july 2011, vol2, no 4

AVBCC First StakeholderIntegration ConferenceCancer care in 2011—the perfect stormBy Burt Zweigenhaft, BS, and Gary M. Owens, MD, CochairsMr Zweigenhaft is President and Chief Executive Officer, OncoMed, and Dr Owens is President, Gary Owens Associates

Payer Trends in Oncology:Challenges and Solutions Reducing care variability will enhance value By Wayne Kuznar

©2011 Engage Healthcare Communications, LLC

In 2011 we find our-selves in the midstof a “perfect storm”

as it relates to cancercare in the UnitedStates. More peopleare being diagnosedwith cancer, more pa -tients are living longerwith cancer, and thecost of caring for canceris rising dramatically.

The Perfect Storm

Rising cancer cases. According tothe American Cancer Society, in 2010>1.5 million new cases of cancer(excluding carcinoma in situ and basal-cell skin cancers) and nearly 570,000deaths occurred from cancer.1 Cancer isresponsible for 1 in 4 deaths in theUnited States and is the leading causeof death for individuals age <85 years. The sheer number of cancer cases in

the United States represents the firstarm of the perfect storm.

Rising cancer costs. Advances inour understanding of the molecularand genetic mechanisms of tumorgrowth are expanding the treatmenthorizons, but these ad vances come at arising cost, and this cost represents thesecond arm of the perfect storm. In aJune 2011 article published in the NewYork Times, the author notes that the costof treating metastatic castration-resistant prostate cancer has increased

www.ValueBasedCancerCare.com

Philadelphia, PA—The “one-size-fits-all” approach to current benefitdesigns does not recognize that healthservices have different levels of value;such an approach, therefore, lacksincentives for patients to adhere todiagnostic tests and treatments withproven effectiveness that may help tocontain costs to various healthcarestakeholders.

This was themessage deliveredby A. Mark Fendrick, MD, Professor,Department of Internal Medicine,Department of Health Managementand Policy, and Founder and Co-Director, University of MichiganCenter for Value-Based InsuranceDesign, Ann Arbor.

Philadelphia, PA—As the cost of cancercare continues to rise, payers are strug-gling with solutions to curtail the costtrend while maintaining value. Thiswas the topic of the preconference ses-sion, which opened the 2-day FirstAnnual Con ference of the Associationfor Value-Based Cancer Care on March29, 2011.The cost of cancer care is on every-

one’s front burner, said moderatorBurt Zweigenhaft, BS, President andChief Executive Officer at OncoMed,

Great Neck, NY. “We’ve seen the aver-age cost per cancer patient go from$53,000 [in 2005] to $115,000 [in2010],” he said. “That’s unsustainable.That’s why it’s on everyone’s radar.”

Employers Looking for Value

Employers are increasingly askingabout the value received for theirmoney spent on cancer care, said MonaChitre, PharmD, CGP, Director ofClinical Services, Strategy and Policy,

Continued on page 8

Continued on page 7

Continued on page 5

JULY 2011 VOL 2 NO 4

Value-Based Insurance Design in Oncology Incentivize high-value rather than low-value services to curb costs By Wayne Kuznar

From left: Maria Lopes, Scott Breidbart, Mona Chitre, Nick Calla.

INTRODUCTION

The First Annual Conference of AVBCC

On March 29-30, 2011, approximately 200 oncologists, payers,employers, managed care executives, drug manufacturers, and can-cer patient advocates gathered in Philadelphia for the First Annual

Conference of the Association for Value-Based Cancer Care (AVBCC), whichfocused on stakeholder integration toward the enhancement of patient careand care delivery. Reflecting on the conference after the meeting, Al B. Benson III, MD, said,

“This type of communication has great potential for each of these groups tounderstand where each component is coming from and understand eachother’s issues.” This issue of VBCC is dedicated to coverage of the conference, providing

summaries of all the major presentations and interviews, highlighting theyearning for a strong spirit of cooperation exhibited by the various stake-holders involved in cancer care. Plan to attend future meetings. The “best of” this meeting will be coming

to your area soon. See page 55 for more details.

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 5:51 PM

h


THE FIGHT IS CHANGING.It’s more personal than ever. Now, genetic biomarker tests may help deliver the right cancer treatment to the right patient.

Bio-specific medicine is changing the way we treat cancer. In many instances, doctors can now test a tumor’s distinct profile with the goal of providing more targeted, more effective treatments with fewer side effects.

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

CRI00102/280033-01 ©2011 P�zer Inc. All rights reserved.


4 I VALUE-BASED CANCER CARE I July 2011 VOL. 2 I NO. 4

IN THIS ISSUE

PublisherNicholas [email protected]

Associate PublisherMaurice [email protected]

Editorial DirectorDalia [email protected]

Associate EditorsBrett [email protected] [email protected]

Director, Client ServicesCristopher [email protected]

Senior Production ManagerRobyn Jacobs

Quality Control Director Barbara Marino

Business ManagerBlanche Marchitto

Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

BPA Worldwide membership applied for August 2010.

Contact Information:For subscription information please contact: [email protected]: 732-992-1538 Fax: 732-992-1881

Permission requests to reprint all or part of any articlepublished in this magazine should be addressed to [email protected]

Address all editorial queries to: [email protected]: 732-992-1889 Fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 7 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2011 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark ofEngage Health care Communi cations, LLC. No partof this publication may be reproduced or transmittedin any form or by any means now or hereafter known,electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publish-er. Printed in the United States of America.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.

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

VBCC Editorial BoardAl B. Benson III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie ComprehensiveCancer Center of NorthwesternUniversity Chicago, ILImmediate Past President, ACCCPast Chair, NCCN Board of Directors

Scott Breidbart, MDChief Medical OfficerEmpire BlueCross BlueShield, NY

Bruce A. Cutter, MD, MMMCutter HealthCare ConsultingSpokane, WA

Craig Deligdish, MDFlorida Comprehensive CancerNetwork, Melbourne, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDITA PartnersPhiladelphia, PA

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

Section EditorDawn Holcombe, FACMPE, MBA,ACHEPresident, DGH ConsultingSouth Windsor, CT

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

Ira Klein, MD, MBAAetnaHartford, CT

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhRegence BlueCross BlueShield of OregonPortland, OR

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology Alliance

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Ed Pezalla, MD, MPHAetna Pharmacy ManagementHartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM. D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHPartnerHealth Policy Strategies, LLCWashington, DC

Brian K. Solow, MD, FAAFPPrescription SolutionsIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSBioPharma Partners, LLCNew York, NY

DIAGNOSTICSRole of Molecular Diagnostics in Cancer Care

ONCOLOGY BENEFIT DESIGNBenefit Design Trends in OncologyMore….

NCCN GUIDELINES NCCN Guidelines Inform Decisions Across the Care Continuum

More….

PERSONALIZED MEDICINEPersonalized Oncology Medicine: ValueImplications

COMMUNITY ONCOLOGY Oncology Clinics under Increasing FinancialPressure

Oncologists Face Economic Challenges More….

PATIENT NAVIGATIONPatient Assistance Programs

REIMBURSEMENT IN ONCOLOGYDrug Reimbursement and AdministrationBenchmarks

More….

HEALTH POLICYGlobal Fees, ACOs, and Medicare TrendsMore….

CARE MANAGEMENT MODELSMedical and Pharmacy Directors’ Strategies

SPECIALTY PHARMACYClinical FragmentationMore….

CONTINUING EDUCATIONEvolving Role of Outcomes and End Points in Evaluating Therapy for HematologicMalignancies

VBCC_July_11_1_Follow ASCO Tabloid 7/14/11 11:52 AM

dramatically in the past year. In the past15 months, 3 new drugs that extendedthe lives of patients with prostatecancer in clinical trials have beenapproved by the US Food and DrugAdministration, and several otherpromising medicines are in clinicaltrials. However, “the price of thesedrugs has already stirred concernsabout the costs of care among patients,pro vid ers, and insurers.”2

With many pricey drugs in thepipeline, said Joel Sendek, an analystat Lazard, “We could be talking easily$500,000 per patient or more over thecourse of therapy, which I don’t thinkthe system can afford, especially since80% of the patients are on Medicare.”2

This concern is not unique to thisauthor. In a 2009 article, Peter Bachnoted that in 1994, only 1 cancer drug—paclitaxel—cost >$2500 per month.3 Asin the case of prostate cancer, new can-cer drugs now routinely cost manytimes more. Mr Bach further notes thatpolicymakers at the Centers forMedicare & Medicaid Services must beconcerned about how to pay for thesenew and expensive treatments withoutbankrupting the system.3

Aging population. In a January 2011article published in the Journal of theNational Cancer Institute, the authorsestimated that the total cost of cancercare in the United States would be $158billion by 2020, assuming that the mostrecent trends of incidence, survival,and cost remain the same.4 Thisestimate represents a 27% increase from2010, reflecting only the projected agingand growth of the US population. Thisdemographic change is yet the thirdaspect of cancer’s perfect storm.4

AVBCC Conference

Accomplishments

These statistics highlight only a fewof the issues that provided the back-drop for the First Conference of theAssociation for Value-Based CancerCare, which convened on March 29-30,2011, in Philadelphia. The meeting wasamong the first of its kind to provide aforum for the multiple stakeholdersinvolved in all aspects of cancer care. The goal was to foster an open dia-

logue between providers, payers,patients, and other members of theoncology team to gain a better under-standing of the issues regarding cost,quality, and access in cancer care. Theparticipants had the opportu nity to:• Identify challenges and potentialsolutions regarding access to afford-able oncology therapies

• Determine the value proposition ofcost, quality, and access whenevaluating the over all management

of patients with cancer• Define appropriate clinical path waysto be used as tools to evaluate thecur rent recommendations for pa -tient management

INTRODUCTION

5VOL. 2 NO. 4 www.ValueBasedCancerCare.com I

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

Act before febrile neutropenia strikesPotential consequences of febrile neutropenia may be serious and can impact patient care

First- and every-cycle Neulasta® achieved:

94% reduction in febrile neutropenia

(17% placebo vs 1% Neulasta®; P < 0.001).1,2

93% reduction in febrile neutropenia–

related hospitalization (14% placebo

vs 1% Neulasta®; P < 0.001).1,2

80% reduction in febrile neutropenia–

related IV anti-infective use (10% placebo

vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety InformationDo not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS.

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebo- treated patients.

Please see brief summary of Neulasta® Prescribing Information on the adjacent page.

* Regimens associated with ≥ 17% risk of febrile neutropenia.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen.

© 2010 Amgen. All rights reserved. MC49047-A-1 04-10 www.neulasta.com

AVBCC First Conference... Continued from cover

Continued on page 6

The meeting was amongthe first of its kind toprovide a forum for themultiple stakeholdersinvolved in all aspects of cancer care.


• Analyze trends in the delivery ofcare for patients with cancer.Some of the many timely topics pre-

sented in this issue are:• Community Oncology Clinics underIncreasing Financial Pressure

• Payer Trends in Oncology: Chal -lenges and Solutions

• Value-Based Insurance Design inOncology

• The Role of Molecular Diagnosticsin Cancer Treatment.

These proceedings represent a first-in-class effort to open the lines of com-munication among all stakeholders incancer care. This meeting was unique inbringing together different viewpointsfrom many oncology stakeholders,

such as health plans, pharmacy benefitmanagers, providers, patients, govern-ment, manufacturers, and caregivers.Ultimately, the conference enabledstakeholders to share their own viewsof the world of oncology care and gainan understanding of the views of otherstakeholders who also have a part incancer care. Opening the lines of communication

among stakeholders with differingviewpoints in oncology was a majoraccomplishment of the conference.This allowed for sharing of issues thatare critical to facilitating the best carepossible for patients with cancer.Ultimately, all stakeholders shared thecommon goal of finding solutions tothe growing concerns in cancer care,while understanding the need to opti-mize the clinical and economic valueof the resources expended. �

References1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin. 2010;60:277-300.2. Pollack A. New drugs fight prostate cancer, but athigh cost. New York Times. June 28, 2011. www.nytimes.com/2011/06/28/health/28prostate.html?_r=2&hp.Accessed June 28, 2011. 3. Bach PB. Limitations on Medicare’s ability to con-trol rising spending on cancer drugs. N Engl J Med.2009;360:626-633.4. Mariotto AB, Yabroff KR, Shao Y, et al. Projections ofthe cost of cancer care in the United States: 2010-2020.J Natl Cancer Inst. 2011;103:117-128.

INTRODUCTION


BRIEF SUMMARY OF PRESCRIBING INFORMATIONNeulasta® (pegfi lgrastim) injection, for subcutaneous use

INDICATIONS AND USAGENeulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically signifi cant incidence of febrile neutropenia.Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfi lgrastim or fi lgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress SyndromeAcute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infi ltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.

Serious Allergic ReactionsSerious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfi lgrastim or fi lgrastim.

Use in Patients With Sickle Cell DisordersSevere sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving fi lgrastim, the parent compound of pegfi lgrastim.

Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte-colony stimulating factor (G-CSF) receptor through which pegfi lgrastim and fi lgrastim act has been found on tumor cell lines. The possibility that pegfi lgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfi lgrastim is not approved, cannot be excluded.

ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:• Splenic Rupture [See Warnings and Precautions]• Acute Respiratory Distress Syndrome [See Warnings

and Precautions]• Serious Allergic Reactions [See Warnings and Precautions]• Use in Patients with Sickle Cell Disorders [See Warnings

and Precautions]• Potential for Tumor Growth Stimulatory Effects on Malignant

Cells [See Warnings and Precautions]The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfi lgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not refl ect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.The following adverse reaction data in Table 1 are from a

randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2

(N = 467)

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

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfi lgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfi lgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfi lgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.The detection of antibody formation is highly dependent on the sensitivity and specifi city of the assay, and the observed incidence of antibody positivity in an assay may be infl uenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reactions have been identifi ed during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta.Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions]Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions]Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, Sweet’s syndrome, generalized erythema and fl ushing [see Warnings and Precautions]Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Cutaneous vasculitis

DRUG INTERACTIONSNo formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these fi ndings when interpreting bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Pegfi lgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on

body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefi t to the mother justifi es the potential risk to the fetus.In animal reproduction studies, when pregnant rabbits received pegfi lgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfi lgrastim approximately 10 times the recommended human dose (based on body surface area).Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing MothersIt is not known whether pegfi lgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric UseSafety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profi le and pharmacokinetics of pegfi lgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfi lgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric UseOf the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal ImpairmentIn a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfi lgrastim.Therefore, pegfi lgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATIONThe recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.NOTE: The needle cover on the single-use prefi lled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfi lgrastim)

Manufactured by:Amgen Inc.One Amgen Center Drive Thousand Oaks, California 91320-1799

© 2011 Amgen Inc. All rights reserved.www.neulasta.com 1-800-77-AMGEN (1-800-772-6436)

v 12.0 MC45288-B

These proceedingsrepresent a first-in-classeffort to open the lines of communication amongall stakeholders in cancercare. This meeting wasunique in bringingtogether differentviewpoints from manyoncology stakeholders.

AVBCC First Conference... Continued from page 5


With current benefit designs, arguedDr Fendrick, co payments, premiums,and de ductibles are similar no matterthe value of the service rendered. Thismisalignment of incentives fails toencourage utilization of high-valuetreatments and discourage utilizationof low-value treatments. By properly aligning incentives,

patient outcomes can be improved atany level of healthcare expenditure, DrFendrick says. “If you move from cur-rent benefit design systems to one thatis value-based, I could give you firstclass for the price of coach.” With cost remaining the principal

focus of healthcare deliberations, the“health” portion of the healthcare costdebate seems to have been forgotten,he says. “Too many are trying to drivedown cost, without any considerationof the product—the health of ourpatients, clients, and family mem-bers,” Dr Fendrick emphasizes.When oncologists or physician

extenders are asked which health serv-ices are underutilized, they mentionhigh-value screenings, diagnostictests, therapies, and monitoring/fol-low-up tests. The probability of receiv-ing such high-value services is no bet-ter than a coin flip for most Americans,says Dr Fendrick.These quality gaps are costing pay-

ers: an extra $500 million is spent onhealthcare because evidence-basedpractices are not followed. He im -plores all stakeholders to encouragewidespread implementation of evi-dence-based clinical practices and tolook beyond the initial cost of imple-menting such services.A redistribution of $2.5 trillion spent

annually on healthcare in this countrycould catapult the United States tonumber one in healthcare metricsamong industrialized countries, heargues, as opposed to last—the posi-tion it now occupies.

The Rationale for VBID

“There are meaningful ways toredistribute money we have in thesystem to bring about more health atthe price we are paying now—themotivation behind value-based healthinsurance design [VBID],” says DrFendrick.Many previous strategies to lower

costs have not lived up to their hype,he insists. Managed care and informa-tion technology have not produced thecost-savings promised, and althoughpatient-centered medical homes arelikely to improve quality of care andvalue, they are not likely to lower costs.Cost-sharing—how much patients

pay at the point of service for various

interventions—in most health plans,public and private, has been imple-mented in a one-size-fits-all way,meaning that every physician visitcosts the same. “Whether you see thetop oncologist for a treatable cancercosts the same as seeing a dermatolo-gist for mild acne that I could barelysee,” he says. “Every diagnostic testcosts the same, whether it is a USPreventive Services Task Force GradeA recommended service or ‘D,’ as indangerous.”

The same is true for drug tiers;patients pay the same out-of-pocket(OOP) amount for drugs in the sametier, regardless of their value. In someplans, all generic drugs may cost aslittle as $4. “There are some genericdrugs I would pay my patients totake,” given the extraordinary benefitthey provide, notes Dr Fendrick,whereas others in the same generic tiermay have little value.One problem with this practice is

that most patients have no way to dis-tinguish a drug that is potentially life-saving from one that has no benefit or,in some rare circumstances, may actu-ally be harmful.Oncologists cite similar coinsurance

for drugs of different value as a majorinefficiency. For example, the coinsur-ance for a drug that can cure a canceris the same as for one used in a late

round of chemotherapy with practicallyno chance for a cure.

Removing Barriers to

High-Value Services

Financial hurdles to proven cancer-screening tests also create disincen-tives for patients. One example is thewoman with multiple family memberswith breast cancer having to pay ahigh cost for a mammogram. Anotheris the patient with familial polyposisbeing asked to pay 20% of the cost of acolonoscopy. In both instances, thecopayment discourages use of thescreening test in populations that pay-ers want to screen.Consumer-directed high-deductible

health plans were considered to be theanswer to cost-sharing, but askingconsumers to make wise choices withtheir healthcare options is unrealistic.“Colleagues who are physicians maketerrible choices with their moneyregarding healthcare,” he says. Ascost-sharing goes up, “people stopbuying the things you don’t wantthem to buy, which is exactly why youshould cost-share, but people also stopbuying the things I beg them to do:immunizations, screening, prescrip-tion drugs, specialist visits, and neces-sary treatments.”In some cases, patients are asked to

share in the cost of procedures forwhich doctors receive bonuses, result-ing in a misalignment of incentives inthe system.Charging copayments for ambulato-

ry doctor visits had the intended effectof limiting visits, along with the unin-tended consequence of increasing thenumber of hospitalizations, therebyeating up any savings generated fromfewer visits.“Consumers are not the appropriate

decision maker, particularly in a clini-cal area as stressful as cancer,” advisesDr Fendrick.Where the evidence is hard and

equivocal, barriers to services (throughlower costs to patients) should beremoved, and physicians and otherproviders should be awarded for theincreased uptake of those services.

VBID: Incentives for Evidence-

Based Services

The VBID concept is one in whichvalue trumps cost alone. The challengewith the approach is in determiningwhich patients derive high value froma particular intervention and which donot. “We can use VBID across thewhole continuum of oncology care,”Dr Fendrick said.“If you’re a first-degree relative of a

colon cancer sufferer, you should be

paid to get colon cancer screening.That’s because the evidence is strongthat screening first-degree relatives notonly improves health enormously, itactually lowers medical spending,” hesaid. “I have argued that people at age50 should get colonoscopy for free,”because of the substantial underuti-lization of this test in this population.High-cost chemotherapy is another

treatment for which incentives for useare misaligned. Most health plansrequire the same OOP expenditure fora chemotherapy agent with multipleindications, even though its use for oneof the indications can cure cancer 50%of the time, whereas its use in anotherindication is dubious on outcomes. Some health plans are now recog-

nizing the value of positive incentivesand pay their doctors to perform evi-dence-based screening and may evenpay their patients in the form of cashor lower premiums to obtain these evi-dence-based services.In diagnostic testing, the use of

genetic markers in some instancescan lead to better targeting of thera-pies, while lessening the risk forpotential harm by avoiding the use ofan agent in patients not likely to ben-efit. “Why not set the patient’s copayon the likelihood of significant bene-fit?” he asks.

The VBID concept was included inthe Patient Protection and AffordableCare Act. In December 2010, theDepartments of Labor, Health, andHuman Services and the Treasuryissued a Request for Information onVBID and preventive care. Thisrequest sought detailed informationon VBID programs in relation to thecurrent health reform legislation toaddress VBID and preventive care.“We hope to see this beyond preven-

tive services into cancer care,” DrFendrick concluded. �

Value-Based Insurance Design... Continued from cover


VALUE-BASED INSURANCE

“If you move from currentbenefit design systems toone that is value-based, Icould give you first class for the price of coach….Toomany are trying to drivedown cost, without any consideration of theproduct—the health of our patients.”

—A. Mark Fendrick, MD

“This misalignment ofincentives fails to encourage utilization of high-valuetreatments and discourageutilization of low-valuetreatments.”

—A. Mark Fendrick, MD


PAYER PANEL DISCUSSION


Excellus Health Plan, FLRx PharmacyManagement, Rochester, NY.“They are asking, ‘Are my patients

living longer, am I reducing medicalcosts? What am I getting for $30,000 adose?’ That’s difficult for us to articu-late,” Dr Chitre pointed out. In west-ern New York, considerable cost-shift-ing to the member is taking place, andpayers are increasingly favoringgenerics.

“The decisions that are occurringwith small, medium, and large em -ploy ers are impactful to our patientpopulation because of cost and ourinability to articulate value,” she said.

Oncology Coverage Decisions

Actuarial predictions have longbeen the basis for adjusting premiums,said Scott Breidbart, MD, ChiefMedical Officer at Empire BlueCrossBlueShield, NY, but limits to premiumincreases are directed by governmentregulations. “So we’re not in a positionwhere we can match our prediction.We know this is our only shot, becausewe’re all worried about what’s goingto happen if we can’t keep costs downand how much government interven-tion there will be.”Everyone is feeling the pressure to

control costs, including employers,patients, providers, and the healthplans. “The bottom line is that evenmembers are concerned about thecost,” noted Maria Lopes, MD, ChiefMedical Officer at AMC Health,Cresskill, NJ. “A great example that aprovider shared with me recently isProvenge [sipuleucel-T vaccine forthe treatment of advanced hormonetherapy–resistant prostate cancer].Mem bers are actually concerned aboutthe cost, outcome, and value. We’re ina world where overall survival andtreatment options are at the forefront.”A major dilemma for payers is that

cancer therapy cost remains at theirrisk. Cancer therapy risk or control is

100% covered under medical orMedicare Part B benefits. Chemo ther -apy drugs remain in the medical cov-erage based on coverage rules if a drugis “incident to physician visit/serviceunder Medicare Part B or in a commer-cial payer world under medical benefitdesigns,” said Mr Zweigenhaft.“Increasingly, all of the control and

spending for cancer is on the medicalside,” he said. “Does anyone havegood data? When it’s in the medicalside, it’s buried under J codes and non-descriptive codes. How do you man-age something as a payer when youdon’t have good data?”“Even when we have the data, we

don’t have staging data that’s so criti-cal from an actuary perspective,”responded Dr Lopes. “For new drugs,we have trained people who look atJ codes. From 5 years ago to today,we’ve made tremendous progress.Our oncologists are on board, and it’sactually become a very collaborativeenvironment in that they want to makesure that they get paid and they followthe rules of the health plan.”

Coverage: Cost versus Evidence

One criticism of coverage decisionsregarding cancer care is that such deci-sions do not seem to adhere to the evi-dence base. In some cases, it becomesfutility care.“From the pharmacy perspective,

we’re seeing payers pay more atten-tion to cancer care and what productsare being used,” said Nick Calla, RPh,Vice President, Trade Relations,Specialty Pharmacy at Walgreens,Carnegie, PA. “We’re starting to see a trend toward

more visibility and more managementin this space.” Mr Calla noted that,“The use of clinical pathways in oncol-ogy is increasing. With that said, can-cer does receive special treatment tosome degree, but we’re trending awayfrom it.”The challenge to payers is that

“we’re seen as all about saving money.

It’s not about evidence,” said DrLopes. “I think we often do sell hopeand not science. A great example isresource utilization in the last 30 daysof life, and how much cancer care weprovide in the last 10 days of life.Maybe we should think about pallia-tive care, which some evidence sug-gests may have additional benefit interms of survival.”More successful partnerships with

physicians, who are in a position tohave critical discussions around “endof life” with the patient, would help,she said. Such discussions shouldoccur much earlier in the continuum ofcare and should take the direction ofinformed consent regarding treatmentoptions and risk versus benefit to allowpatients to make better decisions.

Cancer Drugs Price Spurs Debate

The price of drugs continues to spurcost debates. In the case of metastaticmelanoma, the newly approved drugipilimumab (Yervoy) costs $120,000 fora complete course of therapy, or $1 bil-lion in new costs to payers. One ran-domized clinical trial showed thatpatients treated with ipilimumab hada median of 10 months overall survivalcompared with 6.4 months overall sur-vival for those in the placebo-treatedgroup, an almost 4-month advantagewith this drug; furthermore, 20% ofthe ipilimumab-treated patients had 2years of overall survival. Unfortunately, “we don’t have a

genetic marker to predict who bene-fits,” said Dr Chitre. “From the insur-ance perspective, we can’t make ourdecisions based on value. We have tomake our decisions based on evidence.The concern becomes how we aregoing to determine our premiumsbased on drugs like that, and thepotential population, when we don’tknow staging from our own medicalclaims.” Ipilimumab will be a “buy and bill”

product for the next several years,which is managed through the medical

benefit at the doctor’s discretion, with aslow evolution toward a more tightlymanaged product, advised Mr Calla.

Is Risk Sharing a Viable Option?

In Europe, 54% of oncology drugsare under risk-based contracting, saidMr Zweigenhaft. Dr Lopes said that although such a

contract might work in a single-payersystem, it is not practical in the UnitedStates, where members move from onecarrier to another. In addition, “wedon’t always agree what constitutessuccess, much less what constitutesfailure. How are we going to alignagendas if we can’t define what out-comes look like?”“I don’t think that risk sharing will

work in the United States,” said DrBreidbart. “If we have to look at everyclaim and ask if it’s medically neces-sary, that’s where you get disagree-ment, controversy, and contention.” The amount of time, effort, and

expertise involved would make risk-sharing rebates prohibitive, and “bythe time we get the money back, if wedo, who does it go to: the patient’s cur-rent employer, the last employer?Right now, there’s a lot of pressure onpayers not to spend money on admin-istrative costs, and this would be anadministrative cost…to determine ifthe drug worked,” Dr Breidbartadded. Rebates and shared differentials

may be practical in instances of com-petition, where multiple oral optionsexist for treating a certain cancer, saidDr Chitre.

Clinical Guidelines

Mr Zweigenhaft returned to thetheme of futile care and the opportuni-ty it presents to reduce variation incare and control costs through betteradherence to clinical pathways.During salvage therapy, “we throweverything at them [the patients],” hesaid. “We seem to bombard them atthe end of life. The final dose can be 3times the cost of the first-line therapy,yet we have no outcomes.”Dr Breidbart cited evidence that

institution of hospice care prolongs life,although care may become less aggres-sive. “It does not surprise me that onecan extend life by reducing unneces-sary or unproven care,” he said. “The difficulty is that we as physi-

cians like to help our patients, and thefeeling is that what we’re doing is ben-eficial, even if there isn’t science. Weneed to come up with a system so thatoncologists are more comfortabledelivering care appropriately,” said Dr

Payer Trends in Oncology... Continued from cover

Continued on page 9

“From thepharmacyperspective,we’reseeingpayers paymoreattention

to cancer care and whatproducts are being used.”

—Nick Calla, RPh

“From theinsuranceperspective,we can’tmake ourdecisionsbased onvalue. We

have to make our decisionsbased on evidence.”

—Mona Chitre, PharmD, CGP

“We oftensell hope andnot science.A greatexample isresourceutilization

in the last 30 days of life,and how much cancer carewe provide in the last 10days of life.”

—Maria Lopes, MD


Breidbart. “We need to have difficultconversations with the patients beforethey go on first-line therapy, not afterthey fail it, so the care can continue.”Some large employers are initiating

discussions about living wills and end-of-life care with wellness programsand their members, said Dr Lopes. Sheadded that physicians’ offices or med-ical homes rarely have the infrastruc-ture in place to assist members andtheir families in this way.

Variability in Care

Pharmacy is attempting to reducevariation in care and divergence frompathways by becoming more involvedwith the management of oral oncologyproducts and moving slowly into theinfused products, Mr Calla pointedout. “We’re working with the healthplans and doctors to ensure that doc-tors are adhering to the pathway atleast initially, or if they are deviatingfrom them, [to see if] there is a docu-mented reason,” he said.Perhaps rewarding physicians for

practicing better medicine could im -prove care by reducing variation, buthow best to accomplish this goal isopen to debate. “In many instances we don’t pay

certain doctors enough to deliver thekind of care we want for our membersand our families,” Dr Breidbartacknowledged. “In addition, it is bestto pay in a way that aligns incentives.If we pay somebody for piecework,we’re going to get a whole lot ofpieces,” he said. “If we want the doctor to spend his

or her time thinking, then we shouldpay the doctor for thinking.Sometimes paying the doctor forthinking makes it look like we’re pay-ing the doctor to reduce care, so wehave to be careful about the way wepay,” observed Dr Breidbart. “In cancer care, variability is the

norm. At the heart is how we reducevariability,” Dr Chitre explained. “Howdo we stop paying for things that don’thave value, or pay for things that havevalue, like paying for preventing read-missions? We must change the land-scape as far as how we define outcomesand aligning incentives.” �

PAYER PANEL DISCUSSION


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T

Check

M

at a glance� The pressure to control cancer

costs is affecting employers,

patients, providers, and

health plans

� Oncologists must have difficult

conversations with their patients

regarding treatment options and

risks versus benefits before the

administration of first-line

therapy, not after it fails

� In cancer care, variability is

the norm; the challenge is how

to stop paying for care that has

no value and pay for care with

value, such as preventive

readmissions

“The difficulty is that we as physicians like to help our patients, and the feeling is thatwhat we’re doing is beneficial, even if there isn’t science.”

—Scott Breidbart, MD


DIAGNOSTICS


The Role of Molecular Diagnostics in Cancer TreatmentA pharmacy benefit manager’s perspectiveBy Wayne Kuznar

Philadelphia, PA—The field of oncolo-gy stands to benefit greatly frommolecular diagnostic trends, accordingto Jane F. Barlow, MD, MPH, MBA,Vice President, Clinical Innovation,Medco Health Solutions, who offereda pharmacy benefit manager’s (PBM)perspective of the role of diagnostics,including the use of companion testsin drug development. These compan-ion tests will represent another poten-tial expenditure and coverage decisionfor PBM companies.Currently, more than 800 tests are

available for tumor profiling on solidtumors, Dr Barlow said, and another100 tests are available for hematologicmalignancies. In addition, 22 inheritedcancer syndromes can now be testedfor, and an additional 10 risk profilingand cancer screening tests are available. The entire molecular diagnostics

area is boasting double-digit growth ata rate of 35% yearly (Figure 1). This is

huge compared with other types ofdiagnostics, which are experiencingsingle-digit growth. Yet about 20% ofthe molecular-based tests are believedto be inappropriate, said Dr Barlow.“With the range of oncology tests onthe market, we’re measuring clinicalutility—evidence of utility (eg, BRCAfor inherited breast cancer) versus evi-dence still being developed (eg,Oncotype DX for colon cancer),” shesays (Figure 2).

Drug Companion Tests on

the Rise

There are more drugs in develop-ment for cancer than for any other clin-ical area, according to Dr Barlow, whopoints to 900 drugs in some stage ofdevelopment, many of which are oraloncolytics. Many pharmaceutical com-panies are using diagnostics as part oftheir regimen for evaluating the drugs. In the current oncology drug pipe -

line, an estimated 12% to 50% of drugsare considered to be “personalizedmedicine.” A whopping 80% of com-panies have strategic partnershipsrelated to personalized medicine, shesaid. It is expected that by 2025, 10% to20% of all new drugs will be labeledwith a companion test, in particularcancer drugs, according to April 2010data from Kalorama Information.Dr Barlow discussed 9 pipeline

drugs that have partnerships to devel-op companion diagnostics. The USFood and Drug Administration (FDA)is helping drive the push, she said.“Last year for the first time, the FDA

didn’t approve a leukemia drug forwhich, during the clinical trials, thepharma company had not performedcompanion testing to identify thosewho would benefit from the drug.When the company brought the drugto approval, the companion test ordiagnostics hadn’t been developed forcommercial use. FDA sent it back andsaid get the testing developed so thatwhen the drug is approved it can beused in the appropriate people,” shesaid. “This is the first time that thisoccurred at FDA. It really heraldswhere we’re headed in the future withdiagnostics.”

What It Means for Health Plans

Adding value to diagnostics inoncology requires the alignment ofvarious aspects of care (Figure 3). AtMedco, there is a specialty treatmentmanagement protocol, which is softcoverage management or support.

“When we see drugs that come toplay being dispensed through Medcoor elsewhere, we have questions weask to be sure testing is being done. Wework with patients and with providersto ensure that the right person is get-ting the right drug; if testing is indicat-ed, then testing is done. We’ve mergedfrom our client population into oneumbrella focus. It’s one oncology focusso we can pull orals, injectables, every-thing together,” she said.Medco also works to facilitate dis-

cussions with providers so that pro -viders make the call regarding testing.Yet, there is inherent difficulty in man-aging these tests, whether on thehealth plan side or pharmacy side,because it’s hard to know whetherpeople have had tests.

Education’s Influence

“When we think about drivingvalue-based diagnostics in cancer care,we recognize that it’s a multifacetedprogram,” Dr Barlow said. “It’s not justabout access to testing. We do realizethere’s also a huge role for education.”She notes that in 2008, Medco, along

with the American Medical Associ ation(AMA), sent a fax survey to all AMAphysicians on pharmacogenomics andreceived about 10,000 responses. “What was surprising even to us—

98% of providers recognized that diag-nostics plays a role in choosing thedrug and dose of drug. But only 10%said that they knew enough to put it touse in practice. There’s a huge gap,”she said. “With rapid development ofnew tests, that education gap likelywill remain. There’s a role for policyand how plans think about whatthey’re going to cover and not cover.Then there’s a role for management,whether through a prior authorizationprocess or friendlier management.”Dr Barlow points to a “tremendous”

role for diagnostics in disease treat-ment, especially via the new compan-ion tests. Yet, there must be recognitionthat every new test is something addi-tional to cover. “We have to figure out if we’re going

to spend the same amount or more forthis type of testing. We have to use thatmoney wisely,” she added. �

“What was surprising even to us—98% of providers recognized that diagnosticsplays a role in choosing the drug and dose of drug. But only 10% said that they knew enough to put it to use.”

—Jane F. Barlow, MD, MPH, MBA

Figure 1 Double-Digit Growth in Molecular Diagnostics

Mol

ecul

ar d

iagn

ostic

s co

st, $

bill

ions

2008 2009 2010, estimate

Note: Inappropriate tests = 20% of total costs.Source: Washington G-2 Reports Advisory Services’ 2008 Molecular Diagnostics Survey, health plan data.

�Annu

al Growth

Rate = 35

%

Chromosome analysisBRCAOncotype DXC-kit

Stool DNA testingMammaPrint

BRCAOncoVue

Oncotype DXGenome-wide arraysWhole genome sequencing

LeukemiasInherited breast cancerBreast cancerAML and GIST

Colon cancer screeningBreast cancer

Pancreatic cancerBreast cancer risk

Colon cancerAll cancersAll cancers

AML indicates acute myelogenous leukemia; GIST, gastrointestinal stromal tumor.

Figure 2 Range of Oncology Tests on the Market

Evidence still being developed

Po

licyEducation

Acce

ss

Management

Figure 3 Driving to Value-BasedDiagnostics in Cancer Care

$3.2

$0.8

$1.1

$4.4

$1.6

$6.4

OncologyMolecular

Testing

Evidence of utility


Philadelphia, PA—Third-party oncol-ogy benefits management, tiered net-works, and accountable care organiza-tions (ACOs) are some of the trendsgaining traction in the health insur-ance industry, according to DonaldLiss, MD, Senior Medical Director,Independence Blue Cross of Phila -delphia, who described cancer carefrom a large insurer’s perspective.Health plans, viewed as moderately

simple entities, carry a 3-fold set ofresponsibilities, said Dr Liss. The firstresponsibility of a health plan is tooffer a benefits plan, typically onbehalf of a purchaser (eg, employer,governmental entity, labor union) that

will cover medically necessary, non -experimental services. The secondresponsibility is to contract with a net-work of providers, negotiating forprice, trading volume for discount,and ultimately offering availabilityof access to membership. The thirdresponsibility of health plans is toadjudicate and pay claims. “The goals are to figure out whether

someone is at high risk, and whethera benefit is useless or wasteful,” saidDr Liss, Senior Medical Director ofClinical Programs and Policy atIndependence Blue Cross.

Shifting Makeup of Benefits

In benefit design, there’s a growingtrend among payers toward shiftingthe cost burden more toward thepatient by increasing the out-of-pocketcosts, including premiums, copay-ments, deductibles, and coinsurance atpoint of sale. “These are blunt instru-ments applicable to categories of serv-ices—office visits, outpatient proce-dures, and diagnostic imaging—butthey do not distinguish value of serv-ice,” Dr Liss said.

“Those increased costs for the con-sumer clearly have the intended effectof reducing costs for the insurer, butwhether they are differentiating high-value services and low value is not soclear,” he said. Transparency is another challenge in

benefit design. It concerns issues ofwhere the service is being per-formed—“Is it part of a physician’s

office, an infusion center, or a hospitaloutpatient department?”

Trends to Watch

Among the recent trends in theindustry (Table), tiered networks,regarded as high-quality networks, aregaining a foothold among providers.As recently as 2003 or 2004, nobodycould show significant benefits of

these trends for health outcomes,according to Dr Liss, but the ability toshow significant outcomes with thesestrategies has improved. Self-injectable medications are mov-

ing away from medical benefits topharmacy and pharmacy benefitsmanagement. Of significance is the move toward

more careful review of the high cost ofcancer treatments. Health plans areincreasingly more sensitive to issuessurrounding dosage and frequency,ensuring that claims they are payingare for drugs and treatments that wereactually given.A move toward oncology benefits

management by third parties hasarrived, based on experience in diag-nostic imaging and other focused serv-ice lines, Dr Liss observes. In addition,there is an effort to collaborate withorganized oncology groups. Dr Lisspoints to a macro industry of oncologybenefit management firms that are inexistence today.The ACO is yet another noteworthy

trend to monitor, according to Dr Liss.“How ACOs organize themselves—and cancer care is a fascinating win-dow to view this—is significant,because treatment of cancer is anintense expense for a small group ofpeople,” he says. “If the population for an ACO that is

both clinically and financially account-able simply has bad luck with a coupleof people with very high-cost cancertherapy, they’re screwed. The wholeconcept of health insurance is to spreadrisk across huge populations. An ACOhas got to be big enough to balancethose risks—the law of large numbers.”Expect molecular diagnostics to

present a huge opportunity and chal-lenge in managing the expense oftechnology. With regard to the Patient Protection

and Affordable Care Act (ACA), theelimination of lifetime limits and pre-existing conditions is “a huge deal” inoncology, especially as the cost of can-cer therapeutics increases, according toDr Liss. The ACA helped with theestablishment of essential benefits,which are loosely recognized as servic-es that will be covered in the insuranceplan, and with the determination ofhow each plan will distribute thosebenefits to individual cases. One final trend to watch in the

financing of healthcare involves com-parative effectiveness research, whichis an investment in the analysis ofwhich therapies work. �

ONCOLOGY BENEFIT DESIGN


Benefit Design Trends in Oncology ManagementA large payer’s perspectiveBy Wayne Kuznar

Table Industry Trends

• Most cost-effective setting

• Tiered networks–Cost–Combination of outcomes andcost

• Moving self-injectable medica-tions to pharmacy/pharmacybenefits management

• More onerous utilization reviewand claims review–Dosage and frequency as wellas coverage for drugs

• Oncology benefits managementby third parties–Based on experience in diag-nostic imaging and otherfocused service lines

“Those increased costs forthe consumer clearly havethe intended effect ofreducing costs for theinsurer, but whether they are differentiating high-value services and low valueis not so clear.”

—Donald Liss, MD

Register Now

September 24 • Chicago, IL

October 1 • San Francisco, CA

November 19 • Tampa, FL

Register online atwww.AVBCConline.org

2011 REGIONAL MEETINGS

What Attendees of the First Conference Said: • Great discussion and networking• Better understanding of issues• New approaches to old problems• Nice balance of multiple perspectives• I got a clearer understanding of issues facing payers and clinicians

• Really liked the aspect of addressing “state of the state” in addition to future-looking opinions and ideas

• Would like to see more clinician participation

September 24 • Chicago, IL

October 1 • San Francisco, CA

November 19 • Tampa, FL

Register online atwww.AVBCConline.org



NCCN GUIDELINES


Philadelphia, PA—The National Com -prehensive Cancer Network (NCCN)is an alliance of academic cancer cen-ters in the United States that seeks tooptimize decision-making and policiesfor improving the delivery of appro-priate and effective cancer care, said AlB. Benson III, MD, FACP, AssociateDirector for Clinical Investigations,Robert H. Lurie Comprehensive Can -cer Center and Northwestern Univer -sity, Chicago, immediate Past Presi -dent of the Association of CommunityCancer Centers, and Past Chair of theBoard of Directors of NCCN.The 21-member NCCN represents

clinical communities across the UnitedStates. As one of its main missions, theNCCN evaluates scientific informationto inform and improve the decision-making between patients and physi-cians. The major way it achieves thismission is through the development ofevidence-based guidelines.One type of guideline is a process

map of integrated interventions overtime (Figure). The map addresses coor-dination of care and the continuum ofcare, offering references for each deci-sion pathway. For example, there aremore than 1500 decision pathways inthe guideline for management of breastcancer. “The intent is to deal with real-life clinical situations” that are applica-ble to most patients, said Dr Benson.“We do follow a 5% rule; if there’s a

situation that occurs less than 5% ofthe time, it becomes very difficult tocreate a guideline. For much of whataffects patients on a routine basis, wetry to incorporate guidance in terms ofdecision-making.”

The second type of guidance is asystematic review of a single issue.The systematic review is a comprehen-sive review and analysis of the litera-ture that can address a single decisionpoint. “These aren’t mutually exclu-sive; systematic reviews are consid-ered strongly in the NCCN guidelinedevelopment,” said Dr Benson.

Evidence-Based Clinical

Decision-Making

The various NCCN clinical guide-lines are created by multidisciplinarypanels for cancer screening, diagnosis,treatment, and supportive care. Eachrecommendation is supported by 1 of4 categories of evidence ranging fromcategory 1 (based on high level of evi-dence and uniform consensus) to cate-gory 3 (any level of evidence but majordisagreement that the recommenda-tion is appropriate). Most of the rec-ommendations are supported by cate-gory 2A evidence (based on a lowerlevel of evidence and uniform consen-sus that it constitutes appropriatecare), usually data from clinical trials.“The guidelines are not prescrip-

tive” and are not meant to dictate deci-sion-making but, rather, to informdecision-making. “We contend thatsomething is wrong if a center is 100%concordant with guidelines. It’simpossible with the variability of clin-ical situations seen on a daily basis.However, they are applicable in cancermedicine to the majority of ourpatients,” Dr Benson said.Each guidelines panel has on aver-

age 25 members. The evidence isreviewed continuously and guidelines

are updated accordingly; new studieschange the standard of care over time.The entire process is transparent.

“We spend a great deal of effort tominimize bias,” he said. About 900 cli-nicians serve on the review panels,which represent different geographicalareas and specialties.No industry or other interest group

funds are used to support panel meet-ings, and no industry representativesare allowed at the meetings. Potentialconflicts of interest are declared for-mally (verbal and written), and mem-bers can be removed from a panel per-manently if their association withindustry is too pervasive. Financialconflicts of interest for individuals arepublished on nccn.org.The NCCN Compendium™ sup-

ports decision-making on appropriateuse of drugs and biologics and is usedfor coverage policy by the Centers forMedicare & Medicaid Services andmany private health plans.“Our precertification folks use the

compendium, because virtually all ourchemotherapy regimens are precerti-fied, even oral regimens,” Dr Bensonsaid. “This process is a continuum, soif the guidelines are revised and itaffects the compendium, the com-pendium is revised at the same time toreflect the guideline changes.”

Benchmarking Concordance

with Guidelines

Another critical component ofNCCN is the creation of an outcomesdatabase in 1997. The initial purposewas to monitor and benchmark con-cordance of practice in NCCN institu-tions to the guidelines and to describethe patterns and outcomes of care inthe member institutions. All clinical interventions are collect-

ed, including specific regimens, lines oftherapy, and oral agents. More than 270separate data elements are collected.The database also establishes a

major research repository of data rele-vant to patient situations. As oncologymoves to personalized medicine, datathat reflect subsets of patients based ontumor biology will be important. “When there are biological profiles

such as predictive or prognostic mark-ers available, they get integrated intothe database and are integrated intothe guidelines,” said Dr Benson.The reports from the database

inform discussion of individual rec-ommendations at NCCN guidelinespanel meetings. If a recommendationis not being followed, it can be for oneof several reasons:• The recommendation is unclear,perhaps because of the variability ofevidence

• The recommendation is wrong• Doctors are practicing in advance ofguidelines.“When we send concordance data

to our institutions, we expect a re -sponse,” he said. “We need to under-stand when there is a nonconcordance.So if you have a category 1 level of evi-dence, you would expect concordanceto be around the 90% mark. If it’s not,we need to know why.”The NCCN is interested in develop-

ing a compendium of predictive andprognostic testing. Molecular testinghas the potential to identify:• Patients with more aggressive vari-ants of disease

• Those whose disease may (or maynot) respond to specific interventions

• Select systemic therapies based onthe individual patient and themolecular profile. “We are looking for better ways

to utilize guidelines and decision-mak-ing,” said Dr Benson. “We’re calling itat this moment a therapeutic index. Wewould like to look at each recommen-dation in light of both safety and effica-cy. In a potentially curative situation,more toxicity may be tolerated forgood efficacy, whereas in a palliativesituation, less toxicity is acceptable.” �

NCCN Guidelines Inform Decisions Across the Continuum of Cancer CareBy Wayne Kuznar

“We do follow a 5% rule; ifthere’s a situation that occursless than 5% of the time, itbecomes very difficult tocreate a guideline. For muchof what affects patients on aroutine basis, we try toincorporate guidance interms of decision-making.”

—Al B. Benson III, MD, FACP

• Institutional review• Literature review• Outside submissions

NCCN staffreview andupdate

Panel meeting/teleconference

Panel chairreview

Panelreview

Publication

Monitoring and review of literature

• FDA approval• Significant scientificpublication or presentation

Concurrent development and production of discussion, compendium, andchemotherapy order templates

Clinical Practice Guidelines in Oncology – v.1.2010

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FDA indicates US Food and Drug Administration; NCCN, National Comprehensive Cancer Network.Courtesy of Al B. Benson III, MD.

Figure NCCN Guidelines Update Process


EVIDENCE-BASED PRACTICE


Q: Are you concerned about thegrowing trend of payers demandingincreased concordance with theNational Comprehensive CancerNetwork (NCCN) guidelines?

Dr Benson: There is certainly a trendthat emphasizes expectations that clini-cians will practice evidence-basedmedicine. Providers should try to honein on more appropriate use of drugs foran indication and not use agents whenthere is evidence that a regimen is nolonger effective.

Because imaging can be a very criti-cal expense, and with the growing useof diagnostics, payers will likely bevery interested in how people areusing imaging and diagnostic tests inthe context of cancer treatment guide-lines. It makes sense that we talk aboututilization of healthcare dollars mosteffectively and try to avoid use whenthere is no projected added benefit.

It is equally important that we recog-nize that guidelines are not prescrip-tive but offer a medical decision toolfor specific medical situations. Theappropriate use of guidelines also isvery critical in the discussions aboutmeasuring concordance to a specificguideline. For example, there may bean indication that for most peoplewould be considered effective therapy,but for a patient with comorbid condi-tions may not be appropriate. We knowtherefore that 100% concordance toguidelines cannot be viewed as appro-priate care given the variable of clinicalsituations. We always have to take theindividual patient’s circumstancesinto account.

If a patient adheres more to guidelineswhere appropriate, that should result inbetter healthcare delivery and more effi-cient care, and also in appropriate care interms of resource utilization.

Q: As an oncologist, do you haveany concern about where patientsare getting their information on theinternet about care?

Dr Benson: Absolutely, and it is oneof the reasons the NCCN is workingon offering patient guidelines as aresource. For example, guidelines cre-ated for the layperson but mirror theclinical guidelines will enable patientsto discuss treatment pathways withtheir clinicians. Patients will have adocument to review with the clinicianto see where they fall in a given guide-line and what the rationale is for a deci-sion in a particular situation.

It is vital that people have reliable

information, and it is often difficult forindividuals to know what sites areindeed reliable. There are good re -sources, such as the American Societyof Clinical Oncology, the National Can -cer Institute, the Oncology NursingSoci ety, the Association of CommunityCancer Centers, and the NCCN. But interms of actual treatment algorithms,the NCCN guidelines are actually ableto direct an individual to the appropri-ate section that applies to that person asa component of the continuum of care.

If patients are newly diagnosed, inthe middle of treatment, under surveil-lance, or need to make a treatmentdecision, they can at least see whatexperts and any available evidencesuggest they do. We hope that the pub-lic begins to embrace utilization of evi-dence to help guide decisions.

Q: What if a patient insists on acertain treatment because a studyshowed positive benefits for a drugthat is not in the guidelines?

Dr Benson: That would be a point ofdiscussion. The clinician would need tosee that study and discuss how it is rel-ative to that individual. The clinicianwould also need to see if the drug isavailable and if it applies to that indi-vidual patient. With experimental ther-apy, the drug may simply not be avail-able, or there may be another clinicaltrial for which the person would quali-fy, which would be great. However, ifthe data are not robust enough to inte-grate into routine practice, then thereality is that the patient may be deniedreimbursement, which is another com-ponent in the equation. An increasingnumber of insurance carriers are goingto link reimbursement with evidence,and if a treatment indication does nothave a place in current guidelines, thecarrier will deny that coverage.

Q: When developing guidelines, arethere any cost considerations takeninto account?

Dr Benson: Generally not, becausethe purpose of the guidelines is tolook at what should be best practicebased on the evidence. The introduc-tion of an NCCN therapeutic index,which is currently under develop-ment, is an attempt to fine-tune ther-apeutic selection when there may bemultiple options—for example, tak-ing into account goals of therapy andtoxicity, which is perhaps an evenbetter way to guide selection of atreatment.

Q: Does it surprise you that a recentstudy showed a majority of women

with epithelial ovarian cancer,advanced or not, were not beingtreated according to NCCNguidelines?

Dr Benson: As I have said, if more cli-nicians followed evidence-based prac-tice, and more patients began to acceptthat evidence-based practice is the mostappropriate way to care for people, ingeneral, we not only would have themost optimal healthcare outcomes butalso more effective use of our resources.This is something that people shouldexplore to see why individuals are nottreated according to guidelines and tocome up with some solutions.

Q: Are drug shortages interferingwith the ability of clinicians tofollow the guidelines?

Dr Benson: In general, yes. The drugshortage issue is of enormous concern,because there is a potential that peoplewill not be receiving the component ofa regimen that leads to maximum ben-efit. These regimens are in the guide-lines, so the ability to deliver appropri-ate medical care is affected. It is aparticular concern when no adequatealternative therapy is available, or ifa less effective therapy is the onlyremaining choice. This is a very seriousproblem that must be addressed by theUS Food and Drug Administration, thepharmaceutical companies, and theoncology community at large. �

Evidence-Based Practice Should Drive Patient CareInterview with Al B. Benson III, MD, FACPProfessor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL

“Providersshould try tohone in onmore ap pro -priate use ofdrugs for anindication

and not use agents whenthere is evidence that aregimen is no longereffective.”

“If more clinicians followedevidence-based practice, andpatients began to acceptthat evidence-based practiceis the most appropriate wayto care for people, ingeneral, we not only wouldhave the most optimalhealthcare outcomes but alsomore effective use of ourresources.”

Register Now

Register online at www.AVBCConline.org

2011 REGIONAL MEETINGSSeptember 24Chicago, IL

October 1San Francisco, CA

November 19Tampa, FL


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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 lymphomawho 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 ofantineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment withVELCADE.

Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while beingtreated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and adecreased 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 withpre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheralneuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment withVELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation,hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencingnew 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 inor resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. Thelong-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%. Theseevents are observed throughout therapy. Caution should be used when treating patients with a history ofsyncope, patients receiving medications known to be associated with hypotension, and patients who aredehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensivemedications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset ofdecreased left ventricular ejection fraction have been reported, including reports in patients with no riskfactors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart diseaseshould be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent 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% and4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causalityhas not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknownetiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory DistressSyndrome (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 daunorubicinand VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. Therehave been reports of pulmonary hypertension associated with VELCADE administration in the absence ofleft heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonarysymptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patientsreceiving 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 patientsdeveloping RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previouslyexperiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, andvomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid andelectrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia thatfollow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recoveringprior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases andrecovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence ofcumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In therelapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar onboth the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to eachdose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and scheduleof VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association withVELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, thecomplications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those withhigh tumor burden prior to treatment. These patients should be monitored closely and appropriateprecautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitantmedications and with serious underlying medical conditions. Other reported hepatic events includeincreases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upondiscontinuation of VELCADE. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure isincreased in patients with moderate or severe hepatic impairment. These patients should be treated withVELCADE 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 2weeks 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) andpreviously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, thesafety 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 (includingfatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheralneuropathy 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%), coughand 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%) ofpatients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) andneutropenia (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 withmelphalan/prednisone is consistentwith the known safety profiles of both VELCADE and melphalan/prednisone.The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vsmelphalan/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 CYP3A4inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposureof 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 concomitantlyreceiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closelymonitored 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 areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromVELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount 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 andyounger 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 renalimpairment. 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 dialysisprocedure. For information concerning dosing of melphalan in patients with renal impairment, seemanufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate andsevere hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabeticpatients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADEtreatment may require close monitoring of their blood glucose levels and adjustment of the dose of theirantidiabetic medication.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc.Other trademarks are property of their respective owners.Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139Copyright ©2009, Millennium Pharmaceuticals, Inc.

Brief Summary

All rights reserved. Printed in USA V1215 12/0910V-10-020410

Cambridge, MA 02139

3:39 PM


PERSONALIZED MEDICINE


4 5

Philadelphia, PA—The age of person-alized cancer therapies is upon us.In oncology, personalized medicineencompasses the use of tests to deter-mine the genes and gene interactionsthat can reliably predict an individ-ual’s response to therapy or the chanceof disease recurrence. The use ofmolecular diagnostic testing that pro-vides the genomic profile of an indi-vidual’s tumor facilitates an under-standing of some specific tumors thatallows the selection of a treatmentmost likely to induce a response inthat patient.A session devoted to personalized

oncology therapy examined its currentand future role in cancer care and itsimpact on all oncology stakeholders.

A Broader Perspective Needed

Personalized oncology should beconsidered in a broader sense, incor-porating not just genetic testing butalso comorbidities and pharmacoki-netic characteristics of patients, amongother things, according to Gene Morse,PharmD, Professor and AssociateDirector, University at Buffalo, NewYork State Center of Excellence inBioinformatics and Life Sciences. Guidelines have attempted to intro-

duce best practices into cancer care, butcomorbidities can complicate guide-lines implementation, Dr Morse said.Another level of personalization is

individualized drug dosing based onpharmacokinetic considerations (ie,renal and hepatic sufficiency), which isoften omitted from personalized medi-cine approaches. “The use of therapeu-tic drug monitoring to individualizedosing...all of these technologiesexist but are not really broughttogether in many therapeutic areas,”Dr Morse said. The Human Genome Project has

sequenced the full set of genes in thehuman body, but applying this infor-mation to personalized medicine hasbeen difficult, because the genes’ rela-

tive expressions and their impact ondisease recurrence must first be knownbefore the tests can be useful.

Genetic Testing: A “Wild West”

Situation?

About 1800 genetic tests are current-ly available and more are in develop-ment. Although genetic testing hasgenerated a lot of enthusiasm, “Iwould consider it very experimental,”said Dr Morse. Some of these testshave solid evidence, but results fromothers vary from laboratory to labora-tory. Similarly, gene-expression profil-ing is relatively new and unproven.The concept of molecular tests,

genomics, and proteomics is still main-ly a research area, “yet, there are

patients right now walking in for care,and these tests are being requested,”he said. “The payers may or may notwant to have anything to do with thesetests because the data are not there tosupport this.”“It is a Wild West situation, where

these tests are being developed withlittle regulatory oversight and havequestionable clinical utility and a veryuncertain impact on physician treat-ment choice. In other words, does thetest influence what the physician isgoing to do? If the test isn’t going tochange your treatment approach, whydo the test?” said Gary L. Johnson,MD, MS, MBA, Medical Director,Humana, Clinical Leadership andPolicy Development.The economic value of many genetic

tests is another area of uncertainty,said Dr Johnson, and incorporatingthese tests into clinical guidelines is inearly stages.Finding the best method to manage

testing with these uncertainties is achallenge, he said. The options formanaged care are to observe and even-tually react, rely on external guidelines(that take a long time to develop), ordevelop in-house expertise. Anotheroption is to look externally to organi-zations that act similarly to how apharmaceutical benefits managementcompany acts for pharmaceuticals. “Our organization has chosen this

last approach,” he said. “We partneredwith a genomic testing managementcompany that provides the evidence-based policy development, in collabo-ration with our medical directors, bothfor the pharmaceuticals that we use

and for the tests that are provided.”Pretest counseling and test interpreta-tion counseling services are offered. Inthe future, Dr Johnson envisions “pre-ferred” genomic tests similar to thepreferred pharmaceuticals that are onmany drug formularies.The approach to oncology services

at Premier Source Diagnostics is apatient-centric approach, said PerryDimas, Vice President of BusinessDevelopment, Premier Source Diag -nostics, Orlando, FL.“If the ordering physician finds that

the test is medically necessary and heor she wants to order it, the patientshould get it,” Mr Dimas said. PremierSource Diagnostics has mimicked thetraditional specialty pharmacy modeland applied it to molecular diagnostictests. Physicians are offered no incen-tives (ie, reimbursement) to order amolecular test.

Molecular Testing Will

Revolutionize Care

Molecular testing has the potential torevolutionize the way care is provided,said Richard Bender, MD, ClinicalProfessor of Medicine, UCLA School ofMedicine, and Senior Vice Presidentfor Medical Affairs, Oncology, CarisLife Sciences (formerly Chief MedicalOfficer at Agendia).

The Age of Personalized Oncology TherapiesValue implications for payers, researchers, and manufacturers By Wayne Kuznar

Continued on page 18

“The payers may or may not want to have anythingto do with these testsbecause the data are notthere to support this.”

—Gene Morse, PharmD

“It is a Wild West situation,where these tests are beingdeveloped with littleregulatory oversight and have questionable clinicalutility and a very uncertainimpact on physiciantreatment choice.”

—Gary L. Johnson, MD, MS, MBA



PERSONALIZED MEDICINE

In the case of chronic myelogenousleukemia, for example, treatmentdecisions depended on the absence orpresence of Philadelphia chromo-some–positive disease based on cyto-genetic testing, which was costly andtime-consuming, and it detected onlylarge numbers of cells and not small-volume disease.

“We now can detect tiny transcriptsof the translocations and the genomicabnormalities…so we can monitorsmall numbers of residual tumor cellsand determine very quickly whetherour patient has responded to Gleevec

or has responded to newer-classagents, how the mutations have devel-oped, what the mutations are, andwhat drugs might be appropriate,” hesaid. “This has changed dramaticallythe way we practice healthcare.”

The evolution to molecular testingwill allow for more uniform selection ofsystemic therapies. “I was delighted tohear that the National Compre hensiveCancer Network was going to beorganizing a way to develop standardsfor how these kinds of tests are movedinto the marketplace,” Dr Bender said.“You would be dismayed to know thatorganizations such as the College ofAmerican Pathology, which looks at allof our laboratories and sets standardsfor all of the tasks we do…have no stan-dards for molecular testing.”

The reason for the absence of stan-dards for molecular testing is that nomethod for developing proficiencyexists, he said. Organizations that per-form gene-expression profiling, forexample, use their own tissues to setlaboratory proficiencies. Therefore, itis “difficult for the industry to developa standard. One of the things as anindustry that we absolutely have to dois to have proficiency standards,” saidDr Bender.

Barrier to Molecular Testing:

Medicare 14-Day Rule

A barrier to molecular testing is theMedicare 14-day rule. The rule statesthat any service rendered within 14days of a hospital inpatient or outpa-tient admission must be billed directlyto the hospital as part of the Inter -na tional Classification of Diseases, 9thRe vision (ICD-9)-coded service. There -fore, a laboratory test must be per-formed outside the 14-day window forit to be paid as an outpatient test. Therule causes delays in test ordering,which is not in the best interest of thepatient.

The Centers for Medicare & Medi -

caid Services (CMS) is starting ademonstration project in June 2011,lasting 24 months, in which it willinvestigate paying for certain complexdiagnostic laboratory tests (ie, geneprotein expression, genotyping, cancerchemotherapy sensitivity assay) out-side the 14-day rule. Under thedemonstration, independent and hos-pital-based laboratories may bill sepa-rately for demonstration tests that areordered within a 14-day period after ahospital discharge.

“It will be up to us to demonstratethat this rule, within the CMS andother healthcare codes, needs to bechanged,” said Dr Bender.

Changing the Translational

Research Structure

Many companies are challenged bylimited resources for research, pre-venting them from bringing their ideas

to the level of approval, said Dr Morse.“We think the system should workwith those companies and move thosedrugs and technologies forward,” hesaid. “There are a lot of good ideas, butthe system doesn’t work well for peo-ple who can’t get the support from theventure capitalist.”

Establishing a translational prac-tice–research–payer center interfacecan facilitate drug development andoutcomes research programs. Theintroduction of healthcare informaticscan help bridge drug development,clinical research, and nanopharmacol-ogy with translational science researchand postapproval safety research(Figure), believes Dr Morse.

“In Buffalo, for example, we’vebridged our bioinformatics center,which is one of the largest computingclusters, with what will now be one ofthe largest HIPAA [Health InsurancePortability and Accountability Act]-compliant data centers, through a part-nership with Dell,” he said.

Although the goal of healthcareinformatics is to permit health andeconomics outcomes evaluations toguide clinical use and reimbursementpolicies, “the reality is that state bystate, and region by region, the infor-mation technologies are at differentstages of implementation,” said DrMorse. “Even though we’d like to dothat and that’s our vision, I thinkthere’s a long way to go.”

Wise Resource Utilization Needed

In the process of extending the livesof cancer patients, more healthcareresources are being devoted to oncolo-gy care. “We need to use thoseresources wisely, and that’s the con-cept of value,” said Dr Johnson. “Ourjob in managed care is to be stewardsof these generous but somewhat limit-ed resources. We have a lot of treat-ment variability and we have a lot ofoutcome variability. It’s our job as thestewards of those resources to try tolimit that treatment variability.”

The premise of marketing a test ordrug to every patient is no longervalid, said Dimas. “We want the rightpatient to get the right drug or righttest. It increases the value of that serv-ice,” he said.

Health plan reimbursement for per-sonalized oncology therapies is cur-rently unpredictable and variable. Asnew molecular or genotyping testsand personalized drugs come to mar-ket, affordability cannot be underesti-mated, said Dr Morse. Therefore,methods for applying them cost-effec-tively must be devised. �

The Age of Personalized Oncology... Continued from page 17

Drug interactions

Drug development

Clinical research

Nanopharmacology

Healthcare informatics

Biomedical informatics

Translational science research

Postapproval safety research

Figure Healthcare Informatics Facilitate a Translational Research Model

�

�

��

at a glance� Personalized oncology should

consider each patient’s

comorbidities, pharmacokinetic

characteristics, and drug use

� Payers many not cover genetic

testing for lack of sufficient

evidence for their value

� The management of genetic

testing is a challenge without

established guidelines

� Molecular testing can poten -

tially revolutionize cancer care

and provide more uniform

selection of systemic therapies

� Medicare’s 14-day rule is a

barrier to molecular testing

� Healthcare informatics can

link drug development, clinical

research, and nanopharma -

cology to translational science

“We now can…monitor smallnumbers of residual tumorcells and determine veryquickly...how the mutationshave developed. This haschanged dramatically theway we practice healthcare.”

—Richard Bender, MD“If the ordering physicianfinds that the test ismedically necessary and heor she wants to order it, thepatient should get it.”

—Perry Dimas


Philadelphia, PA—The new biologictherapy eribulin (Halaven) was recent-ly approved by the US Food and DrugAdministration for the treatment ofpatients with metastatic breast cancer.Stephen C. Malamud, MD, AttendingPhysician, Beth Israel Medical Center,New York City, discussed the benefitsand risks associated with this newtreatment option at a special sessionduring the meeting. Eribulin is a nontaxane microtubule

dynamics inhibitor indicated for thetreatment of metastatic breast cancerin patients who have previouslyreceived treatment with at least 2chemotherapeutic medications thatinclude a taxane and an anthracyclinein the adjuvant or metastatic setting.According to Dr Malamud, the

mechanism of action of eribulin is“slightly different from that of theother microtubules, in that eribulininhibits the growth phase rather thanshortening the phase of the micro-tubules.” In an open-label, phase 3, random-

ized, multicenter clinical trial investi-gating the safety and efficacy of eribu-lin, the drug extended overall survival(OS) by 2.5 months: median OS was13.1 months with eribulin (N = 508)compared with 10.6 months in the con-trol group (N = 254), a significant dif-ference (P = .041).

Ongoing Patient Monitoring

As with all chemotherapeuticagents, patients must be monitored onan ongoing basis and must be askeddirectly for any potential adverseevents. “If I don’t ask them, they don’ttell me,” said Dr Malamud.Indeed, he added, “the incentive for

patients to stay on [chemotherapy] isusually so great that they are usuallywilling to forgo some symptomatol-ogy, so you have to push them to findout what’s going on.” When adverseevents occur, Dr Malamud cautioned,“adjust dosing, hold dosing to main-tain functionality.”

Adverse Events

The most common adverse events inclinical trials have been neutropeniaand peripheral neuropathy. Of 503participants in one trial, severe neu-

tropenia lasting >1 week occurred in12% of patients, leading to discontinu-ation of eribulin in <1% of patients.Grade 3 peripheral neuropathyoccurred in 8% of the patients and

grade 4 in 0.4%. Peripheral neuropa-thy was the most common cause fortherapy discontinuation in phase 1and phase 3 clinical trials.Embryo-fetal toxicity has not been

well studied with eribulin; however, itis expected to cause harm to the fetuswhen used during pregnancy. �

A New Option for Metastatic Breast Cancer By Wayne Kuznar

BREAST CANCER


With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology

offers health plans and oncology practices a comprehensive solution that enhances the quality and

consistency of patient care. With evidence-based medicine as the foundation of the program, we

further help patients by providing direct, personalized support and education between office visits

as well as advance care planning regarding future treatment and care preferences. Through this

patient-centric approach, we help health plans and oncology practices collaborate by aligning

incentives to drive better patient outcomes as well as encourage the efficient use of healthcare

resources. After all, isn’t cancer a disease we should manage together?

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

“If I don’t ask them, theydon’t tell me. The incentivefor patients to stay on[chemotherapy] is usually sogreat that they are usuallywilling to forgo somesymptomatology.”

—Stephen C. Malamud, MD


COMMUNITY ONCOLOGY


Philadelphia, PA—Changes in oncolo-gy reimbursement have driven the con-solidation of community oncologypractices, as more of these practices arebeing squeezed financially, accordingto Ted Okon, BS, MBA, ExecutiveDirector, Community Oncology Al -liance. Consoli dation decreases alterna-tives, and that means reduced competi-tion, as many oncologists lose theirpractices. The transformation of cancer care

from the inpatient setting to the outpa-tient community setting over the past3 decades resulted in an improvementin the quality of care and overall cost-savings, even as the treatment cost percase has increased substantially. The total cost of inpatient cancer

care has fallen from 64.5% in 1987 to27.5% this decade, for an overall cost-savings of $5.5 billion. At the sametime, Americans live longer with acancer diagnosis than patients withcancer in Europe, he said.Today, 4 of every 5 patients with

cancer are treated in communityoncology clinics. “Many of these arefairly integrated clinics, with compre-hensive facilities that provide a broadscope of patient care,” said Mr Okon,referring to clinics that perform com-puted tomography and positronemission tomography imaging in

addition to laboratory work andchemotherapy and radiation adminis-tration.

Reimbursement Pressure

However, community oncologypractices have been under increasingpressure since the Centers forMedicare & Medicaid Services (CMS)changed its oncology reimbursementin 2004/2005 and have made subse-quent payment cuts. Since 2004, Medi -care reimbursement has fallen by 35%. A study by Avalere Health showed

that Medicare covered only 57% of thecost of drug administration in 2008,and it covers even less now. As aresult, community oncology clinics areclosing at an accelerating pace, andmore private practices are being soldor absorbed by hospitals (Figure). The Medicare payment system that

is based on the flawed sustainablegrowth rate (SGR) has created addi-tional pressures on cash flow (whenclaims are held) and business planning.The healthcare reform law will

mean more Americans aged <65 yearscovered by insurance, but 50% willcome under Medicaid, at a time whenmore states are under pressure to cutMedicaid coverage and provider reim-bursement. Eliminating cost-sharing for certain

diagnostic tests is expected to increasethe number of cancer cases detected.Patients with cancer who have private

health insurance may have greaterout-of-pocket responsibilities overtime, warned Mr Okon. “The problemwith cancer care is not going to be ‘noinsurance’; it’s going to be ‘under -insurance,’” he said.

Affordable Care Act: Pros, Cons

The Patient Protection and Afford -able Care Act of 2010 contains somepositive changes for oncology—break-ing down barriers to cancer care, suchas the elimination of annual and life-time caps, removing preexisting condi-tions as a reason for coverage exclu-sion, and the prohibition of rescindinginsurance policies retroactively, saidMr Okon.In addition, the Medicare doughnut

hole will be closed fully by 2020.Elimination of individual cost-sharingwill lower the barrier to certain pre-ventive care services. New safeguardsin the use of comparative effectivenessresearch are provided through thecreation of the Patient-Centered Out -comes Research Institute, to offerobjective data to providers.

The healthcare reform bill, however,has also created uncertainties foroncology. It includes no fix for theMedicare/SGR payment system. If thesystem is not fixed, oncology practicesmay not be able to survive, Mr Okonwarned. Under reform, Medicare willtransition physicians to a value-basedpurchasing reimbursement systemusing quality and cost measures.Reimbursement will be tied to CMSreporting on physicians’ relative pat-terns of use, but it is unclear how thiswill be implemented for oncology.The creation of the Independent

Payment Advisory Board “is a disasterto me, like SGR on steroids,” said MrOkon. Any recommendations from theboard will be fast-tracked into law, asthey will be difficult for Congress tooverride.The Physician Quality Reporting

Initiative changes from an incentive toa penalty program for nonparticipants.

Community Oncology Clinics under Increasing Financial PressureBy Wayne Kuznar

“If we don’t come together, there’s going to be less quality,higher cost, and inefficiencies all over the map.”

—Ted Okon, BS, MBA

Figure Impact of Financial Pressure on Private Oncology Practices, March 31, 2011

Acquired by hospital

Clinics closed

Merged/acquired by another entity

Practices sending patients elsewhere

Practices struggling financially

1042 clinics/practices have been affected in thepast 3.5 years, as of March 31, 2011: 199 clinics closed369 practices struggling financially48 practices sending ALL patients elsewhere fortreatment315 practices acquired by a hospital111 practices merged/acquired by another entity

Source: Community Oncology Association Practice Impact Tracking database as of March 31,2011. Courtesy of Ted Okon.


“The problem with cancercare is not going to be ‘noinsurance’; it’s going to be‘underinsurance.’”

—Ted Okon, BS, MBA

at a glance� Changes in reimbursement

have driven the consolidation of

community oncology practices

� Since 2004, Medicare reim -

bursement has fallen by 35%

� In 2008, Medicare covered only

57% of the cost of drug admini s -

tration; it covers even less now

� By 2020, 1 in every 4 patients

with cancer will be short an

oncologist

� If the flawed Medicare/SGR

payment system is not fixed,

oncology practices may not

survive


Progression-free survival (PFS) after progression on sunitinib or sorafenib1

100

80

60

40

20

Time (months)

Prob

abili

ty (%

)

Afinitor

4.9 months

1.9 months

Placebo

Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9)

Log rank P value=<0.0001

Hazard Ratio=0.3395% CI [0.25, 0.43]

0 2 4 86 10 12 14

4.9 months median PFS with Afinitor + BSC† (vs 1.9 months with placebo + BSC; P<0.0001)1

HR 0.33=67% reduction in risk of progression

Effective for patients with all prognostic scores1

Afinitor doubled median PFS after progression on sunitinib*1

In advanced RCC:

For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.comFor reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648).

*In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2

†BSC=best supportive care.

Important Safety InformationThere have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oralulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions ofhemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Please see Important Safety Information on right side of page.Please see Brief Summary of full Prescribing Information on the following pages.

While taking

A


References: 1. Afinitor [prescribing information]. East Hanover, NJ: NovartisPharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cellcarcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet.2008;372:449-456.

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis Printed in U.S.A. 10/10 AFI-1002330

22..55mmgg 55mmgg 1100mmgg

Afinitor is indicated for the treatment of patients withadvanced renal cell carcinoma after failure of treatmentwith sunitinib or sorafenib.Important Safety InformationAfinitor is contraindicated in patients with hypersensitivityto everolimus, to other rapamycin derivatives, or to any ofthe excipients.Non-infectious pneumonitis is a class effect of rapamycinderivatives, including Afinitor. Fatal outcomes have beenobserved. If symptoms are moderate or severe, patientsshould be managed with dose interruption until symptomsimprove or discontinuation, respectively. Corticosteroidsmay be indicated. Afinitor may be reintroduced at 5 mgdaily depending on the individual clinical circumstances.Afinitor has immunosuppressive properties and maypredispose patients to bacterial, fungal, viral or protozoaninfections, including infections with opportunisticpathogens. Localized and systemic infections, includingpneumonia, other bacterial infections, invasive fungalinfections, and viral infections including reactivation ofhepatitis B virus have occurred. Some of these infectionshave been severe (e.g. leading to respiratory or hepaticfailure) or fatal. Complete treatment of pre-existing invasivefungal infections prior to starting treatment. While takingAfinitor be vigilant for signs and symptoms of infection; ifa diagnosis of infection is made, institute appropriatetreatment promptly and consider interruption ordiscontinuation of Afinitor. If a diagnosis of invasivesystemic fungal infection is made, discontinue Afinitor andtreat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oralmucositis) have occurred in patients treated with Afinitor. Insuch cases, topical treatments are recommended, butalcohol- or peroxide-containing mouthwashes should beavoided. Antifungal agents should not be used unlessfungal infection has been diagnosed.Elevations of serum creatinine, glucose, lipids, andtriglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinicaltrials. Renal function, hematological parameters, bloodglucose, and lipids should be evaluated prior to treatmentand periodically thereafter. When possible, optimal glucoseand lipid control should be achieved before starting apatient on Afinitor.Avoid concomitant use with strong CYP3A4 or PgPinhibitors. If co-administration with moderate CYP3A4 orPgP inhibitors is required, use caution and reduce dose ofAfinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer.Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepaticimpairment.The use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with Afinitor.Fetal harm can occur if Afinitor is administered to apregnant woman.The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia(33%), fatigue (31%), cough (30%), and diarrhea (30%).The most common grade 3/4 adverse reactions (incidence≥3%) were infections (9%), dyspnea (8%), fatigue (5%),stomatitis (4%), dehydration (4%), pneumonitis (4%),abdominal pain (3%), and asthenia (3%). The mostcommon laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%),hypertriglyceridemia (73%), hyperglycemia (57%),lymphopenia (51%), and increased creatinine (50%). Themost common grade 3/4 laboratory abnormalities(incidence ≥3%) were lymphopenia (18%), hyperglycemia(16%), anemia (13%), hypophosphatemia (6%), andhypercholesterolemia (4%). Deaths due to acute respiratoryfailure (0.7%), infection (0.7%), and acute renal failure(0.4%) were observed on the Afinitor arm.


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

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

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

5 WARNINGS AND PRECAUTIONS5.1 Non-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the ran-domized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. Theincidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, considerinterrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITORmay be reintroduced at 5 mg daily.For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy andthe use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR maybe re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.5.2 InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infec-tions, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virushave occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading torespiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk ofinfection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to startingtreatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if adiagnosis of an infection is made, institute appropriate treatment promptly and consider interruption ordiscontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinueAFINITOR and treat with appropriate antifungal therapy.5.3 Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the ran-domized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, ororal mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topi-cal treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoidedas they may exacerbate the condition. Antifungal agents should not be used unless fungal infection hasbeen diagnosed [see Drug Interactions (7.1)].5.4 Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions(6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum cre -atinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipidcontrol should be achieved before starting a patient on AFINITOR.Hematological ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of com plete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.5.5 Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong inhibitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithro mycin, atazanavir, nefazodone, saquinavir, telithromycin,ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grape-fruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also beavoided during treatment [see Dosage and Administration (2.2) in the full prescribing information andDrug Interactions (7.1)].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) orPgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Inter -actions (7.1)].An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer(e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, car-bamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in thefull prescribing information and Drug Interactions (7.2)].5.6 Hepatic ImpairmentThe safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderatehepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure wasincreased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) andshould not be used in this population [see Dosage and Administration (2.2) in the full prescribing infor-mation and Use in Specific Populations (8.7)].5.7 VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps,rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.5.8 Use in PregnancyPregnancy Category DThere are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraception

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

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].• Infections [see Warnings and Precautions (5.2)].6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observed inclinical practice.The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized,controlled trial in patients with meta static renal cell carcinoma who received prior treatment with sunitiniband/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78%were male. The median duration of blinded study treatment was 141 days (range 19-451) for patientsreceiving AFINITOR and 60 days (range 21-295) for those receiving placebo.The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue,cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections,dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most commonlaboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia,hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnor-malities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hyper -cholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure(0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergentadverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% forthe AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irre-spective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections,stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. Themost common medical interventions required during AFINITOR treatment were for infections, anemia, andstomatitis.Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organclass, the adverse reactions are presented in order of decreasing frequency.

Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate

in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day Placebo

N=274 N=137All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any Adverse Reaction 97 52 13 93 23 5Gastrointestinal Disorders

Stomatitisa 44 4 <1 8 0 0Diarrhea 30 1 0 7 0 0Nausea 26 1 0 19 0 0Vomiting 20 2 0 12 0 0

Infections and Infestationsb 37 7 3 18 1 0General Disorders and Administration Site Conditions

Asthenia 33 3 <1 23 4 0Fatigue 31 5 0 27 3 <1Edema peripheral 25 <1 0 8 <1 0Pyrexia 20 <1 0 9 0 0Mucosal inflammation 19 1 0 1 0 0

Respiratory, Thoracic and Mediastinal DisordersCough 30 <1 0 16 0 0Dyspnea 24 6 1 15 3 0Epistaxis 18 0 0 0 0 0Pneumonitisc 14 4 0 0 0 0

Skin and Subcutaneous Tissue DisordersRash 29 1 0 7 0 0Pruritus 14 <1 0 7 0 0Dry skin 13 <1 0 5 0 0

Metabolism and Nutrition DisordersAnorexia 25 1 0 14 <1 0

Nervous System DisordersHeadache 19 <1 <1 9 <1 0Dysgeusia 10 0 0 2 0 0

Musculoskeletal and Connective Tissue DisordersPain in extremity 10 1 0 7 0 0

Median Duration of Treatment (d) 141 60CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most commonbeing nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis(3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).

cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonarytoxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with anincidence of <10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills(4%), impaired wound healing (<1%)Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%),rhinorrhea (3%)Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythro -dysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion(4%), acneiform dermatitis (3%)Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset ofdiabetes mellitus (<1%)Psychiatric disorders: Insomnia (9%)Nervous system disorders: Dizziness (7%), paresthesia (5%)Eye disorders: Eyelid edema (4%), conjunctivitis (2%)


Vascular disorders: Hypertension (4%)Renal and urinary disorders: Renal failure (3%)Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)Musculoskeletal and connective tissue disorders: Jaw pain (3%)Hematologic disorders: Hemorrhage (3%)

Key treatment-emergent laboratory abnormalities are presented in Table 2.Table 2

Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Armthan the Placebo Arm

Laboratory Parameter AFINITOR 10 mg/day PlaceboN=274 N=137

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

Hematologya

Hemoglobin decreased 92 12 1 79 5 <1Lymphocytes decreased 51 16 2 28 5 0Platelets decreased 23 1 0 2 0 <1Neutrophils decreased 14 0 <1 4 0 0

Clinical ChemistryCholesterol increased 77 4 0 35 0 0Triglycerides increased 73 <1 0 34 0 0Glucose increased 57 15 <1 25 1 0Creatinine increased 50 1 0 34 0 0Phosphate decreased 37 6 0 8 0 0Aspartate transaminase (AST)

increased 25 <1 <1 7 0 0Alanine transaminase (ALT)

increased 21 1 0 4 0 0Bilirubin increased 3 <1 <1 2 0 0

CTCAE Version 3.0aIncludes reports of anemia, leukopenia, lymphopenia, neutropenia, pancyto penia, thrombocytopenia.

Information from further clinical trialsIn clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, includingfatal outcomes.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.7.1 Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone therewere significant increases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and

15.0-fold, respectively.• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and

4.4-fold, respectively.• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and

3.5-fold, respectively.Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions(5.5)].Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alterna-tive treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2)in the full prescribing information]7.2 Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimustreatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers ofCYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP ifalternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpre-dictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].7.3 Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactionsbetween AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and prava -statin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)]There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraceptionwhile receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating andthrough organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantationand post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) andretarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetaltoxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommendeddose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oraldose approximately 1.6 times the recommended human dose on a body surface area basis. The effect inrabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lacta-tion. At approximately 10% of the recommended human dose based on body surface area, there were noadverse effects on delivery and lactation and there were no signs of maternal tox icity. However, therewas reduced body weight (up to 9% reduction from the control) and slight reduction in survival in off-spring (~5% died or missing). There were no drug-related effects on the developmental parameters(morphological development, motor activity, learning, or fertility assessment) in the offspring.Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).8.3 Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseIn the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percentwere 75 and over. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivity of some older individuals cannot beruled out [see Clinical Pharmacology (12.3) in the full prescribing information].No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full pre-scribing information].8.6 Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renalimpairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recom -mended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].8.7 Hepatic ImpairmentFor patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mgdaily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions(5.6) and Clinical Pharmacology (12.3) in the full prescribing information].The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in thispatient population is not recommended [see Warnings and Precautions (5.6)].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGEStore AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).[See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture.Keep this and all drugs out of the reach of children.Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

Revised: June 2010 T2010-56

Manufactured by:Novartis Pharma Stein AGStein, Switzerland

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

©Novartis


COMMUNITY ONCOLOGY


Q: In your presentation, you saidthat oncology is in crisis—what didyou mean by that?

Mr Okon: When I say cancer care isin crisis, I mean that we have a perfectstorm brewing. First, we have thegraying of America, so we are going tohave an increasing incidence of cancer.Second, we have a growing unhealthypopulation that is going to result inincreased cases of cancer. Third, wehave an oncologist population that isflat or declining in the face of increas-ing demand for cancer care. We have asituation that is going to produce a cri-sis, and we are not going to see whenwe hit it. Congress won’t be able tostimulate its way out of that.Delivering cancer care is very com-

plex: we are not going to be able to cre-ate oncologists overnight. So we havea real crisis brewing.

Q: Do you have suggestions forsolving this crisis?

Mr Okon: The suggestions rightnow are unrealistic. What the govern-ment is doing reflects the reimburse-ment system changes for cancer carethat were introduced in the 2003Medicare Modernization Act (MMA).Medicare is 50% cancer care, which isthe 800-pound gorilla in the room.Medicare influences everything on theprivate pay side as well. The reim-bursement is just not realistic. If we look at the increasing expenses

of running a practice as measured by

the MMA, the effective decline ofreimbursement has been 47%. We can-not operate a business where we areseeing such steep declines.We need to look at the reimburse-

ment system differently. We should bepaying oncologists for one of the mostimportant things they do: treatmentplans. We should be paying oncolo-

gists for cognitive services, such astreatment plans. Oncologists are reimbursed in 3

ways. First, they are reimbursed fortheir evaluation and management, likeall physicians. Second, they are reim-bursed for administering chemothera-py drugs in the office, including forrelated services. Third, they are reim-bursed for the drugs. All the other cog-nitive services, such as planning fortreatment, follow-up care, and sur-vivorship, are not reimbursed.The reimbursement system flies in

the face of value-based insurancedesign. If we want to create value inthe system, that is where we have tofocus the reimbursement, and it isnot. If some things are not done now,and we let some aspects of health-care reform go into play—for exam-ple, the Independent Payment Ad -visory Board, where there is justgoing to be wholesale and immediatecuts to Medicare when spending tar-gets are exceeded—it will hit pro -viders, and we are going to put aknife in cancer care.

Q: Why are so many cancer sitesclosing?

Mr Okon: We have had roughly 200individual sites that have closed since2008. In some cases, entire practiceshave closed. It has hit some rural andunderserved areas hard, because itbecomes extremely expensive to oper-ate clinics in the face of this decliningreimbursement. We are seeing a bigescalation in practices that are beingacquired on the hospital side. I do notmean to be disrespectful to hospitals,but we are going to end up decreasingcompetition. We are going to createmega-entities, and it is going to costpayers and patients more.

Many hospitals now have good out-patient centers. When that gets consol-idated—and there are lots of hospitalsthat are in trouble—many hospitals aregoing to close. When the market con-solidates down that far, it reducesalternatives. Therefore competition inthe market is never healthy in terms ofquality and value.

Q: Several states are talking aboutcutting Medicaid. Will it have alarge impact on oncology practices?

Mr Okon: Typically an oncologypractice will not have a large Medicaidpopulation, but it is going to get bigger.There are going to be an additional 32million to 34 million Americans cov-ered by insurance in 2014, if the law isnot declared unconstitutional by then,and that is going to increase theMedicaid population by 16 millionindividuals. As a result, there is goingto be even more strain, because statesare cutting Medicaid benefits for theindividual. This is unrealistic, becausefewer states are going to be able toafford to cover cancer care.And the issue of dual-eligible per-

sons with both Medicare and Medicaidis going to be a huge problem.

Q: Does sustainable growth rate(SGR) still have a negative effect on oncology practices?

Mr Okon: Yes, it has an inordinateadverse impact on oncology practicesevery time there is an SGR patch thatresults in held claims. SGR affects onlythe services, not the drugs. But when aservice claim is held up, that serviceclaim is tied to a drug. If we decouplethose, we are going to run the risk ofnever getting paid for the drug. Onaverage, an oncologist is responsiblefor $2.2 million to $2.5 million annual-ly in terms of drugs administered, sothey are essentially subsidizing Medi -care when claims are held. The prob-lem is that a medical practice has tooperate as a business, or it will die.This involves business and strategicplanning, but that planning cycle hasbeen thrown out the window. The fed-eral government is not held to thesame laws. A practice has to worryabout its cash flow and planning. Medical practices that experience

patch after patch on the SGR cannotefficiently operate and plan. We do notknow what future reimbursement willlook like. When we have a potential 29.4%

Medicare cut by the end of the year,how do practices plan and staff? Itmakes providers think of closing facil-ities. So, the SGR is a huge problem forall providers, but it inordinatelyimpacts oncology, because of the mag-nitude of the capital outlay that oncol-ogy practices have to make in drugpurchases and facilities.

Q: Does failure to sustain thegrowth rate ultimately drive upcosts for everyone?

Mr Okon: Absolutely. It could havebeen fixed 5 to 6 years ago at approxi-

The Crisis in Cancer CareInterview with Ted Okon, BS, MBAExecutive Director, Community Oncology Alliance, Washington, DC

Community Oncology... Continued from page 20

“The oncology measures are weak atbest,” said Mr Okon.A Physician Compare database will

be implemented, similar to the Hos -pital Compare database, but howoncologists are going to be comparedhas not been elucidated.

Grim Outlook for Oncology

Healthcare reform “will likely pres-sure a cancer care delivery systemalready under pressure,” as reim-bursement is decreased in numerousways, said Mr Okon. Costs for payersare likely going to increase as competi-tion is reduced through the consolida-tion of community clinics. In addition,demand for cancer care may outstripthe supply of oncologists. It has beenestimated that by 2020, the equivalentof “1 in every 4 patients with cancerwill be short an oncologist,” he said.

Payer-Provider Collaboration

Oncology payers and providersneed to come together to preserveand enhance the delivery system. “Ifwe don’t come together, there’sgoing to be less quality, higher cost,and inefficiencies all over the map,”Mr Okon noted.Working together to use evidence-

based clinical pathways can enhancetreatment quality and efficiencies, hesaid, but just as important is the inclu-sion of a feedback loop to gauge howclinical pathways are working andhow they can be improved. In addi-tion, appropriate payment should beconsidered for key cognitive services,such as treatment planning and fol-low-up care planning. “Treatmentplanning is the key thing you wantyour oncologists to do when you havecancer,” he concluded. �

“We have a perfect stormbrewing. We have thegraying of America…agrowing unhealthypopulation…[and] anoncologist population that is flat or declining in the face of increasing demandfor cancer care.”

“Medicare is 50% cancercare, which is the 800-poundgorilla in the room. If wewant to create value in thesystem, that is where wehave to focus the reimburse -ment, and it is not.”



ONCOLOGY PRACTICES


Oncologists Face Economic Challenges while Improving Patient CareStakeholder partnership can enhance clinical practiceBy Wayne Kuznar

Philadelphia, PA—The estimated costfor physician practices to interact withhealth insurance plans is $23 billion to$31 billion annually, according to a2009 national survey conducted byCasalino and colleagues (Health Aff.2009;28:w533-w543). In the survey, physicians reported

spending 3 hours weekly interactingwith health plans; nursing and clericalstaff spent much larger amounts oftime. “This describes the cost to prac-tices over and above the costs of carefor the uninsured and the cost to man-age preauthorization and prior ap -proval,” said Craig Deligdish, MD,Chief Medical Officer, Florida Compre -hensive Care Network, Melbourne. “This is something that patients

don’t see. It is something in an oncol-ogist’s office that requires a great dealof time and effort. And it is one of themajor reasons I suspect that certainpractices do not buy and bill anymore,because administering treatmentsthat, in 1 session, can cost $30,000 ispotentially challenging when yourreimbursement is only 2% greaterthan the cost of that treatment in agiven day.”Today, an average encounter in an

oncologist’s office could result in a$10,000 or $20,000 bill, which is prob-lematic when a denial comes, because

the practice did not obtain properpreauthorization. A recent survey conducted by the

American Medical Association (www.ama-assn.org/ama/pub/news/news/survey-insurer-preauthorization.page)reveals that policies requiring physi-cians to ask permission from apatient’s insurance company beforeperforming a treatment have a nega-tive impact on patient care. The surveyresults suggest that: • 37% of physicians face a 20% rejec-tion rate from insurers on first-timepreauthorization requests for testsand procedures

• 57% of physicians face a 20% rejec-tion rate from insurers on first-timepreauthorization requests for drugs

• 46% of physicians have difficultyobtaining approval from insurers on≥25% of preauthorization requestsfor tests and procedures

• 63% of physicians typically waitseveral days to receive preautho-rization from an insurer for tests andprocedures; 13% wait >1 week

• 64% of physicians have difficultydetermining which tests and proce-dures require preauthorization byinsurers.

Assisting the Uninsured

“To my recollection, one of the rea-

sons for healthcare reform initially wasto cover the uninsured,” Dr Deligdishsaid. “Today, I don’t think that hasoccurred.”According to the US government,

50.3 million Americans are uninsuredthis year; by 2020, as many as 61.1 mil-lion will be uninsured. “And as oncologists in practice,

whether in a hospital or a private set-ting, we are faced with taking care ofthese people. I do not know too manypractices anywhere in the country thatturn away patients who have cancer. Ittakes a great deal of time and effort toprovide care to these patients,” DrDeligdish said.In response to these challenges,

some practices have stopped buying

and billing chemotherapy, some havemerged with hospitals, and some haveclosed their doors. The remaining prac-tices that seek to remain independenthave hired financial counselors to con-trol costs. There is a true need to reducethe administrative burden.“Your 2 largest expenses in an oncol-

ogy practice are the drugs and yourpayroll, and you have to manage bothof them well in order to survive,” saidLeonard H. Natelson, Chief Exec -utive Officer, Hematology/OncologyAssociates of Rockland, NY. “Keepingyour doors open is good for thepatient, and you may have to reinventyour business model.“I don’t have to do the patient assis-

tance, because I use a specialty phar-macy,” Mr Natelson continued. “Everydrug company has a patient assistanceprogram. Most therapies are multi -drug, multicompany therapies. It costsyou money to have somebody sit onthe phone and go back and forth withcompanies to get all this money. Youtake it out of your practice, so youdon’t have to cover the payroll for theperson doing it.”Specialty pharmacies also reach out

to private foundations, which commu-nity oncology practices generally donot have. This is another avenue tohelp patients with significant copays.If there is considerable financial hard-ship, a patient can go through an assis-tance program instead of the physi-cian’s office. “Generally, patients do not like to

discuss blockades to getting patientcare, and they certainly do not wantto discuss it with their physician oranyone in the practice. The programgives them someone completely sepa-rate, and it’s just a telephone call,unrelated to our practice. I have anumber of patients on those pro-

“We believe the communitysetting is one of the bestplaces to receive cancertreatment, so we are workingwith practices and healthplans to hopefully provide themost cost-effective treatmentin the most cost-effectivesetting.”

—Craig Deligdish, MD

mately $50 billion. Now it is well over$300 billion.

Q: Do oncologists get reimbursed forcounseling patients on adherence?

Mr Okon: No, oncologists do notget reimbursed for counseling pa -tients on the details, which can beextensive, associated with prescrib-ing oral cancer drugs. Some payersmistakenly believe that they can dealwith all of the details by contractingwith a specialty pharmacy or otheroutside provider, but we have seendisaster in some cases. We have seencases where an outside nurse will calla patient and ask why the patient isnot taking his/her drug, when thereason is the oncologist just stoppedthe drug because of side effects. Thisdisjointed communication is veryconfusing to the patient and can leadto inefficiencies and, at worse, badpatient outcomes. A major problem is that with oral

oncolytics practices receive absolutelyno reimbursement for patient man-agement and counseling. Rather thanprovide appropriate reimbursementand optimize the coordination of care,using an outside provider often leadsto disjointed, inefficient care. This willbe a growing problem with oraloncolytics because the drug pipelineis huge.We have 100% adherence with intra-

venous drugs, because oncologistsknow if the patient came in andreceived chemotherapy treatment onsite. Unless there was a mistake in giv-ing the drug, we know the exact doseand when the patient received it. In contrast, we have major issues

with oral medications. There is the pos-sibility of side effects, and we don’teven know if the patient is taking thedrug. The oncologist does not knowwhether the drug did not work, or ifthe drug was not taken. The drugcould have been so expensive that the

patient cut it in half, as many patientsdo with their heart medications, ormay not have even filled it in the firstplace. A practice trying to manage sucha patient is not reimbursed for that.

Q: Do you support healthcarereform that can give nurses moreresponsibility in patient care?

Mr Okon: Absolutely, I support it. Ithink that oncology nurses are the realglue in any clinic. I think we shouldsupport practices using mid-levelproviders and physician assistants,because they are so critical. Nursepractitioners add a lot of value. I sup-port increasing not only the popula-tion but also the education incentivesof physician assistants, nurse practi-tioners, and oncology nurses. They arepart of the oncology team, especiallywhen we see the number of oncolo-gists decreasing relative to demand. Itis great to see practices that truly workas an integrated team. �

The Crisis in Cancer... Continued from page 26



ONCOLOGY PRACTICES


Oncologists Face Economic Challenges... Continued from page 27

grams....It keeps them on their treat-ment schedule, which is very impor-tant,” Mr Natelson said.Mr Natelson added that specialty

pharmacies have an advantage overoncology practice offices, because theyget immediate adjudication. “Theyknow that the claim blew up right thenand there,” he said. “On the otherhand, an oncology office will give adrug, file a claim, and 2 weeks later, itblows up. Now what do I do? I didn’thave a chance to change the therapy orsay, ‘Is there another therapy that’sclinically close that I can get approvedfor the patient?’”

Working with Payers, Patients

One of Dr Deligdish’s solutions toeconomic hardships is his collaborationwith physicians in Florida. As a mem-ber of the Florida Comprehensive CareNetwork, he is in a partnership ofphysicians through a clinically integrat-ed network working with technologysolutions, advanced care, palliative careprograms, and oncology benefit man-agement programs working with pay-ers who also face challenges from theirself-insured clients to try to reduce thecost of cancer treatment.“It provides physicians and health

plans with the tools to manage path-way and guideline adherence, createphysician guidelines, and realign in -centives around buy and bill,” DrDeligdish said. “But more important, it

provides patients with the tools theyneed to determine appropriate care, theappropriate time to stop treatment, andthe appropriate time to enter hospice.” Although many people have been

critical of some components of theircare delivery system, Dr Deligdish saidthey have put together what theybelieve to be an integrated comprehen-sive approach to managing the costand the care that patients receive. Thegoals of the network include sustainingcommunity oncology. “We believe the community setting

is one of the best places to receive can-cer treatment, so we are working withpractices and health plans to hopefullyprovide the most cost-effective treat-ment in the most cost-effective set-ting,” Dr Deligdish said.The network also aims to provide

technology for consistent delivery ofquality care that allow both practicesand health plans to measure outcomesand monitor adherence to pathways,and decrease the administrative bur-den by simplifying and obviating theprior authorization process and usingtechnology.“We focus to a large degree as a

clinically integrated network,” DrDeligdish added. “What does thatmean? Clinical integration is necessaryfor accountable care organizations to bea reality. It’s an active and ongoing pro-gram to evaluate and modify practicepatterns by the network’s physicianparticipants to create a high degree ofinterdependence and cooperation tocontrol costs and ensure quality.“The Federal Trade Commission

needs to formulate additional rulessuch that physicians and hospitals willbe able to deliver care in a clinicallyintegrated setting,” he continued. “Butit requires a tremendous amount ofeffort, both financial capital andhuman capital, by physicians to cometogether and put together guidelinesand pathways that work, and to workwith health plans to achieve thosegoals,” he said.

Value-Based Personalized

Medicine

The concept of personalized medi-cine should result in the greatest valuefor patients and payers by providingbest clinical outcomes and most effec-tive use of resources, according to Yu-Ning Wong, MD, MSCE, a medicaloncologist and health services re -searcher at Fox Chase Cancer Center,Philadelphia, PA. As a physician inacademic practice, Dr Wong is workingtoward increasing the value of newtreatments in development.

“I think of this as an attempt to helpphysicians like me identify the best,most effective, and least toxic treatmentfor the individual patient,” she said.Personalized medicine “should resultin the best clinical outcomes forpatients, and it should result in themost effective use of resources for pay-ers, because we won’t be treatingpatients with expensive therapies that

have a low likelihood of helping them.”Breast cancer may be the furthest

along in terms of personalized medi-cine, according to Dr Wong. The vastmajority of patients with estrogen-receptive–positive breast cancer under-go surgery and receive hormonal ther-apy alone, but until very recently,identifying the patients who were mostlikely to have a recurrence was diffi-cult, and physicians were overtreatingwith chemotherapy.Clinical trials and the introduction of

the Oncotype DX assay are helpingphysicians in clinical practice to identi-fy patients who are likely to benefitfrom chemotherapy and those whocould be spared the toxicity becausethey are unlikely to benefit.“We need payers to eliminate the

barriers to coverage for clinical trials,”Dr Wong said. “Only about 5% ofAmerican patients enter clinical trials,and it is very difficult to get them on.The irony of this is that, in most cases,the standard of care we’re asking pay-ers to cover is very similar, if not iden-tical, to what we would be treatingthese patients with off study. But whenwe treat them off study, the data do nothelp to benefit future patients. It’simportant for practices to discuss andsupport clinical trials early on.”In her practice, Dr Wong focuses

mainly on kidney cancer, and treat-ment has changed dramatically in thepast 5 to 6 years, with the approval of 6new agents that have more than dou-bled overall survival.“Because there have been so many

trials in recent years, this is actually adisease site that has the most NationalComprehensive Care Network catego-ry 1 evidence. And one would assumethat it’s now easy to treat kidney cancerbecause we have a lot of guidelines.But unfortunately it’s really not,” shenoted. There are 3 regimens for kidneycancer often used in the frontline set-ting, Dr Wong said, but at this point,there are no published data to demon-strate the most effective drug. Ongoingclinical trials will help with sequencingpatients in the first, second, and subse-quent lines of therapy.“Personalized medicine for kidney

cancer comes down to some seeminglysimple, but actually complicated, dis-cussions that we have at the bedside,”she explained. “We don’t know whatthe best treatment is for the individualpatient. We need to decide if a treat-ment is working, or if oral or intra-venous treatment is better. Will sideeffects keep a patient from working,and what will the treatment cost be tothe practice and to the patient?” �

at a glance� An average encounter in anoncologist’s office could result in a $10,000 or $20,000 bill

� The estimated annual cost forphysician practices to interactwith health insurance plans is$23 billion to $31 billion

� There is a need to reduce the administrative burden foroncology practices

� By 2020, 61.1 millionAmericans will be uninsured

� Payers need to eliminate thebarriers to coverage for clinicaltrials to encourage greaterpatient participation in thedevelopment of improvedtherapies

“We need payers toeliminate the barriers tocoverage for clinical trials.Only about 5% of Americanpatients enter clinical trials,and it is very difficult to get them on.”

—Yu-Ning Wong, MD, MSCE

“Your 2 largest expenses in an oncology practice arethe drugs and your payroll,and you have to manageboth of them well in order to survive.”

–Leonard H. Natelson


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discontinuation of therapy� DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation� DOXIL® can cause fetal harm when used during pregnancy� Recall reaction has occurred with DOXIL® administration after radiotherapy� DOXIL® may interact with drugs known to interact with the conventional formulation

of doxorubicin HCl� In patients with recurrent ovarian cancer, the most common all-grade adverse reactions

(ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%)

— In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively)

were neutropenia (12% vs 76%) and anemia (6% vs 29%)� In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL®

plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%)

— In addition, 19% vs <1% reported HFS

Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages.

VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

DOXIL® C.A.R.E.S. Provides Help and Support


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

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

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

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

Table 1: Number of Patients With Advanced Breast CancerDOXIL (n=250)

Patients who Developed Cardiotoxicity 10(LVEF Defined)

Cardiotoxicity (With Signs & Symptoms of CHF) 0Cardiotoxicity (no Signs & Symptoms of CHF) 10

Patients With Signs and Symptoms of CHF Only 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiacfailure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema andpulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% ineach group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decreasebelow the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF.

Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in therandomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms:flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest andthroat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Inmost patients, these reactions resolve over the course of several hours to a day once the infusion is terminated.In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treatedwith DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDS-related Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because ofinfusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusionreactions have been reported. Medications to treat such reactions, as well as emergency equipment, should beavailable for immediate use. The majority of infusion-related events occurred during the first infusion. Similarreactions have not been reported with conventional doxorubicin and they presumably represent a reaction to theDOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimizethe risk of infusion reactions [see Full Prescribing Information].

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

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

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling,pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of thepatients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skintoxicity. HFS toxicity grades are described in Dosage and Administration section [see Full PrescribingInformation]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% ofpatients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to twoweeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manageHFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and mayrequire discontinuation of treatment.

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

Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman.There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy,or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to thefetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of thedrug must be considered. Women of childbearing potential should be advised to avoid pregnancy duringtreatment with Doxil. [see Full Prescribing Information].

Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies.Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-inducedtoxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration ofdoxorubicin HCl.

Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequentlyand at a minimum prior to each dose of DOXIL [see Warnings and Precautions].

ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in moredetail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [seeWarnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [seeWarnings and Precautions]

The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis,vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia andanemia. The most common serious adverse reactions observed with DOXIL are described in Section AdverseReactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including:239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiplemyeloma.

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

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

Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian CancerDOXIL Topotecan

Patients Patients(n = 239) (n = 235)

Neutropenia500 - <1000/mm3 19 (7.9%) 33 (14.0%)<500/mm3 10 (4.2%) 146 (62.1%)

Anemia6.5 - <8 g/dL 13 (5.4%) 59 (25.1%)<6.5 g/dL 1 (0.4%) 10 (4.3%)

Thrombocytopenia10,000 - <50,000/mm3 3 (1.3%) 40 (17.0%)<10,000/mm3 0 (0.0%) 40 (17.0%)

Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study ofDOXIL compared to topotecan.

Table 3: Ovarian Cancer Randomized StudyNon-Hematologic DOXIL (%) treated Topotecan (%) treatedAdverse Reaction 10% or Greater (n = 239) (n =235)

All Grades All Grades grades 3-4 grades 3-4

Body as a WholeAsthenia 40.2 7.1 51.5 8.1Fever 21.3 0.8 30.6 5.5Mucous Membrane 14.2 3.8 3.4 0DisorderBack Pain 11.7 1.7 10.2 0.9Infection 11.7 2.1 6.4 0.9Headache 10.5 0.8 14.9 0

DigestiveNausea 46.0 5.4 63.0 8.1Stomatitis 41.4 8.3 15.3 0.4Vomiting 32.6 7.9 43.8 9.8Diarrhea 20.9 2.5 34.9 4.2Anorexia 20.1 2.5 21.7 1.3Dyspepsia 12.1 0.8 14.0 0

Nervous Dizziness 4.2 0 10.2 0

RespiratoryPharyngitis 15.9 0 17.9 0.4Dyspnea 15.1 4.1 23.4 4.3Cough increased 9.6 0 11.5 0

Skin and AppendagesHand-foot syndrome 50.6 23.8 0.9 0Rash 28.5 4.2 12.3 0.4Alopecia 19.2 N/A 52.3 N/A

WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTALSUBSTITUTION1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage maylead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a startingdose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500-550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclinesor anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may alsooccur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrentcyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, butnot limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in thechest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In mostpatients, these reactions resolve over the course of several hours to a day once the infusion is terminated. Insome patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treatsuch reactions, as well as emergency equipment, should be available for immediate use. DOXIL should beadministered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings andPrecautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should bereduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidentalsubstitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substitutedfor doxorubicin HCl on a mg per mg basis [see Full Prescribing Information].


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

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

Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2%Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. Themedian time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m2

and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immunesystem, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 countwas 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count atstudy entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs incombination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or moreantiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% onzalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) onsulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarilyfluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir,and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim)sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patientswith AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adversereactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis,progression of a non-KS tumor, allergy to penicillin, and unspecified reasons.

Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s SarcomaPatients With Total Patients

Refractory or Intolerant WithAIDS-Related AIDS-Related

Kaposi’s Sarcoma Kaposi’s Sarcoma(n = 74) (n = 720)

Neutropenia<1000/mm3 34 (45.9%) 352 (48.9%)<500/mm3 8 (10.8%) 96 (13.3%)

Anemia<10 g/dL 43 (58.1%) 399 (55.4%)<8 g/dL 12 (16.2%) 131 (18.2%)

Thrombocytopenia<150,000/mm3 45 (60.8%) 439 (60.9%)<25,000/mm3 1 (1.4%) 30 (4.2%)

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

Adverse Patients With Total PatientsReactions Refractory or Intolerant With

AIDS-Related AIDS-RelatedKaposi’s Sarcoma Kaposi’s Sarcoma

(n = 77) (n = 705)Nausea 14 (18.2%) 119 (16.9%)Asthenia 5 (6.5%) 70 (9.9%)Fever 6 (7.8%) 64 (9.1%)Alopecia 7 (9.1%) 63 (8.9%)Alkaline Phosphatase 1 (1.3%) 55 (7.8%)Increase Vomiting 6 (7.8%) 55 (7.8%)Diarrhea 4 (5.2%) 55 (7.8%)Stomatitis 4 (5.2%) 48 (6.8%)Oral Moniliasis 1 (1.3%) 39 (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’ssarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills.Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouthulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia.Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis,moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block,congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic andNutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages:maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis.

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

myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology.

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Blood and lymphatic system disordersNeutropenia 36 22 10 22 11 5Thrombocytopenia 33 11 13 28 9 8Anemia 25 7 2 21 8 2General disorders and administration site conditionsFatigue 36 6 1 28 3 0Pyrexia 31 1 0 22 1 0Asthenia 22 6 0 18 4 0Gastrointestinal disordersNausea 48 3 0 40 1 0Diarrhea 46 7 0 39 5 0Vomiting 32 4 0 22 1 0Constipation 31 1 0 31 1 0Mucositis/Stomatitis 20 2 0 5 <1 0Abdominal pain 11 1 0 8 1 0

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiplemyeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRATerminology. (continued)

Adverse DOXIL + bortezomib BortezomibReaction (n=318) (n=318)

Any Grade Grade Any Grade Grade(%) 3 4 (%) 3 4

Infections and infestationsHerpes zoster 11 2 0 9 2 0Herpes simplex 10 0 0 6 1 0InvestigationsWeight decreased 12 0 0 4 0 0Metabolism and Nutritional disordersAnorexia 19 2 0 14 <1 0Nervous system disordersPeripheral Neuropathy* 42 7 <1 45 10 1Neuralgia 17 3 0 20 4 1Paresthesia/dysesthesia 13 <1 0 10 0 0Respiratory, thoracic and mediastinal disordersCough 18 0 0 12 0 0Skin and subcutaneous tissue disordersRash** 22 1 0 18 1 0Hand-foot syndrome 19 6 0 <1 0 0*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathyperipheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS.

**Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular,rash pruritic, exfoliative rash, and rash generalized.

Post Marketing Experience: The following additional adverse reactions have been identified during post approvaluse of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic andMediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders:Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whosetreatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interactwith drugs known to interact with the conventional formulation of doxorubicin HCl.

USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients havenot been established.

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

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

0016716-5BManufactured by:Ben Venue Laboratories, Inc.Bedford, OH 44146Distributed by:Ortho Biotech Products, LPRaritan, NJ 08869-0670

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

TM

An ALZA STEALTH®

Technology Product


PATIENT NAVIGATION


Patient Navigation and Patient Assistance Programs in Oncology By Wayne Kuznar

Philadelphia, PA—The medically under -served population needs easier accessto healthcare and tools that provide aseamless transition between all phasesof the treatment process, from screen-ing through therapy and survivorship.Payers play an important role in thefuture of oncology and need to be inthe decision-making network.Patient assistance and patient navi-

gation programs aim to provide

patients with reliable education toinform their decision-making, butthese programs are sometimes referredto as “add-ons,” and they cost money. “Patient navigation is a concept that

evolved in the 1990s,” said StevenPatierno, PhD, Executive Director,George Washington University CancerInstitute, Washington, DC. “It wasoriginated to access healthcare barri-ers, and we need to keep focusing onovercoming these barriers.” The 3 main barriers include structur-

al, socioeconomic, and financial barri-ers (Table). To overcome these barri-ers, Dr Patierno and colleagues from 9centers across the country took part inthe National Cancer Institute (NCI)Patient Navigation Research Program,a $29 million program funded by theNCI to study patient navigation. Thestudy focused on narrowing the win-dow between cancer-related findings,diagnosis, and the onset of treatment.It also examined its cost-effectiveness. After 6 years of research, which is

slated for publication, the team devel-oped specific models, including thelongitudinal patient navigation model. “To keep it as cost-effective as possi-

ble, patient navigation was envisionedas picking up people at suspiciousfinding, navigating them to the onsetof treatment, and then stoppingbecause it was obviously too expen-sive to do otherwise,” Dr Patiernosaid. “So we’ve created this idea oflongitudinal navigation that dovetailswith outreach. It actually helps peopleget into and through screening, pastdiagnosis, and into treatment, and

then it follows 2 or 3 years into theposttreatment survivorship period.”

Defining Value in Patient

Navigation

Patient navigation has an impact oncare and cost, and defining the conceptis still a challenge. “As the concept of

patient navigation has ‘steamrolled’across the country, it has morphed intomany different things. In some areas,patient navigation has evolved intoactually little more than a ‘medicalconcierge service,’” Dr Patierno said. “They say, ‘Come to our center and

meet with our patient navigators.’That’s great, because it’s very hard foreven intelligent people with advanceddegrees to navigate their way throughthe labyrinth of our cancer healthcaresystem, but the people who are desper-ately in need of patient navigation arethe ones who are affected by barriers.” Dr Patierno and Dawn Holcombe,

MBA, President, DGH Consulting,and Executive Director, ConnecticutOncology Association, agree that defi-nition is a clear challenge. “There is not just one definition for

value in patient navigation, and thecriteria are not consistent,” MsHolcombe said. “We can’t define it as avalue if we don’t know what it is.” Certain criteria should be consid-

ered in defining the value and qualityof navigation systems, and theseinclude education and training of nav-igators and certification programs, sheadded. The systems should focus onscreening and outreach, barriers, andservices. Additional challenges include lack

of reimbursement, HIPAA accessissues, care delivery models, andhealthcare reform. Currently, the vastmajority of patient navigation pro-grams are supported by philanthropyand small grants from foundations, DrPatierno said.“The most demonstrable success

comes from programs that focus onscreening and outreach,” said MsHolcombe. For example, 2 hospital-based navi-

gation programs focusing on screeningand outreach saw a 30% increase in5-year survival rates in women diag-nosed with breast cancer, and anothercenter reduced the rate of no-showsfrom 67% to 10%. The program also demonstrated a

decreased wait time from initial visit tothe procedure and increased earlydetection by as much as 50%. “We findthat navigation programs can increasescreening and adherence to diagnosticfollow-up,” she said. In addition to the NCI Patient

Navigation Research Program, theAmerican Cancer Society PatientNavigation Program aims to provide

“Patient naviga tion is aconcept that evolved in the1990s. It was originated toaccess healthcare barriers,and we need to keepfocusing on overcomingthese barriers.”

—Steven Patierno, PhD

“There is not just one de finition for value inpatient naviga tion, and thecriteria are not consistent.We can’t define it as a valueif we don’t know what it is….Navigation programs can increase screening andadherence to diagnosticfollow-up.”

—Dawn Holcombe, MBA

Table Patient Navigation: Overcoming Access Barriers

Logistic/structural barriers Sociocultural barriers Financial barriers

Barriers presenting a logistic challenge toengaging in care have a potential logisticaction or resource available

Arising as a result of patients’ ethnic,social, and cultural beliefs and may not be easily overcome by logistic actions

Related to socioeconomic status that can-not be easily explained by patients’ cultur-al background and may not be overcomeby simple logistic actions

Transportation Fear Child care

Location of facility Perceptions about tests Adult care

System scheduling problems Literacy Housing

Out of town/country Social/practical support Financial problems

DisabilityMental/medical comorbidities

Communication concerns with medicalpersonnel

Employment issues

Language Attitudes toward providers

InsuranceContinued on page 33


PATIENT NAVIGATION


reliable patient education and informa-tion to support informed decision-making and resources and emotionalsupport, and the Centers for Medicare& Medicaid Services Cancer Pre -vention and Treatment Demonstrationfor Ethnic and Racial Minorities aimsto help minority beneficiaries navigatethe health system in a timely andinformative manner. “There are also a number of home-

grown models, which you can find athospitals, cancer centers, physicianoffices, and through the pharmaceuti-cal industry,” Ms Holcombe said. “Butnone of them have the same defini-tion” of concept or value.Ms Holcombe said she believes there

is so much variation because each pro-gram has a different agenda, a differentgoal, and access to different patients.“When considering a patient naviga-tion system, one should identify theaim, figure out how the value andresults will be measured, identify thetarget population and scope of servicesand resources, identify who will pay,and figure out if the patient can receivefollow-up care.”

Treatment in the Office Setting

Leonard Natelson, Chief ExecutiveOfficer, Hematology/Oncology Asso -ci ates of Rockland, NY, is 1 of 5 physi-cians in a community oncology prac-tice; he said he does not fullyunderstand why there is a big push toget patients to hospital settings fortreatment. “That’s basically what is happen-

ing,” he said. “Some physicians aresaying they cannot be bothered withhuman resources, accounting, and

payables. They just want to treat theirpatients. But you have to create thatenvironment.” By no longer using the “buy and

bill” method and by using specialtypharmacies, Mr Natelson is now ableto treat his patients in the office. “That has saved our practice. I have

a bigger practice, we offer more serv-ice, and my physicians can treat theway they want,” he said. “They do nothave the financial impact on what’sgoing on with reimbursements for thedrugs. And this saves our payers a tonof money.

“The biggest issue is giving yourphysicians an alternative,” Mr Natelsoncontinued. “We have to be able to work

with our patients, keep their commutesdown, and give them a nice setting tobe treated in.”

Patient Advocacy Set Up

by Survivors

Monica Knoll, who was diagnosedwith breast cancer in 2000 and withovarian cancer in 2006, founded CAN-CER101, a nonprofit organization toempower patients with cancer to man-age their own care.Ms Knoll said that physicians must

take responsibility for letting theirpatients and caregivers know all of thefacts when recommending chemother-apy treatments. “Oncologists should research and

share with their patients clinical trialopportunities that are available insideand outside of their own cancer cen-ters,” she said. “They shouldn’t letfinancial gain win over what is best forthe patient.” In addition, when a drug becomes

cost-prohibitive for a patient, it is theoncologist’s responsibility to explainthe pros and cons as well as to recom-mend another drug that will not createfinancial hardship to the patient andfamily, she added.

“It’s important that the patient andfamily are aware that a treatmentmight offer a 10% chance of increasedsurvival over another treatment, but italso may make the patient so sick thathis or her quality of life will suffergreatly,” Ms Knoll said. “Saving lives isone thing, but ending someone’s lifewith dignity is another.” Ms Knoll suggested that it is irre-

sponsible for an oncologist to continueto offer treatment recommendationswhen the pa tient is clearly dying andis no longer experiencing any qualityof life. When the time comes, theoncologist needs to gently addresshospice and end-of-life instead of rec-ommending another drug and givingthe patient and the family false hope. “The more conversations you have

with your patients and your families,the easier it gets,” Ms Knoll said.Regretfully, Ms Knoll died on June 20,2011, a few months after her presenta-tion at the conference. �

“That has saved our practice.I have a bigger practice, weoffer more service, and myphysicians can treat the waythey want.”

—Leonard Natelson

at a glance� Navigation programs can

increase screening and

adherence to diagnostic

follow-up

� Two hospital-based navigation

programs saw a 30% increase in

5-year survival rates in women

with breast cancer

� Oncologists must inform

patients and caregivers of all the

facts when recommending

chemotherapy treatments

� Oncologists should inform their

patients about clinical trial

opportunities

� When clinically appropriate,

oncologists must address

hospice and end-of-life issues

instead of recommending

another therapy

Monica Knoll

In 2000, at age 36, MonicaKnoll was diagnosed withstage II breast cancer, and in2006 with ovarian cancer.While being treated for breastcancer, Ms Knoll foundedCANCER101, de signed toem power cancer patients andtheir caregivers to fight thedisease from the moment ofdiagnosis. Monica died onJune 20, 2011. CANCER101 isnow used by thousands ofpatients across the country.Ms Knoll worked tirelessly tofurther the cause of patientswith cancer. Donations to hercause can be made online atwww.CANCER101.org.

“Oncologists should research and share with their patientsclinical trial opportunitiesthat are available inside andoutside of their own cancercenters. They shouldn’t letfinancial gain win over whatis best for the patient.”

—Monica Knoll


MCM0000417100 06/11

R

The VEGF ligand is one of the fi rst 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

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

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

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

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

V E G F I N H I B I T I O N

THE PROPOSED EFFECTS OF

AVASTIN®

The VEGF ligand is one of the fi rst pro-angiogenic factors and is present throughout the tumor life cycle1,2,3

VEGF

VEGF Inhibition

Avastin

B


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

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.

Boxed WARNINGS and additional important safety informationGastrointestinal (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 rangedfrom 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 fi stula 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 fi rst 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.


Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe 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 ComplicationsThe 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).]HemorrhageSevere or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to �ve-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).]

1 INDICATIONS AND USAGE1.1 Metastatic Colorectal Cancer (mCRC)Avastin is indicated for the �rst- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-�uorouracil–based chemotherapy.1.2 Non-Squamous Non–Small Cell Lung Cancer (NSCLC)Avastin is indicated for the �rst-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 GlioblastomaAvastin 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 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious 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 �stula formation. The majority of cases occurred within the �rst 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 ComplicationsAvastin 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 HemorrhageAvastin 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 �ve-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 FormationSerious and sometimes fatal non-gastrointestinal �stula 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 �rst 6 months of Avastin therapy.Discontinue Avastin in patients with �stula formation involving an internal organ. [See Dosage and Administration (2.4).]5.5 Arterial Thromboembolic EventsSerious, 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 HypertensionThe 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%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension after discontinuation of 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 encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to con�rm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed �ndings consistent with thrombotic microangiopathy.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 dipstick reading should undergo further assessment with a 24-hour urine collection.

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 ReactionsInfusion 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 �rst 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 REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the label:

Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] 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 ExperienceBecause 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 re�ect the rates observed in practice.The data below re�ect 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 �rst- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 �rst-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 ComplicationsThe 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 �uid 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).]HemorrhageThe 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 EventsThe 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 InfectionThe 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 �rst 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%.ProteinuriaGrade 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 FailureThe 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.

Table 1 NCI-CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI-CTC Grade 3-4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra-Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central 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.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the �rst approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2 NCI-CTC Grade 1-4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5-FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second-line mCRCOnly Grade 3-5 non-hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in Study 4. Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events (occurring 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 (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary in�ltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non-hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety pro�le of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 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 compared to 304 patients receiving IFN-α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN-α plus Avastin compared to the IFN-α plus placebo arm are presented in Table 4.

Table 4 NCI-CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN-α + Avastin vs. IFN-α + Placebo)

System Organ Class/ IFN-α + Placebo IFN-α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal re�ux 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) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and speci�city of the assay. Additionally, the observed incidence of antibody positivity in an assay may be in�uenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identi�ed during post-approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular in�ammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous �oaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no signi�cant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of speci�c gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential bene�t to the pregnant woman justi�es the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for 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 (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic pro�le of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insuf�cient information to determine the safety and ef�cacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.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 Precautions (5.8).]In Study 5, there were insuf�cient numbers of patients ≥ 65 years old to determine whether the overall adverse events pro�le was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any 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 cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in �ve randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with 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 (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080-4990


REIMBURSEMENT ISSUES


Philadelphia, PA—When preparing totackle oncology drug reimbursementconcerns, it is critical to understand thebenchmarks that influence reimburse-ment, according to John F. Aforismo,BScPharm, RPh, FASCP, Chief Execu -tive Officer, RJ Health Systems Inter -national, Rocky Hill, CT.At a payers’ session on reimburse-

ment issues, Mr Aforismo said that thecommercial sector evaluates thesebenchmarks when managing oncolo-gy drug reimbursement. The bench-marks, which are part of provider con-tracts, include the average sales price(ASP), average wholesale price (AWP),maximum allowable cost (MAC),whole sale acquisition cost (WAC),Inter national Classification of Diseases,Ninth Revision (ICD-9), HealthcareCommon Procedure Coding System(HCPCS) versus National Drug Code(NDC), and clinical guidelines.Peyton Howell, MHA, President,

Consulting Services, and Senior VicePresident, Business Development,AmerisourceBergen, Frisco, TX, notedthat ASP, which came about via theMedicare Modernization Act and car-ries a 2-month lag time in reimburse-ment, has “dramatically changed” thereimbursement for oncology care,because Medicare and most privatepayers use some form of ASP-basedpayment. She cited 2 key “flaws” inthe current system: reimbursementsfor cancer care management and treat-ment administration are inadequate—financial “losers.”“Because of reimbursement issues

involved with ASP, it makes no sensecurrently to do the right thing as aprovider for your oncology carepatients. That is why it is important tofind models to incent,” she said. In addition, the actual definition and

reporting of ASP have significantflaws, which create inconsistent pay-ment. Ms Howell said that one of thebiggest flaws of ASP is that it promoteshigh-cost products and discouragesthe use of low-cost products. “Theseare critical issues that have createdinconsistencies in the adequacy of ASPreimbursement, but congressionalaction is needed to clarify many ofthese issues,” Ms Howell said.

AWP, MAC, and WAC Benchmarks

The AWP (the price at which awholesaler sells a product to aprovider) is determined by 4 nationaldata sources—First DataBank, Medi-Span, Red Book, and Gold Standard.

All sources produce an AWP thatproviders use to bill for a product orthat payers use to reimburse for aproduct. According to Mr Aforismo, the

provider and physician communityuse Red Book as their guidance. Thepayer community uses either FirstDataBank or Medi-Span as a basis fortheir reimbursement methodology.Conse quently, the sources do notmatch, because there is a lag timebetween pricing that enters Red Bookand pricing that enters the payer’s sys-tem. “As a result, there is much talk asto whether AWP is going away. Theterm ‘AWP’ will eventually go away.Someone’s just got to come up withanother name, as the methodology isstill there,” he said.

Wholesalers set the AWP by percentprofit or another method—and theyset it immediately, because they haveto make a profit, Mr Aforismo noted.Currently, many manufacturers donot provide an AWP, but they willprovide a suggested AWP combinedwith a WAC. Commercial payers use MAC not

only on the pharmacy side but also onthe medical side, according to MrAforismo. Controversy about MAC onthe pharmacy side is abundant, yetsome payers are looking at MAC asanother way of reimbursing a provider. “The MAC on an HCPCS drug code

level probably is a lot better than anASP plus level. It gives incentive toproviders to use a generic if a genericis available,” he said. There’s alsoMAC on an NDC level. Acquisitioncosts are used as a reference. The WAC is yet another benchmark

to review. “The only problem in aWAC-based system is you will notreceive a WAC in a generic environ-ment, nor will you see it in a repack-aged environment. WAC is onlyfor a limited supply of drugs,” MrAforismo said.

Guidelines and Coding

The reimbursement meth odologyreviews the guidelines, tying theminto the drug component. “It’s abouthow to pay for a drug adequately,as well as pay for the service. Payersare struggling with this,” MrAforismo noted. Controversy surrounds the HCPCS

versus NDC benchmark. Accordingto Mr Aforismo, payers are asking forthe NDC in nonclassified codes. Phar -

maceutical companies have put a newcrease in this. With the ability to cap-ture an NDC, pharmaceutical compa-nies are able to receive data. Payers areable to be remunerated for the datathey receive. Finally, Mr Aforismo addressed the

ICD-9. With this benchmark, payersare using methodologies that willassociate an ICD-9 code (US Food andDrug Admin istration– and compen-dia-listed) with pricing and othercharacteristics and adjudicate a claimfinancially and clinically.

Future Trends

One trend to look for involves pay-ers’ adherence to clinical guidelines forappropriate use of pharmaceuticals.Another trend entails episodes of careper treatment regimen relating to howpatients should be treated, and how aprovider should be reimbursed.

Ms Howell elaborated on trendslinked to the growth in pharmaceuti-cals, especially in oncology. The fore-casted growth between 2009 and 2014for specialty (6%) and nonspecialty(4%) pharmaceuticals is substantial.The growth is disproportionate inoncology (7%). “It’s a challenge, because the same

healthcare providers who are focusedon oncology patients have a dispro-portionate share of Medicare patients.Because Medicare is the primary payerfor most cancers, this creates a lot ofpressure on managed care contracts,”Ms Howell commented. Perhaps not surprising is the trend

that oncology practices are struggling,Ms Howell said. In recent surveys byAmerisourceBergen, oncology prac-tices answered a series of questionsabout their financial health over time.The vast majority of respondents (70%of the total) indicated they are in aworse situation than before. To offsetlost revenue, most have diversifieddramatically outside of their coreoncology focus. Practices were surveyed regarding

their most significant negative drivers.For 74% of respondents, the top driverwas Medicare reimbursement. Privatereimbursement is also an issue, and63% ranked this in the top 3 drivers. Inresponse to financial pressures, manypractices are considering closing loca-tions or seeking acquisition by anotherentity. Underserved or rural areas mayfind it especially difficult to reversesome of these trends, Ms Howell said. Scott Breidbart, MD, Chief Medical

Officer, Empire Blue Cross/BlueShield, NY, said that the patient mustbe kept at the forefront of all reim-bursement issues. “Our job is to makesure treatment is based on patients’best interest. We need to reimburse ina manner that is appropriate and doesnot incentivize other uses,” he said.Some options to consider when

evaluating reimbursement of oncolo-gists include offering global paymentby diagnosis, monitoring use of es -tablished protocols, requiring priorauthorization, and using an oncologypharmacy vendor. �

Oncology Drug Reimbursement and Administration BenchmarksBy Wayne Kuznar

Guide line re -imburse ment is“about how topay for a drugad e quately, aswell as pay forthe service.

Payers are struggling with this.”

—John F. Aforismo, BScPharm, RPh, FASCP

“Because of reimbursement issues involved with ASP, itmakes no sense currently to do the right thing as a providerfor your oncology care patients. That is why it is important tofind models to incent.” —Peyton Howell, MHA


MEDICARE TRENDS


Philadelphia, PA—Growth in Medi -care Part B spending, increasing rolesin specialty pharmacy, formationof accountable care organizations(ACOs), and bundling of payments forcare are all anticipated trends in theMedicare and reimbursement arenas,according to Jayson Slotnick, JD, MPH,Partner, Health Policy Strategies,Wash ington, DC. In 2009, a total of 46.3 million

Americans were covered by Medi -care, and approximately 10,000 newpeople are becoming Medicare eligi-ble every day as a result of the babyboomers coming of age. Conse quent -ly, the government is faced with thehuge spending for Medicare Part B,said Mr Slotnick. “Some figures from the most recent

Medicare Trustees Report note thatgovernment is looking at huge growthin Part B spending. Within Part Bspending is specialty drugs—especial-ly physician-administered drugs,” MrSlotnick said. “Part B costs are grow-ing rapidly, averaging 8.3% annualgrowth over the past 5 years,” henoted. This continuing expansion andgrowth evokes 3 independent issues inMedicare Part B:• How much of the cost will be reim-bursed?

• Will there be any payment at all?• How will it be billed?

Healthcare Reform Specifics

From a broader perspective, thehealthcare reform, or the PatientProtection and Affordable Care Act(ACA), addresses coverage and deliv-ery system reforms—in the form ofACOs and comparative effectivenessresearch—among other grand-scaleinitiatives.“Our federal government can create

markets, change markets, and destroymarkets. With the latest reiteration ofhealth reform, we have all 3 occurringat the same time,” said Mr Slotnick,who represents innovative companiesin the pharmaceutical/biotechnologydevice and diagnostic base, monitor-ing what goes on at the Centers forMedicare & Medicaid Services (CMS)

and the US Food and Drug Admin -istration regarding commercializationof products.The ACA does nothing to change

compendia policy or coverage criteria;however, it includes an expansion ofthe 340B drug discount program. Also,the ACA preserves current averagesales price payment methodology forsmall molecule pharmaceuticals andfor biologics administered in physi-cians’ offices. The ACA’s newly created CMS’s

Center on Medicare and MedicaidInnovation will test new ways toimprove quality and manage costs.Demonstrations of payment and deliv-ery system reforms in Medicare,Medicaid, and both programs will beestablished and may require more fed-eral money if quality is improved.Successful models may go nationwidewithout further congressional action.

ACOs Gaining Momentum

The ACA’s Medicare shared savingsprogram creates the option for health-care providers to form ACOs. A newnationwide ACO option in Medicarestarts January 2012. Physicians, hos -pitals, and other providers will beresponsible for quality and overall careof Medicare patients through an ACO.Medicare’s program will share sav-

ings from better quality, fewer hospi-talizations, and elimination of unnec-essary costs with ACO providers.Payment models will include fee-for-service with shared savings, andpartial capitation. The formation ofmultipayer ACOs is likely with partici -pa tion from state Medicaid programs.Many provider groups will be able

to form an ACO, including hospitals,physicians, physician groups, andother healthcare professionals via ajoint venture or partnership arrange-ment. In addition, physicians andother healthcare professionals ingroup practices or a network of prac-tices, along with integrated hospital–physician systems, will have an oppor-tunity to establish ACOs. The ACO option further extends to

hospitals, physicians, and post–acute

care providers, such as skilled nursingfacilities and home healthcare agen-cies. Although ACOs need not includea hospital, ACOs do require physicianparticipation.

Global Fees Enhance Patient Care

Continued consolidation of physi-cians’ offices will be seen in the nearfuture. Mr Slotnick indicated therewould be an increased migration ofspecialty products to the pharmacybenefit, specifically pertaining to theuse of pharmacy benefit tools on spe-cialty products and paying for adher-ence to clinical guidelines.The specialty pharmacy arena will

also have an increased role in datacollection and demonstrating valueproposition.Currently, the federal government is

establishing demonstrations to replacethe traditional fee-for-service paymentwith global fees to achieve incentivesfor quality. With global fees, the

provider gets to keep any savings fromgreater care efficiency and eliminationof unnecessary services.There are many opportunities to

improve quality, access, and cost-effec-tiveness through the use of global fees.To be effective, an adequate global feeis required, along with risk adjust-ment, capacity, infrastructure, newworkflow, and care redesign.

Bundled Payment

In the new Medicare bundled pay-ment initiative, a national Medicarepilot program is under way to investi-gate the single, bundled paymentbased on an episode of care rather thanthe fee-for-service payment system.This bundled payment approachwould include all inpatient, physician,outpatient, and post–acute care serv -ices from 3 days before admissionthrough 30 days after discharge. Thedemonstration project is set to beginby January 2013.As an option, state Medicaid pro-

grams could participate in this projector demonstrate their own bundledpayment models. If the state healthplans are successful, the overallMedicare bundled payment mayexpand nationwide in 2016.

Reimbursement Trends

Significant new reimbursementtrends include measurement and pub-lic reporting of clinical performance;expectation for evidence-based, patient-centered clinical practice; paymentmethods that place physicians, hospi-tals, and other providers financially atrisk for low-quality performance,which is in contrast to “insurance risk”experienced by health plans; andbundling of payments for an episodeof care or a condition.Other increasing reimbursement

trends involve using cost-effective -ness and comparative effectiveness re -search in making coverage decisions;payment rates and methods that areincreasingly driven by budget consid-erations; and recognition that the fiscaloutlook for Medicare is very poor,according to Mr Slotnick. �

“Our federal government can create markets, changemarkets, and destroymarkets. With the latestreiteration of healthcarereform, we have all 3occurring at the same time.”

—Jayson Slotnick, JD, MPH

Global Fees, ACOs, and New Reimbursement Trends Will Influence Medicare’s FutureBy Wayne Kuznar


ONCOLOGY PHARMACY


Philadelphia, PA—An expanding rolefor oncology pharmacy in the opti-mization of cancer care is likely toemerge over the next 3 to 5 years, aspayers seek better outcomes for theirmoney, said Jeff Ulanet, MBA, VicePresident, Oncology, Medco, at aroundtable payers’ discussion.Oncology pharmacy is a specialty

that will likely progress to mimic amedical specialty that a physician canuse to optimize treatment more than inthe past. “In fact, we can make the casethat specialization matters more in

oncology than in almost any other dis-ease,” Mr Ulanet said, as the roles ofpharmacogenomics and moleculartesting expand, along with symptommitigation and the management ofnutrition, drug–food interactions, andside effects.An expected shortage of oncologists

in the coming years will mean thatphysicians will look to pharmacists asan extension of their practice, he pre-dicted, in an attempt to obtain betteroutcomes for all the drugs and treat-

ments they render.The management of the cancer bene-

fit will be an ongoing challenge, as pay-ers try to find the right balance betweencost and efficacy. “If payers are goingto spend $100,000 on a patient, theywould like to see a better outcome,”said Mr Ulanet. “It’s not all about cost,but it is about outcomes for that cost.Pharmacy management and therapymanagement is the way in which youcan assure a better and greater use ofthe dollars you’re spending.”As precision therapies emerge, a

combination of technologies and activ-ities performed within the pharmacywill advance to optimize those thera-pies, he said. Expect the use of advanced electron-

ic prescribing to support decision toolsfor diagnostic tests and response mon-itoring that aid the pharmacy in theselection of patients for particulardrug therapies, said Mr Ulanet. Molecular testing will eventually be

incorporated into the pharmacy as amore efficient way to ensure optimaldrug delivery. Electronic medicalrecords and third-party payers willplay a role in automating the integra-tion of molecular testing and drug

delivery. Tools for enhancing patient self-

management may also emerge, as theaverage patient with cancer is receiv-ing a complex drug regimen thatincludes 10 oral drugs daily, he said.

Cost-Effective Delivery

of Cancer Care

In today’s market, keeping the buy-and-bill option in the physician’s officeis the best strategy for a commercialpayer to deliver cancer care, said AlanM. Lotvin, MD, President and ChiefExecutive Officer, ICORE Healthcare.It provides physicians a purchasingadvantage of about 17%, on a weight-ed average basis, over any pharmacy.The logistics of oncology drug dis-

pensing is also in favor of the physi-cian distributing the drug, because ofwaste in oncology drug delivery.“There’s no way around that problemunless you have a compounding phar-macy close to the doctor’s office thatwill deliver on demand…it’s not nec-essarily an easily scalable approach,”he said. The second challenge to removing

buy-and-bill from the physician is eco-nomics. When a vial of an oncologydrug is shipped to the physician’soffice, “the plan is going to be billedfor an entire vial,” said Dr Lotvin.Most physicians still want to be in

the buy-and-bill business, because it isa revenue generator that inflates at 7%to 8% annually. “The biggest challenge with taking

these drugs out of the physician’soffice is not just that the physician hasa lot of cost built into it, but that thewaste goes up dramatically and theamount that gets billed goes up dra-matically,” he said. “If you want to getrid of incentives, change the pricingto eliminate incentives; don’t worryabout the distribution model, and ifyou want to think about the distribu-tion model and where the drugs arecoming from, the doctors pulling themoff the shelves is often the least costlyand least wasteful.”About 70% of a community oncolo-

gist’s top-line revenue flows throughthe dispensing of drugs, said Kimberly

Bergstrom, PharmD, Chief ClinicalOfficer, McKesson Specialty CareSolutions. Traditionally, “we havefocused on fixing the reimbursementissue, but the real issue is appropriateutilization,” she said.One method for managing drug dis-

tribution is to pay physicians more forchoosing a generic when appropriate,providing them with an incentive toact in the plan’s best interest whileensuring that they’re never “underwater” in their drug purchases, saidDr Lotvin.

Dr Bergstrom agrees that a differen-tiated reimbursement for the use ofgenerics would allow communityoncologists to administer them with-out losing money. But the way reim-bursement is currently designed,providers stand to lose money bychoosing generics.As more equivalent oncologic drugs

(eg, more vascular endothelial growthfactors) make their way through thepipeline, Dr Lotvin sees some of thedecision-making in their use shiftingfrom provider to payer. “We’re still afew years away from having enoughcompetition; part of that is the pipelinerate coming out of the FDA, and part isdue to every drug having a uniqueindication, so it is hard to call themclinically equivalent,” he said. “We’llsee it more with the common thera-pies, but we’re not there yet.” �

Oncology Pharmacy as a SpecialtyNew distribution channels neededBy Wayne Kuznar

“If payers are going to spend$100,000 on a patient, theywould like to see a betteroutcome. It’s not all aboutcost; it is about outcomes for that cost.” —Jeff Ulanet, MBA

“The biggest challenge withtaking these drugs out of thephysician’s office is…that thewaste goes up dramatically,and the amount that getsbilled goes up dramatically.”

—Alan M. Lotvin, MD

“We have focused on fixingthe reimbursement issue, butthe real issue is appropriateutilization.”

—Kimberly Bergstrom, PharmDat a glance� The role of oncology pharmacy

is expected to increase as

payers seek better outcomes

for their money

� With fewer oncologists

available, physicians will look

to pharmacists as an extension

of their practice

� About 70% of a community

oncologist’s revenue is

generated through the

dispensing of drugs

� Advanced electronic

technologies will aid the

pharmacy in the selection of

patients for particular drug

therapies

� Molecular testing will

eventually be incorporated into

pharmacy to ensure optimal

drug delivery


KNOW YOUR PATIENTS’ HISTOLOGY AND BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL

ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer.

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

Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy.ALIMTA is available in 100 mg and 500 mg vials.

Important Safety Information for

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

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

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

ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities.

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

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

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

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

Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA.

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

PM70198 0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.ALIMTA® is a registered trademark of Eli Lilly and Company.

ALIMTA®

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0511 PRINTED IN USA © 2011, Lilly USA, LLC. ALL RIGHTS RESERVED.A

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ALIMTA® (pemetrexed for injection)

Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA.

See Warnings and Precautions for specifi c information regarding ibuprofen administration.

Use in Specifi c Patient PopulationsIt is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, takinginto account the importance of the drug for the mother.

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

Dose adjustments may be necessary in patients with hepatic insuffi ciency.

Dosage and Administration GuidelinesComplete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA.

Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

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

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

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

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

PM_HCP_ISI_NSCLC1_04052011

insideALIMTA.com


ALIMTA® (pemetrexed for injection) PV 5209 AMP ALIMTA® (pemetrexed for injection) PV 5209 AMP

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

1 INDICATIONS AND USAGE

1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with CisplatinALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or

metastatic nonsquamous non-small cell lung cancer.

1.5 Limitations of UseALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies

(14.1, 14.2, 14.3) in the full Prescribing Information].

2 DOSAGE AND ADMINISTRATION

2.1 Combination Use with CisplatinNonsquamous Non-Small Cell Lung CancerThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of

each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information.

2.2 Single-Agent UseNonsquamous Non-Small Cell Lung CancerThe recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of

each 21-day cycle.

2.3 Premedication RegimenVitamin SupplementationTo reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or

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

CorticosteroidSkin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with

dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)].

2.4 Laboratory Monitoring and Dose Reduction/Discontinuation RecommendationsMonitoringComplete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients

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

Dose Reduction RecommendationsDose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum

nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow suf�cient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin.

Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities

Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. 75% of previous dose (pemetrexed and cisplatin).

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

Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. 50% of previous dose (pemetrexed and cisplatin).

a These criteria meet the CTC version 2.0 (NCI 1998) de�nition of ≥CTC Grade 2 bleeding.

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

Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b

Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2)

Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose

Any diarrhea requiring hospitalization (irrespective of Grade) or Grade 3 or 4 diarrhea

75% of previous dose 75% of previous dose

Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

a NCI Common Toxicity Criteria (CTC).b Excluding neurotoxicity (see Table 3).

In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced.

Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity

CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2)

0-1 100% of previous dose 100% of previous dose

2 100% of previous dose 50% of previous dose

Discontinuation RecommendationALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity

after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed.Renally Impaired PatientsIn clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those

recommended for all patients. Insuf�cient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHSALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile

single-use vials containing 100 mg or 500 mg pemetrexed.

4 CONTRAINDICATIONSALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other

ingredient used in the formulation.

5 WARNINGS AND PRECAUTIONS

5.1 Premedication RegimenNeed for Folate and Vitamin B12 SupplementationPatients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce

treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered.

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

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

5.2 Bone Marrow SuppressionALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or

pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)].

5.3 Decreased Renal FunctionALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine

clearance ≥45 mL/min. Insuf�cient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)].

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

5.4 Use with Non-Steroidal Anti-In�ammatory Drugs with Mild to Moderate Renal Insuf�ciencyCaution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate

renal insuf�ciency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)].

5.5 Required Laboratory MonitoringPatients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is

≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)].

5.6 Pregnancy Category DBased on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed

administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Speci�c Populations (8.1)].

5.7 Third Space FluidThe effect of third space �uid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically

signi�cant third space �uid, consideration should be given to draining the effusion prior to ALIMTA administration.

6 ADVERSE REACTIONS

6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly

compared to rates in other clinical trials and may not re�ect the rates observed in clinical practice.In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were

fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation.

Non-Small Cell Lung Cancer (NSCLC) - Combination with CisplatinTable 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with

NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12.

Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa

ReactionbALIMTA/cisplatin

(N=839)Gemcitabine/cisplatin

(N=830)

All Grades Toxicity (%)

Grade 3-4 Toxicity (%)

All Grades Toxicity (%)

Grade 3-4 Toxicity (%)

All Adverse Reactions 90 37 91 53

Laboratory Hematologic Anemia Neutropenia Leukopenia Thrombocytopenia

33291810

61554

46382127

1027813

Renal Creatinine elevation 10 1 7 1

Clinical Constitutional Symptoms Fatigue 43 7 45 5

Gastrointestinal Nausea Vomiting Anorexia Constipation Stomatitis/Pharyngitis Diarrhea Dyspepsia/Heartburn

5640272114125

7621110

5336242012136

4610020

Neurology Neuropathy-sensory Taste disturbance

98

00c

129

10c

Dermatology/Skin Alopecia Rash/Desquamation

127

0c

0218

1c

1a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible

relationship to ALIMTA.b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity.c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2.

No clinically relevant differences in adverse reactions were seen in patients based on histology.In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC

and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm.

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

Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitisIncidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy

Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients.

Post-Marketing ExperienceThe following adverse reactions have been identi�ed during post-approval use of ALIMTA. Because these reactions are

reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies.Gastrointestinal — colitisGeneral Disorders and Administration Site Conditions — edema

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ALIMTA® (pemetrexed for injection) PV 5209 AMP ALIMTA® (pemetrexed for injection) PV 5209 AMP

Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy.Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal.

7 DRUG INTERACTIONS

7.1 Non-Steroidal Anti-In�ammatory Drugs (NSAIDs)IbuprofenAlthough ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with

ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insuf�ciency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information].

Other NSAIDsPatients with mild to moderate renal insuf�ciency should avoid taking NSAIDs with short elimination half-lives for a period

of 2 days before, the day of, and 2 days following administration of ALIMTA.In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients

taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity.

7.2 Nephrotoxic DrugsALIMTA is primarily eliminated unchanged renally as a result of glomerular �ltration and tubular secretion. Concomitant

administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA.

8 USE IN SPECIFIC POPULATIONS

8.1 PregnancyTeratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)].Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no

adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossi�cation of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA.

8.3 Nursing MothersIt is not known whether ALIMTA or its metabolites are excreted in human milk. Because many drugs are excreted in

human milk, and because of the potential for serious adverse reactions in nursing infants from ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother.

8.4 Pediatric UseEf�cacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion

over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12�and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea.

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

8.5 Geriatric UseALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be

greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)].

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

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

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

8.6 Patients with Hepatic ImpairmentThere was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical

Pharmacology (12.3)].Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2

[see Dosage and Administration (2.4)].

8.7 Patients with Renal ImpairmentALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and

greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment.

8.8 GenderIn the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR

for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population.

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

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

8.9 RaceIn the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians,

and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population.

In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population.

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

10 OVERDOSAGEThere have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia,

mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician.

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

The ability of ALIMTA to be dialyzed is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityNo carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo

micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy.

17 PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling.Patients should be instructed to read the patient package insert carefully.

17.1 Need for Folic Acid and Vitamin B12

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

17.2 Low Blood Cell CountsPatients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact

their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur.

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

17.4 Concomitant MedicationsPatients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter

medications including those for pain or in�ammation such as non-steroidal anti-in�ammatory drugs [see Drug Interactions (7.1)].

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

Literature revised March 17, 2011

Eli Lilly and Company Indianapolis, IN 46285, USA

Copyright © 2004, 2011, Eli Lilly and Company. All rights reserved.

PM_HCP_BS_NSCLC1_04052011

PV 5209 AMP PRINTED IN USA

12:04 PM


HEALTHCARE REFORM


Q: What concerns do you haveabout how healthcare legislationmight affect oncology?

Dr Bailes: The healthcare reformlegislation involves many potentialissues that can affect oncology, forexample, how minimum benefits aredefined. First, there are required mini-mum benefits that all health plans andother insurers have to meet, and wehave to make sure that cancer care isincluded. Second, the group called the

Independent Payment Advisory Board(IPAB) has the ability—the way thelaw is set up—to make recommenda-tions that could be implemented inMedicare through the Centers forMedicare & Medicaid Services (CMS),unless Congress overrides these rec-ommendations. Third, the reform bill relies on

Medicaid expansion to a great extent;and because Medicaid is a joint feder-al/state program, Medicaid expansionmeans more pressure on states. Statebudgets are already under pressure,and we worry about adding potentialbarriers to access. These barrierswould require patients with cancer tojump through hoops and perhaps notget needed therapy.Those are just some of the big issues

that those involved in oncology careare worried about within the contextof the healthcare reform bill.

Q: What do you see as some of thepositive things in the healthcarereform bill?

Dr Bailes: There are many positivethings in the healthcare reform bill,especially for individuals with seriousdiseases, such as cancer. There is theelimination of preexisting conditions,so patients can get any insurance,regardless of whether they have canceror have had cancer. There is the elimi-nation of lifetime caps on insurance; ifpatients have a serious illness or haveto have a transplant, they won’t facebeing told they can’t have further carebecause they have reached their life-time maximum benefits.

There is also the elimination of whatis known as rescissions, where peopleare denied coverage because of some-thing on an insurance application fromprevious years. In addition, there is

coverage for patients’ costs that areassociated with participation in clini-cal trials in private insurance.

Q: Do you think the provision willultimately lead to lower costs for thehealthcare system overall?

Dr Bailes: Ultimately, yes. If we lookat malignancy, the most expensivetreatment is when it is diagnosed lateor not diagnosed correctly. If we screenearly, we find cancers at a stage wherethey are treatable. That is where thetreatment is cost-effective for the indi-vidual, because the patient is treatedand is back to work. There are a lot ofbenefits to the system in being able toaccess the healthcare system early andget the appropriate treatment.

Q: Will the IPAB committee—thatis going to make recommendationsto Medicare—include an oncologist?

Dr Bailes: The IPAB is set up by thehealthcare reform bill to replace theMedicare Payment Advisory Com mit -tee. It will be able to make recommen-dations within certain parameters thatare in the law that CMS could thenimplement, unless Con gress stoppedit. There is no explicit provision torequire an oncologist on the IPAB.

Q: Do you think the debate overhealthcare reform may hurt theability of an oncologist to talk aboutterminal care with patients?

Dr Bailes: I do not think it will hurt,but the unfortunate thing about thedebate was that it got off topic fromwhat is important, that is, the need foroncologists, patients with cancer, andtheir families to have a candid discus-sion about the benefits, or lack of ben-

efits, of a particular therapy at a specif-ic time. We saw that in the rule whenthat part of the proposed physician feeschedule was decided.I believe we got off on a tangent in

that case and lost sight of what wasimportant. Many organizations—theAmerican Society of Clinical Oncol -ogists among them—have guidelinesand much background material onhow to speak with individuals whohave a terminal illness and evaluatewith the individual and the familywhich therapy makes sense. That is theresponsibility of the oncologist and thehealth oncology team. The more wecan do to help the oncology team withthat, the better.

Q: Do you think some oncologistshesitate following parts of the lawthat are already in practice becauseit is being disputed in the courts?

Dr Bailes: I do not think that is anissue right now. Oncologists are dedi-cated individuals, and they see therehas been a lot of publicity about thepositive parts of the healthcare reformlaw. And many of the other parts havenot been implemented yet.

Q: What are some improvementsthat you would make to the bill?

Dr Bailes: There needs to be a littlemore flushing out of what the patient-oriented research authority—the com-parative effectiveness research group—does, and what their authority is.Those in charge of benefit design inhealth plans need to make sure thatthere is input from all parties involved,such as patient advocates, physicians,specialty societies, policymakers, andstates. �

Implications of Healthcare Reform for Oncologists and Cancer Care Interview with Joseph S. Bailes, MDOncologist and Partner, Texas Oncology, Houston, TX

“We worry about addingpotential barriers to access,which would require patients with cancer to jump through hoops andperhaps not get neededtherapy.”

“There are many positivethings in the healthcarereform bill, especially forindividuals with seriousdiseases, such as cancer. There is the elimination of preexisting conditions, so patients can get anyinsurance, regardless ofwhether they have cancer or have had cancer.”

Register Now






CARE MANAGEMENT MODELS


Philadelphia, PA—Implementing path -ways to sustain community oncologyand offering additional nursing andcare management models are recentstrategies being adopted by variouspractices and payers to reduce themedical and pharmacy costs in cancermanagement and improve the qualityof care.

Care Management Model

“We want to create a sustainablemodel where community oncologycan be ‘buy and bill,’” said DanielMcCrone, MD, Chief Medical Officer,New Century Health in California.“The way that we support the physi-cian is a 4-step approach.” As can be seen in Figure 1, the 4-step

model combines “fee schedule nor-malization, which leads to consistentpayments; prior authorization, whichleads to evidence-based treatment;quality improvement programs, whichlead to aligned physician interests; anda high-performance provider network,which leads to quality care at optimalcost,” added Dr McCrone. “We believe this 4-step process is

exactly the way to manage the escalat-ing pharmacy trends,” he said. “Ofthe 20% we could reduce a payer’sexpense by, 5% to 25% of that 20% is infee normalization, and prior authori-zation brings it up to about 55%. Whenwe include the pathways, the savingsis up to 75%, and consolidating thenetwork would save 75% and more.”Care management is about improv-

ing quality of care, and the focus, saidDr McCrone, should be on reducinghospital admissions and emergency

department visits. A care managementprogram requires the following:• Oncology nurses or oncology-trained nurses

• Patient treatment plan and schedule• Financial incentive to physicians torefer patients

• Patient support, such as homeadministration of intravenous flu-ids, and manufacturer support.“Our idea was that this additional

nursing would more than pay for itselfby less utilization of hospital andemergency room visits,” Dr McCronesaid. The duration of the active care man-

agement model is about 5 months perpatient; 2500 patients enrolled in theprogram in its first year. Emergencydepartment visits decreased by 10%,regardless of the treatment plan. For

stable regimens for the managementof breast, prostate, lung, and bladdercancers, hospital admissions de -creased by 9%. But for rapidly evolving regimens,

such as those for head/neck, colon,and brain cancers, there was a 10%increase in hospitalizations during thefirst year of the program.“In addition, because of our nurse

program, 70% of patients who expiredwere in hospice or home hospice,” DrMcCrone added.

Care Integration Networks

According to Craig Deligdish, MD,Chief Medical Officer, Florida Com -pre hensive Care Network (FCCN),although much of the effort to managecancer costs revolve around drugcosts, other contributing cost factorsare molecular diagnostics, advancedimaging, radiation therapy, supportivecare, maintenance therapy, and end-of-life care. The FCCN is based on a partnership

of physicians through this clinicallyintegrated network. This networkworks with technology solutions,advanced care, palliative care pro-grams, and oncology benefit manage-ment programs, working with payerswho also face challenges from theirself-insured clients to try to reduce thecost of cancer treatment.FCCN “provides physicians and

health plans with the tools to managepathway and guideline adherence, cre-ates physician guidelines, and realignsincentives around buy and bill,” DrDeligdish said.The goals of the network include

sustaining community oncology, pro-

viding technology for consistent deliv-ery of quality care that allows bothpractices and health plans to measureoutcomes and monitor adherence topathways, and decreasing the admin-istrative burden by simplifying andobviating the prior authorizationprocess and using technology.“We focus to a large degree as a

clinically integrated network,” DrDeligdish added. “Clinical integrationis an active and ongoing program toevaluate and modify practice patternsby the network’s physician partici-pants to create a high degree of inter-dependence and cooperation to con-trol costs and ensure quality.”Dr Deligdish suggested that ad -

vanced care and palliative care pro-grams need to feature an integratedcare plan, focused education andpatient intervention, and 24-houraccess. The benefits of these programsinclude improved patient/physiciansatisfaction, decreased hospitalizations,and increased hospice enrollment.

Payer–Physician Collaboration

The community tries to pit managedcare organizations (MCOs) againstproviders, saying they are 2 pieces ofsandpaper coming together, saidWinston Wong, PharmD, AssociateVice President, Pharmacy Manage -ment, CareFirst Blue Cross BlueShield. In reality, MCOs and providers

Medical and Pharmacy Directors’ Strategies to ImproveCancer Care ManagementBy Wayne Kuznar

“We’ve taken a differentapproach at CareFirst, and we’re actually trying to collaborate with our phy sicians.”

—Winston Wong, PharmD

“We believe this 4-step process is exactly the way to managethe escalating pharmacy trends.”

—Daniel McCrone, MD


Technology

Optimal care + cost

Phase I

Treatment pathways

Reduced facility cost

Outcomes-based

Fee schedule normalization

Phase IIPrior authorizationvia nationally accepted guidelines

Phase IIIQuality improvementprogram

Phase IV

High-performanceprovider network

Evidence-basedtreatment

Consistent payments

Quality care atoptimal cost

Aligned physician interests

• Sustainable savings requires acomprehensive management model

• An integrated approach is focused on total cost management—this allows us to achieve quantifiable savings over the short- and long-term

Utilize a “phase-in” approach that allows us to individually target each key component of oncology care

Figure 1 Oncology Management Approach

Savings Opportunity ��


CARE MANAGEMENT MODELS


are in agreement on current issues,challenges, and goals.“We are all looking at the perfect

storm coming together,” Dr Wongsaid. “The basis of the storm right nowis the biological pipeline, which is richin expensive oncologic agents. We alsohave the threat of an increase in theuninsured population becoming cov-ered through government programs.”He said that “we’re looking at an

increase in utilization overall in oncol-ogy care, which means an increase incost. But the real issue is variability ofcost because of variability of care.”What do MCOs do when faced with

an increase in cost? The typical knee-jerk reaction is to tighten the fee sched-ule. To change this, payers and physi-cians need a new paradigm.“We’ve taken a different approach at

CareFirst, and we’re actually trying to

collaborate with our physicians. We’reusing a paradigm, and we’re pullingtogether representatives out of ouroncology network and creating anoversight committee to take a look atoncology care,” Dr Wong said.His company is partnering with P4

Healthcare, which helps facilitatepathway development with physi-cian groups, as well as monitoringdata and educating physicians. Thisparadigm promotes individualizedmedicine and physicians’ discretionand provides incentives for compli-ance, creating a win-win-win sce-nario for patients, physicians, and thehealth plan. Dr Wong began this pathway pro-

gram in 2008. “It’s a true pay-for-qual-ity program, in that physicians whoelect not to participate in our programare reimbursed at our standard feeschedule,” he said. “However, physi-cians who comply with our pathwaystandards are reimbursed at our stan-dard fee schedule plus a differential.Hence, we are not hurting any prac-tices who are not participating; we’re

simply giving the incentive to workwith us on the program.”At the end of the 2-year period,

pathways for breast, lung, and coloncancers resulted in savings of approxi-mately $17 million, the net of theincentive that was provided to physi-cians (Figure 2).“We were able to show that the use

of a pathway program, where youhave physicians working with us, can

actually function pretty well,” he said.The reason behind the program is totry to maintain the viability of thecommunity practice, he added. Ira Klein, MD, Senior Medical

Director, Aetna Oncology Strategy,agrees that to improve quality man-agement, payers and providers needto work together.Based on results of a collaborative

study between Aetna and USOncology (Neubauer MA, et al. J OncolPract. 2010;6:12-18), the use of path-ways did not alter the overall morbid-ity or mortality in patients with non–small-cell lung cancer (NSCLC)treated in the outpatient communitysetting. However, it did reduce the costof drugs for patients with NSCLC. Thestudy demonstrated a cost-savings of35% over 12 months. “But that’s really the beginning,”

Dr Klein said. “Pathway-based careshould represent an evidence-basedand holistic patient-centric approach.To do this with providers, we neednew contractual relationships thatdrive quality improvements andchanges, and these are about aligningincentives while keeping the focus onthe cancer patient.” �

Medical and Pharmacy Directors’ Strategies... Continued from page 45

$12,354,845

Figure 2 24-Month Breast, Colon, and Lung Savings: Antineoplastics, Supportive Care, and Service Costs

$20,000,000

$18,000,000

$16,000,000

$14,000,000

$12,000,000

$10,000,000

$8,000,000

$6,000,000

$4,000,000

$2,000,000

$0 Antineoplastics Supportive care Service costs Total

$8,811,862

$1,036,698

$17,203,405

“Pathway-based care shouldrepresent an evidence-basedand holistic patient-centricapproach. To do this withproviders, we need newcontractual relationships thatdrive quality improvements.”

—Ira Klein, MD

at a glance� Implementing pathway pro -

grams and care management

models can reduce the cost

of cancer care and improve

its quality

� Flexible fee schedules

encourage individualized

medicine and provide significant

incentives for compliance

� The focus of care manage -

ment programs should be on

reducing hospital admissions

and emergency department

visits

� A clinically integrated network

provides physicians and health

plans with the tools to manage

pathway and guideline

adherence, create guidelines,

and realign incentives


©2011 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

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

goal

One goal: discovering and delivering breakthrough medicines to combat cancer.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in

oncology worldwide — with more than 17 compounds in development for a broad range of solid and

hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease

pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition,

apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a

dramatic impact on cancer therapeutics over the next decade.


THERAPY FRAGMENTATION


Philadelphia, PA—Fragmentation inoncology care significantly influencesphysicians’, payers’, and patients’understanding of how cancer thera-pies lead to improved quality of care.The main reason for fragmentation isthe challenge in linking pharmacy andmedical data in a way that generatesusable information, according toAtheer A. Kaddis, PharmD, Vice Presi -dent, Managed Markets, DiplomatSpecialty Pharmacy.

The Oncology Drug Marketplace

“Improving the capture of data onthe medical and pharmacy benefitssides and integrating data to apply thisinformation to decision-making willhelp us meet the challenge,” DrKaddis said. The oncology drug market is under-

going a major shift from injectable tooral oncolytics, which to a large extentrevolves around Medicare. Plans offer-ing Medicare Part D prescriptiondrugs must include in their formularyall approved drugs in a specific catego-ry or class.

A significant evolution has occurredin the number and types of medica-tions. Before 1985, specialty diseasestates had limited or zero drug treat-ment choices. Today, several specialtydisease states—including multiplemyeloma, breast cancer, and trans-plant—are treated mostly with oraltherapies. And several specialty dis-ease states are expected to have an oraldrug option within 2 years, including

acute myelogenous leukemia andmelanoma.As a result of the increased number

of specialty therapies, Dr Kaddis said,“My bold prediction is that there’sgoing to be a bigger role for specialtypharmacies going forward when itcomes to oncology. Part of that is beingdriven by oral oncolytics, and also it isbecause of what’s going on in clinicalpathways, accountable care organiza-tions, and even 340B programs and thetrend toward contracted pharmacies.”The clinical and economic implica-

tions of oncology drugs are:• Reimbursement remains the pri-mary method for controlling chemo -therapy costs and utilization from amanaged care perspective

• Oral oncolytics are changing thedirection of channel management

• Integration of pharmacy and med-ical data presents a significantchallenge.

Management Challenges

The oncology drug managementchallenges are directly related tohealth insurance or payer benefitdesign, according to Kirby J. Eng, RPh,Director, Medical Pharmacy Manage -ment, CVS Caremark. The clinicalchallenges include the site of serviceand coordination of care, therapyinformation, and adherence to therapy.The drug formulation has several

implications to health plans (Figure). Ifa drug is a tablet or a capsule, the siteof service typically would be a phar-macy channel. Benefit coverage, giventhe site of service and drug formula-tion, overwhelmingly, would fallunder pharmacy benefit. For self-administered injectable drugs, the siteof service would be the physician’soffice or, increasingly, the pharmacy—

retail or specialty. Health plans weresplit on benefit coverage for self-administered injectables; increasinglyit is placed under the pharmacy ratherthan the medical benefit. If a drug is intravenous or injectable,

it is likely going to be administered ina physician’s office or a specialty phar-macy, and coverage would fall undermedical benefit. Mr Eng said that the stakeholder

implications of oncology drug therapymanagement depends on the partyinvolved, in the following way:• Patients:–Out-of-pocket costs–Therapy information (eg, from theWeb, physician, nurse, pharmacy)–Therapy adherence and coordina-tion of care

• Payers:–Providing access to quality and cost-effective care –Benefit coverage determination

• Pharmacy:–Medication therapy management,including education and patientadherence –Coordination of care

• Physicians:–Education and coordination of care

• Manufacturers:–Market management of hospitals,patients, payers, pharmacy, andprescribers.Another health plan, Excellus Health

Plan, Blue Cross Blue Shield, initiated areview of all the drugs going throughtheir medical benefit, as well as thehigh cost of these therapies a few yearsago, said Kristen M. Reimers, RPh,Clinical Pharmacy Operations Manag -er, Excellus, and Director of SpecialtyPharmacy Pro grams at FLRx Phar -macy Management. Excellus actively targeted some of

the clinical fragmentation of the oncol-ogy drug market. On the pharmacyside, the plan evaluated the therapiesand determined there needed to be agroup that would manage high-costtherapies, said Ms Reimers. Excellus formed a team of specially

trained, highly specialized nurses andpharmacists and medical directors to ini-tially manage 3 therapies. Now thehealth plan manages >60 therapies,

The Impact of Therapy Type on Clinical Fragmentationin Oncology CareBy Wayne Kuznar

“My bold prediction is thatthere’s going to be a biggerrole for specialty pharmaciesgoing forward when it comesto oncology. Part of that isbeing driven by oraloncolytics.”

—Atheer A. Kaddis, PharmD


Figure Drug Formulation Implications

aEMD Serono Digest, 5th edition.PBM indicates pharmacy benefit manager.

Drug formulation

Tablet or capsule

Injectable (self-administered)

Intravenous or injectable

Benefit coveragea

Site of service (outpatient)

PharmacyPBMRetail

SpecialtyPhysician office

Physician officePharmacy

Retail Specialty

Physician officePharmacy

Retail Specialty

Pharmacy (93%)

Medical (7%)

Medical (53%)

Pharmacy (47%)

Medical (98%)

Pharmacy (2%)

��

��

� �


THERAPY FRAGMENTATION


which are primarily focused in oncology. Management tools for the pharmacy

benefit include specialty pharmacycontracts, formulary management andphysician reimbursement, and opera-tional improvements. Critical to spe-cialty pharmacies is the patient-cen-tered approach, such as patientadherence. The hot issue in specialty drug man-

agement, according to Ms Reimers, isrelated to oral oncolytics management.The challenges identified by Excellusare: • Lack of respect for some drugswhen first introduced

• Lack of control: physicians wereused to ordering therapies in theoffices, and patients would thenreceive them in the office

• Therapeutic and clinical risk ifpatients were not taking drugs (non-adherence) or were not taking themas prescribed; risk of drug interac-tions and severe adverse effects; nofeedback loop to physician offices,so physicians are left in the dark asto whether patients were getting thetherapies

• Cost issues, including high-costtherapies and risk of waste.Among physicians, patients, and

payers, there were similar concernswith regard to oral oncology manage-ment. For one, oncologist offices hadlack of control, because they didn’tknow if patients were taking the med-ications and if they took them as pre-scribed. In addition, getting drugs cov-ered for the patient can be difficultwhen therapies are available only inlimited distribution channels.On the payer’s side, there was high

cost and risk of high waste. “Payersdon’t want to pay for drugs thatpatients aren’t taking,” Ms Reimerssaid.From a member’s perspective, the

concern is simple—expense. “Patientsdon’t know if they can afford therapiesor if it’s even worth it for them to takethese therapies,” she said.

Specialty Drug Program

Excellus worked with specialtypharmacies to develop a high-touchspecialty drug program for oral oncol-ogy agents to ensure appropriate uti-lization of the medications. Educationwas deemed necessary to the programto address adverse events and how tomanage such events.

“The program was designed to behigh-touch so patients felt they werepart of their own care,” Ms Reimerssaid.As part of the program, oral oncolo-

gy agents were incorporated into themandatory specialty network. Allpatients using these therapies wererequired to receive them from one ofExcellus’ specialty pharmacies; theycould then participate in programsthat were clinician based at the phar-macies. Nurses and pharmacists whowere trained in oncology would makeassessments. When therapy was firstinitiated, assessments occurred every 7to 10 days. Patients were instructed inhow to manage issues such as adverseeffects.“Excellus also wanted to address

concerns of the physician and close theloop on what they saw as fragmenta-tion in not knowing whether the

patient was actually getting their ther-apy,” Ms Reimers said.The program included a concise 1-

page document in the form of aprogress note that included informa-tion about when patients started andstopped therapy and whether therewere adverse events. Everything wasdocumented.In the first 18 months of running the

high-touch specialty pharmacy pro-gram, 400 patients were using oraloncology therapies, and 256 of thoseopted into the program. (They wereconsidered in the program unless theychose not to participate.)Patients had access to clinicians and

pharmacists 24 hours a day, 7 days aweek. There were follow-up remind -ers, assessments on patients, andreports back to physicians and thehealth plan.The adherence rate of patient-

missed doses was only 8.2%. The dis-continuation rate on advice of physi-cians was 10% (27 of 256 patients). Thisis in contrast to the national discontin-uation rate of oral oncology medica-tions, which is about 30%. To prevent future fragmentation,

the health plan has instituted newongoing strategies to manage drugtherapies: • Monitoring the drug pipeline fordrugs being developed

• Off-label use program• Development of unique medicaldrug treatment to manage intra-venous therapies

• Continue to manage provider feeschedule

• Seek ways to manage waste andvials

• Development of adherence pro-grams, especially on the medicalside

• Provider discussions with commu-nity oncologists seeking input onour programs

• Tracking health plan data andtrends to determine where to elimi-nate fragmentation. �

“Payers don’t want to payfor drugs that patients aren’ttaking. Excellus also wantedto…close the loop on whatthey [physicians] saw asfragmentation in notknowing whether thepatient was actually getting their therapy.”

—Kristen M. Reimers, RPh

at a glance� Medicare Part D benefits are

driving the shift from injectable

to oral oncolytics

� Oncologists often cannot

confirm if their patients are

taking their medications as

prescribed

� Patients often cannot get

coverage for drugs that are

available only through limited

channels

� Specialty pharmacies will

play a larger role as oncology

therapy shifts more toward

oral oncolytics

� A high-touch specialty drug

program for oral oncology

agents can help to ensure

appropriate utilization of the

medications and improve

adherence

Health plans were split onbenefit coverage for self-administered injectables;increasingly it is placedunder the pharmacy ratherthan the medical benefit.

—Kirby J. Eng, RPh

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CONTINUING EDUCATION


While healthcare reform is on thehorizon, the pipeline for new cancertherapies continues to grow and can-cer care costs are on the rise. More than90% of the anticancer agents approvedby the US Food and Drug Admin -istration (FDA) between 2004 and 2008cost more than $20,000 for a 12-weekcourse of treatment.1 The practice ofmanaged care pharmacy frequentlyinvolves making decisions aboutwhether a given drug or a regimen iscovered under a patient’s pharmacybenefit or health insurance plan. Thequestion that managed care payers areasking is, will the health outcomesproduced by these expensive therapiesjustify the increased cost? Payers areincreasingly insisting that newly intro-duced agents and regimens demon-strate improvement in patient out-comes before their cost will be fullyreimbursed.

End Point versus outcome: what

is the difference?

Avedis Donabedian, MD, MPH,

public health pioneer, defined out-comes as the “consequences to thehealth and welfare of individuals andof society.”2 He noted that “outcomes,by and large, remain the ultimate vali-dation of the effectiveness and qualityof medical care.”2 Ultimately, cure isthe desired outcome for patients withany disease. However, this is not cur-rently a realistic goal for most patientswith cancer who are undergoing thetherapies available today. As advancesare made in our understanding ofmolecular oncology and new targetedtherapies are developed, many malig-nancies are being treated as chronicdiseases, and patients diagnosed todaymay expect to live longer than patientsdiagnosed in years past. A patient’squality of life and freedom from dis-ease progression may become moreimportant outcomes than survival ifdifferences in overall survival (OS) arenot apparent when comparing thera-pies and regimens.The economic evaluations involved

in making managed care decisions

often consider the likely costs and out-comes of new therapies over time,based primarily on safety and efficacyend point data from the clinical trialsthat led to the approval. A clinical trialwill usually define or specify a pri-mary end point as an objective meas-ure that will indicate the success of thetherapy being investigated. A trial mayalso define 1 or more secondary endpoints that will be measured and areexpected to be met. Some of these end points may be

surrogate end points, which are bio-markers that may correlate with a realclinical outcome but do not necessarilyhave a guaranteed relationship. Inaddition, a primary end point thatsupports efficacy in previous andongoing clinical trials may be differentfrom the primary end point in subse-quent trials, making it difficult to com-pare agents and regimens and theireffect on the desired outcome. Although an improvement in OS

had historically been the gold stan-dard end point for a new oncology

drug approval, 68% of the regularapprovals and 100% of the acceleratedapprovals for oncology drugs between1990 and 2002 were based on clinicaltrial end points other than survival,including the objective response rate,progression-free survival (PFS), dis-ease-free survival (DFS), and time toprogression (TTP).3

In 2003, the FDA began a project toevaluate potential end points for can-cer drug approval.4 End points wereexamined for the most common can-cers during public workshops, impor-tant issues were identified, and theseissues were discussed in meetings ofthe Oncologic Drugs Advisory Com -mit tee. Subsequently, a guidance doc-ument was published in 2007, describ-ing the FDA’s current thinking on endpoints for cancer drug approval.5

Although the FDA still regarded OS asthe preferred end point in a cancertrial, FDA members found a clear dis-advantage in the necessity of a longobservation period. During this same

The Evolving Role of Outcomes and End Points in EvaluatingTherapy for Hematologic Malignancies: Value-Driven BenefitDesign and Utilization Management StrategiesProgram P11067E

Initial Release Date: July 15, 2011 • Expiration Date: July 15, 2012.Estimated time to complete activity: 1 hour.SPonSor

This activity is jointly sponsored by Medical Learning Institute, Inc. (MLI), a nonprofit med-ical accreditation company, and Center of Excellence Media, LLC.TargET audiEncE

This activity was developed for health-system pharmacists and oncology pharmacists.LEarning objEcTivES

At the end of this activity, participants will be able to: • Compare and contrast the primary end points used in pivotal clinical trials for hemato -logic malignancies

• Determine which end points are the most appropriate and clinically relevant for assess-ing the efficacy of novel targeted agents for multiple myeloma, chronic myeloid leukemia,and non-Hodgkin lymphoma

• Evaluate surrogate end points as they relate to optimal long-term outcomes for patientswith hematologic malignancies

• Analyze the results from clinical trials to assess the justification of incorporating noveltargeted agents into standards of care and effective benefit design and utilization man-agement approaches

commErciaL SuPPorT acknowLEdgmEnT

This activity is supported by educational grants from Millennium Pharmaceuticals andNovartis Pharmaceuticals.inSTrucTionS for crEdiT

There is no fee for this activity. To receive credit, participants must read this CEactivity in its entirety and complete the posttest and evaluation. The posttest andevaluation can be completed online at www.mlicme.org/p10067E.html. Upon

completion of the evaluation and scoring 70% or better on the posttest, you will immedi-ately receive your certificate online. If you do not achieve a score of 70% or better on theposttest, you will be asked to take it again. Please retain a copy of the certificate for yourrecords.

For questions regarding the accreditation of this activity, please contact Medical LearningInstitute, Inc., at 609-333-1693 or [email protected] Pharmacy dESignaTion

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education(ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for thisactivity is 0468-9999-11-029-H01-P.diScLoSurES

Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any finan-cial interest and/or relationship(s) they might have with any commercial interest producinghealthcare goods/services to be discussed during their presentation(s): honoraria, expens-es, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. Allidentified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc., forfair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.Shelly Chun, PharmD, a reviewer for MLI, has nothing to disclose.Linda Ritter, PhD, Center of Excellence Media, has nothing to disclose.ChairJames T. Kenney Jr., RPh, MBA, has nothing to disclose. FacultyMichael Mauro, MD, receives research grants from Novartis Oncology and Bristol-Myers Squibb.Gary Yee, PharmD, FCCP, BCOP, has nothing to disclose.diScLaimEr

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition.Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred.

The Evolving Role of Outcomes and End Points in Evaluating Therapy for HematologicMalignancies: Value-Driven Benefit Design and Utilization Management Strategies





period (2001 to present), the targetedtherapies for multiple myeloma (MM),non-Hodgkin lymphoma (NHL), andchronic myeloid leukemia (CML) thatare in common use today entered theclinical arena.

Multiple Myeloma

MM is the second most frequentlydiagnosed hematologic malignancy.6

Although MM remains incurable, out-comes have significantly improved inrecent years with the introduction ofnovel agents, such as the immun o -modulatory drugs thalidomide andlenalidomide and the proteasomeinhibitor bortezomib, and withadvancements in supportive care(Table). The early introduction ofeffective management strategies thatinclude ≥1 of these novel agents haveimproved survival for patients withMM. In fact, between 1975 and 1979, apatient receiving a diagnosis of MMhad only a 53% probability of surviv-ing 2 years.7 In comparison, 2-year sur-vival rates for patients diagnosedwithin the past few years have beenreported as high as 88%, and the 5-year survival rate has increased tomore than 40% for patients diagnosedin 2003.7

Consistency in the conduct of clini-cal trials and in the analysis andreporting of results is essential toensuring valid and reliable results thatcan be compared with those of othertrials. Early in 2011, the InternationalMyeloma Workshop Consensus Panel1 recommended PFS as the primaryend point for clinical trials in lieu oflong-term OS data.8 An analysis of PFSincludes all patients and is calculated

from the beginning of treatment to dis-ease progression or death from anycause. TTP has also been used as theprimary end point in clinical trials forMM. An analysis of TTP is essentiallythe same as that for PFS, but deathsthat are not directly related to the dis-ease are not counted in TTP. However,as data from trials initiated in the pastdecade mature, a PFS or TTP trial endpoint benefit does not always translateinto an OS benefit.

Transplant-ineligible patients

The combination of melphalan andprednisone (MP) had historically beenthe regimen of choice for newly diag-nosed MM in patients who were noteligible for autologous stem-cell trans-plant (ASCT). In 2008, the FDAapproved bortezomib “for the treat-ment of patients with multiple myelo-ma.” This approval was based on theVISTA (Velcade as Initial StandardTherapy in Multiple Myeloma) trial, inwhich the combination of bortezomib,melphalan, and prednisone (VMP)was compared with MP in 682 patientswith newly diagnosed MM who wereineligible for ASCT.9 The medianTTP—the primary efficacy end pointin the study—was 24.0 months in theVMP group compared with 16.6months in the MP group (P <.001). In December 2009, survival benefit

was added to the VMP label after fur-ther analysis of the VISTA trial demon-strated that OS continued to improvesignificantly in the VMP arm duringa median follow-up of 36.7 monthsdespite subsequent therapies, includ-ing bortezomib-based regimens.10

Median OS was not reached with VMP

versus 43.1 months with MP (P <.001);after 3 years, the OS rates were 68.5%versus 54.0%, respectively.9

Several phase 3 trials have com-pared the use of melphalan, pred-nisone, and thalidomide (MPT) withthat of MP for the treatment of newlydiagnosed MM in patients who werenot eligible for ASCT,11-15 showingmixed results. Although these trialshave consistently shown better re -sponse rates with MPT than with MP,only 4 of the 5 trials showed a signifi-cant improvement in PFS, and only 2showed a significant improvement inOS (P <.05). A meta-analysis of these 5trials (N = 1568) showed a pooled haz-ard ratio (HR) of 0.68 for PFS (P <.001;95% confidence interval [CI], 0.55-0.82)and 0.80 for OS (P = .07; 95% CI, 0.63-1.02) in favor of MPT.16 Although theaddition of thalidomide to MP resultsin significantly improved PFS, MPalone demonstrates only a nonsignifi-cant improvement in OS, with theadditional burden of significantlyincreased toxicity.Recently, data were reported from a

phase 3 trial comparing the combina-tion of lenalidomide plus MP (MPR)with MP in patients aged ≥65 yearswho were ineligible for ASCT (N =459).17 Patients were randomized toreceive either MP alone, MPR (fixeddose schedule), or MPR followed bycontinuous lenalidomide maintenance(MPR-R). At a median follow-up of 25months, patients who received MPR-Rdemonstrated a significant improve-ment in PFS (31 months) comparedwith patients who received MPR (14months) or MP (13 months; P <.001).However, the significant PFS advan-

tage did not apply to patients aged >75years (MPR-R vs MPR; P = .118).Although a median OS has not beenreached among any of the 3 arms,there is currently no significant differ-ence between the arms in the estimat-ed 1-year and 2-year OS rates.

Transplant-eligible patients

The quality of posttransplantationresponse, especially the achievementof complete response (CR), is now wellestablished as a prognostic indicatorof improved long-term survival forpreviously untreated MM in patientswho receive high-dose therapy andASCT.18,19 In a retrospective analysis of344 patients with MM who underwenttransplantation between 1989 and1998, after a median follow-up of 12.75years, the OS rate at 12 years was 35%for patients achieving CR, 22% forthose demonstrating near CR (nCR),and 16% for those achieving very goodpartial response (VGPR).20 Significantdifferences in OS and PFS were foundbetween the CR and nCR groups (P =.01 and P = .002, respectively), as wellas between CR and VGPR (P = .0001and .003). A plateau in OS was ob -served after 11 years; 35% of patientsachieving CR are alive at 17 years. For patients who are transplant-

eligible, recent clinical trials have eval-uated combined modality inductionregimens with the novel agents in anattempt to increase the rate of responseto induction therapy to improve thequality of response to transplanta -tion. In the HOVON-65/GMMG-HD4(Dutch-Belgian Hemato-Oncology/German Cooperative Groups) trial,patients were randomized to induc-tion therapy with bortezomib, doxo -rubicin, and dexamethasone (PAD) orwith vincristine, doxorubicin, anddexamethasone (VAD).21 After under-going high-dose therapy and ASCT,patients who were randomized toPAD received bortezomib as mainte-nance therapy for as long as 2 years,and those randomized to VADreceived thalidomide. The postinduc-tion response rate of VGPR or bet -ter was 42% in patients receivingPAD and 15% in those receiving VAD(P <.001). The response rates improvedto 61% and 36%, respectively, post-transplantation and to 76% and 55%during maintenance. Patients receiv-ing PAD induction with bortezomibmaintenance showed significantlyimproved PFS (HR = 0.75; P = .005)and OS (HR = 0.73; P = .02).In the phase 3 GIMEMA (Gruppo

Italiano Malattie Ematologiche dell’Adulto) trial, the safety and efficacy ofinduction therapy and consolidationwith thalidomide plus dexamethasone


aThalomid [package insert]. Summit, NJ: Celgene; 2010.bRevlimid [package insert]. Summit, NJ: Celgene; 2010.cVelcade [package insert]. Cambridge, MA: Millennium; 2010.

LD indicates lenalidomide/dexamethasone (high-dose); MM, multiple myeloma; MP, melphalan/prednisone; ORR, overall response rate; TD, thalidomide/dexamethasone (high-dose); TTP, time to progression; VMP, bortezomib/melphalan/prednisone.

Table Label Indication and Registration Trial Information for Thalidomide, Lenalidomide, and Bortezomib

Registration trial

Drug Indication Design/patientsPrimary end point Result

Thalidomidea In combination with dexamethasonefor the treatment of patients withnewly diagnosed MM

Newly diagnosed patients with MMN = 207TD vs high-dose dexamethasone

ORR, % 51.5 vs 35.6

Lenalidomideb In combination with dexamethasonefor the treatment of patients withMM who have received at least 1previous therapy

Relapsed/refractory MM(at least 1 previous treatment)Study 1: N = 353Study 2: N = 351LD vs high-dose dexamethasone

Median TTP, mo

Study 1: 13.9 vs 4.7 P <.001Study 2: 12.1 vs 4.7 P <.001

Bortezomibc Treatment of patients with MM Newly diagnosed patients with MMN = 682VMP vs MP

Median TTP, mo

20.7 vs 15.0 P <.0001

Relapsed/refractory MM (after 1-3 previous therapies)N = 669Bortezomib vs high-dose dexamethasone

Median TTP, mo

6.2 vs 3.5 P <.0001




(TD) is being compared with that ofbortezomib, thalidomide, and dexa -methaone (VTD) in combination withdouble ASCT and dexamethasonemaintenance.22 The addition of borte-zomib to TD significantly im provedthe CR rate after induction, first trans-plantation, second transplantation,and consolidation. Treatment withVTD resulted in a significant 37%reduction in the relative risk for pro-gression or death (HR = 0.63; P =.0061), but at a median follow-up of 36months, no difference in OS has beenseen (HR = 0.76; P = .3071).

Two additional promising novelcombination regimens in phase 2 stud-ies have reported high rates of CR afterinduction. One is the combination ofbortezomib, lenalidomide, and dex-amethasone (VRD), and the other isthat of bortezomib, dexamethasone,and cyclo phos phamide (VDC).23,24

VRD showed a VGPR rate of 74%, andVDC (modified to add an additionaldose of cyclophosphamide at day 15)showed a VGPR rate of 53%. In addi-tion, until more data and longer fol-low-ups are available, consolidationand maintenance therapy with novelagents may improve posttransplantresponses and provide patients with asignificant survival advantage.

Chronic Myeloid Leukemia

Approximately 0.6 to 2.0 cases ofPhiladelphia chromosome-positive(Ph+) CML are diagnosed globally per100,000 persons each year. Approx -imately 1.5 cases per 100,000 personsare diagnosed each year in the UnitedStates.7,25 Historically, chemotherapywith alkylating agents and hydroxy -urea provided a median survival ofonly 3 to 4 years.26 Median survivalimproved to 6 to 7 years in the early1980s with the advent of interferon-alpha, but the 10-year survival ratewas still only 30% to 40%, and patientshad few options after the failure offirst-line therapy.27

Before 2000, survival was the pri-mary goal of therapy for patients withCML in chronic phase (CML-CP). Theintroduction of the tyrosine kinaseinhibitor (TKI) imatinib in 2001 hasrevolutionized management strate-gies, refocusing the outcome on pre-vention of progression rather than onsurvival. The annual mortality rate hasdecreased to approximately 1% to 2%,and the estimated 5-year survival ratehas increased to approximately 90%.7

This translates to an increasing preva-lence that may exceed 200,000 cases inthe United States within the next 20years.26

The importance of early optimal

response

It was established that patients withCML had prolonged survival afterachieving a cytogenetic response(CyR) to interferon-alpha.28 In 2001,imatinib was approved for newlydiagnosed CML-CP based on the sur-rogate end points of major CyR andcomplete CyR (CCyR).29 Since then,much has been learned regarding theaccepted milestones for response tofirst-line therapy and the timing ofthose responses. Patients with subopti-mal or poor response within the first 6months of therapy are far more likelyto experience early disease progres-sion to advanced phase or blast crisis,in which long-term responses to TKIsare unlikely to occur and overallhealthcare costs are much higher.

In a study comparing patients witha suboptimal response or failure with-in 6 months of initiating imatinib ther-apy and those who responded duringthat same period, the likelihood ofachieving CCyR was 39% versus 96%,respectively (P <.0001), the rate of PFSwas 87% versus 98% (P = .04), and therate of OS was 70% versus 92% (P =.001).30 In the IRIS (Insulin ResistanceIntervention after Stroke) trial, patientswho achieved a CCyR had a lowerannual incidence of events (loss ofresponse, transformation to advancedphase or blast crisis, or death) than theoverall group after 5 years of follow-up.31 In addition, 100% of patients inthe imatinib arm of the IRIS trial whohad achieved both a CCyR and a majormolecular response (MMR) by 12months were free from progression toadvanced phase or blast crisis at 8years, and the achievement of CCyRby 12 months was associated withimproved survival.32

Second-generation TKIs

Second-generation TKIs (nilotinib,dasatinib, and bosutinib) are beingcompared with imatinib in clinical tri-als in patients with newly diagnosedCML-CP. Nilotinib (300 mg twicedaily) received FDA approval in June2010 for the treatment of newly diag-nosed CML, based on results from theENESTnd (Evaluating Nilotinib Ef -ficacy and Safety in Clinical Trials—Newly Diagnosed Patients) trial. Theprimary end point in this trial is theMMR rate at 12 months. After a medi-an follow-up of 18.5 months, the rateof MMR for nilotinib at 12 months(44%) was twice (22%) that for ima-tinib (P <.0001).33 By 12 months, therate of CCyR was also significantlyhigher among patients receiving nilo-

tinib (80%) than among those receiv-ing imatinib (65%; P <.001). TheKaplan-Meier estimate of the mediantime to MMR was shorter (8.6 months)for patients receiving nilotinib than forthose receiving imatinib (median notyet achieved).

An updated analysis of data cover-ing a median follow-up of 24 monthswas presented at the 2010 AmericanSociety of Hematology’s (ASH) annualmeeting.34 At 24 months, the MMR ratewas 62% for nilotinib versus 37% forimatinib (P <.0001) and the CCyRrates were 87% versus 77%, respective-ly (P = .0018). In addition, significantlyfewer patients receiving nilotinib(0.7%) than those receiving imatinib(4.2%) had progressed to advancedphase or blast crisis or had died (P =.0059). Fewer patients receiving nilo-tinib discontinued therapy because ofadverse events.

Dasatinib received FDA approvalfor newly diagnosed CML-CP inOctober 2010 based on results from theDASISION (Dasatinib versus ImatinibStudy in Treatment-Naïve CMLPatients) trial, which compared dasa-tinib with imatinib. The primary endpoint was the rate of confirmed CCyRat 12 months.35 After a median follow-up period of 14 months, the rate ofconfirmed CCyR at 12 months was sig-nificantly higher in patients receivingdasatinib (77%) than in those receivingimatinib (66%; P = .007). In addition,the rate of MMR at any time was sig-nificantly higher among patientsreceiving dasatinib (52%) than amongpatients receiving imatinib (34%; P<.0001). Among patients who achievedan MMR, the median time to MMRwas 8.3 months for dasatinib and 11.8months for imatinib. Fewer patientsreceiving dasatinib (1.9%) than thosereceiving imatinib (3.5%) had pro-gressed to advanced phase or blast cri-sis. The rates of discontinuation as aresult of adverse events were similarfor dasatinib and imatinib. An updat-ed analysis of data covering a medianfollow-up of 18 months was presentedat ASH 2010.36

First-line second-generation TKIs

provide optimal outcomes

In January 2011, nilotinib and dasa-tinib were added to the NationalComprehensive Cancer Network(NCCN) treatment guidelines as cate-gory 1 options for the primary treat-ment of Ph+ or BCR-ABL+ CML. With3 FDA-approved and NCCN-recom-mended therapies, what will drive thechoice of treatment? Should the highercost of the second-generation TKIs be a

factor? A recent study examined theassociation between adherence to ima-tinib therapy and direct healthcarecosts and resource utilization in a largegroup (N = 592) of privately insuredpatients with CML.37 Patients withCML who do not adhere to treatmentmay have suboptimal outcomes andhigher rates of progression to ad-vanced phase or blast crisis. In thisstudy, patients with low adherencehad more all-cause inpatient visits(4.1) compared with those whodemonstrated higher adherence (0.4;P <.001) and more all-cause inpatientdays (14.8 days vs 1.8 days, respective-ly; P <.001).

In regression models, non-imatinibcosts were 283% higher in the nonad-herent group ($324) than in the adher-ent group ($56; P <.001). Therapy fail-ure occurred in approximately 22% ofpatients receiving first-line imatinibtherapy (the vast majority of failuresbeing early events) compared withapproximately 4% of patients receiv-ing first-line therapy with a second-generation TKI.

One may ask, “Why not wait untilpatients have a suboptimal response toimatinib or fail treatment before pre-scribing a higher-priced second-gener-ation TKI?” This may be too risky, and,in the long run, incur higher costs.Treatment at suboptimal response orfailure is salvage therapy. In suchcases, the likelihood that the patienthas developed drug-resistant muta-tions has increased, requiring the useof a third-generation TKI or a veryexpensive stem-cell transplant.

The 8-year analysis of the IRIS trialdemonstrated that imatinib was effec-tive in preventing prospective eventsbut not the loss of response or progres-sion events that occur early (Figure).32

The ENESTnd and DASISION trialssuggest that frontline therapy withsecond-generation TKIs produceshigher rates of CCyR and MMR thanthe standard-dose imatinib, and theseresponses are achieved at earlier timepoints. On the basis of data derivedfrom the IRIS trial that highlighted theprognostic importance of achievingearly CCyR and MMR, it is reasonableto expect that the use of nilotinib ordasatinib in the frontline setting mightrender higher rates of event-free sur-vival and transformation-free survivaland may therefore offset the high costsassociated with progression.

Non-Hodgkin Lymphoma

NHL is a highly heterogeneousgroup of cancers affecting the lymph


The Evolving Role of Outcomes and End Points... Continued from page 51




system, with variable cytogenetic, cel-lular, and clinical features and naturalhistories that range from indolent tovery aggressive.38 NHL is the mostcommon hematologic malignancy inthe United States.6 It is estimated that65,540 Americans were diagnosedwith various forms of NHL in 2010,and 20,210 deaths were attributed tothe disease. The prevalence of NHL inthe United States is approximately440,000 patients.7 Most patients withNHL have a B-cell subtype: 31% ofpatients with NHL have diffuse largeB-cell lymphoma (DLBCL), 22% havefollicular lymphoma, 5% to 10% havemarginal zone lymphoma (MZL), and6% have mantle-cell lymphoma(MCL).39 T-cell lymphomas compriseabout 15% of NHL cases.40

Indolent versus aggressive:

desired outcomes of therapy

Both B-cell and T-cell lymphomasare categorized into indolent andaggressive types. DLBCL, MCL, per iph -eral T-cell lymphoma, and anaplasticlarge-cell lymphoma (ALCL) are con-sidered aggressive lymphomas. Thegoal of treatment is to cure an aggres-sive lymphoma; this may be achievedin 30% to 60% of patients for some sub-types.41 DLBCL can be cured in a sig-nificant proportion of pa tients,42 butMCL cannot.43 The re sponse rate andOS are often the end points in clinicaltrials for aggressive lymphomas thatare curable, whereas response rate andduration of response and PFS are endpoints in trials for those that are not.

For aggressive lymphomas that can-not be consistently cured at this time,the search continues for treatment thatcan become a curative standard ofcare. The lack of cure along with treat-ment failure exacts an enormoussocioeconomic toll. For example, themean cost of treatment failure inaggressive NHL has been reported tobe as high as $14,174 monthly andreaches $85,934 over a period of <2years (in 1999-2000 dollars).44

In contrast, indolent lymphomas arecharacterized by long, slowly pro -gressive clinical courses; examplesinclude follicular lymphoma, MZL,Waldenstrom’s macroglobulinemia,and the cutaneous T-cell lymphomamycosis fungoides. The goal of treat-ment is often long-term management,as indolent lymphomas are rarelycured unless diagnosed when stilllocalized. The response rate, DFS,event-free survival, duration ofresponse, and PFS are often the pri-mary end points in clinical trials forindolent lymphomas.

Clinical trials have attempted toimprove on the best available acceptedtherapy by adding an additional agent

or substituting one active agent foranother; therefore, there is a virtual“alphabet soup” of therapeutic regi-mens available to treat this group ofcancers. In the past decade, the treat-ment of NHL has changed dramatical-ly, with the advent of molecularlytargeted anticancer therapies. Forexample, the development of the CD20monoclonal antibody rituximab haschanged the treatment paradigm forB-cell lymphomas and, in some sub-types of the disease, has markedlyimproved prognosis.

Bortezomib, lenalidomide, ben-damustine, alemtuzumab, and othernovel agents have also demonstratedclinical benefit in B-cell lymphomas.T-cell subtypes and ALCL are beingtreated with a number of approvedand investigational targeted agents,including romidepsin, pralatrexate,brentuximab vedotin, denileukin difti-tox, and vorinostat. The use of targetedtherapies for NHL, combined withrefinements in cytotoxic chemothera-py and stem-cell transplantation, con-tinue to alter the therapeutic landscapeat a rapid pace.

Indolent versus aggressive: clinical

trial end points

In 1999, an international workinggroup of clinicians, radiologists, andpathologists with expertise in the eval-uation and management of patientswith NHL published guidelines forresponse assessment and outcomesmeasurement.45 These were revised in2007, when interobserver and intraob-server variations were identified andrecommended technologies were nolonger considered state-of-the-art.46 Inaddition to defining response criteriaand making recommendations for dis-ease evaluation, this group proposedthat the major end points of clinical tri-als should reflect the histology, clinical

situation, and objectives of the studyand be defined consistently acrossclinical trials.

Response rates as a trial end pointare greatly influenced by the definedresponse criteria used. In addition,response rates do not necessarily influ-ence other measures of overall clinicalbenefit or outcome in patients withNHL. OS is the least ambiguous of thetrial end points, but it is not optimalfor use in an indolent or incurableaggressive lymphoma trial. PFS isoften considered the preferred endpoint in lymphoma clinical trials, espe-cially those involving incurable sub-types (indolent and aggressive).Event-free survival is generally notencouraged by the FDA, because itcombines efficacy, toxicity, and patientwithdrawal. However, it may be use-ful in the evaluation of novel agentsthat may be highly toxic and have ahigh risk-benefit ratio. Duration ofresponse, if associated with measuresof clinical benefit, may also be animportant and relevant end point inlymphoma trials.

One of the most important out-comes for patients with NHL has beenevidence of clinical benefit. Clinicalbenefit may reflect improvement inquality of life or a reduction in symp-toms, transfusion requirements, fre-quent infections, or other parameters.As the symptoms associated with lym-phoma can greatly impact a patient’squality of life, time to reappearanceor progression of lymphoma-relatedsymptoms may also be an importantmeasure, especially for incurable lym-phomas.

Rituximab was first approved by theFDA in 1997 for the treatment ofrelapsed or refractory low-grade orfollicular, B-cell NHL as a single agentbased on the overall response rate.47

Since that time, rituximab has received

5 additional indications as a singleagent or as part of a chemotherapeuticregimen. The Appendix (available atwww.valuebasedcancercare.com/P10067E) lists some of the targetedagents and new therapies approvedwithin the past decade for various sub-types of NHL and the primary and sec-ondary end points used in the registra-tion trials. Care must be taken whenmaking cross-trial comparisons toensure that the patient populations arecomparable and that defined endpoints and response criteria have beenused consistently.

Evolving Outcomes and End

Points and Value-Based Care

As progress is made in the treatmentof MM, CML, and NHL, as with anycancer, the ultimate outcome of thera-py for patients also evolves. AlthoughOS remains the optimal outcome forpatients with MM, surrogate endpoints used in clinical trials do notalways translate into a survival benefitas long-term data mature. The use ofTKIs for CML-CP has drasticallychanged the natural history of this dis-ease. Freedom from treatment failureand from progression to advancedphase or blast crisis is the preferredoutcome. Early and durable CCyR andMMR are reliable surrogate end pointsfor this outcome. For patients withsome subtypes of aggressive NHL, acure is possible and OS is both the trialend point and the desired outcome.However, for patients with indolentand incurable-aggressive NHL, anextended period without progressionthat may be compounded by lym-phoma-associated symptoms is pre-ferred. PFS and duration of responseare acceptable surrogate end points forthis outcome. �

References1. Cohen H. Drug Topics Red Book 2008. 112th ed. Mont -vale, NJ: Thomson Healthcare/Thomson PDR; 2008.2. Donabedian A. Evaluating the quality of medical care.Milbank Memorial Fund Quarterly. 1966;44:166-206.3. Johnson JR, Williams G, Pazdur R. End points andUnited States Food and Drug Administration ap prov -al of oncology drugs. J Clin Oncol. 2003;21:1404-1411.4. US Food and Drug Administration. The Center forDrug Evaluation and Research. Cancer Drug Approv alEndpoints. www.fda.gov/AboutFDA/CentersOffices/CDER/ucm117709.htm#background. Acces sed July23, 2010.5. US Food and Drug Administration. Guidance forIndustry: Clinical Trial Endpoints for the Approval ofCancer Drugs and Biologics. May 2007. www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf.Accessed July 23, 2010.6. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics,2010. CA Cancer J Clin. 2010;60:277-300.7. Howlader N, Noone AM, Krapcho M, et al, eds.SEER Cancer Statistics Review, 1975-2008, NationalCancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEERdata submission, posted to the SEER Web site, 2011.Accessed June 30, 2011.8. Rajkumar SV, Harousseau JL, Durie B, et al, for theInternational Myeloma Workshop Consensus Panel 1.Consensus recommendations for the uniform report-


Figure Kinetics of Resistance to Imatinib in the IRIS Trial

AP/BC indicates advanced phase/blast crisis; CHR, complete hematologic response; IRIS, Insulin Resistance Interventionafter Stroke; MCyR, major cytogenetic response.Source: Deininger M, et al. Blood. 2009;114(suppl):462. Abstract 1126.

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0.4




ing of clinical trials. Blood. 2011;117:4691-4695.9. San Miguel JF, Schlag R, Khuageva NK, et al.Bortezomib plus melphalan and prednisone for initialtreatment of multiple myeloma. N Engl J Med. 2008;359:906-917.10. Mateos MV, Richardson PG, Schlag R, et al.Bortezomib plus melphalan and prednisone com-pared with melphalan and prednisone in previouslyuntreated multiple myeloma: updated follow-up andimpact of subsequent therapy in the phase III VISTAtrial. J Clin Oncol. 2010;28:2259-2266.11. Facon T, Mary JY, Hulin C, et al, for the IntergroupeFrancophone du Myélome. Melphalan and pred-nisone plus thalidomide versus melphalan and pred-nisone alone or reduced-intensity autologous stemcell transplantation in elderly patients with multiplemyeloma (IFM 99-06): a randomised trial. Lancet.2007;370:1209-1218.12. Palumbo A, Bringhen S, Liberati AM, et al. Oralmelphalan, prednisone, and thalidomide in elderlypatients with multiple myeloma: updated results of arandomized controlled trial. Blood. 2008;112:3107-3114.13. Hulin C, Facon T, Rodon P, et al. Efficacy of mel-phalan and prednisone plus thalidomide in patientsolder than 75 years with newly diagnosed multiplemyeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:3664-3670.14.Wijermans P, Schaafsma M, Termorshuizen F, et al,for the Dutch-Belgium Cooperative Group HOVON.Phase III study of the value of thalidomide added tomelphalan plus prednisone in elderly patients withnewly diagnosed multiple myeloma: the HOVON 49Study. J Clin Oncol. 2010;28:3160-3166.15.Waage A, Gimsing P, Fayers P, et al, for the NordicMyeloma Study Group. Melphalan and prednisoneplus thalidomide or placebo in elderly patients withmultiple myeloma. Blood. 2010;116:1405-1412.16. Kapoor P, Rajkumar SV, Dispenzieri A, et al.Melphalan and prednisone versus melphalan, pred-nisone and thalidomide for elderly and/or transplantineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696. 17. Palumbo A, Dimopoulos MA, Delforge M, et al. Aphase III study to determine the efficacy and safety oflenalidomide in combination with melphalan andprednisone (MPR) in elderly patients with newlydiagnosed multiple myeloma. Presented at the 51stAmerican Society of Hematology Annual Meeting;

New Orleans, LA; December 5-8, 2009. Abstract 613.http://ash.confex.com/ash/2009/webprogram/Paper22787.html. Accessed June 28, 2011.18. Harousseau JL, Avet-Loiseau H, Attal M, et al.Achievement of at least very good partial response isa simple and robust prognostic factor in patients withmultiple myeloma treated with high-dose therapy:long-term analysis of the IFM 99-02 and 99-04 trials.J Clin Oncol. 2009;27:5720-5726.19. van de Velde H, Liu X, Chen G, et al. Completeresponse correlates with long-term survival and pro-gression-free survival in high-dose therapy in multi-ple myeloma. Haematologica. 2007;92:1399-1406.20.Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in multiplemyeloma after stem cell transplantation. Blood. 2011Apr 11. Epub ahead of print.21. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al.HOVON-65/GMMGHD4 randomized phase III trialcomparing bortezomib, doxorubicin, dexamethasone(PAD) vs VAD followed by high-dose melphalan(HDM) and maintenance with bortezomib or thalido-mide in patients with newly diagnosed multiplemyeloma (MM). Presented at the 52nd AmericanSociety of Hematology Annual Meeting; Orlando, FL;December 4-7, 2010. Abstract 40. http://ash.confex.com/ash/2010/webprogram/Paper29306.html.Accessed June 28, 2011.22. Cavo M, Perrone G, Buttignol S, et al. Bortezomib-thalidomide-dexamethasone compared with thalido-mide-dexamethasone as induction and consolidationtherapy before and after double autologous transplan-tation in newly diagnosed multiple myeloma: resultsfrom a randomized phase 3 study. Presented at the52nd American Society of Hematology AnnualMeeting; Orlando, FL; December 4-7, 2010. Abstract 42. 23. Richardson PG, Weller E, Lonial S, et al.Lenalidomide, bortezomib, and dexamethasone com-bination therapy in patients with newly diagnosedmultiple myeloma. Blood. 2010;116:679-686.24. Kumar S, Flinn IW, Richardson PG, et al. Novelthree- and four-drug combination regimens of bor -tezomib, dexamethasone, cyclophosphamide, andlenalidomide, for previously untreated multiplemyeloma: results from the multi-center, randomized,phase 2 EVOLUTION Study. Presented at the 52ndAmerican Society of Hematology Annual Meeting;Orlando, FL; December 4-7, 2010. Abstract 621.

25. Rohrbacher M, Hasford J. Epidemiology of chronicmyeloid leukaemia (CML). Best Pract Res ClinHaematol. 2009;22:295-302.26. Kantarjian H, O’Brien S, Cortes J, et al. Therapeuticadvances in leukemia and myelodysplastic syndromeover the past 40 years. Cancer. 2008;113(7 suppl):1933-1952.27. Faderl S, Talpaz M, Estrov Z, Kantarjian HM.Chronic myelogenous leukemia: biology and therapy.Ann Intern Med. 1999;131:207-219.28. Kantarjian H, Smith TL, O’Brien S, et al. Prolongedsurvival in chronic myelogenous leukemia after cyto-genetic response to interferon-a. The LeukemiaService. Ann Intern Med. 1995;122:254-261.29. O’Brien SG, Guilhot F, Larson RA, et al. Imatinibcompared with interferon and low dose cytarabine fornewly diagnosed chronic-phase chronic myeloidleukemia. N Engl J Med. 2003;348:994-1004.30. Marin D, Milojkovic D, Olavarria E, et al.European LeukemiaNet criteria for failure or subopti-mal response reliably identify patients with CML inearly chronic phase treated with imatinib whose even-tual outcome is poor. Blood. 2008;112:4437-4444.31. Druker BJ, Guilhot F, O’Brien SG, et al. Five-yearfollow-up of patients receiving imatinib for chronicmyeloid leukemia. N Engl J Med. 2006;355:2408-2417.32. Deininger M, O’Brien SG, Guilhot F, et al.International randomized study of interferon vsSTI571 (IRIS) 8-year follow up: sustained survival andlow risk for progression or events in patients withnewly diagnosed chronic myeloid leukemia in chronicphase (CMLCP) treated with imatinib. Presented atthe 51st American Society of Hematology AnnualMeeting; New Orleans, LA; December 5-8, 2009.Abstract 1126. 33. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinibversus imatinib for newly diagnosed chronic myeloidleukemia. N Engl J Med. 2010;362:2251-2259. 34. Hughes TP, Hochhaus A, Saglio G, et al. ENESTndupdate: continued superiority of nilotinib versus ima-tinib in patients with newly diagnosed chronicmyeloid leukemia in chronic phase (CML-CP).Presented at the 52nd American Society ofHematology Annual Meeting; Orlando, FL; December4-7, 2010. Abstract 207. 35. Kantarjian H, Shah NP, Hochhaus A, et al.Dasatinib versus imatinib in newly diagnosed chron-ic-phase chronic myeloid leukemia. N Engl J Med.

2010;362:2260-2270. 36. Shah N, Kantarjina H, Hochhaus A, et al. Dasatinibversus imatinib in patients with newly diagnosedchronic myeloid leukemia in chronic phase (CML-CP)in the DASISION Trial: 18-month follow-up. Pre -sented at the 52nd American Society of HematologyAnnual Meeting; Orlando, FL; December 4-7, 2010.Abstract 206. 37. Wu EQ, Johnson S, Beaulieu N, et al. Healthcareresource utilization and costs associated with non-adherence to imatinib treatment in chronic myeloidleukemia patients. Curr Med Res Opin. 2010;26:61-69. 38. National Comprehensive Cancer Network. Non-Hodgkin’s Lymphoma. V.2.2009. www.nccn.org.Acces sed June 23, 2011.39. Fauci AS, Braunwald E, Kasper DL, et al, eds.Harrison’s Principles of Internal Medicine. 17th ed. NewYork: McGraw-Hill; 2008. 40. Portlock C, Vose JM, Cheson BD. T-cell lympho -mas. www.lymphoma.org/atf/cf/%7B0363CDD6-51B5-427B-BE48-E6AF871ACEC9%7D/T-CELL%20LYMPHOMAS.PDF. Accessed June 23, 2011.41. PDQ (Physician Data Query) Modification ofREAL Classification of Lymphoproliferative Diseases.National Cancer Institute of the National Institutes ofHealth. www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/healthprofessional/allpages#Section_31. Accessed June 28, 2011.42. Coiffier B. Standard treatment of advanced-stagediffuse large B-cell lymphoma. Semin Hematol.2006;43:213-220. 43.Witzig TE. Current treatment approaches for man-tle-cell lymphoma. J Clin Oncol. 2005;23:6409-6414.44. Kutikova L, Bowman L, Chang S, et al. Medicalcosts associated with non-Hodgkin’s lymphoma in theUnited States during the first two years of treatment.Leuk Lymphoma. 2006;47:1535-1544.45. Cheson BD, Horning SJ, Coiffier B, et al. Report ofan international workshop to standardize responsecriteria for non-Hodgkin’s lymphomas. NCI Spon -sored International Working Group. J Clin Oncol.1999;17:1244.46. Cheson BD, Pfistner B, Juweid ME, et al. Revisedresponse criteria for malignant lymphoma. J ClinOncol. 2007;25:[email protected]. Drug details. Rituximab. www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed June 28, 2011.

The Evolving Role of Outcomes and End Points... Continued from page 53

The management of complexoncology drugs in pharmacyand in medical benefits presents

unique challenges for all parties whoseek cost-effective, positive clinicaloutcomes for patients with cancer.New therapies are offering the excitingprospect of improved outcomes, pro-longed life, and, in some cases, a curefor specific diseases. Targeted oncolyt-ics and pharmacogenomics, whichcarry the promise of improved likeli-hood of successful treatment, havebecome welcome additions to the cur-rent standards of care. The concept ofcancer as a chronic disease is becomingaccepted in pharmacy oncology man-agement. Targeted therapies are nowstandard treatments for multiplemyeloma (MM), non-Hodgkin lym-phoma (NHL), and chronic myeloge-nous leukemia (CML).Recent trials in MM have used time

to progression and progression-freesurvival as primary end points (asrecommended by the InternationalMyeloma Workshop Consensus Panel1). The use of different end points inclinical trials for the same disease,however, has complicated the analysisand evaluation process for the phar-macy and therapeutics (P & T) com-mittees of health plans in comparingcompeting therapies to select the mostefficacious and cost-effective treatmentoptions for their members. The abilityto diagnose cancer earlier in the dis-ease process and to begin life-savingtreatments sooner place additionalstrain on pharmacy managers to max-imize the value from all therapies inthe treatment algorithm of a particularcancer type.The tyrosine kinase inhibitors (TKIs)

have revolutionized the treatment ofCML by extending survival. It is now

possible to achieve long-term successwith these agents if treatment is initiat-ed early enough in the course of dis-ease, and a positive early response canbe a good predictor of long-term sur-vival. As clinical studies are able todemonstrate clinically meaningful dif-ferentiations between first- and sec-ond-generation TKIs, health plans canconsider promoting specific treatmentpathways to maximize cost-savingsand outcomes.NHL affects a diverse population of

patients with various disease subtypesthat require careful diagnosis to bematched with specific drug treatmentprotocols. The International WorkingGroup has attempted to define appro-priate clinical trial end points andresponse criteria to effectively differen-tiate treatments. This process is criticalfor managed care plans to managespecific therapies effectively and con-

trol costs in the treatment of NHL andother cancer types.It is clear that in the near-term,

overall survival will remain the goldstandard for P & T committees in theirassessment of drug efficacy. However,other end points will continue to beassessed as clinical trial resultsbecome available. The developmentof pharmaceuticals with biomarkerscan increasingly give providers andhealth plans the confidence thatpatients will have a greater likelihoodof response. This new trend also hasthe potential to decrease waste andthe risk of untoward side effects inpatients who are not good candidatesfor a particular treatment. As healthplans progress in the management ofoncology drugs, the ability to targetpatients, predict outcomes, andreduce costs will drive the most suc-cessful programs. �

New End Points Create Novel Challenges for HealthPlans in Oncology Drug Management By James T. Kenney Jr, RPh, MBAMr Kenney is Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

COMMENTARY


AVBCC is the fastest growing national specialty organization dedicated to improving the care of

cancer patients and their quality of life.

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

and their families.


Sponsorship Opportunities Available

www.AVBCConline.orgRegister online at

Past Sponsors:

September 24Chicago, IL



2012 NATIONAL MEETINGMarch 29-31, Houston, TX

��

September 24, 2011JW Marriott

151 West Adams Street Chicago, Illinois

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

October 1, 2011Marriott Marquis55 Fourth Street

San Francisco, California

November 19, 2011Marriott Waterside

700 South Florida AvenueTampa, Florida

PROGRAM OVERVIEWAs a result of the resounding success of our First AnnualConference, we have been asked to incorporate “The Bestof AVBCC” into three regional meetings. We continueto be guided by the expertise of leaders in these fields pro-viding attendees with a thorough understanding of theevolution of the value equation as it relates to cancer ther-apies and will be able to implement, improve, and sustaintheir companies and institutions, while improving accessfor patients and ultimately patient care.

WHO SHOULD ATTENDAll stakeholders in a position to impact cancer patientcare are invited to join this exciting forum. Specificallythis conference is intended for:•Medical Oncologists •Advanced Practitioners•Hematologists/Oncologists •Managed Care Professionals•Surgical Oncologists •Medical Directors•Nurses • Pharmacists•Practice Managers/ • Pharmacy Benefit ManagersAdministrators (PBMs)

CONTINUING EDUCATION INFORMATIONGoalThe Association for Value-Based Cancer Care will fosteran open dialogue between providers, payers, and/or othermembers of the oncology team in order for attendees togain a better understanding of various points of view regarding cost, quality, and access in cancer care.

Objectives• Examine the impact of healthcare reform on allstakeholders involved in the management of patientswith cancer

• Identify issues and potential solutions to challengeswith access and affordability of oncology therapeutics

• Determine the value equation of cost, quality, andaccess when evaluating the diagnosis, treatment, andoverall management of cancer patients

• Define appropriate comparative effectiveness research and clinical pathways as tools to evaluatecurrent recommendations for patient management

• Analyze trends in the delivery of care in the management of cancer patients

ACCREDITATION INFORMATIONPhysician AccreditationScience Care designates this activity for a maximum of5.25 AMA PRA Category 1 Credit(s)™. Science Care isaccredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuingmedical education for physicians. Physicians should onlyclaim credit commensurate with the extent of their par-ticipation in the activity.Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of RegisteredNursing, Provider Number 15106, for 5.25 contact hours.Registered Pharmacy Designation

Medical Learning Institute is accredited by theAccreditation Council for Pharmacy Education

(ACPE) as a provider of continuing pharmacy educa-tion. Completion of this activity provides for 5.25 con-tact hours (0.525 CEUs) of continuing education credit.The Universal Activity Number for all three regionalmeetings is 0468-9999-11-033-L01-P.September 24, 2011 – Chicago, ILOctober 1, 2011 – San Francisco, CANovember 19, 2011 – Tampa, FL

ChairGary Owens, MDPresident, Gary Owens Associates

Invited FacultyStephanie Akbari, MDDonald Balfour III, MDAdam Brufsky, MD, PhD, FACPCraig Deligdish, MDJohn Fox, MD Scott Gottlieb, MDGary Johnson, MD, MS, MBATed OkonWinston Wong, PharmD

8:00 – 9:00 am Registration & Breakfast9:00 – 9:15 am Welcome & Introduction9:15 – 10:45 am The Challenges of Personalized

Cancer Care10:45 – 11:30 am Community Oncology Crisis:

An Uncertain Future11:30 – 12:15 pm Improving Patient Care Through

Collaboration & Partnerships12:15 – 1:45 pm Lunch Symposium1:45 – 2:30 pm Regional Insurer’s Perspective

on Cancer Care2:30 – 3:15 pm The Impact of New Healthcare

Legislation3:15 – 3:30 pm Summary & Concluding Remarks

CONFERENCE REGISTRATION$125 Includes 1-year association membership

Registration InformationChicago, www.regonline.com/avbcc-chicago2011San Francisco, www.regonline.com/avbcc-sanfran2011Tampa, www.regonline.com/avbcc-tampa2011

CONTACT/SUPPORTIf you have any questions please contact:Association for Value-Based Cancer Care™241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831Phone: 732-992-1040 [email protected]

PRELIMINARY AGENDA

COMMERCIAL SUPPORT ACKNOWLEDGEMENTThere is no commercial support for this activity.

� �� VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 7:12 PM

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