AHDB August Vol 4 No 4 Special Issue

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

AUGUST 2011 I VOL 4, NO 4 I SPECIAL ISSUE

ASCO 2011: Payers’ Perspectives

Can Episode Payments Reduce Cost Get Ready for the New Era of Maintain Quality Cancer Care?

“Genomic Chaos” in Cancer Care and UnitedHealthcare is testing how to fix the broken system

By Wayne Kuznar Courtesy of ASCO/GMG/Todd Buchanan 2011

By Caroline Helwick

F

or containing the cost of cancer care while maintaining or even enhancing quality, UnitedHealthcare is betting that payment for episodes of care, rather than fee-for-service (FFS), is a viable strategy.

“Episode payments are by no means a perfect model, or the only solution, but it’s one solution,” said Lee N. Newcomer, MD, MHA, Senior Vice President of Oncology Services with UnitedHealth Group, who described his company’s program at 2011 ASCO.

“The system is badly broken. In 1970, a minimum-wage worker with a family of 4 could buy health insurance with 15% of his income. By 2005, it took 100% of his income to buy the same policy, and this percentage is now at 170%. The problem has gone from the minimum-wage worker to the middle class,” Dr Newcomer said.

“We also have a drug pricing problem,” he stated. “The cost of prostate cancer care has doubled in 8 months because the drugs that extend survival Continued on page 7

A

new era of cancer care, in which genomic advances alter the landscape of cancer care and clinical research, is emerging. As “genomic chaos” rules this landscape, the healthcare system must be prepared to incorporate genetic technology into cancer care, and clinical trial design

must adapt as well, said George W. Sledge, Jr, MD, American Society of Clinical Oncology (ASCO) President and Professor of Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, in his presidential address at the 2011 ASCO Annual Meeting in Chicago, IL. Continued on page 6

Novel Approaches to Therapy in the Oncology Pipeline

By Caroline Helwick

T

he cancer drug pipeline is bursting with promising new therapies for a variety of tumors. Of the many investigational drugs presented at ASCO 2011, some of the most promising agents now in phase 2 or 3 clinical trials are discussed below and throughout this special issue.

Cabozantinib—an oral inhibitor of MET kinase and the vascular endothe-

lial growth factor (VEGF) receptor— produced high rates of disease control in several solid tumor types and fully or partially eliminated bone metastases in a randomized phase 2 study that was spotlighted at a press briefing during the meeting.

Disease control rates (demonstrated by response rate and stable disease) were 76% in liver cancer, 71% in Continued on page 5

Patients Want to Discuss Cost of Care, Oncologists Often Avoid It But OOP share should not affect clinical decisions

By Wayne Kuznar

P

atients are more willing than their oncologists to discuss the cost of cancer care, according to a recent survey of patients with cancer.

Discussion of cost has been promoted as a way to decrease spending on cancer care, and although oncologists recognize the importance of cost discussions, many are uncomfortable and ill-equipped to initiate them, according to Erin W. Hofstatter, MD, Assistant Professor of Medicine in Medical Oncology, Yale Cancer Center, New Haven, who presented the survey

Continued on page 6

IN THIS ISSUE HEALTH ECONOMICS

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11

High OOP costs degrade quality of care Bankruptcy rates greatest for cancer survivors

BREAST CANCER

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PROSTATE CANCER

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Exemestane: new option for prevention METASTATIC MELANOMA

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Novel agents boost survival

MULTIPLE MYELOMA . . . . . . . . . . .

21

A new paradigm for drug development from bench to bedside

Medicaid reimbursement for cancer screening

©2011 Engage Healthcare Communications, LLC

results. In previous surveys, only 36% of oncologists reported feeling comfortable discussing Andrea J. cost with their patients.

Bullock, MD “I’m not sure that fellows in general receive much training about how to talk to patients about the topic. As a result of that, oncologists even 10 to 20 years in practice aren’t used to talking about it,” said Dr Hofstatter.

She and colleagues surveyed 256 patients from an academic ambulatory clinic in Massachusetts. Approx-

20

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New treatments for castrationresistant disease RECTAL CANCER

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30

Patients with insurance often overtreated PAYERS’ PERSPECTIVE

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34

What do payers want in oncology diagnostics?

in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s va ral l y le n l M unt tag ye re e lo at m ed a

If You Define Value as an Overall Survival Advantage:

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

MEDIAN OS NOT REACHED FOR VcMP

90

% Patients Patients 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

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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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

Oncology Pipeline FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

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VOL. 4

NO. 4

SPECIAL ISSUE

Novel Approaches to Therapy... prostate cancer, 58% in ovarian cancer, 45% in melanoma, 45% in breast cancer, and 40% in non–small-cell lung cancer (NSCLC). Complete or partial resolution of bone metastases on bone scans was seen in 80% of patients. Several phase 3 trials are being planned.

Iniparib, the PARP (poly ADP ribose polymerase) inhibitor being studied for the treatment of ovarian cancer, showed promise in a phase 2 trial of 41 platinum-sensitive patients in the setting of first recurrence. The overall response rate was 65%, and median progression-free survival (PFS) was 9.5 months. In a separate phase 2 study in the second line, the response rate was 25%, and 81% of patients derived clinical benefit.

Ganetespib is another agent investigated for NSCLC. Treatment with the heat shock protein 90 inhibitor ganetespib was associated with a disease control rate of 54%. The drug was evaluated for single-agent activity in a phase 2 study of 76 patients with advanced disease, many of whom carried tumor mutations. A phase 2b/3 trial has been initiated for ganetespib in combination with docetaxel.

Continued from page 1

Crizotinib—an oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants—is yet another agent in clinical studies in the setting of NSCLC. Crizotinib was associated with a 1-year survival rate of 74% and a 2-year survival rate of 54% in a study of 82 patients with ALK gene rearrangement. By comparison, historical controls who receive chemotherapy have a 1-year survival rate of 44% and a 2-year survival rate of only 12% (see also article on page 28).

Semuloparin, an experimental anticoagulant (an ultra-low-molecular-weight heparin), reduced the risk of thromboembolic events by 64% in patients undergoing chemotherapy.

In the phase 3 Evaluation of AVE5026 in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy (SAVEONCO) study of 3212 patients, mostly with metastatic disease, 20 patients who received semuloparin (1.2%) and 55 who received placebo (3.4%) experienced a thromboembolic event (P <.001), with similar rates of bleeding.

Semuloparin is administered 20 mg daily subcutaneously. Based on the

results of this trial, its manufacturer, Sanofi Oncology, will soon submit regulatory filing for semuloparin.

Ruxolitinib, a Janus kinase inhibitor, reduced spleen size in 2 separate phase 3 studies in the treatment of 3 forms of myelofibrosis. The manufacturer, Incyte, filed for marketing approval in June 2011 (see also article on page 32).

Two thirds of patients with advanced gastric or gastroesophageal junction cancer responded to a combination of telatinib (a small molecule inhibitor of VEGF receptors 2 and 3), capecitabine, and cisplatin as first-line therapy in an open-label study of 39 patients.

Cixutumumab, a monoclonal antibody that targets the insulin-like growth factor 1 receptor, demonstrated in a phase 2 clinical trial that 57% of 113 patients with adipocytic sarcoma experienced stable disease when they received this new therapy.

Axitinib, a promising selective VEGF receptor 1, 2, and 3 inhibitor, extended PFS more than sorafenib as secondline therapy for metastatic renal-cell carcinoma. The median PFS was 6.7 months with axitinib versus 4.7 months with sorafenib. ■

EDITORIAL BOARD CLINICAL EDITOR

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA GOVERNMENT EDITOR

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC ACTUARY

David Williams Milliman Health Consultant Windsor, CT

MANAGED CARE AND GOVERNMENT AFFAIRS F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharad Mansukani, MD Chief Strategic Officer, Nations Health Sharon, MA Senior Advisor, Texas Pacific Group, FL ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA HEALTH INFORMATION TECHNOLOGY

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH CANCER RESEARCH Professor and Director, Center for Health Al B. Benson, III, MD, FACP Communications Research Professor of Medicine University of Michigan Schools of Public Associate Director for Clinical Health and Medicine, Ann Arbor Investigations Founder and Chief Visionary Officer Robert H. Lurie Comprehensive Cancer HealthMedia, Johnson & Johnson Co. Center, Northwestern University HEALTH OUTCOMES RESEARCH Immediate Past President, ACCC Diana Brixner, RPh, PhD Past Chair, NCCN Board of Directors Professor and Chair Samuel M. Silver, MD, PhD, FACP Department of Pharmacotherapy Professor, Internal Medicine Executive Director, Outcomes Research Director, Cancer Center Network Center, University of Utah College of Division of Hematology/Oncology Pharmacy, Salt Lake City Assistant Dean for Research Gordon M. Cummins, MS University of Michigan Health Systems Director, IntegriChain CARDIOLOGY RESEARCH Kavita V. Nair, PhD Michael A. Weber, MD Associate Professor, School of Pharmacy Professor of Medicine University of Colorado at Denver Department of Medicine (Cardiology) Gary M. Owens, MD State University of New York President, Gary Owens Associates EMPLOYERS Glen Mills, PA Alberto M. Colombi, MD, MPH Timothy S. Regan, BPharm, RPh Corporate Medical Director Executive Director, Xcenda PPG Industries, Pittsburgh, PA Palm Harbor, FL Wayne M. Lednar, MD, PhD HEALTH & VALUE PROMOTION Global Chief Medical Officer Albert Tzeel, MD, MHSA, FACPE Director, Integrated Health Services National Medical Director DuPont, Wilmington, DE HumanaOne Arthur F. Shinn, PharmD, FASCP Milwaukee, WI President, Managed Pharmacy Consultants, Lake Worth, FL AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN

Paul Anthony Polansky, BSPharm, MBA Sr Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals Inc., Chadds Ford, PA MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHP Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Sr Director, Branded Specialty Geisinger Health System, Danville, PA Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care POLICY & PUBLIC HEALTH Business Unit, PA Joseph R. Antos, PhD Charles E. Collins, Jr, MS, MBA Wilson H. Taylor Scholar in Health Care Vice President, Managed Markets Strategy Retirement Policy Fusion Medical Communications American Enterprise Institute PATIENT ADVOCACY Jack E. Fincham, PhD, RPh William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy, School of Pharmacy Professor of Pharmacy Law & Ethics University of Missouri, Kansas City Vice Chair, Dept. of Pharmacotherapy Walid F. Gellad, MD, MPH College of Pharmacy, Washington Assistant Professor of Medicine State University, Spokane, WA University of Pittsburgh PERSONALIZED MEDICINE Staff Physician, Pittsburgh VA Medical Wayne A. Rosenkrans, Jr, PhD Center Chairman and President, Personalized Associate Scientist, RAND Health Medicine Coalition, Distinguished Fellow, Alex Hathaway, MD, MPH, FACPM MIT Center for Biomedical Innovation President & Founder, J.D. BioEdge PHARMACOECONOMICS Health quality and biomedical research Jeff Jianfei Guo, BPharm, MS, PhD consultancy Associate Professor of Pharmacoeconomics J. Warren Salmon, PhD & Pharmacoepidemiology, College of Professor of Health Policy & Pharmacy, University of Cincinnati Administration Medical Center, OH School of Public Health PHARMACY BENEFIT DESIGN University of Illinois at Chicago Joel V. Brill, MD RESEARCH & DEVELOPMENT Chief Medical Officer, Predictive Michael F. Murphy, MD, PhD Health, Phoenix, AZ Chief Medical Officer and Scientific William J. Cardarelli, PharmD Officer Director of Pharmacy, Atrius Health Worldwide Clinical Trials Harvard Vanguard Medical Associates Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardLeslie S. Fish, PharmD MIT Division of Health Sciences and Sr Director of Pharmacy Services Technology, Cambridge, MA Fallon Community Health Plan, MA SPECIALTY PHARMACY Michael S. Jacobs, RPh Atheer A. Kaddis, PharmD National Clinical Practice Leader Vice President, Managed Markets Buck Consultants, Atlanta Diplomat Specialty Pharmacy Matthew Mitchell, PharmD, MBA Swartz Creek, MI Manager, Pharmacy Services James T. Kenney, RPh, MBA SelectHealth, Salt Lake City, UT Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

www.AHDBonline.com

5

Health Economics Targeted therapies marked a true breakthrough in cancer treatment.

DNA sequencing technology represents the next frontier, and the technology is becoming less expensive and more powerful at an alarming rate: companies are already marketing a person’s genome delivered on a USB drive, although the price is still substantial, Dr Sledge said.

Preparing for the Coming Challenges “What happens when the next 10 patients you see require 8 different combinations based on their tumor genomes? Our current system is not designed to handle genomic chaos,” Dr Sledge said. Although the data will help inform physicians about a given patient’s tumor biology, at the same time cancer management will become “very, very complicated…we will actually be able to measure the degree and kind of mutations in an individual’s tumor.”

In the not-too-distant future, patients will walk into physicians’ offices with a memory stick “loaded with gigabytes of personal genomic data.”

Although the rate of cancer deaths has decreased partly as a result of better application of diagnostics, new systemic treatments, and a decline in tobacco use, a rising tide of cancer in an aging population will challenge that trend, he said. A rapid increase in therapeutic options will push demand for cancer care. Soon, the demand for care will exceed the number of providers, providing yet another challenge. Add in the rising cost of cancer care and the decline in the number of physicians willing to conduct clinical investigations, and cancer care in the coming years looks particularly daunting.

The first complete sequencing of human cancer genomes was published only 3 years ago. “Today, as a result of efforts such as the National Institute of Health’s Cancer Genome Atlas Project and the International Cancer Genome Consortium, several thousands of cancers covering 20 major tumor types are being sequenced,” he said. “Such large-scale sequencing will rapidly change our understanding of cancer biology, it will identify new targets in previously hard to treat diseases, and it will explain the causes of drug resistance. Within the next few years, perhaps by the end of this decade, we will likely see the beginning of population-based deep sequencing of patients’ tumor genomes.”

“Stupid” versus “Smart” Mutations The promise of the genomic era

6

Courtesy of ASCO/GMG/Phil McCarten 2011

Get Ready for the New Era of “Genomic Chaos”...

“What happens when the next 10 patients you see require 8 different combinations based on their tumor genomes? Our current system is not designed to handle genomic chaos.”

—George W. Sledge, Jr, MD

was revealed in a recent article (Welch JS, et al. JAMA. 2011;305:1577-1584), in which deep sequencing of a patient’s leukemic cells was used to select a retinoic acid inhibitor therapy.

“We can look forward to a future in which the unraveling of the secrets of the genetic code is commonplace, expected, and routinely drives care,” said Dr Sledge. “But this case, as won-

derful as it is as a harbinger of our collective future, is not the whole story.

Not every story will end this happily.”

The problem is that cancers are segregating into “stupid cancers” and “smart cancers.” “Stupid cancers have a single dominant mutation and a small mutational load,” he said. “Targeting that dominant driver is regularly effective, and resistance is rare, often occurs late, and can frequently be reversed via other attacks on the same pathway. Smart tumors have multiple simultaneous drivers, carry a large mutational load, and require the targeting of multiple drivers. Resistance is common in smart cancers and occurs early into treatment.”

Mutation rates can vary between cancers by >1000-fold. Several hematologic and childhood tumor types have <1 mutation for every 1000 bases, whereas melanoma, head and neck, colorectal, lung, and squamous-cell cancers have a median close to 10 mutations per 1000 DNA bases and can reach 100.

Chronic myelogenous leukemia is an example of a stupid cancer, with an easy target that is treated effectively by imatinib.

An example of a smart cancer is non–small-cell lung cancer (NSCLC) caused by cigarette smoking. In one study, investigators determined that a patient’s tumor had 1 mutation for every 3 cigarettes smoked. Agents such as crizotinib work preferentially in NSCLC in nonsmokers, who have a lower mutational load.

ring at frequencies <5%, cancers can be considered as a “whole series of orphan diseases,” each requiring a different treatment. There will be no magic bullet for these tumors.

Investigating treatments for cancers with multiple drivers (kinases) is an enormous task. With 2 drivers that would require 2 tyrosine kinase inhibitors to treat, for example, 154

“We can look forward to a future in which the unraveling of the secrets of the genetic code is commonplace, expected, and routinely drives care.”

—George W. Sledge, Jr, MD

patients would have to be screened to find 1 relevant patient. “Who in their right mind would screen 154 patients to enter 1 into a clinical trial? And forget 3-drug combinations of novel agents,” said Dr Sledge.

In this new era, ASCO must be committed to advance into the field of health information technology [HIT], a concept known as the “rapid learning system.”

“HIT will be central to the rapid learning system in the genomic era.

Doctors will need real-time access to clinical data from all practice settings.

This, in turn, will require interoperable databases using common terminology,” Dr Sledge concluded. ■

Health Information Technology Key With many gene mutations occur-

Patients Want to Discuss Cost... imately two thirds (63%) were female, and 87% were white; 65% had private or employer-based insurance coverage, and 24% had Medicare with supplemental coverage.

A total of 59% of the patients indicated that they would like their doctor to discuss out-of-pocket (OOP) costs related to recommended cancer tests and treatments, and 78% said that they were comfortable talking about the cost of cancer care with their doctor.

The respondents were divided when they were asked if they would prefer to discuss the cost of cancer care with someone other than their doctor (eg, practice coordinator): 30% indicated a preference or strong pref-

AMERICAN HEALTH & DRUG BENEFITS

Continued from page 1

Continued from page 1

“Oncologists need to have better training in how to talk about it, and what their resources are. This study did suggest that there is a role for a third party to talk about finances with patients…to address oncologists’ discomfort.”

—Erin W. Hofstatter, MD

erence, 44% indicated no preference, and 23% said that they would not prefer such an option.

More than two thirds (68%) indicated that they agreed or strongly agreed with the statement, “I prefer Continued on page 7

August 2011

VOL. 4

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Health Economics

Can Episode Payments Reduce Cost... were priced, basically, at what we used to pay for a lifetime of prostate cancer care. We cannot keep raising premiums to pay this.”

Sophisticated new technology, however, is not to blame. “Technology is never a bad thing. What is worrisome is whether we have the evidence to say something really works and is being used in a scenario for which we know it works,” Dr Newcomer said. “For example, we know that 45% of the time bevacizumab is given completely outside of NCCN [National Comprehensive Cancer Network] guidelines. That’s a lot of money without supporting evidence. We need to get rid of this waste.”

ACOs versus Episode of Care: Macro/Micro Risk Under the standard FFS system, the physician could “do more and earn more,” Dr Newcomer noted, whereas under healthcare reform, the risk is shifted to the physician and hospital organizations. To succeed, these organizations have to figure out how to solve the cost problem, he maintained.

“They can lower what they pay for each piece of work or they can decide

which pieces of work are essential.

They can get better at things that really do make a difference in value,” he said. “This takes tough discussions about what is added value and what is not.”

Two new approaches of interest are accountable care organizations (ACOs) and episode payments.

Dr Newcomer contended that the ACO model is a poor fit for oncology.

Under ACOs, “macro risk” is spread across all specialties, leading to “large financial exposure across the continuum of illness and wellness.”

There are multiple specialties “having discussions about trade-offs, so there cannot be a focus on smaller problems,” he offered.

“As an oncologist, I am not a big fan of ACOs, because I think the cancer discussion will get lost in the hip discussion, the diabetes discussion, and the cardiac discussion,” he said.

Episode payments, by contrast, have a “micro-risk” patient-level focus. The risk is spread across fewer specialties, with complete focus and accountability. “If something does not go well, you don’t bankrupt the provider,” Dr Newcomer observed.

Patients Want to Discuss Cost... Continued from page 6 to know about the out-of-pocket costs for my treatment before I am treated,” whereas 36% either disagreed or strongly disagreed, and 45% neither agreed nor disagreed.

Despite the substantial cost burden, most patients did not want cost considered in medical decision-making, said Andrea J. Bullock, MD, lead investigator and gastrointestinal malignancies specialist, Beth Israel Deaconess Medical Center, Boston.

Only 33% of respondents indicated that they wanted their doctor to consider OOP costs when making a medical decision, and 24% said that they considered their own OOP costs when making a decision about their cancer treatment.

If patients aren’t receiving cost information from their oncologists, where do they go for such information? “I think it’s variable,” said Dr Bullock. “It depends on the size of the practice and if they have other resources…care managers, case managers, financial assistants available. I suspect that in a lot of practices there aren’t resources.”

Dr Hofstatter noted, “To translate the research, it’s telling us that oncologists need to have better training in

VOL. 4

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SPECIAL ISSUE

how to talk about it, and what their resources are. This study did suggest that there is a role for a third party to talk about finances with patients…to address oncologists’ discomfort.”

“I’m not really sure that patients understand the value they’re getting for their money.”

—Erin W. Hofstatter, MD

The survey stemmed from cost-ofcare guidelines that ASCO published in 2009, which suggested that a potential method to curb costs is to raise the issue with patients, indicated Dr Hofstatter. “To be honest, a lot of doctors and a lot of patients don’t have any idea how much money they’re spending,” she said. “I’m not really sure that patients understand the value they’re getting for their money. It’s difficult because if you start talking about value, that leads to a discussion about prognosis, which can be very difficult.” ■

Continued from page 1

“Episode payments are by no means a perfect model, or the only solution, but it’s one solution.”

took into account profit margins on all drugs, national averages for hospital visits, and disease management fees.

The need for the participating oncologists to reach consensus on treatment regimens for all the different tumor types became clear, he said, when “in our discussion with a 40-physician group, the chief medical officer told us he had 18 protocols just for administering 5-FU [5-fluorouracil].”

Dr Newcomer noted that such a variety of regimens for 1 tumor type was not an uncommon scenario, and this needed to be pared down and incorporated into a single treatment approach. This was important because a single approach reduces treatmentrelated mistakes and creates a cohort that can be assessed and compared, he pointed out.

—Lee N. Newcomer, MD, MHA

Episodes can be defined as a single procedure and one provider; a single disease and multiple providers; a chronic disease and a single provider; or a chronic disease and multiple providers.

UnitedHealthcare’s Experimental Model “I am describing one attempt to begin to define and manage risk with real doctors and practices,” Dr Newcomer told the audience.

UnitedHealthcare recently set up an episode payment model with 5 independent oncology groups. There were 4 main objectives: to identify and reward best practices; to reward consistent, evidence-based care; to retain oncologists’ incomes at present levels; and to end oncologists’ dependence on drug selection for practice survival.

The program was developed with 4 components: • Step 1: Create clinical categories (eg, stage III colon cancer or hormoneresistant breast cancer). These were time-defined episodes, and episodes occurred in 4-month intervals • Step 2: Reach consensus on a single uniform treatment regimen per condition, with exceptions made only for medical contraindications and enrollment on clinical trials • Step 3: Create performance measurements, which included comparing results for total cost of care per episode, patient survival, time to progression after the first regimen for metastatic disease, and admissions for uncontrolled pain • Step 4: Calculate payments, which

“What is worrisome is whether we have the evidence to say something really works and is being used in a scenario for which we know it works.”

—Lee N. Newcomer, MD, MHA

“If you treat all your patients the same, we can compare the performance of your regimen with other regimens in our organization. This is real-time comparative effectiveness research of evidence-based regimens, and with this we can see which regimen outperforms the others,” Dr Newcomer explained.

Healthcare providers receive the same amount of money as under the prior FFS system. “To change this number going forward, the physicians have to achieve better outcomes or reduce the cost of care,” he said. Drug regimens can be altered as new drugs are approved or expensive drugs go generic, but the fee remains stable.

The model for the 5 pilot groups has been in place for 14 months.

UnitedHealthcare will assess their data later this year and this will determine how to move the program forward, he said.

“I don’t know if this program will save money,” Dr Newcomer acknowledged. “If best practices are used and are not saving money, then we will have to move to more expensive best practices. This may cost me more, not less, but because it is better care, at least we will know we are spending money for a good reason.” ■

www.AHDBonline.com

7

V E G F

I N H I B I T I O N

THE PROPOSED EFFECTS OF

AVASTIN

®

VEGF

Avastin VEGF Inhibition

The The VEGF ligand is one of the first pro-angiogenic factors

and is present throughout the tumor life cycle1,2,3 Avastin directly binds VEGF to inhibit angiogenesis4,5

Avastin is designed to directly bind to VEGF extracellularly to prevent interaction

with VEGF receptors (VEGFR) on the surface of endothelial cells, thereby inhibiting its biologic activity5 Cessation of anti-VEGF treatment may diminish impact on tumors6,7,8 TO CONTACT YOUR ACCOUNT MANAGER FOR MORE INFORMATION ON AVASTIN VISIT:

genentechmm.com

Indications Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent, or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

The mechanism of action of anti-VEGF agents has been elucidated primarily in preclinical models. Its clinical significance is unknown.

Boxed WARNINGS and additional important safety information

Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade *3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (*1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation ()0.3%), arterial thromboembolic events (grade *3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Based on animal data, Avastin may cause fetal harm and may impair fertility. Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin. For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother Please see the following brief summary of full Prescribing Information, including Boxed Warnings, for additional important safety information.

References: 1. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 2. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 3. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 4. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 5. Avastin Prescribing Information. Genentech, Inc. February 2011. 6. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 7. Baluk P, Hashizume H, McDonald DM. Curr Opin Genet Dev. 2005;15:102-111. 8. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.

©2011 Genentech Inc., So. San Francisco, CA MCM0000417100 06/11

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis.

[See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.

[See Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: L Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

L Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

L Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

L Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

L Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

L Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

L Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

L Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

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

The data below reflect exposure to Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.

Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin as compared to 4% (1/25) of patients who received bolus-IFL alone.

In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo.

Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival.

There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever.

Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery.

In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%.

[See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm.

Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3−4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin.

IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).]

NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).]

Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy.

14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24-hour urine collection.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2.

NCI-CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

System Organ Class/ IFN-α + Placebo IFN-α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5-FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1).

Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin.

Only Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under-estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

(3% vs. 0%).

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone.

(3% vs. 0.3%) and proteinuria (3% vs. 0%).

8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk.

NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).]

Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established.

Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose-related and were partially Metabolic/Nutrition reversible upon cessation of treatment.

Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients.

Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients.

Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).]

(26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients.

163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN-α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma).

1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus South San Francisco, CA 94080-4990 ©2011 Genentech, Inc. Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Health Economics

High Out-of-Pocket Costs Degrade Quality of Cancer Care Financial toxicity common in oncology

By Wayne Kuznar

A

survey-based study from Duke University and the Dana-Farber Cancer Institute reveals that insured patients with cancer often face high out-of-pocket (OOP) expenses for their very expensive treatments and prescription drugs.

As patients are working less and insurers are shifting more costs to patients, the overall ranks of the underinsured have grown—to 20% in 2007 and likely much more in 2011, said S. Yousuf Zafar, MD, Division of Medical Oncology, Duke University, Durham, NC. Dr Zafar shared eye-opening survey responses, in which patients with cancer reported not having money for food, or becoming homeless, as a result of paying for their cancer care, which often carries heavy OOP expenses, even for those with medical insurance.

The study was based on 216 survey responses by patients (age, 33-88 years; mean, 64 years) from the HealthWell Foundation, which helps patients with uncovered medical costs, and from the Duke Cancer Institute. Most patients were white (80%) and female (88%). All patients were receiving chemotherapy or hormonal therapy for solid tumors; 76% of them had breast cancer, and of these, 32% were metastatic.

Underinsurance for Patients with Cancer Patients completed cost diaries for 4 months. Most of them had insurance coverage, “Two thirds of our sample had Medicare…99% were insured, and 83% had prescription drug coverage,” Dr Zafar emphasized, but underinsurance was clearly a problem. “Underinsured” was defined as OOP expenses totaling at least 10% of a family’s income (5% for low-income families), or as deductibles totaling at least 5% of the income.

of “financial toxicity”—reduced standard of living; impacts on quality of care as patients skipped appointments, medications, and tests; and reduced satisfaction with care.

Clinical Implications of Financial Toxicity To cope with drug costs, 26% of patients did not fill prescriptions, and 22% filled them partially. “Keep in mind that 83% of our respondents endorsed having drug coverage,” Dr Zafar said.

“By understanding that out-of-pocket expenses actually impact health outcomes and patient satisfaction, we can start including that in the discussion and get a better judgment of where that cost-sharing spectrum should fall.”

—S. Yousuf Zafar, MD The mean OOP expenses were $712 per month (median, $459). Funds were used mainly for insurance premiums, medications, and lost wages. Based on their responses, of these patients: • 39% had a moderate financial burden • 30% had a significant burden • 11% had a catastrophic burden.

Financial burden triggered 3 types

Patients also altered the way they obtained medications (eg, requesting samples from their doctor or purchasing them from another country).

Lifestyle changes included using an assistance program (64%—mainly HealthWell), reducing spending on basics such as food and clothing (51%), and borrowing money (43%).

Other coping strategies patients used to minimize cost included spreading out or missing chemotherapy or clinic appointments and forgoing recommended tests or procedures. In addition, 48% used a portion or all of their savings, 47% reduced spending on basics, 36% borrowed money, and 18% sold possessions or property. On patients exhausting their savings, Dr Zafar commented, “Keep in mind that the median age of our sample was 65.”

Finally, there was a significant correlation between the use of these coping strategies and a low level of satisfaction with care.

Several relevant questions to consider are, as patients are taking fewer medications, is treatment-related toxicity affected? Is disease-related survival affected by curtailing treatments and tests? Could overall costs actually be higher as a result of incomplete or insufficient care?

The source of the financial toxicity is in large part a health policy that shifts the costs of care to patients, Dr Zafar said. “By understanding that out-ofpocket expenses actually impact health outcomes and patient satisfaction, we can start including that in the discussion and get a better judgment of where that cost-sharing spectrum should fall,” he ended. ■

Financial Incentives Encourage Patients to Choose Less Expensive Regimens

By Caroline Helwick

F

or antiemetic prophylaxis, a model of shared cost-savings using incentives such as cash rebates might reduce the high cost of some pharmaceuticals while maintaining patient access to optimal care, according to oncologists from Michigan.

The investigators wanted to determine whether patients receiving chemotherapy could be enticed to choose a less expensive antiemetic regimen if given a choice. “We considered using a ‘carrot’ instead of a ‘stick’—a cash rebate earned by choosing less costly care,” said Emily Z. Touloukian, DO, an oncologist at Providence Hospital, Southfield, MI. Although costly copays serve as disincentives for patients to ask for more costly regimens, the potential cost-saving impact of this is often thwarted by manufacturers’ patient assistance pro-

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grams, Dr Touloukian noted. She and her colleagues chose antiemetic regimens for the model, because choice does not affect patient survival, but her findings could have implications for other types of treatment choices.

Of the 162 study participants, 80% were female, 75% had cancer, and 50% had received previous chemotherapy.

All participants completed a survey that portrayed 2 antiemetic programs.

Program A would have a 60% chance of completely eliminating nausea/vomiting at a cost of $200 per cycle. Program B would have 80% efficacy at a cost of $800 per cycle. If program A was ineffective, the patient could switch to program B at any time.

Both programs were described as covered by insurance; however, patients who selected program A would participate in the savings by

receiving 50% of the cost difference, a $300 rebate per cycle.

“We were greatly surprised that as many as 38% of patients who had trouble with prior nausea still chose the less effective program.”

—Emily Z. Touloukian, DO

More patients (58%) chose program A than program B (42%). Neither a previous history of cancer nor previous receipt of chemotherapy significantly affected program selection.

Within the cohort who had previously received chemotherapy, 63% of patients who had experienced mild or no

nausea in the past chose program A compared with 38% with moderate-tosevere nausea, “but we were greatly surprised that as many as 38% of patients who had trouble with prior nausea still chose the less effective program,” she said.

If all patients received 6 cycles of program B, the cost would be $777,600.

By giving the patients a choice and reassigning the theoretical 40% of patients whose nausea was ineffectively controlled by program A to program B after 1 cycle, the cost dropped to $556,820.

This represented a savings of $220,780, or 28% of the total cost of the program, without limiting access to effective antiemetic care. One half of the savings went to the patients and half was saved by the payers, Dr Touloukian said. ■

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Health Economics

Economic Recession Affects Rates of Cancer Incidence and Treatment Unemployed patients forgo testing and life-saving therapies

By Wayne Kuznar

T

he number of cancer diagnoses and the number of patients adhering to cancer treatments decline with high unemployment rates during an economic recession, based on a new analysis presented by Ronald D. Ennis, MD, Director of Radiation Oncology, St Luke’s-Roosevelt Hospital, New York City.

Dr Ennis and colleagues assessed the effect of economic cycles on the diagnosis and treatment of cancer, hypothesizing that during an economic recession, people would choose to forgo screenings and treatments for cancer.

The investigators anticipated that this effect would be more pronounced for a cancer for which a screening test is available and that has minimal presenting symptoms (eg, breast cancer).

In contrast, there would be less of an effect for a cancer that has no screening test and has symptoms that are harder to ignore (eg, pancreatic cancer). Breast and pancreatic cancers were chosen as these 2 types of cancers meeting the study criteria.

Unemployment was used as a measure of recession per monthly data obtained from the Bureau of Labor

Statistics. Surveillance, Epidemiology and End Results (SEER) data were used for monthly incidence rates for treatment with radiotherapy and surgery for all cancers, and for breast and pancreatic cancers separately. Data

the analysis of the effect of the economy on the use of radiotherapy in breast cancer.

“As expected, the effect was much more profound for breast cancer than for pancreatic cancer,” said Dr Ennis.

“There was a smaller but still present effect on the use of treatment during unemployment for pancreatic cancer, but much less than for all cancers and dramatically less than for breast cancer.”

—Ronald D. Ennis, MD

were used from the original 9 SEER registries for the period between 1973 and 2007.

Because a dramatic increase took place in the use of radiotherapy for breast cancer between 1990 and 2000—as a result of the emergent use of lumpectomy plus radiotherapy as an alternative to mastectomy—data for that decade were excluded from

Overall, for all cancers, every 1% increase in unemployment was accompanied by a 2.7% decrease in cancer incidence (or diagnosis), an 8.7% decrease in the use of radiotherapy, and a 12.1% decline in the use of surgery.

The correlation was higher in breast cancer: every 1% increase in unemployment resulted in a 7.4% decrease in breast cancer diagnosis, a 16.8%

decline in the use of radiotherapy for breast cancer treatment, and a 23.9% reduction in breast cancer surgeries.

“There was a smaller but still present effect on the use of treatment during unemployment for pancreatic cancer, but much less than for all cancers and dramatically less than for breast cancer,” Dr Ennis said. No significant relationship was found between unemployment and the diagnosis of pancreatic cancer, a 1.5% decrease in the use of radiotherapy for pancreatic cancer with every 1% increase in unemployment, and an 8.5% decrease in surgery for this cancer.

The impact of a recession on administration of cancer treatments may go beyond unemployment to include the fear of losing one’s job, said Dr Ennis. “There might be a cohort of patients who, despite not having lost their job or fear losing their job…would still go for their mammogram or biopsy, but then, when faced with the daunting task of going through treatment and potentially having to be out of work or copays…don’t carry through with the treatment because of those barriers,” he said. ■

Value of Targeted Therapies in Patients Lacking a Molecular Target Questioned High discontinuation rate leads to increased initial Rx cost

By Caroline Helwick

T

argeted drugs are very effective in patients with a well-specified molecular target. Examples include imatinib (Gleevec) in patients with chronic myelogenous leukemia and trastuzumab (Herceptin) in HER-2– positive breast cancer.

However, evidence has shown only modest improvements in outcomes when targeted agents are given to “unselected patients,” that is, those lacking a tumor characteristic (or mutation) that is specifically addressed by a given drug.

“Little data exist regarding the true impact of targeted therapy in routine clinical practice,” said Janakiraman Subramanian, MD, of Washington University School of Medicine, St Louis, MO. “Intolerable side effects are infrequent with targeted drugs, and discontinuation is primarily due to progres-

12

sive disease,” he noted. “Identifying the proportion of patients who are ‘minimum users,’ defined as those who failed to refill their prescription more than once, would be one way of assessing treatment efficacy in routine practice.”

Dr Subramanian and his colleagues used studied claims in the Express Scripts pharmacy claims database from 2007 to 2009 for imatinib, lapatinib (Tykerb), erlotinib (Tarceva), sorafenib (Nexavar), sunitinib (Sutent), and everolimus (Zortress). Each patient’s age, sex, and duration of prescription were identified; the database does not include information on diagnosis and outcomes.

Prescription claims for 14,300 patients were examined; most prescriptions were for erlotinib (43%), followed by imatinib (28%).

A surprising proportion of patients

AMERICAN HEALTH & DRUG BENEFITS

August 2011

“Little data exist regarding the true impact of targeted therapy in routine clinical practice….Targeted therapy for cancer in unselected patients leads to very high rates of early discontinuation.”

—Janakiraman Subramanian, MD did not refill their prescription after 60 days, including approximately 10% for imatinib, 21% for lapatinib, 31% for erlotinib, 38% for sorafenib, 44% for sunitinib, and 56% for everolimus.

The proportion of prescription claims that were not filled past 60 days significantly differed between drugs prescribed to biomarker-selected pa-

tients (ie, imatinib and lapatinib) and drugs prescribed for nontargeted (unselected) patients (ie, erlotinib, sunitinib, sorafenib, and everolimus).

Among the biomarker-selected patients, only 12% failed to refill prescriptions compared with 34% of the unselected patients (P <.001).

“Targeted therapy for cancer in unselected patients leads to very high rates of early discontinuation,” Dr Subramanian observed.

In light of the frequent treatment discontinuation among unselected patients, the cost of the initial prescriptions (claims ≤60 days) may appear unjustifiably high in these drugs, resulting in the following rates: $2,695,945 for imatinib; $1,534,059 for lapatinib; $12,878,656 for erlotinib; $4,937,772 for sorafenib; $9,280,050 for sunitinib; and $218,916 for everolimus. ■

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Health Economics

Most End-of-Life Costs for Patients with Cancer Are Not Drug-Related

By Wayne Kuznar

M

ost end-of-life costs accrued by patients with cancer are related to health services rather than the use of drugs, according to an analysis of claims from a large health plan (UnitedHealth).

“The bottom line is that most of the costs were not related to drugs but to healthcare services plus the inpatient hospitalizations,” said April Teitelbaum, MD, coinvestigator and a practicing oncologist and Senior Medical Director, Life Sciences, Hematology/ Oncology, Innovus, Eden Prairie, MN. For this analysis, end-of-life healthcare costs were examined for 28,530 patients with cancer who died while enrolled in a large health plan. The most frequent type of malignancy was lung cancer (18% of the cohort).

The total cancer-related monthly costs increased as the period before death shortened (Table), from a mean of $7835 during the sixth month before

death to more than $25,000 in the last month of life.

Total cancer-related costs over the last 6 months of life were $74,212: $30,254 for outpatient services; $40,702 for acute inpatient hospitalization; and $3256 for hospice.

“The bottom line is that most of the costs were not related to drugs but to healthcare services plus the inpatient hospitalizations.”

—April Teitelbaum, MD

“We only looked at the last 6 months because there’s a misconception that there are a lot of needless drug costs spent in futility. In reality, those costs are minimal compared to

Bankruptcy Rates Markedly Greater for Cancer Survivors S urviving is just one hurdle for cancer survivors. A new study funded by the National Cancer Institute shows that the risk of bankruptcy is a serious threat for those who survive cancer and increases along with the length of survival.

“On average, bankruptcy rates increased 4-fold within 5 years of diagnosis,” said the study’s lead investigator, Scott Ramsey, MD, PhD, a healthcare economist and internist at Fred Hutchinson Cancer Research Center, Seattle, WA. Dr Ramsey and colleagues linked Washington state cancer registry data from nearly 232,000 adult cancer survivors with federal bankruptcy court records in 13 western Washington counties. “By linking 2 irrefutable government records of cancer and bankruptcy, we are able to determine how financial insolvency risk varies by cancer type, treatment, and other factors,” he said.

The rate of bankruptcy after a first cancer diagnosis was measured, and factors that increased bankruptcy risk among people with common cancers were identified. After a mean followup of 4.3 years, 2.1% of the cancer survivors filed for bankruptcy.

Compared with the bankruptcy rate among the general population, the rate among cancer survivors was

almost doubled 1 year after diagnosis, and the median time to bankruptcy was 2.5 years after cancer diagnosis.

Bankruptcy risk varied widely across cancer types. The risk was highest for patients with lung cancer, thyroid cancer, and leukemia/ lymphoma.

“On average, bankruptcy rates increased 4-fold within 5 years of diagnosis….

Patients diagnosed with cancer may face significant financial stress due to income loss and out-ofpocket costs associated with their treatment.”

—Scott Ramsey, MD, PhD

Patients aged >65 years, who are typically covered by Medicare, had a much lower risk of bankruptcy than younger patients.

“Patients diagnosed with cancer may face significant financial stress due to income loss and out-of-pocket costs associated with their treatment,” said Dr Ramsey.—WK ■

Table Mean Costs during the Last 6 Months of Life, by Month before Death Months before death, N

Mean Mean total inpatient cost, $ cost, $

Mean hospice cost, $

Mean Mean outpatient outpatient chemotherapy service cost, $ cost, $

6

7835

1785

28

3849

2172

5

9229

3269

61

3751

2149

4

10,051

4087

95

3762

2107

3

10,364

4646

173

3692

1852

2

11,471

6356

435

3242

1437

1

25,260

2059

2464

1632

606

the inpatient hospitalizations,” said Dr Teitelbaum.

“Ultimately, cancer-related services cost much much more than any of the drug services could possibly ever cost,” she said. Of the outpatient cancer-related costs: • $10,323 was spent on chemotherapy (including biologic and hormonal therapy) and related care (ie, use of erythropoiesis-stimulating agents, granulocyte macrophage colonystimulating factor) • $3710 was for radiation therapy • $10,123 was for outpatient services • $4040 was for office visits.

The $10,323 spent for chemotherapy and related medications accounted

for only 13.9% of the total costs over the last 6 months of life.

The use of services such as inpatient hospitalization and hospice care increased noticeably while the use of chemotherapy declined over time, especially during the last 1 to 3 months of life.

“One of the key points is that there needs to be better communication between the physicians, ancillary staff, and the patients and their families in regard to what their wishes are,” said Dr Teitelbaum. “A lot of patients are hesitant to say that they’re not interested in any more care because they’re afraid of abandonment. The term ‘hospice’ has a negative connotation.” ■

Inappropriate Antineoplastic Agents Use for Metastatic Cancer Costs Insurers Millions

O

ne of 8 patients with metastatic colon cancer receives therapy with antineoplastic agents not supported by evidence-based medicine or outside of clinical practice guidelines from the National Comprehensive Cancer Network (NCCN), found Jonas A. de Souza, MD, an oncology/hematology fellow at the University of Chicago, and colleagues.

As a result, patients are unnecessarily exposed to the potential side effects associated with such drugs, despite current practice guidelines, and at a cost of >$2 million for these drugs alone.

These findings were obtained from reimbursement data from United Healthcare on 1041 insured patients with metastatic colon cancer who received treatment between January 2007 and June 2010.

The researchers evaluated the use

of 3 agents in the following clinical settings that do not reflect current NCCN clinical guidelines recommendations: • Bevacizumab (Avastin), which has insufficient data to support its use in patients whose cancer had progressed despite a combination regimen of bevacizumab and chemotherapy • Monotherapy with capecitabine (Xeloda), which has been shown to be ineffective as a salvage therapy after failure with a fluoropyrimidine-containing regimen • Panitumumab (Vectibix), which is not supported by any data or compelling reason to be administered after progression occurs in patients who had previously received an epidermal growth factor receptor antibody; this also applies to cetuximab (Erbitux).

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Inappropriate Antineoplastic Agents Use...

Cost of Non–Evidence-Based Therapy Among the 884 patients with metastatic colon cancer who received bevacizumab, 90 patients (10%) had received it beyond disease progression, resulting in 636 claims for reimbursement at a cost of $1,326,696.

In the context of metastatic colon cancer, use of non– evidencebased drug therapies cost payers >$2 million for the drugs alone.

—Jonas A. de Souza, MD

Capecitabine was administered to 121 patients, 49 (40%) of whom received it without evidence-based support, resulting in 281 claims, at a total cost of $621,463.

Among 38 patients who received panitumumab, non–evidence-based use was found in 6 patients (16%), at a total cost of $69,665.

The cost of the non–evidence-based

Socioeconomic Status Affects Cancer Care

S

ocioeconomic status (SES) affects how cancer treatment is delivered, according to Sandra L. Wong, MD, Assistant Professor of Surgery, University of Michigan, Ann Arbor.

Lung, esophageal, and pancreatic cancers cause 35% of cancer deaths in the United States. Dr Wong’s group at the University of Michigan, Ann Arbor, studied whether SES adversely affects utilization of hospital-based treatment or survival among patients with these cancers.

The study used Medicare data from 1992 to 2005 for patients with lung (N = 68,167), esophageal (N = 4350), and pancreatic (N = 12,779) cancer and assessed the effects of SES on treatment and survival rates. The study was limited to fee-for-service Medicare beneficiaries aged >65 years.

Similar imaging (mainly computed tomography) was performed for all groups, but specialized imaging (positron

use of these drugs totaled $2,009,480, which did not include infusion expenses, diagnostics, hospitalizations, and management of adverse effects, said Dr de Souza.

The goals of practice guidelines are well established, commented Marcelo Blaya, MD, Assistant Professor of

Continued from page 13

Medicine, Section of Hematology and Medical Oncology, Tulane University Health Sciences Center, New Orleans.

He listed these goals as aiming to: • Reduce unwanted variation in practice • Bring clinical practice in line with the best available evidence • Improve quality care

• Provide decision support.

Dr Blaya added that patients with advanced cancer who receive non– evidence-based treatment are receiving better treatment in the context of clinical trials; otherwise, providers should shift their focus to palliative care.—WK ■

ISTODAX® (romidepsin) for injection is indicated for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

Important Safety Information WARNINGS AND PRECAUTIONS:

• Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Due to the risk of QT prolongation, ensure that potassium and magnesium are within the normal range before administration • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • Based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) • ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections.

The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%),

thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%).

Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection.

The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%).

DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS.

Continued on page 15

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Health Economics Socioeconomic Status Affects Cancer Care... Continued from page 14 emission tomography) was performed more often in the group with the highest SES. For treatment, “there was a higher utilization of cancer-directed treatments across all 3 of the cancer types and across all modalities of care,” Dr Wong said.

For all the cancer types and for all

socioeconomic groups, 30% to 60% received no cancer-directed treatment at all (in hospital), but patients with low SES were much more likely to receive no treatment.

For lung cancer, because 35% of patients in all SES groups presented with distant disease, “there may be underutilization of cancer-directed

services across the board, but it is much more pronounced in the lowest SES group,” she said (46% patients with low SES vs 38% for those with high SES).

The finding that aggressive treatment had little effect on survival is “confounded by the fact that these are such poor-prognosis cancers,” Dr Wong explained.

The study revealed a pronounced variation in the types of cancer treatment received by the different socioeconomic groups. Reducing variation in treatment strategy could improve healthcare efficiency without deleterious effects on outcomes, the study suggested. These findings may not be generalizable to younger patients, Dr Wong said.—WK ■

Introducing choice in treating PTCL ISTODAX® is now indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated

Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 06/11 IST11004

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For more information: Please visit www.ISTODAX.com or call 1-888-423-5436

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Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.

• Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.

These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the therapy.

2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.

• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.

• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.

Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.

• Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.

2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)].

5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)].

5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)].

In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.

Due to the risk of QT prolongation, potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)].

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AMERICAN HEALTH & DRUG BENEFITS

August 2011

5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate.

5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse outcomes.

If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)].

5.6 Use in Women of Childbearing Potential Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogen-containing contraceptives. An in vitro binding assay determined that romidepsin competes with ß-estradiol for binding to estrogen receptors [See Nonclinical Toxicology (13.1)].

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

Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1.

Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.

Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) (continued)

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Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8)

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsorconducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

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Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital)

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Health Economics

Medicaid Reimbursement for Cancer Screening Lags Inflation

By Wayne Kuznar

M

edicaid reimbursement for many cancer screenings is not keeping pace with inflation, at least in the 4 states examined in an analysis

by Michael T. Halpern, MD, PhD, Senior Health Scientist, Health Serv-

ices and Social Policy Research, RTI International, a provider of research and technical services to governments and businesses based in Washington, DC. In describing the impetus for the

may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action, ISTODAX may cause fetal harm when administered to a pregnant woman. A study in rats did not expose pregnant animals to enough romidepsin to fully evaluate adverse developmental outcomes. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential harm to the fetus.

In an animal reproductive study, pregnant rats received daily intravenous romidepsin during the period of organogenesis up to a dose of 0.06 mg/kg/day (0.36 mg/m2/day). This dose in rats is approximately equivalent to 18% the estimated human daily dose based on body surface area and resulted in 5% reduction in fetal weight. Embryofetal toxicities associated with the use of ISTODAX were not adequately assessed in this study.

8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of endstage renal disease on romidepsin pharmacokinetics has not been studied.

Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal

18

AMERICAN HEALTH & DRUG BENEFITS

August 2011

study, Dr Halpern noted, “low reimbursements for cancer screening services among Medicaid enrollees may limit their access to these services and thus decrease the likelihood of early cancer diagnosis.”

vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose.

Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

• Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

• Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flulike symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

• Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

• Use in Women of Childbearing Potential If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

ISTODAX binds to estrogen receptors. Advise women of childbearing potential that ISTODAX may reduce the effectiveness of estrogencontaining contraceptives [See Warnings and Precautions (5.6)].

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

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 ISTBVPI.002/PPI.002 06/11

Examining Medicaid outpatient claims data from Georgia, Illinois, Louisiana, and Maine from 2000 to 2003, Dr Halpern and colleagues assessed annual changes in Medicaid reimbursements for cancer screening services.

“The patterns of changes in reimbursements varied by state, with 2 states showing reimbursements that did not keep pace with inflation for all or almost all services examined.”

—Michael T. Halpern, MD, PhD

Claims for screening tests for breast cancer (mammography), cervical cancer (Pap smear), colorectal cancer (barium enema, flexible sigmoidoscopy, colonoscopy, fecal occult blood test), and prostate cancer (prostate-specific antigen [PSA] test), as well as for physician office visits, were identified using Current Procedural Terminology codes.

Average reimbursement rates were assessed annually and adjusted for inflation using the medical care component of the Consumer Price Index from the Bureau of Labor Statistics.

“The patterns of changes in reimbursements varied by state, with 2 states showing reimbursements that did not keep pace with inflation for all or almost all services examined,” said Dr Halpern.

After adjustment for inflation, Medicaid reimbursement for all colorectal cancer screening tests in each of the 4 states decreased from 2000 to 2003. Decreases in colonoscopy reimbursements over these 4 years ranged from $10.66 (3.8%) in Louisiana to $44.60 (17.3%) in Illinois.

Reimbursements for PSA testing also decreased over time in all 4 states, ranging from 12.2% to 19.2%. Mammography reimbursements during the study period increased by almost 5% in Georgia (from $29.62 to $31.00) but decreased in the other 3 states, including a decrease of >40% in Maine (from $22.78 to $13.00).

The average reimbursements for physician office visits increased in Georgia (9.1%) and Louisiana (5.3%) but decreased in Illinois and Maine (both 12.2%). ■

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Breast Cancer A potential shift in management

By Audrey Andrews

U

hibitors, exemestane was selected for evaluation in a breast cancer prevention trial. The study is the first randomized trial to assess an aromatase inhibitor for breast cancer prevention in healthy women.

The MAP.3 trial enrolled 4560 postmenopausal women with at least 1 risk factor that increased their chances of developing breast cancer (although none carried the BRCA mutation).

Courtesy of ASCO GMG/Scott Morgan 2011

ntil recently, women at risk for breast cancer have had 2 pharmacologic options to reduce their risk— tamoxifen (Nolvadex) and raloxifene (Evista). Now a third option has been shown effective, the aromatase inhibitor exemestane (Aromasin).

Five years of treatment with exemestane significantly reduced invasive and preinvasive breast cancers in postmenopausal women at increased risk for the disease in the Canadian National Cancer Institute of Canada Clinical Trials Group MAP.3 trial, presented at ASCO 2011

by Paul Goss, MD, PhD, Harvard Medical School.

Tamoxifen and raloxifene are associated with the potential for rare but serious side effects, including venous thromboembolism and endometrial cancer, and many women avoid these drugs for this reason. “Our study not only showed an impressive reduction in breast cancers but also an excellent side effect profile,” said Dr Goss.

Exemestane is currently indicated for adjuvant endocrine treatment but is not approved by the US Food and Drug Administration for the prevention of breast cancer. Because of the drug’s more favorable effects on bone, compared with other aromatase in-

“Our study not only showed an impressive reduction in breast cancers but also an excellent side effect profile.”

—Paul Goss, MD, PhD Approximately half of the population was considered at risk simply because they were aged ≥60 years.

The women were randomly assigned to 5 years of exemestane 25 mg daily or to placebo. After a median follow-up of 3 years, 11 breast cancers occurred in the exemestane group

compared with 32 in the placebo group, representing an annual incidence of 0.19% versus 0.55%, respectively (P = .002). This translated into a 65% reduction of invasive cancers with exemestane, Dr Goss reported.

The protective effect was most striking among the estrogen receptor–positive subset, who experienced a 73% relative risk reduction (P = .008). There were also reductions in preinvasive breast cancer and ductal carcinoma in situ, as well as precursor lesions such as atypical ductal hyperplasia.

Serious toxicities were not seen over 3 years, although significantly more women who received exemestane reported bodily pain than those receiving placebo (46% vs 41%, respectively; P <.001).

The effect appeared to be more durable than what is observed with tamoxifen, Dr Goss noted. In addition, fewer women taking exemestane—26 compared with 95 women taking tamoxifen (in other studies)—must be treated to prevent 1 case of breast cancer over 5 years, he said.

“The findings from MAP.3 indicate that exemestane is a promising new option for preventing breast cancer in menopausal women,” Dr Goss commented.

Regional Lymph Node Irradiation Indicated for Early Breast Cancer I n the National Cancer Institute of Canada Clinical Trials Group MA.20 trial, regional irradiation to the lymph nodes (RNI) added to whole brain irradiation (WBI) improved disease-free survival (DFS), with a trend toward improved overall survival (OS), reported Timothy Whelan, MD, of McMaster University and the Juravinski Cancer Centre in Hamilton, Ontario.

Locoregional recurrences were reduced by 42% and distant recurrences by 36%. “Results from MA.20 suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities,” Dr Whelan said.

Specialty guidelines recommend locoregional radiation after mastectomy for women with tumors >5 cm or those who have >3 positive axillary lymph nodes. The benefit in women with 1 to 3 positive nodes has been unclear.

WBI may involve radiation to the lower axillae and some of the internal mammary nodes; RNI to the internal

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mammary, supraclavicular, and high axillary lymph nodes may provide added benefits to WBI, but it can be more toxic.

The MA.20 trial, therefore, evaluated the benefit of RNI added to WBI after breast-conserving surgery for women with node-positive or highrisk node-negative early breast cancer.

The study randomized 1832 patients to WBI or to WBI plus RNI. At a median follow-up of 62 months, the addition of RNI to WBI significantly improved DFS—preventing locoregional recurrences and, more surprisingly, recurrences elsewhere in the body. A nonsignificant trend toward improved OS was also seen.

DFS at 5 years, defined as any recurrence, contralateral breast cancer, or breast cancer death, was 84.0% in the WBI arm and 89.7% in the WBI/RNI arm, a significant 33% reduction in events. Locoregional DFS was 94.5% with WBI and 96.8% with WBI/RNI, a 42% reduction in risk.

The protection against distant recur-

rences was an unexpected benefit of the approach, Dr Whelan said. Distant DFS was 87.0% with WBI and 92.4% with WBI/RNI, representing a 36% risk reduction. At 5 years, 90.7% of the patients in the WBI group were alive compared with 92.3% in the WBI/RNI group, a 23% reduction in mortality.

These results “suggest that all women with node-positive disease be offered regional node irradiation provided they are made aware of the associated toxicities.”

—Timothy Whelan, MD The trade-off for a clinical improvement was an increased toxicity with the combined radiotherapy approach.

Compared with WBI alone, the combination of WBI/RNI was associated with more episodes of radiation dermatitis (50% vs 40%, respectively; P <.001),

Courtesy of ASCO GMG/Zach Boyden-Holmes 2011

Exemestane: New Option for Breast Cancer Prevention “MAP.3 provides a paradigm shift for breast cancer prevention. Avoiding breast cancer with manageable toxicity is possible today.”

—Andrea De Censi, MD Although exemestane has been an expensive hormonal therapy, its patent has expired and “the cost is plummeting,” he said, predicting the cost of treatment will soon be “comparable to tamoxifen.”

A Possible Paradigm Shift in the Prevention of Breast Cancer “MAP.3 provides a paradigm shift for breast cancer prevention. Avoiding breast cancer with manageable toxicity is possible today,” said Andrea De Censi, MD, of the E.O. Ospedali Galliera in Genoa, Italy, who was invited to discuss the findings.

Although tamoxifen remains the favored preventive approach for atrisk premenopausal women, exemestane may become a preferred option in the postmenopausal group, Dr De Censi said. ■

pneumonitis (1.3% vs 0.2%; P = .01), and lymphedema (7% vs 4%; P = .004).

Although cosmetic outcomes were similar at 3 years, more of the RNI group considered the outcome “fair or poor” at 5 years (36% vs 29%, respectively).

Findings Are Practice-Changing Thomas Buchholz, MD, of the University of Texas M.D. Anderson Cancer Center, Houston, commented that the findings “add to the conclusive evidence that radiation eradication of local-regional microscopic disease reduces subsequent distant metastases and can improve survival.”

He said that the benefits of adding regional irradiation “now clearly outweigh the risks.”

“I agree with the investigators’ conclusions,” Dr Buchholz said. “We should offer RNI for higher-risk patients with 1 to 3 positive lymph nodes, but we should await additional data for low-risk patients with 1 to 3 nodes.”—AA ■

www.AHDBonline.com

19

Metastatic Melanoma

Novel Agents Boost Survival in Metastatic Melanoma

By Audrey Andrews

M

Positive Results with BRAF Inhibitor Approximately 50% of patients with melanoma have a V600E mutation in the BRAF gene, which is involved in cell proliferation and other aspects of cell survival. This mutation can be targeted with the BRAF inhibitor vemurafenib, which, in a phase 3 study reported at ASCO, reduced the risk of death by 63% (P <.001).

Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center in New York, reported the first interim analysis of the international study at the ASCO plenary session, noting that an improvement in the survival of advanced disease “is really a huge step toward personalized care in melanoma.”

Other experts agreed, predicting the drug would lead to a paradigm shift in how this disease is treated.

The open-label BRIM-3 (BRAF Inhibitor in Melanoma 3) trial compared vemurafenib against standard treatment with dacarbazine in 675 patients with inoperable, previously treated stage IIIC or IV metastatic melanoma harboring a V600E mutation.

Progression-free survival was 5.3 months with vemurafenib versus 1.6 months with dacarbazine (DTIC), for a 74% reduced risk of progression (P <.001).

Estimated overall survival (OS) at 6 months was 84% versus 64%, respectively, and the risk of death from melanoma was reduced by 63% (P <.001). Vemurafenib also led to a significantly higher response rate, 48.4% versus 5.5% with dacarbazine, Dr Chapman reported.

As a result of the very encouraging early results, the trial was halted early to allow placebo recipients to receive vemurafenib. In this and other studies, many patients have prolonged remissions lasting ≥1 year.

Although adverse events were generally relatively mild (approximately 10% grade 3+ toxicity), dose interruption or modification were required in 38% of patients.

“Vemurafenib is the first single drug for melanoma to improve response rate, progression-free survival, and overall survival compared with standard chemotherapy,” Dr Chapman noted. “It is a promising new therapy for patients with metastatic BRAF V600E–mutated melanoma and a

20

foundation upon which to build combination therapies.”

Courtesy of ASCO/GMG/Scott Morgan 2011

etastatic melanoma traditionally carries a dismal prognosis, and few patients live >1 year after the diagnosis. But the tide is turning, with the emergence of 2 novel treatments shown to prolong survival.

“Vemurafenib is the first single drug for melanoma to improve response rate, progression-free survival, and overall survival compared with standard chemotherapy.”

—Paul Chapman, MD

Vemurafenib is now available in an expanded access program, and US Food and Drug Administration (FDA) approval is expected for patients with BRAF mutations.

Immunotherapy Drug Also Improved Survival One drug that will be evaluated in combination with vemurafenib is the

immune-mediating agent ipilimumab (Yervoy), which also produced solid benefits in treatment-naïve patients and received FDA approval in March 2011 for the second-line setting.

Study 024, presented at ASCO 2011, confirmed ipilimumab’s activity as a first-line agent for metastatic melanoma. The 502 previously untreated patients in this study were randomized to the standard of care with dacarbazine (ie, control group) or to dacarbazine plus ipilimumab.

Median OS was 11.2 months with ipilimumab plus dacarbazine versus 9.1 months with dacarbazine alone, a significant 28% reduction in the risk for death from melanoma (P = .009), reported Jedd Wolchok, MD, of Memorial Sloan-Kettering Cancer Center, New York.

At 1 year, the survival rate in the combination therapy group was 47.3% compared with 36.3% in the control group. The survival rates were 28.5% versus 17.9%, respectively, at 2 years, and 20.8% versus 12.2% at 3 years.

As with vemurafenib, many responses are durable, with an average remission of 19.3 months with ipilimumab plus dacarbazine compared with 8.1 months with dacarbazine.

“This is the second randomized ipilimumab phase 3 trial to show a significant survival improvement in metastatic melanoma,” Dr Wolchok said.

Great News, Clinical Challenges Kim A. Margolin, MD, of the University of Washington Fred Hutchinson Cancer Research Center in Seattle, was impressed with the results but noted that these treatments were not without side effects.

Notable adverse events with ipilimumab are hepatotoxicity, endocrine abnormalities, and immune-mediated adverse reactions, for which ipilimumab already carries a black box warning. Grade 3-4 increases in liver enzymes were observed in approximately 20% of patients.

“Both agents require experience and commitment by the physician and patient to manage these unique toxicities.”—Kim A. Margolin, MD

With vemurafenib, the adverse events include cutaneous toxicity, gastrointestinal upset, and arthralgias.

Skin toxicities include hyperkeratotic follicular eruption, extreme sun sensitivity, tender calluses of the extremities, and squamous cancers and keratoacanthomas.

“Both agents require experience and commitment by the physician and patient to manage these unique toxicities,” she suggested.

Clinicians will undoubtedly want to use these agents, and they will need to learn how, Dr Margolin said.

She suggested the BRAF inhibitor be prescribed for patients with disease symptoms, who need immediate tumor shrinkage and symptom relief.

In contrast, ipilimumab works at a slower pace and might be the first option for patients with less tumor burden and fewer symptoms, or those whose disease recurs while still taking vemurafenib. ■

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VOL. 4

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SPECIAL ISSUE

Multiple Myeloma

Multiple Myeloma Treatments Are Moving Rapidly from Bench to Bedside A new paradigm in drug development

T

reatments for multiple myeloma have advanced rapidly over the past 15 years as research has fostered an improved understanding of the mechanisms of the disease. These discoveries have been translated into effective drugs, most notably bortezomib (Velcade), thalidomide (Thalomid), and lenalidomide (Revlimid).

“Bench-to-Bedside Translation of Targeted Therapies in Multiple Myeloma,” was the title of the Karnofsky Lecture delivered by Kenneth C. Anderson, MD, Kraft Family Professor of Medicine, Harvard Medical School, and Director, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma, Dana-Farber Cancer Institute, Boston. Dr Anderson was awarded the David A. Karnofsky Memorial Award to recognize his outstanding achievement over 3 decades in multiple myeloma research.

Combination therapy with melphalan (Alkeran) and prednisone was long the standard of care for the treatment of multiple myeloma, with stemcell transplant reserved for select patients.

Advances beyond these therapies have emerged rapidly as the research

by Dr Anderson broadened beyond the myeloma cell surface to the bone marrow microenvironment as a driver of disease pathogenesis.

“Multiple myeloma represents a new paradigm in drug development,

Courtesy of ASCO/GMG/Phil McCarten 2011

By Wayne Kuznar

“Multiple myeloma represents a new paradigm in drug development, due to the remarkable therapeutic efficacy of targeting tumor cells in their microenvironment.”

—Kenneth C. Anderson, MD

due to the remarkable therapeutic efficacy of targeting tumor cells in their microenvironment,” he said. Newly discovered agents interfere with the mechanisms by which myeloma cells grow, survive, develop resistance, and migrate within the bone marrow.

Rapid Drug Development and Approval for Myeloma The proteasome inhibitor bortez-

omib is an example of a new therapy for multiple myeloma that progressed from bench to bedside rapidly (<3 years). The drug, which has an action that targets multiple myeloma cells in the bone marrow macroenvironment, was approved as initial therapy for multiple myeloma after demonstrating an improvement in median survival from 3 to 7 years.

The immunomodulatory drug lenalidomide, which directly induces apoptosis but also targets cells in the tumor microenvironment, was another result of Dr Anderson’s work.

Lenalidomide also progressed rapidly from bench to bedside and was approved in 2006 for use with dexamethasone (Decadron) for the treatment of relapsed multiple myeloma.

Along with thalidomide and bortezomib, lenalidomide is used routinely in conventional cytotoxic and transplant regimens for multiple myeloma.

Novel Classes in the Pipeline Nevertheless, the need for more effective and tolerable drugs remains, said Dr Anderson. Second-generation proteasome inhibitors include carfilzomib, which is associated with less neuropathy than bortezomib, and oral chymotryptic inhibitors, which appear more potent at inhibiting myeloma cell growth.

Pomalidomide, another immunomodulatory agent currently under development, has shown good activity

Investigational Regimens with Bortezomib for Multiple Myeloma S everal new regimens with bortezomib (Velcade) are currently being investigated in combination with different agents for various subpopulations of patients with multiple myeloma or were presented at ASCO 2011.

Bortezomib and Dexamethasone Bortezomib is currently approved for the treatment of multiple myeloma.

Because twice-weekly bortezomib is associated with toxicity such as neuropathy, some studies are investigating new regimens with only once-weekly administration of the drug.

In one study in which patients received a once-weekly regimen of bortezomib for 4 weeks, oral dexamethasone (Decadron) was taken on

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the day of and the day after receiving bortezomib, for 6 cycles. Among all the patients who have received at least 1 cycle of bortezomib, 64% have achieved a partial response or better, with 15% of them achieving a complete or near-complete response.

An intent-to-treat analysis showed an objective response rate of 78% in 41 patients. Only 1 patient has developed grade 3 neuropathy.

Bortezomib plus Bendamustine Another trial was an open-label phase 1 study that assessed bortezomib in combination with bendamustine (Treanda) in a heavily pretreated population of patients with relapsed or refractory multiple myeloma.

Results showed that the combination was well tolerated, and the objective response rate was nearly 50%, including an approximately 40% response rate in patients who previously received bortezomib, and a clinical benefit rate (responses plus stable disease) of more than 90%.

Other Regimens Under Way The use of bortezomib in combination with oral panobinostat and dexamethasone is under study in a phase 3 trial of 672 patients with relapsed/ refractory multiple myeloma. Results are pending.

A new regimen of pegylated liposomal doxorubicin, bortezomib, dexamethasone, and lenalidomide (Revlimid)

in patients resistant to lenalidomide and bortezomib.

Other novel classes of drugs are histone deacetylase inhibitors (eg, panobinostat), heat shock protein 90

Second-generation proteasome inhibitors include carfilzomib, which is associated with less neuropathy than bortezomib, and oral chymotryptic inhibitors, which appear more potent at inhibiting myeloma cell growth. inhibitors, and the alkylphospholipid AKT inhibitor perifosine. Some of these are being explored as a part of rational combinations of therapies.

For example, the combination of bortezomib and panobinostat is synergistic, as panobinostat blocks ubiquitinated protein via the aggresomal pathway and bortezomib blocks these same proteins via the proteasomal pathway.

The use of genomics to personalize approaches to the treatment of multiple myeloma is another research interest of Dr Anderson’s. Genetic profiling is identifying genes that are upregulated or downregulated in the progression to multiple myeloma. ■

is under investigation in 40 patients with relapsed/refractory multiple myeloma. Interim data from 27 patients show objective responses in

Interim data from 27 patients show objective responses in 70% of patients, including a 19% complete response rate.

70% of patients, including a 19% complete response rate.

To date, 1 of these patients has experienced grade 4 reversible thrombocytopenia and 8 patients have developed peripheral neuropathy.—WK ■

www.AHDBonline.com

21

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The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

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Prostate Cancer

New Treatment Options for Castration-Resistant Prostate Cancer

By Wayne Kuznar

W

ith the recent US Food and Drug Administration (FDA) approval of 4 new agents for patients with castration-resistant prostate cancer (CRPC), more options to extend life or prevent cancer treatment–associated skeletal-related events (SREs) are now available.

In addition to the new 4 drugs— sipuleucel-T (Provenge), denosumab (Prolia), cabazitaxel (Jevtana), and abiraterone (Zytiga)—a number of other agents are currently in latestage clinical trials and promise to change how prostate cancer is treated, said Kim Chi, MD, Associate Professor of Medicine, University of British Columbia, Vancouver.

New therapies are evolving “across a diversity of targets, including androgen signaling, chaperone proteins, DNA repair, apoptosis, and a whole host of cell signaling from cell-surface receptors to intracellular signaling,” said Dr Chi. Sipuleucel-T An immune response to cancer occurs in the same way as any adaptive immune response, said Charles Drake, MD, PhD, Assistant Profes-

New therapies are directed at “a diversity of targets, including androgen signaling, chaperone proteins, DNA repair, apoptosis, and a whole host of cell signaling from cell-surface receptors to intracellular signaling.”

—Kim Chi, MD

sor of Oncology, Immunology, and Urology, Johns Hopkins University, Baltimore. Sipuleucel-T is thought to focus on activated dendritic cells, which present their target antigens to CD4 and CD8 T-cells, “upregulating the cytotoxic machinery.” Sipuleucel-T is an “active” cellular immunotherapy, using patients’ own white blood cells as part of its mechanism of action.

In the IMPACT (Immunotherapy for

Initial Treatment of Prostate Cancer in Medicare Moving Toward High-Cost Technologies

T

he combination of an aging population and the use of newer highcost technologies will accelerate future Medicare spending for prostate cancer, according to Michaela A. Dinan, PhD, and colleagues from the Duke Clinical Research Institute, Durham, NC. Dr Dinan and colleagues analyzed current trends in the treatment of patients with prostate cancer who are Medicare beneficiaries, showing that the more expensive, intensity-modulated radiation therapy (IMRT) has replaced 3-dimensional conformal radiotherapy (3D-CRT) as the primary form of radiotherapy for this patient population.

Using a nationally representative 5% sample of claims from the Centers for Medicare & Medicaid Services, the investigators conducted a retrospective claims-based review of radiation therapy, surgery, and androgen-deprivation therapy in the first 12 months after a diagnosis of prostate cancer.

The study included 20,399 Medicare beneficiaries aged ≥67 years, with incident prostate cancer that was diag-

24

nosed between 1999 and 2007.

The overall rates of surgery and radiotherapy remained unchanged during the first 12 months of diagnosis across the study period, but those receiving androgen-deprivation monotherapy decreased by approximately half between 2003 (25.6%) and 2007 (14.1%).

The proportion of patients without evidence of active treatment increased from 14.7% in 2003 to 22.5% in 2007.

Minimally invasive radical prostatectomy replaced open approaches and comprised 50% of all radical prostatectomies by 2007.

“IMRT replaced 3D-CRT as the most common method of prostate radiotherapy from 2002 to 2007 and was used in two thirds of all Medicare prostate cancer patients receiving any radiotherapy by 2007,” Dr Dinan and colleagues noted.

The increasing trend favoring the use of IMRT over 3D-CRT has significant financial implications, because Medicare reimbursement for IMRT averages $48,000 compared with only $22,000 for 3D-CRT.—WK ■

AMERICAN HEALTH & DRUG BENEFITS

August 2011

Prostate Adenocarcinoma Treatment) trial that led to the drug’s approval, asymptomatic patients who received sipuleucel-T had a median overall survival (OS) benefit of 4.1 months over placebo. The drug is indicated for men with minimally symptomatic metastatic CRPC.

Investigational Agents A viral vaccine approach (PROSTVAC-VF) is currently in development for CRPC, Dr Drake added. The fully human monoclonal antibody ipilimumab (Yervoy), recently approved by the FDA for the treatment of metastatic melanoma, is also being evaluated for this patient population.

“Sipuleucel-T now has a strong indication for a survival benefit for metastatic, minimally symptomatic CRPC patients.” —Thomas Flaig, MD Denosumab Many factors militate against healthy bone in men with prostate cancer, said Thomas Flaig, MD, Assistant Professor, University of Colorado, Denver. Besides androgen deprivation and the use of glucocorticoids, tumors themselves contribute to osteoporosis.

Denosumab is a fully human monoclonal antibody and osteoclast inhibitor. It inhibits the RANK-ligand, the activator of osteoclastic activity that is upregulated by tumor growth.

There is less concern for renal toxicity with denosumab than with zoledronic acid (Zometa, Reclast). “For those patients with renal insufficiency, I think this will be a very good option,” said Dr Flaig.

Osteonecrosis of the jaw and hypocalcemia, however, are still a risk. In a study comparing denosumab with zoledronic acid, denosumab extended the time to a first SRE by a median of 3.6 months compared with zoledronic acid.

Denosumab is approved for the prevention of SREs in patients with bone metastases from solid tumors.

Cabazitaxel Cabazitaxel is a microtubule inhibitor and traditional cytotoxic chemotherapy agent, Dr Drake said.

In the phase 3 TROPIC trial, which addressed metastatic CRPC that progressed in patients who initially received docetaxel chemotherapy, the

median OS in patients who received cabazitaxel was 15.1 months compared with 12.7 months for those who received mitoxantrone.

Cabazitaxel was associated with more bone marrow suppression than mitoxantrone, and with higher rates of neutropenia and febrile neutropenia. Febrile neutropenia occurred in 8% of patients receiving cabazitaxel versus 1% with mitoxantrone.

In addition, there is a risk of early infectious disease with cabazitaxel, which led to more deaths than with mitoxantrone (4.9% vs 1.9%). Cabazitaxel is approved for use with prednisone for the treatment of metastatic CRPC previously treated with docetaxel.

Abiraterone With chemical or surgical castration, testosterone (or androgen) levels are reduced by 90% to 95%, but not to zero, said Dr Flaig. In addition, tumor tissue produces testosterone.

Abiraterone is a CYP17 inhibitor that blocks all testosterone production.

In patients with metastatic CRPC who had received 1 or 2 courses of chemotherapy, including docetaxel, abiraterone significantly improved OS compared with placebo (14.8 months vs 10.9 months, respectively).

Abiraterone “is a very welltolerated oral drug that has given a survival advantage.”

—Thomas Flaig, MD Mineralocorticoid excess, fluid retention, hypokalemia, and cardiac disorders are some adverse effects of the drug.

Abiraterone is approved for use with prednisone for metastatic CRPC after initial therapy with docetaxel. “So here is a very well-tolerated oral drug that has given a survival advantage—really, a hormonal drug—in the postchemotherapy setting,” Dr Flaig added.

New Standard of Care “What a difference a year makes,” said Dr Flaig when discussing the new standards of care. “Sipuleucel-T now has a strong indication for a survival benefit for patients with metastatic, minimally symptomatic CRPC. Once patients have progressed while using docetaxel, there are some great options—abiraterone, with a 4-month survival advantage, or cabazitaxel….

And denosumab has been shown to be superior to zoledronic acid in preventing the first SRE.” ■

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Prostate Cancer

Cabozantinib Shows Dramatic Effects on Bone Metastases in Advanced Prostate Cancer

By Wayne Kuznar

A

previous treatments for metastatic castration-resistant prostate cancer, including docetaxel (Taxotere)-based chemotherapy and abiraterone acetate (Zytiga).

Courtesy of ASCO/GMG/Scott Morgan 2011

n unprecedented complete or partial resolution of bone metastases was observed with the investigational tyrosine kinase inhibitor cabozantinib in a trial of men with metastatic castration-resistant prostate cancer.

Interim results from the phase 2 discontinuation trial were reported by Maha Hussain, MD, Associate Director for Clinical Research, University of Michigan Comprehensive Cancer Center, Ann Arbor.

Cabozantinib is a dual inhibitor of the tyrosine kinases MET and vascular endothelial growth factor receptor (VEGFR) 2. MET is upregulated in many tumor types and promotes tumor cell invasion and metastasis.

Both MET and the VEGFR2 signaling pathways appear to direct crosstalk between tumor cells, osteoblasts, and osteoclasts, said Dr Hussain.

In the study, 171 patients with metastatic castration-resistant prostate cancer with progressive measurable soft-tissue disease received cabozantinib during a 12-week lead-in phase, after which further treatment was based on response. The patients with a complete or partial response received open-label cabozantinib, those with stable disease were randomized to cabozantinib or to placebo, and those with disease progression or adverse events discontinued cabozantinib.

Of the 171 patients, 74 had received

In 151 patients with at least 1 postbaseline assessment, 74% showed meaningful evidence of tumor regression, which occurred irrespective of previous treatments.

—Maha Hussain, MD Bone Metastasis Bone metastasis was evident in 87% of the patients, and 91% had metastasis at ≥2 sites. Bone pain was reported by 54% of the patients, and 42% were using narcotics for bone pain.

Randomization was suspended after 122 patients, based on the high rate of clinical activity of cabozantinib; 79 men had at least a partial response and entered the open-label extension phase and 31 with stable disease entered the randomized portion of the

trial. The disease control rate (no progression) at week 12 was 68%.

The safety and tolerability of cabozantinib were consistent with previous experience with the drug. In the lead-in phase, the most common grade 3 adverse event was fatigue (in 16% of patients). Adverse events necessitated cabozantinib dose reduction in 51% of the patients.

In 151 patients with at least 1 postbaseline assessment, 74% showed meaningful evidence of tumor regression, said Dr Hussain. The tumor regression occurred irrespective of previous treatments, she said.

Progression-Free Survival In the randomized discontinuation phase, median progression-free survival (PFS) was 21 weeks in the cabozantinib group and 6 weeks in the placebo group (P = .007), an 87% reduction in the risk of progression for patients assigned to cabozantinib versus placebo.

Excluding the patients randomized to placebo, the median PFS was 29 weeks for the overall population. The median PFS was 24 weeks in the subset of docetaxel-naïve patients and 29 weeks in patients who previously received docetaxel, which suggests that cabozantinib treatment results in durable disease control in both docetaxel-naïve and previously treated populations.

Bone Scan Findings and Clinical Progress The bone scan–assessable population included 108 patients with evidence of bone metastasis, a baseline bone scan, and at least 1 postbaseline bone scan assessment. Of these, 61 had partial resolution and 21 had complete resolution of bone metastases; 21 had stable disease on bone scan, and only 3 had progressive disease.

Of the 83 patients with bone metastases and bone pain at baseline, 68% had improvement of pain at either week 6 or 12. Of the 67 patients who required narcotic analgesics at baseline to control bone pain, 70% were able to decrease or discontinue narcotic medication for bone pain.

In addition, 55 patients had bone pain at baseline, 10 had complete resolution, 32 had partial resolution, and 13 had stabilization of disease with cabozantinib by bone scan evaluation.

Of these patients, 80% with complete resolution, 84% with partial resolution, and 38% with disease stabilization reported improvements in bone pain.

These findings are the first to show an association between changes in lesions on bone scans and improvement in clinical symptoms of disease.

Of 67 patients assessable for postbaseline review of narcotic consumption, 47 (70%) were able to decrease or discontinue narcotic medication for bone pain. ■

Lymphoma

HBV Screening before Lymphoma Treatment Improves Outcomes, Is Cost-Effective

S

creening all patients for hepatitis B surface antigen (HBsAg) before initiating chemotherapy for lymphoma is associated with improved clinical outcomes and is economically favorable, according to an analysis presented by researchers at the University of Toronto and St Michael’s Hospital, Toronto, Ontario.

Reactivation of the hepatitis B virus (HBV) during chemotherapy may lead to disruption of chemotherapy, hospitalization for HBV infection, and even death. Screening for HBV is often recommended but is not always performed, although effective prophylactic therapy in the form of lamivudine (Epivir) is available. Whether screening justifies the additional cost has not been investigated.

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The researchers developed a decision-analytic model for patients with lymphoma undergoing chemotherapy with R-CHOP (rituximab [Rituxan], cyclophosphamide, hydroxydaunorubicin [Adriamycin], vincristine [Oncovin], prednisone). Three HBV screening strategies were evaluated: screen all patients, screen only those at high risk, and screen nobody. Patients who tested positive for HBsAg received lamivudine until 6 months after the completion of chemotherapy.

Unscreened patients received lamivudine only if they developed HBVrelated hepatitis.

The risks of HBV-related hepatitis recovery, HBV-related death, and lymphoma outcomes were derived from a systematic literature review.

AMERICAN HEALTH & DRUG BENEFITS

August 2011

The following cost estimates (in Canadian dollars) were used in the model: HBV DNA test, $133; HBsAg

Screening all patients resulted in a net savings of $62 per patient. test, $13; lamivudine, $180 per month; R-CHOP, $35,704 per cycle; end-of-life care, $46,465 hepatitis-related and $42,632 lymphoma-related.

Screening all patients was the dominant strategy. It was both the least costly and the most effective in increasing the 1-year survival rate. One-year survival was 85.0% with the screen-all strategy versus 84.96% with the high-

risk patient–only strategy and 84.86% with the screen-nobody strategy. The number of HBV-related hepatitis hospitalizations per 1000 patients was 0.1 with the screen-all strategy, 0.9 with the high-risk patient–only strategy, and 3.0 with the screen-nobody strategy.

Screening all patients resulted in a net savings of $62 per patient versus not screening and of $8 per patient versus screening only high-risk patients, presuming that all high-risk patients were correctly identified.

A second analysis presented at the meeting by researchers from the University of Texas M.D. Anderson Cancer Center showed that HBV screening before chemotherapy for nonhematologic tumors is not costeffective.—WK ■

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Lymphoma/Leukemia

Optimal Length of Treatment of Non-Hodgkin Lymphoma Debated

By Caroline Helwick

Courtesy of ASCO/GMG/Silas Crews 2011

single-agent rituximab.

After a median follow-up of 37 months, the rates of overall survival (OS) and progression-free survival (PFS) were similar, as were objective response rates, reported David Cunningham, MD, of the Royal Marsden Hospital, who presented the results for the UK National Cancer Research Institute Lymphoma Clinical Study Group.

After a median follow-up of 37 months, overall survival and progression free survival were similar with the 21-day and 14-day regimens, which does not warrant a shift in practice.

—David Cunningham, MD No subgroup appeared to derive a greater benefit from accelerated RCHOP. Neutropenia and febrile neutropenia were more frequent in patients receiving the 21-day regimen, probably because the 14-day group

received growth factors, although thrombocytopenia was more frequent with R-CHOP-14, probably because of greater dose intensity. According to Dr Cunningham, the results do not support a shift in clinical practice from R-CHOP-21 to R-CHOP-14.

Transplant Improves Outcomes in High-Grade Aggressive NHL Julie M. Vose, MD, of the University of Nebraska Medical Center, Omaha, discussed the UK trial’s findings and agreed. But she added that in younger patients at high risk for recurrence, R-CHOP-21, followed by autologous transplantation of peripheral stem cells, should be offered as a standard of care.

This strategy was shown to be effective in the phase 3 intergroup SWOG S9704 trial of 253 patients with NHL that was presented at the meeting

by Patrick J. Stiff, MD, of Loyola University Medical Center, Chicago.

ASCT after CHOP-based induction therapy improved PFS in patients who had an aggressive form of the disease, as indicated by their high or highintermediate International Prognostic Index score.

Patients responding to CHOP, with or without rituximab, had a 2-year PFS rate of 69% with ASCT compared with

56% with the induction therapy alone, which translates to a 72% increase in PFS (P = .005).

Courtesy of ASCO/GMG/Silas Crews 2011

S

everal studies addressed key questions in the treatment of nonHodgkin lymphoma (NHL). One evaluated a shorter, more intense rituximab (Rituxan)-based regimen, and another evaluated the benefit of autologous stem-cell transplantation (ASCT) in high-risk patients. The 21-day regimen of R-CHOP (rituximab plus cyclophosphamide, doxorubicin [Adriamycin], vincristine [Oncovin], and prednisolone) is still the standard of care for this patient population.

Rituximab revolutionized the care of NHL and is essentially part of the treatment for all patients with this disease, but researchers continue to evaluate various schedules for delivering the drug.

One debate during ASCO 2011 has focused on whether the standard 21day regimen can be shortened to 14 days; however, investigators from the United Kingdom reported no advantage with the 14-day regimen.

This randomized phase 3 trial involved 1080 patients with diffuse large B-cell NHL, all of whom were to receive R-CHOP. Treatment-naïve patients were randomly assigned to receive either 8 cycles of R-CHOP for 21 days or 6 cycles of R-CHOP for 14 days plus granulocyte colony-stimulating factors, succeeded by 2 cycles of

In younger patients at high risk for recurrence, R-CHOP-21, followed by autologous transplantation of peripheral stem cells, should be offered as a standard of care.

—Julie M. Vose, MD The 2-year OS rates were similar between the 2 groups, at 74% and 71%, respectively; however, many patients in the control arm underwent a salvage transplant, which may have confused this analysis, Dr Stiff pointed out.

The survival benefit was most apparent in patients with high International Prognostic Index scores for whom the 2-year PFS rate was 75% with transplant compared with 41% with standard care and the 2-year OS rates were 82% and 64%, respectively. ■

High-Dose Methotrexate Improves Survival in High-Risk B-Cell Precursor Acute Lymphoblastic Leukemia

H

igh-dose methotrexate improves 5-year event-free survival over the standard regimen of escalating methotrexate plus asparaginase (Elspar; together known as Capizzi methotrexate) as maintenance therapy in children and young adults with highrisk acute lymphoblastic leukemia (ALL), reported Eric C. Larsen, MD, Director, Maine Children’s Cancer Program and the Division of Pediatric Hematology/Oncology, Barbara Bush Children’s Hospital, Maine Medical Center, Portland.

The high-dose methotrexate regimen produced the superior event-free survival with no additional significant side effects compared with the standard regimen in a phase 3 study of 3154 patients with newly diagnosed high-risk B-cell precursor ALL. With the advent of novel therapies several years away, investigators were forced to review the history of therapy for ALL, including the intensification of central nervous system (CNS)directed therapy (ie, radiation thera-

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py), but this option was discarded to reduce the side effects of treatment.

They decided to focus on systemic therapies for improving CNS control, including high-dose methotrexate during interim maintenance.

Patients aged <30 years meeting National Cancer Institute high-risk criteria, which include patients aged ≤10 years with a white blood cell count of ≥50,000 cells/µL, were eligible for the study. They were randomly assigned to prednisone or dexamethasone as induction therapy, followed by consolidation for 8 weeks. They were then randomized to high-dose methotrexate or Capizzi methotrexate during a 2-month interim phase.

When the protocol for the study was developed 10 years ago, there was a shift in the pattern of disease recurrence to a relative increase in CNS failure over marrow failure.

“The planning group for the protocol focused specifically on strategies that might improve CNS control,” said Dr Larsen.

At a planned interim analysis, the 5-year, event-free survival rate for patients who received high-dose methotrexate was 82% compared with 75.4% for patients receiving the esca-

High-dose methotrexate is “the new standard of care for high-risk ALL.” —Martin S. Tallman, MD lating methotrexate regimen. There were also significantly fewer bone marrow relapses (42 vs 68, respectively) and CNS relapses (22 vs 32, respectively) in the high-dose group. The trial was halted early as a result, after 2426 patients completed the interim maintenance phase, and certain patients were eligible to then receive the high-dose methotrexate regimen.

Patients receiving high-dose methotrexate had a lower incidence (5.2%) of febrile neutropenia than those receiving the standard regimen (8.2%).

There were no differences in other significant toxicities.

Patients with slow early responses to therapy appeared to gain the most benefit from high-dose methotrexate, according to Dr Larsen.

Among the 435 patients with slow early responses, the 5-year event-free survival rate was 79.5% with highdose methotrexate and 65.4% with Capizzi methotrexate. In the 1843 patients with rapid early responses, there was no significant difference in 5-year event-free survival between the 2 groups (86.6% with high-dose methotrexate vs 82.7% with Capizzi methotrexate).

Given the longer survival with highdose methotrexate and a superior toxicity profile with this regimen, highdose methotrexate is “the new standard of care for high-risk ALL,” declared Martin S. Tallman, MD, Chief of the Leukemia Service at Memorial Sloan-Kettering Cancer Center, and Weill Cornell Medical College, New York City. ■

www.AHDBonline.com

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Lung Cancer

Maintenance with Pemetrexed Extends Progression-Free Survival in Advanced Nonsquamous NSCLC C

Courtesy of ASCO/GMG/ Scott Morgan 2011

ontinuing pemetrexed (Alimta) as maintenance therapy after its use as part of a 2-drug, 4-cycle induction regimen improves progression-free survival (PFS) in patients with advanced nonsquamous non–smallcell lung cancer (NSCLC).

Data from the phase 3 PARAMOUNT study, the first large trial to demonstrate the efficacy of longer-term maintenance therapy in advanced NSCLC, were presented by Luis Paz-Ares, MD, PhD, Chair of Oncology, Seville University Hospital, Spain.

Most patients with advanced NSCLC initially receive 4 cycles of cisplatin (Platinol) and pemetrexed; treatment is then stopped until the disease recurs, when a second-line therapy is administered.

Pemetrexed has demonstrated efficacy in combination with cisplatin as a first-line doublet and as a maintenance agent after therapy with a nonpemetrexed platinum doublet (“switch” maintenance).

The results of PARAMOUNT “suggest that patients can still continue to benefit from the use of the same drug rather than ‘use up’ an alternative early in the course of treatment,” Dr PazAres said. “This could change the standard of care for these patients, at least in terms of maintenance treatment.”

was 71.8% in the pemetrexed arm and 59.6% in the placebo arm.

In commenting on the trial, Martin J. Edelman, MD, Director of Solid Tumor Oncology, University of Maryland Greenebaum Cancer Center, Baltimore, cautioned that PFS “does not necessar-

ily predict for overall survival [OS],” as other studies have demonstrated.

ALK Inhibitors Prolong Survival An investigational drug in a class known as anaplastic lymphoma kinase (ALK) inhibitors appears to double

Celgene is now joining the battle against metastatic breast cancer

“This could change the standard of care for these patients.”

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

—Luis Paz-Ares, MD, PhD The 939 patients with advanced nonsquamous NSCLC received the standard 4 courses of first-line induction therapy with pemetrexed and cisplatin. The 539 patients whose disease had stabilized were then randomized to maintenance pemetrexed and best supportive care or to placebo and best supportive care. Approximately 90% of patients in each group had stage IV disease.

Maintenance pemetrexed therapy showed a 38% reduction in disease progression risk, with 4.1-month PFS in the pemetrexed group compared with 2.8 months in the placebo group.

The PFS results were consistent across all subgroups analyzed. The median independently reviewed PFS (N = 472; 297 events), measured from randomization, was 3.9 months in the pemetrexed arm and 2.6 months in the placebo arm. The disease control rate

28

survival in patients with advanced NSCLC who have a certain genetic variant, said the lead investigator of an early-phase study, Alice T. Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital Cancer Center, Boston.

If you need help accessing ABRAXANE for your patients, please call Celgene Patient Support ® at 800-931-8691 or visit www.abraxane.com.

Please see Important Safety Information on adjacent page.

Please see brief summary of full Prescribing Information on the following pages.

AMERICAN HEALTH & DRUG BENEFITS

ABRAXANE® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation

August 2011

03/11

ABR11012

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C

Lung Cancer The drug, crizotinib, is an oral inhibitor of ALK and MET tyrosine kinases and their oncogenic variants; it targets tumors that have a rearrangement of the ALK gene. Approximately 4% of patients with NSCLC have tumors with ALK gene rearrangements, which stimulate the growth and survival of the tumors.

In this study, 82 patients with NSCLC who had the ALK fusion gene and whose tumors progressed despite

receiving a median of 2 chemotherapy regimens received crizotinib 250 mg twice daily. There was no comparison group; instead, survival was compared with that of crizotinib-naïve controls with the ALK gene rearrangement and with patients with NSCLC without the ALK gene rearrangement.

The objective response rate was 57%, and the disease control rate was 87%. More than 90% of the patients’ tumors regressed.

Of the 82 patients enrolled in the study, 75% were alive after 1 year and 54% after 2 years. Median OS has not yet been reached, because >50% of the patients enrolled are still alive.

By comparison, among ALK-positive controls who received standard chemotherapy for NSCLC, 1-year survival is 44% and 2-year survival is only 12%, said Dr Shaw. Median OS in this group is 6 months.

Median OS among patients with

NSCLC without the ALK rearrangement is not significantly different from those with the ALK rearrangement.

The median OS in the patients who received crizotinib in this study, compared with that in the historical controls (crizotinib-naïve patients who lack the ALK rearrangement or the epidermal growth factor receptor genetic mutation), was significantly improved in those with the ALK rearrangement.—WK ■

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

IMPORTANT SAFETY INFORMATION WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. ADDITIONAL WARNINGS s The use of ABRAXANE has not been studied in patients with renal dysfunction.

In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL Pregnancy-Teratogenic Effects: Pregnancy Category D s ABRAXANE can cause fetal harm when administered to a pregnant woman s If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus s Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE Use in Males: s Men should be advised to not father a child while receiving treatment with ABRAXANE Albumin (human): s ABRAXANE contains albumin (human), a derivative of human blood PRECAUTIONS Drug Interactions: s No drug interaction studies have been conducted with ABRAXANE s Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 Hematology: s ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 s It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE s Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 s In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended Nervous System: s Sensory neuropathy occurs frequently with ABRAXANE s The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification s If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE Hepatic Impairment: s Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

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s The starting dose should be reduced for patients with moderate and severe hepatic impairment Injection Site Reaction: s Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial s Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration Nursing Mothers: s It is not known whether paclitaxel is excreted in human milk s Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy Ability to Drive and Use Machines: s Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines ADVERSE EVENTS s Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial s These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension s Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely s During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction were observed, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%), infections (24%), vomiting (any 18%; severe 4%), and mucositis (any 7%; severe <1%).

Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In clinical trials and during postmarketing surveillance, dehydration was common and pyrexia was very common. Rare occurrences of severe hypersensitivity reactions have also been reported during postmarketing surveillance.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

www.AHDBonline.com

29

Rectal Cancer

Adherence to Rectal Cancer Guidelines High, Insured Patients Overtreated

By Caroline Helwick

A “

dherence to national clinical practice guidelines is an especially salient benchmark for rectal cancer, given the high degree of consensus among various guideline-generating

agencies,” said Ryaz Chagpar, MD, of University of Texas M.D. Anderson Cancer Center, Houston. “But a nationwide hospital-based assessment of current practices with respect to

stage-specific treatment of rectal cancer is lacking.”

Dr Chagpar and colleagues assessed; current practice trends and adherence to the National Comprehensive Cancer Network (NCCN) guidelines for >47,000 persons diagnosed with rectal cancer between 2003 and 2007.

Rx Only

(paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Brief Summary of Full Prescribing Information.

WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of < 1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D: ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving 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 while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability).

Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see CLINICAL PHARMACOLOGY).

Hematology ABRAXANE® therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).

Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Hepatic Impairment) Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately

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AMERICAN HEALTH & DRUG BENEFITS

August 2011

This population included 10,084 patients with stage I disease; 13,117 with stage II disease; 15,864 with stage III disease; and 8334 with stage IV disease. The demographics were fairly comparable across the disease stages.

“Overall, the majority of patients (64%) were treated in accordance with

1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/ degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS).

Pregnancy: Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).

Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE® therapy.

Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. Ability to Drive and Use Machines Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines.

ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE® or paclitaxel injection for the treatment of metastatic breast cancer.

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=225) (n=229) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 < 0.5 x 109/L 9 22 Thrombocytopenia 9 < 100 x 10 /L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 2 2 Bleeding Hypersensitivity Reactione 4 12 All Severef 0 2 Cardiovascular Vital Sign Changesg Bradycardia <1 <1 5 5 Hypotension 4 Severe Cardiovascular Eventsf 3 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsf 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 Severe Symptomsf 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsf <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsf <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 (continued)

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SPECIAL ISSUE

Rectal Cancer NCCN guidelines,” Dr Chagpar noted, but this leaves one third that were not.

Patients with stage IV disease were most likely to receive guideline-adherent treatment (73%). Nonadherence in stage I rectal cancer was largely associated with overtreatment (20%), primarily with neoadjuvant therapy (83%).

The undertreatment rate for stage I disease was 14%, evident when no sur-

gical resection was performed or when transanal excision was used inappropriately for larger tumors.

Across all stages, most cases of undertreatment were related to a failure to use adjuvant therapy for stage II (44%) or stage III (40%) disease.

For stage I rectal cancer, age >50 years and a Charlson-Deyo comorbidity index ≥1 were independently

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule, Continued Percent of Patients ABRAXANE® Paclitaxel Injection b 260/30min 175/3hc,d (n=229) (n=225) Hepatic (Patients with Normal Baseline) AST (SGOT) Elevations 39 32 <1 1 Injection Site Reaction a Based on worst grade. b ABRAXANE dose in mg/m2/duration in minutes. c paclitaxel injection dose in mg/m2/duration in hours. d paclitaxel injection pts received premedication. e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity. g During study drug dosing.

Myelosuppression and sensory neuropathy were dose related.

Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE® in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2.

In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm.

Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm.

Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia.

Rare reports of pancytopenia have been observed in clinical trials and during postmarketing surveillance of ABRAXANE. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension.

Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study.

The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.

Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.

In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm.

The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial.

Cranial nerve palsies and vocal cord paresis have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety.

Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2).

These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage.

Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/ myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE® administration, and resolved within a few days.

Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%,

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associated with guideline adherence; the opposite trend was found for stage II to stage IV disease. “This is the result of younger, healthier clinical stage I patients being overtreated with neoadjuvant chemotherapy,” Dr Chagpar said.

Across all stages, patients with private or Medicare insurance, and those who received treatment at a compre-

36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in the randomized trial.

Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise.

Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. In clinical trials and during postmarketing surveillance of ABRAXANE, dehydration was common and pyrexia was very common.

The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Accidental Exposure No reports of accidental exposure to ABRAXANE® have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel.

Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 4. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely. (See CLINICAL PHARMACOLOGY: Hepatic Impairment and PRECAUTIONS: Hepatic Impairment) Table 4: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels Bilirubin Levels ABRAXANE a Mild <10 x ULN >ULN to ≤ 1.25 x ULN 260 mg/m2 Moderate <10 x ULN AND 1.26 to 2.0 x ULN 200 mg/m2 Severe <10 x ULN 2.01 to 5.0 x ULN 130 mg/m2 b > 10 x ULN OR > 5.0 x ULN not eligible a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance.

Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. HOW SUPPLIED: Product No. 103450 NDC No. 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton.

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

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

This Brief Summary is based on the ABRAXANE Full Prescribing Information Revised: March 2010

ABRAXANE and Abraxis are registered trademarks of Abraxis BioScience, LLC. ©2010 Abraxis BioScience, LLC. All Rights Reserved.

U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006

hensive cancer center/teaching hospital or at a community cancer center were most likely to receive treatment according to NCCN guidelines.

The investigators concluded that young patients with stage I rectal cancer who were insured were likely to be overtreated, whereas patients with stage II and III cancer who were older, had comorbid conditions, were underinsured, or received treatment at community hospitals were likely to be undertreated. ■

Oxaliplatin for Advanced Rectal Cancer

O

xaliplatin (Eloxatin) has shown impressive benefits in several colorectal cancer settings, but its role in advanced rectal cancer is uncertain.

German investigators reported the results of a phase 3 clinical trial, showing that the addition of oxaliplatin to 5fluorouracil (FU; Adrucil) before and after surgery for the treatment of locally advanced rectal cancer can be done with high compliance.

The objective of the German Rectal Cancer Study Group’s CAO/ARO/ AIO-04 trial was to determine if oxaliplatin added to adjuvant 5-FU–based chemotherapy would increase the 3year disease-free survival rate in locally advanced rectal cancer.

“This is the only phase 3 trial worldwide that has included oxaliplatin preoperatively and postoperatively for locally advanced rectal cancer.”

—Claus Rödel, MD Of the total 1265 patients, half received a modified FOLFOX6 regimen (5-FU, leucovorin, oxaliplatin) as adjuvant treatment; they also received oxaliplatin preoperatively plus radiation and surgery. The regimen was designed to be less toxic than similar oxaliplatin-containing regimens, and it was completed as scheduled by most of the patients.

Complete resection was possible in 90% of patients, and pathologic complete responses were significantly higher in patients receiving oxaliplatin compared with the patients in the control arm who received 5-FU only.

“This is the only phase 3 trial worldwide that has included oxaliplatin preoperatively and postoperatively for locally advanced rectal cancer,” said Claus Rödel, MD, of the University of Frankfurt. ■

www.AHDBonline.com

SPECIAL ISSUE 1

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Other Highlights

JAK Inhibitor Improves Response, Symptoms in Patients with High-Risk Myelofibrosis

By Wayne Kuznar

T

he Janus kinase (JAK) 1/2 inhibitor ruxolitinib dramatically improves response rates in treating 3 forms of myelofibrosis, according to results from 2 randomized phase 3 clinical trials, known as COMFORT (Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment) I and II. In both COMFORT trials, ruxolitinib was significantly superior to the best available therapy in reducing spleen size and symptom burden and improving quality of life. The studies are the first randomized trials of drug therapy for myelofibrosis.

The findings of significant benefit over currently available therapies should change the standard of care for many patients with myelofibrosis, said COMFORT I study coinvestigator Alessandro Vannucchi, MD, Associate Professor of Hematology, the University of Florence, Italy.

“These patients responded very quickly to ruxolitinib—within 2 to 4 weeks. This therapy has the potential to significantly change the treatment landscape for these patients and could

greatly improve their outlook,” Dr Vannucchi said.

The median overall survival (OS) associated with myelofibrosis can exceed 5 years, but high-risk patients live only 2 to 4 years after the diagnosis. Approximately 50% of all patients carry a mutation in the JAK2 gene, although all have an activated JAKsignaling pathway. Ruxolitinib is active in these patients regardless of whether patients have a JAK2 mutation.

In the open-label COMFORT II, 219 adults with intermediate- or highrisk primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (PPV-MF), or postessential thrombocythemia myelofibrosis (PET-MF), were randomized to either ruxolitinib or to best available therapy. After 48 weeks, 28.5% of patients assigned to ruxolitinib achieved a ≥35% reduction in spleen size compared with 0% with best available therapy.

Marked improvement in quality-oflife measures were obtained with ruxolitinib beginning at week 8 and continuing through week 48. In contrast, patients receiving best available thera-

Assay Can Streamline Use of Temozolomide in Glioblastoma

By Caroline Helwick

P

atients with newly diagnosed glioblastoma who have the best chance of responding to temozolomide can be selected via a prognostic marker that has been incorporated into a commercial assay.

The assay looks in the brain tumor for MGMT (O6-methylguanine-DNA methyltransferase), which is a key DNA repair enzyme produced by the MGMT gene. High levels of MGMT are associated with lesser response to DNA-damaging therapies such as temozolomide.

“The MGMT gene test (MDxHealth) was confirmed in the RTOG [Radiation Therapy Oncology Group] 0525 clinical trial to define prognosis for patients with newly diagnosed glioblastoma. Ongoing clinical trials have incorporated this now-validated prognostic marker to determine if subsets of patients require alternative therapies,” said Mark Gilbert, MD, of the University of Texas M.D. Anderson Cancer Center, Houston.

The application of a molecular risk classification to samples from the 763 patients in the RTOG 0525 trial (which evaluated 2 schedules of temozolo-

32

mide) selected patients who had significant increases (P <.001) in overall survival. The approach improved on current means of prediction, by revealing an additional distinct risk group.

“This study confirmed the prognostic significance of MGMT methylation in glioblastoma.”—Mark Gilbert, MD In particular, patients whose tumors demonstrated MGMT methylation had a median survival of 21.2 months versus 14 months without methylation (P <.001), as well as longer progression-free survival (8.7 vs 5.7, respectively; P <.001). Treatment arm and radiation technique did not predict for survival.

“This study confirmed the prognostic significance of MGMT methylation in glioblastoma,” Dr Gilbert said.

The results suggest that treatment decisions based on the molecular characteristics of the tumor are not only feasible but make a clinical difference, he said. ■

AMERICAN HEALTH & DRUG BENEFITS

August 2011

py showed no change or worsening of symptoms during the study.

Adverse events, including anemia and thrombocytopenia, caused 8.2% of patients assigned to ruxolitinib to stop treatment compared with 5.5% of patients randomized to best available therapy. Grade 3/4 thrombocytopenia occurred in 8% of patients receiving

“These patients responded very quickly to ruxolitinib— within 2 to 4 weeks. This therapy has the potential to significantly change the treatment landscape.”

—Alessandro Vannucchi, MD ruxolitinib and in 7% of those receiving best available therapy; grade 3/4 anemia was observed in 42% and 31% of patients, respectively. OS was not an end point in this study but is an end point in ongoing studies.

In COMFORT I, 309 patients with intermediate- or high-risk PMF, PPV-MF,

or PET-MF were randomly assigned to twice-daily oral ruxolitinib or placebo. Approximately 25% of patients in the placebo arm crossed over to the ruxolitinib arm as a result of disease progression.

After a median follow-up of 32 weeks, significantly more patients in the ruxolitinib arm attained the primary end point of ≥35% reduction in spleen volume after 24 weeks of therapy (41.9% vs 0.7% with placebo). More ruxolitinib recipients had a ≥50% reduction in symptom burden (including abdominal discomfort, pain under the left ribs, early satiety, night sweats, bone or muscle pain, and inactivity) than placebo recipients.

Ruxolitinib was generally well tolerated. As in COMFORT II, the 2 grade 3/4 adverse events that occurred more often with ruxolitinib than with placebo were thrombocytopenia (12.9% vs 1.3%, respectively) and anemia (45.2% vs 19.2%); both were manageable with dose adjustments.

Only 1 patient in each arm discontinued treatment because of toxicity. ■

New Standard of Care for Childhood Neuroblastoma

A

new regimen of oral busulfan (Myleran) and melphalan (Alkeran) extended event-free survival over a regimen of carboplatin (Paraplatin), etoposide (Eposin), and melphalan (CEM) in a phase 3 clinical trial of patients with high-risk pediatric neuroblastoma.

The trial was terminated early once the superiority of the busulfanmelphalan myeloablative regimen became evident, said lead investigator Ruth Ladenstein, MD, Associate Professor of Pediatrics, University of Vienna, and St Anna Children’s Cancer Research Institute, Vienna.

The standard practice should now be the busulfan-melphalan combination for children with high-risk disease in whom the long-term survival rate was <40% before this regimen.

“The study’s results are important for patients with this extremely difficult-to-treat disease,” said Dr Ladenstein. “These results...mean that we could potentially improve overall prognosis by up to 35%. We overcome the 50% threshold in survival rates by choosing the right high-dose myeloablative regimen for these patients.”

Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of all childhood cancer deaths.

The study included 563 patients

(median age, 3 years) with stage IV, high-risk disease with distant metastases or local disease with MYCN oncogene amplification.

All patients received a rapid induction regimen. They were then randomized to busulfan and melphalan or the CEM regimen.

“We overcome the 50% threshold in survival rates by choosing the right high-dose myeloablative regimen.”

—Ruth Ladenstein, MD After a median follow-up of 3.5 years, the event-free survival rate was 49% in the busulfan-melphalan group versus 33% in the CEM group.

Randomization was stopped early at an interim analysis.

The busulfan-melphalan advantage was consistent across all disease stages and appeared to be most effective in patients with residual disease.

The 3-year overall survival was 60% with busulfan-melphalan versus 48% with CEM without immunotherapy.

The busulfan-melphalan group had a lower relapse rate and progression (47%) than the CEM group (60%). The overall toxicity profile was significantly lower with busulfan-melphalan, despite some exceptions.—WK ■

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SPECIAL ISSUE

Strategies for Optimizing Value in Cancer Care Delivery The Best of the Association for Value-Based Cancer Care Conference

September 24, 2011 JW Marriott 151 West Adams Street Chicago, Illinois

October 1, 2011 Marriott Marquis 55 Fourth Street San Francisco, California

November 19, 2011 Marriott Waterside 700 South Florida Avenue Tampa, Florida

ACCREDITATION INFORMATION Physician Accreditation

Chair

As a result of the resounding success of our First Annual Conference, we have been asked to incorporate “The Best of AVBCC” into three regional meetings. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

Science Care designates this activity for a maximum of 5.25 AMA PRA Category 1 Credit(s)™. Science Care is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity.

President, Gary Owens Associates

WHO SHOULD ATTEND

Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 5.25 contact hours.

PROGRAM OVERVIEW

All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Pharmacists • Practice Managers/ • Pharmacy Benefit Managers Administrators (PBMs)

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

Objectives •

• •

•

•

Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management Analyze trends in the delivery of care in the management of cancer patients

Registered Nurse Designation

Registered Pharmacy Designation Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 5.25 contact hours (0.525 CEUs) of continuing education credit.

The Universal Activity Number for all three regional meetings is 0468-9999-11-033-L01-P. September 24, 2011 – Chicago, IL October 1, 2011 – San Francisco, CA November 19, 2011 – Tampa, FL

COMMERCIAL SUPPORT ACKNOWLEDGEMENT There is no commercial support for this activity.

Gary Owens, MD

Invited Faculty Stephanie Akbari, MD Donald Balfour III, MD Adam Brufsky, MD, PhD, FACP Craig Deligdish, MD John Fox, MD Scott Gottlieb, MD Gary Johnson, MD, MS, MBA Ted Okon Winston Wong, PharmD

CONFERENCE REGISTRATION $125 Includes 1-year association membership

Registration Information Chicago, www.regonline.com/avbcc-chicago2011 San Francisco, www.regonline.com/avbcc-sanfran2011 Tampa, www.regonline.com/avbcc-tampa2011

PRELIMINARY AGENDA 8:00 – 9:00 am

Registration & Breakfast 9:00 – 9:15 am Welcome & Introduction 9:15 – 10:45 am The Challenges of Personalized Cancer Care 10:45 – 11:30 am Community Oncology Crisis: An Uncertain Future 11:30 – 12:15 pm Improving Patient Care Through Collaboration & Partnerships 12:15 – 1:45 pm Lunch Symposium 1:45 – 2:30 pm Regional Insurer’s Perspective on Cancer Care 2:30 – 3:15 pm The Impact of New Healthcare Legislation 3:15 – 3:30 pm Summary & Concluding Remarks

CONTACT/SUPPORT If you have any questions please contact: Association for Value-Based Cancer Care™ 241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831 Phone: 732-992-1040 association@AVBCConline.org

Payers’ Perspective

What Do Payers Want in Oncology Diagnostics? Insights from a National Survey of Top Commercial and Medicare Health Plans

By Gene Trogan, PhD Director, Commercial Strategy and Market Access, Reimbursement Intelligence (gtrogan@reimbursementintelligence.com)

P

ersonalized medicine is expected to transform healthcare. Its success depends on whether molecular diagnostic tests will allow drugs to be tailored to individuals or patient types, leading to improved drug efficacies and reduced drug side effects.

Healthcare payers stand to benefit, because personalized medicine promises to reduce healthcare costs in the long-term. However, if molecular diagnostic tests face overwhelming barriers or an unclear path in securing coverage from healthcare payers, then companies will be less likely to develop them.

Reimbursement Intelligence, a market access consulting firm, conducted research with 50 of the top-ranked managed care health plans to better understand the current and future dynamics of the management and reimbursement of oncology diagnostics. This article reviews some of the key insights from the survey and suggests ways that diagnostic companies can better navigate the complex reimbursement landscape to maximize the clinical utility of the diagnostic tests.

Reimbursement Challenges for Oncology Diagnostics Molecular diagnostic test developers face 2 critical healthcare payer challenges: (1) obtaining coverage and (2) securing appropriate reim-

bursement for new tests. Many factors influence payers’ coverage and reimbursement of diagnostic tests (Figure 1).

In addition, diagnostic developers do not have a clear set of expectations for the level of evidence that is necessary for reimbursement (eg, specific clinical trial requirements, optimal outcome measures).

The robustness of clinical data available for biomarker tests is the strongest predictor of gaining coverage. Results from our Oncology Reimbursement: 2011-2012 Report, which surveyed commercial and government managed care health plans covering >150 million lives, showed that diagnostics in breast cancer receives coverage by 83% of the payers surveyed (Figure 2).1 This is likely because the utility of diagnostic tests, such as testing for the epidermal growth factor receptor (EGFR) or HER2 overexpression, are directly tied to clinical utility.

As a result, the American Society of Clinical Oncology (ASCO)2 and the National Comprehensive Cancer Network (NCCN),3 the 2 leading oncology organizations, recently recommended HER2 mutation testing for patients with invasive breast cancer.

Indeed, based on our survey, 90% of the payers indicated that clinical guidelines influence their decision to

Figure 1 Factors Impacting Payer Reimbursement of Oncologic Diagnostics

cover an oncology diagnostic test, with ASCO and NCCN guidelines given equal preference.

Clinical utility studies for molecular diagnostics are often not carried out, because they are complicated, expensive, and time-consuming to run, and moreover, they are not directly required by the US Food and Drug Administration (FDA) for the approval of tests. In some instances, however, it may be possible to use surrogate end points (eg, progressionfree survival [PFS] or time to progression) to shorten the cost and duration of such studies.

Nevertheless, payers in our survey indicated that diagnostic tests must demonstrate a higher degree of sensitivity and specificity for them to have greater relevance and wider adoption (Figure 3, right graph, page 35). At the extreme, many of the esoteric diagnostic tests are marketed without FDA review as “home brew” tests under the regulatory oversight of the Clinical Laboratory Improvement Act (CLIA). Therefore, the coverage determination for this category of tests may not even have the benefit of FDA review to determine their safety and efficacy. CLIA standards do not require evidence that diagnostic tests are clinically useful, only that the tests can be performed consistently and accurately.

Health plans are reluctant to reimburse biomarker tests without evidence of clinical utility, because these

may prove ineffective in improving patient outcomes, and therefore, are financially wasteful at a time when it has become critical to control increasing healthcare costs. Indeed, 62% of payers in our survey indicated that, for oncology diagnostic tests to gain wider acceptance, the tests must be accompanied by a demonstration of cost-effectiveness (Figure 3).1 Early in Genomic Health’s development of the Oncotype DX breast cancer assay, the company studied the potential cost-savings of its test on the healthcare system and found that even with pricing the test at roughly $3500, the resulting average cost-savings to the system was approximately $2000 per patient. The savings are derived from the test’s ability to help steer patients with a high recurrence score to chemotherapy and those with a low recurrence score, who are less likely to benefit, away from chemotherapy.

To raise the credibility and visibility of its analyses, the company published its study in May 2005,4 just over 1 year after the launch. Similarly, Expression Diagnostics (XDx) published a health economics study for AlloMap that projected a savings of about $6500 per patient in 5-year monitoring costs, which more than justified the $2950 price for the diagnostic.5 Companion Diagnostics: How Will They Be Reimbursed?

A seemingly easier path to reim-

Figure 2 Breast Cancer Receives Highest Reimbursement for Genetic Tests 100 83%

Advocacy/ employer groups

Clinical guidelines

Payer influences

Clinical utility

Type of test Competitor coverage policies

Technical assessments Test complexity

Respondents, %

80

60 52% 41%

40

31% 20

17%

Claim coding FDA approval

0 Breast cancer

FDA indicates US Food and Drug Administration.

Source: Reimbursement Intelligence, 2011.

34

41%

AMERICAN HEALTH & DRUG BENEFITS

August 2011

Non–small-cell lung cancer

Multiple myeloma

Non-Hodgkin lymphoma

Metastatic melanoma

Prostate cancer

Q: For which tumor types, if any, do you currently reimburse for genetic/molecular testing? Please select all that apply.

Source: Reimbursement Intelligence, 2011.

VOL. 4

NO. 4

SPECIAL ISSUE

Payers’ Perspective Figure 3 Predicting Efficacy and Selecting Appropriate Treatment Are Primary Benefits of Genetic Testing

Figure 4 Majority of Plans Reimburse Diagnostic Testing Separately from Therapeutic EGFR testing & erlotinib

Desirable data for broader diagnostic test acceptance and utilization

Payer rankings of primary utility of genetic testing Item Predict efficacy of therapy

Overall rank

Responders, % 0

1

Select appropriate treatment

1

Predict tolerance to treatment

2

Molecular profiling for prognosis

3

Vaccine therapy specific to patient

4

Other,a 3%

20

40

60

80

Proof of greater specificity/sensitivity Cost-effectiveness data More clinically meaningful targets

Reimburse for the diagnostic test and the therapy together, 14%

BRAF testing & cetuximab/panitumumab Other,a 3%

Do not reimburse for the diagnostic test, 17%

100

Do not reimburse for the diagnostic test, 17%

79% 62%

Do not reimburse for the diagnostic test, 21%

48%

Q: Please rank the choices based on Clinical trials with a 35% larger sample size your perception of the primary benefit of using genetic testing in oncology from highest benefit to Q: In order for genetic testing to gain wider lowest benefit.

(Score is a weighted calculation. Items acceptance, what type of data will be required ranked first are valued higher than the from the tests? Please select all that apply. following ranks. The score is the sum of all weighted rank counts.)

Source: Reimbursement Intelligence. 2011.

Reimburse for the diagnostic test and the therapy separately, 66%

Reimburse for the diagnostic test and the therapy separately, 69%

Q: How does your plan currently reimburse for EGFR mutation test for lung cancer patients who may be candidates for erlotinib (Tarceva) therapy?

Q: How does your plan reimburse for BRAF mutation analysis to predict nonresponse to cetuximab (Erbitux) and panitumumab (Vectibix) in the treatment of metastatic colorectal cancer and small bowel adenocarcinoma?

a

bursement is when the diagnostic is tied to the use of a drug (ie, companion diagnostic) to identify patients who are the best candidates for a particular targeted therapy. For example, in the Iressa Pan-Asia Study (IPASS), after gefitinib (Iressa), an EGFR inhibitor, failed to provide a significant overall survival benefit in a broad population of patients with non–small-cell lung cancer, it was investigated in selected patients with lung cancer (Asian nonsmokers or light smokers with EGFRpositive mutation), and showed a significant benefit in PFS versus chemotherapy. In contrast, in EGFRnegative patients, gefitinib worsened outcomes compared with chemotherapy alone (1.5 months vs 5.5 months PFS).6 The FDA announced in late July the publication of a much-anticipated draft guidance on in vitro companion diagnostic devices, indicating that, with a few exceptions, the agency will require approval or clearance of the diagnostic at the same time it approves the therapeutic.7 However, the reimbursement for companion diagnostics is much less clear-cut. In our survey, 44% of payers indicated that they will cover companion diagnostic testing differently from their current approach to standalone diagnostics. Many respondents indicated that the companion diagnostic tests may be coupled with therapy as part of prior authorization (PA) and/or will require PA to determine if a patient is a candidate.

KRAS mutation analysis is indicated

VOL. 4

NO. 4

SPECIAL ISSUE

for patients with colorectal cancer initiating EGFR inhibitor therapy. Payers describe KRAS testing’s path to reimbursement as relatively eventless because of its inclusion in the FDA label for drugs such as panitumumab (Vectibix) and cetuximab (Erbitux).

Payers in our survey indicated that diagnostic tests must demonstrate a higher degree of sensitivity and specificity for them to have greater relevance and wider adoption.

This is supported by the results from our payer survey, in which a majority of payers indicated that they currently reimburse EGFR (for lung cancer) and BRAF testing (for colorectal cancer) for identifying patients appropriate for erlotinib (Tarceva) and panitumumab/cetuximab therapies, respectively (Figure 4).

In addition, 66% and 69% of payers indicated that they currently reimburse the respective diagnostic tests separately from the therapeutic, with only 14% and 7% bundling the EGFR and BRAF test together with the therapy (Figure 4).

Securing Reimbursement Rates that Tie In with Value of the Diagnostic By and large, genetic testing has yet

Unsure.

Source: Reimbursement Intelligence. 2011.

to be specifically recognized in the reimbursement system. Because of a lack of codes tied to testing for different genes or mutations, laboratories often must build insurance claims using a strategy called code “stacking,” employing a series of codes for methodology-based steps that add up to a molecular test. However, at least for Oncotype DX, stacking existing codes based on laboratory analyses would have yielded significantly lower reimbursement, roughly one sixth of the $3500 list price.8 Although miscellaneous codes represent attractive options for developers, they are often red flags for payers, especially when the associated price is high. Furthermore, miscellaneous codes are not trackable, therefore payers cannot ascertain the volume of use without taking additional steps. These limitations in the current coding system make it difficult for payers to receive value-based reimbursement.

Specific reimbursement codes have been developed for the first time for >100 genetic tests. During a recent session held at the Centers for Medicare & Medicaid Services, the agency discussed 101 new genetic analyte codes proposed by the American Medical Association and whether they should ultimately be included in the clinical laboratory fee schedule or in the physician fee schedule. However, no

final decisions were made, and they will not be adopted by Medicare until at least 2013.9 ■ References 1. Reimbursement Intelligence. www.reimbursement intelligence.com/2011_asco_special_ report/. Accessed August 1, 2011.

2. Wolff AC, Hammond ME, Schwartz JN, et al.

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118-145.

3. Carlson RW, Moench SJ, Hammond ME, et al.

HER2 testing in breast cancer: NCCN Task Force report and recommendations. J Natl Compr Canc Netw. 2006;4(suppl 3):S1-S22.

4. Hornberger J, Cosler LE, Lyman GH. Economic analysis of targeting chemotherapy using a 21-gene RT-PCR assay in lymph-node-negative, estrogenreceptor-positive, early-stage breast cancer. Am J Manag Care. 2005;11:313-324. Erratum in Am J Manag Care. 2005;11:476.

5. Evans RW, Williams GE, Baron HM, et al. The economic implications of noninvasive molecular testing for cardiac allograft rejection. Am J Transplant. 2005;5:1553-1558.

6. Fukuoka M, Wu YL, Thongprasert S, et al.

Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced nonsmall-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29:2866-2874.

7. US Food and Drug Administration. Draft guidance for industry and Food and Drug Administration staff. In vitro companion diagnostic devices. July 14, 2011. www.fda.gov/downloads/ MedicalDevices/ DeviceRegulationandGuidance/GuidanceDocuments /UCM262327.pdf. Accessed August 4, 2011.

8. Pothier K, Gustavsen G. How to earn the economic payback diagnostics companies deserve. In Vivo. 2009:70-75.

9. G2 Intelligence. CMS delays pricing new molecular pathology codes—questions remain for local contractors. 2011. www.g2intelligence.com/ezine/article/ ART847115?channel=20110722_G2INSIDER. Accessed August 1, 2011.

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