoscopy, but programmatic costs are higher, and are related to the cost of the CTC,

Current Colorectal Cancer Screening* Prevalence WA ME

ND

MT

VT NH

MN

OR

WI

SD

ID

NY

WY NE

NV

IL

UT

CO

CA

AZ

PA

IA

WV KS

OK NM

MO

TX

VA

KY

NC

TN SC

AR MS

AL

NJ DE MD DC

OH

IN

MA RI CT

MI

Screening, % 66.1 - 71.5

GA

61.1 - 66.0

LA

57.3 - 61.0

AK

53.1 - 57.2

FL

HI

Colorectal cancer screening prevalence (%) among adults ≥50 years, 2006-2008. *A fecal occult blood test within the past year or a sigmoidoscopy or colonoscopy within the past 10 years. These estimates do not distinguish between screening and diagnostic examinations.

Source: Centers for Disease Control and Prevention.

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HOPA ANNUAL MEETING

A Pharmacist Reviews Cancer Drugs in the Pipeline Few prolong survival but most offer reduced toxicity

By Christin Melton Salt Lake City, UT—A review of promising investigational drugs at the 2011 Hematology/Oncology Pharmacy Association annual meeting shows that the pharmaceutical industry is responding to the call for more targeted agents in oncology. Although a few drugs moving through the pipeline offer little survival advantage over the current standard of care, clinical trials suggest their greater selectivity is associated with lower rates of serious toxicity.

Robert T. Dorr, PhD, RPh, Professor of Pharmacology at the Arizona Cancer Center in Tucson, said he expects a handful of new therapeutics to be approved and come to market in the United States in the next year.

Prostate Cancer MDV3100 is an emerging therapy for metastatic castration-resistant prostate cancer, but Dr Dorr said abiraterone’s success has hindered trial recruitment for the phase 3 trials needed to support Medivation’s new drug application for MDV3100. Preliminary data from one phase 3 study show that the androgen receptor antagonist produced fairly high rates of prostate-specific antigen response in chemotherapy-naive and previously treated patients, and he believes it will ultimately receive US Food and Drug Administration (FDA) approval.

Breast Cancer In discussing breast cancer therapeutics, Dr Dorr said disappointing results from a trial of iniparib delivered a setback to PARP inhibitors in breast cancer. TDM-1, a novel agent for HER2-positive breast cancer, suffered its own setback when the FDA deferred approving the drug pending stronger evidence of its efficacy. TDM1 combines trastuzumab (Herceptin) and a derivative of the microtubule antibody maytansine, and Dr Dorr considers it superior to trastuzumab.

He expects forthcoming trial data to provide the FDA with enough evidence that TDM-1 improves response and overall survival (OS) to warrant approval.

“At the highest dose, you actually get regression with this construct….In some breast tumors, you can get neartotal suppression,” he said. Although trastuzumab inhibits tumor growth, it does not typically spur tumor regression. Also, phase 2 studies suggest the newer agent is far less toxic than trastuzumab. “This is a big improve-

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ment for patients, that you can get the same outcome with markedly reduced toxicity,” Dr Dorr noted.

Non–Small-Cell Lung Cancer Crizotinib, which Dr Dorr called “a home run,” is another drug he expects to receive approval in the coming months. Crizotinib is an oral small molecule inhibitor, and its use is restricted to the 5% of patients with non–small-cell lung carcinoma who have chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene.

Results of a phase 1/2 trial (N = 82) showed that 90% of heavily pretreated patients achieved partial response, complete response, or stable disease (Kwak EL, et al. N Engl J Med. 2010; 363:1693-1703). Dr Dorr said a followup analysis slotted for the 2011 American Society of Clinical Oncology meeting is expected to show the responses were fairly durable and is likely to report improvement in OS. Crizotinib appears to be relatively safe, with most toxicities not surpassing grade 1. “The only grade 3 toxicities we are seeing are AST [aspartate aminotransferase] and ALT [alanine aminotransferase] elevations, and 80% of these patients could go down to 200 mg twice daily,” noted Dr Dorr. He added that dose-limiting fatigue was seen at a dose of 300 mg twice daily.

Approval could be delayed if the FDA does not approve the companion diagnostic test submitted for consideration at the same time.

TDM-1, a novel agent for HER2-positive breast cancer “is a big improvement for patients, that you can get the same outcome with markedly reduced toxicity.”

—Robert T. Dorr, PhD, RPh Chronic Myeloid Leukemia The pace of drug development in chronic myeloid leukemia (CML) does not appear to be slowing, and Dr Dorr said at its current rate, we would see “a nib a year” for this disease. Of the most promising investigational agents, bosutinib (SKI-606) is probably the furthest along. Like the currently approved tyrosine kinase inhibitors imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna), bosutinib is

also ineffective in patients with the T315I mutation.

“BRAF is not believed to be an initiating mutation.

It’s believed to be a propagating mutation, which makes it a much better target for therapy.”

—Robert T. Dorr, PhD, RPh Bosutinib’s primary targets are ABL, SRC, and CAMK26, and it has a maximum tolerated dose of 500 mg once daily. Bosutinib has demonstrated activity in phase 2 trials, showing complete responses and major molecular response in 74% of patients resistant to or unable to tolerate imatinib and in patients resistant to dasatinib or nilotinib. Trials report low rates of grade 3/4 toxicities, with diarrhea, neutropenia, and hypomagnesemia among the most common.

“The problem that happened with bosutinib is that the so-called pivotal 3000 trial that was supposed to show a superior cytogenetic response rate [over imatinib] at 1 year did not reach its primary end point,” he said.

Despite this, Pfizer filed a new drug application with the FDA in the hopes that it might be approved as a secondor third-line agent, which Dr Dorr believes is likely.

Renal-Cell Carcinoma Patients with renal-cell carcinoma refractory to sorafenib (Nexavar) could have a new option soon. A 2007 phase 2 trial of the oral drug axitinib, which Dr Dorr described as a “pure” inhibitor of vascular endothelial growth factor (VEGF) 1, 2, and 3, demonstrated a 44% overall response rate using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, time to progression

of 15.7 months, and median OS of 29.9 months.

A total of 62 heavily pretreated patients with refractory metastatic renal-cell carcinoma were enrolled in a single-arm trial of axitinib and found that the majority experienced partial response or standard deviation (Rini BI, et al. J Clin Oncol. 2009;27:44624468).

“I think [renal-cell carcinoma] is turning out to be a little like CML. You’ll start on a drug and ultimately fail on it, move to another one and then another one, and there’s a possibility you can later go back to an original drug and get response,” said Dr Dorr.

Grade 3/4 adverse events included hand-foot syndrome, which he noted is a class effect of VEGF inhibitors.

Thyroid Cancer A number of novel and marketed multikinase inhibitors that target RET signaling are being investigated in thyroid cancer, including motesanib, sorafenib, and XL-184. Dr Dorr said RET mutations appear to be a driver of medullary thyroid cancer.

At the meeting, vandetanib was introduced as furthest along in development and was correctly predicted to receive FDA approval soon after the meeting, which it did on April 6, 2011 (see page 4), for nonresectable and/or metastatic medullary thyroid cancer.

This agent inhibits VEGF receptor and epidermal growth factor receptor and has been the subject of approximately 23 clinical trials, including 10 unsuccessful studies in non–small-cell lung cancer. The partial response rate for patients with medullary thyroid cancer has been low, but submitted trial data showed a median progression-free survival (PFS) of 22.6 months for patients treated with vandetanib, compared with 16.4 months for patients taking placebo. Dose-limiting toxicities consist primarily of rash and diarrhea, which Dr Dorr said have been manageable with minor dose reductions.

BRAF Mutations Drug developers have become increasingly interested in BRAF pathway mutations. Constitutively active BRAFV600E mutations are found in 60% of patients with melanoma, 40% with papillary thyroid cancer, 30% with serous ovarian cancer, 10% with colorectal cancer, and 10% with prostate cancer. “BRAF is not believed to be an Continued on page 50

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A Pharmacist Reviews Cancer Drugs...

Continued from page 49

initiating mutation. It’s believed to be a propagating mutation, which makes it a much better target for therapy,” Dr Dorr explained.

PLX4032 (also known as RG7204), a powerful inhibitor of BRAFV600E, is the furthest along in development. Early trial results in advanced melanoma showed that most patients with a BRAFV600E mutation achieved partial or complete response and that 81% of patients had their tumors shrink by at least 30%, which prompted numerous headlines touting PLX4032 as a possible cure.

Many patients ultimately become refractory to the drug, however, and some researchers are looking at whether combining it with a MET inhibitor might provide more durable responses.

In a January 2011 press release, the manufacturer of PLX4032 announced that upcoming preliminary data would show improved OS and PFS for patients taking PLX4032 as part of a phase 3 trial. “I think the molecular drug will probably be approved sometime next year,” Dr Dorr noted.

Another BRAF inhibitor under investigation for advanced melanoma

is GSK2118436, which shrank tumors anywhere from 20% to 100% in 9 of 10 patients, according to data presented at the 2010 annual meeting of the European Society of Medical Oncology. Multiple metastatic sites also demonstrated response, including metastases of the central nervous system. Adverse effects were modest, consisting primarily of fatigue, pyrexia, and dehydration.

—Robert T. Dorr, PhD, RPh

superior to existing agents in terms of efficacy but praised its lower toxicity profile. An added benefit of carfilzomib is that patients do not need steroid treatment while taking it.

Pomalidomide is another promising drug for refractory multiple myeloma.

It is an oral immunomodulatory agent, and preliminary phase 1/2 trial data presented last year at the American Society of Hematology indicated that it was highly active in patients with heavily pretreated disease.

They reported an overall response rate of 62%, and Dr Dorr said 24% of partial responses fell into the “very good” category. One third of patients experienced neutropenia ≥grade 3, which might be something to watch for in future analyses.

Multiple Myeloma Dr Dorr discussed some agents progressing down the multiple myeloma drug pipeline. Carfilzomib is a new proteasome inhibitor undergoing investigation in a large, closely watched phase 3 trial enrolling patients refractory to bortezomib. He expressed skepticism as to whether it would prove

Pancreatic Cancer Dr Dorr briefly reviewed a handful of additional investigational agents at earlier stages of development.

Ganitumumab (AMG479) was given with gemcitabine in a phase 2 trial of patients with metastatic pancreatic cancer. The 1-year OS rate was 40% compared with 20% for gemcitabine plus conatumumab and 23% for gem-

“I think the molecular drug [PLX4032] will probably be approved sometime next year.”

citabine monotherapy, and the drug was “very well tolerated.”

Advanced Solid Tumors BMK120 is an oral pan-class 1 PI3K inhibitor in trials for patients with advanced solid tumors. An early phase study that accrued 15 patients found a 50% to 80% rate of down regulation of pS6 and an 80% response rate (8 of 10 patients evaluable).

Going back to PARP inhibitors, Dr Dorr said although they have not done well in breast cancer in the past year, some are optimistic about preliminary data last year that showed activity with oliparib in serous ovarian cancer.

Dr Dorr predicted that in the coming year, we would likely see many more novel targeted agents making their way out of the crowded oncology pipeline. He expects a number of RET and MET inhibitors and drugs that affect RAS signaling to start generating interest.

“We have maybe 15 or 16 kinase inhibitors in the armamentarium now,” Dr Dorr said, but with more than 500 protein kinases identified in humans, a tremendous amount of room remains for future discovery. ■

FROM THE LITERATURE Continued from page 7 Bisphosphonates Reduce Colorectal Cancer Risk in Postmenopausal Women

Changing Oncologists’ Practice and Attitudes Can Save Billions of Dollars

Bisphosphonates have been shown recently to reduce the risk for breast cancer. Results of a new study suggest that these agents may also reduce the risk for colorectal cancer (CRC; Rennert G, et al. J Clin Oncol. 2011; 29:1146-1150).

A health plan’s pharmacy records of 933 pairs of postmenopausal women taking bisphosphonates between 2000 and 2006 and matched controls were compared in the ongoing populationbased, case-controlled study. Bisphosphonate therapy lasting for >1 year before CRC diagnosis, but not for <1 year, was associated with a significantly reduced relative risk for CRC by 59%, even after adjusting for confounders.

Inhibition of angiogenesis and of tumor-cell adhesion and promotion of apoptosis are other antitumor mechanisms that have been suggested for the benefits associated with bisphosphonates. Patient adherence was estimated to be 89% to 96% and depended on the dosing schedule. These data suggest that bisphosphonates should be considered for future cancer prevention studies.

The annual direct cancer care costs, which were $106 billion in 2006, are projected to rise to >$173 billion by 2020, driven by a significant cost of therapy and the level of care. And with this comes waste. Finding ways to reduce this escalating trend has become a top priority.

Responding to a challenge to identify practical ways to substantially reduce costs without affecting clinical outcomes, 2 oncologists from the Massey Cancer Center have come up with 10 changes oncologists can make that could save the healthcare system billions of dollars; these are outlined in their article, “Bending the Cost Curve in Cancer Care” (Smith TJ, et al. N Engl J Med. 2011;364:2060-2065).

“We must find ways to reduce the costs of everyday care to allow more people and advances to be covered without bankrupting the healthcare system,” the authors write. They admit that implementing the necessary changes will not be easy, because it requires some fundamental changes in the behavior of medical oncologists, as well as changes in their attitudes

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and practices. Their 10-point evidencebased recommendations are often in agreement with practice guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network.

The recommendations highlight the need to limit chemotherapy and surveillance testing to situations in which a benefit can be demonstrated or a positive outcome clearly expected.

Using monotherapy is preferred to combination therapy in second- and third-line treatment as is lower doses of chemotherapy over colony-stimulating factors.

In addition, oncologists and patients must accept the necessity for frank and open discussions about treatment goals and end-of-life concerns. When the cancer is incurable, clinicians must be willing to introduce, and patients to accept, palliative care when a tumor does not respond to 3 consecutive courses of chemotherapy.

Compensation should be realigned to reflect a greater value for cognitive services than for chemotherapy, and oncologists must accept the need for comparative effectiveness and costeffectiveness analyses, as well as for some limits on care.

Abiraterone Improves Overall Survival in Metastatic Prostate Cancer Androgen deprivation has long been the standard of care for men with advanced prostate cancer, preventing or delaying the recurrence of metastases. Recent results have demonstrated that the androgen biosynthesis inhibitor abiraterone acetate prolongs overall survival in patients with metastatic castration-resistant prostate cancer whose disease progressed after docetaxel-based chemotherapy (de Bono JS, et al. N Engl J Med. 2011;364: 1995-2005). These results were the basis for the recent FDA approval of the drug.

This phase 3, multinational study included 1195 patients who had previously received docetaxel chemotherapy and were randomized to oral abiraterone plus prednisone or placebo plus prednisone.

Overall survival was 14.8 months with abiraterone compared with 10.9 months with placebo; progression-free survival was 5.6 months versus 3.6 months, respectively. Adverse events were low grade and largely minimized by concurrent low-dose prednisone therapy. ■

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