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The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ august 2013 Vol 6, No 6 I SPECIAL ISSUE

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Payers’ Perspectives in Oncology Including ASCO 2013 Highlights

ASCO President Highlights Off-Label Drug Use in Oncology for 18% of Spending Bridges to Conquer Cancer Accounts Mean number of claims for unapproved indications By Wayne Kuznar

averages 11 per patient By Caroline Helwick

Photo by © ASCO/Silas Crews 2013

Chicago, IL—An examination of the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 1998 to 2008 revealed that a significant number of patients with cancer receive drugs that are neither indicated by the US Food and Drug Administration (FDA) for the specific condition nor endorsed by the National Comprehensive Cancer Network (NCCN) compendia—and 18% of the spending on cancer drugs is for off-label drug use.

Chicago, IL—“Building Bridges to Conquer Cancer” was the theme of the 2013 American Society of Clinical Oncology (ASCO) annual meeting, as well as of the address of AS-

CO’s outgoing President Sandra M. Swain, MD. Dr Swain’s address focused on 3 pillars of the theme: (1) ensuring global health equity, (2) the need to

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Immunotherapies Take Center Stage in Melanoma

New drug therapies will push value questions to the forefront By Audrey Andrew Chicago, IL—Data continue to build for the application of immunotherapy for patients with metastatic melanoma. At ASCO 2013, several sessions were devoted to recent advances in melano-

ma, focusing on new ways to boost the activity of current therapies, introducing a new class of immunotherapy in development, and a new form of immunotherapy—an oncolytic vaccine.

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Cancer Drug Pipeline Is Bustling By Caroline Helwick and Wayne Kuznar Chicago, IL—Targeted therapies and immune-focused agents with novel mechanisms of action yielded impressive outcomes in the early- and late-phase studies that were reported at ASCO 2013. Melanoma The MEK inhibitor selumetinib is the first drug to prove effective in patients with metastatic uveal (ocular)

melanoma, according to phase 2 clinical trial results. In a study of 98 patients, 50% of those receiving selumetinib had tumor regression compared with 11% of the patients in the control group who received temozolomide (Temodar). The median progression-free survival (PFS) was 15.9 weeks and 7.0 weeks (P = .005), respectively, a 54% risk reduction. Lynn Mara Schuchter, MD, Program Leader,

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in th is is s u e Health Economics . . . . . . . . . . . Nearly 1 in 5 patients with cancer reports financial distress Eliminating copay increases mammography screening rates EMERGING THERAPIES. . . . . . . Pazopanib for ovarian cancer

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PERSONALIZED MEDICINE. . . . 27 Strategies to overcome the challenges of personalized medicine HEALTH POLICY. . . . . . . . . . . . . 28 Will FDA approve surrogate end point for neoadjuvant breast cancer? © 2013 Engage Healthcare Communications, LLC

“We found a lot of off-label use,” said Dawn L. Hershman, MD, MS, Associate Professor of Medicine and Epidemiology, Division of He­ma­tology/ Oncology, Columbia Uni­versity Medical Center, New York, who presented these findings at ASCO 2013. The extent of off-label use is a policy concern, because the clinical benefits of such use for patients may not outweigh the costs or the adverse health outcomes, Dr Hershman said.

BREAST CANCER. . . . . . . . . . . 34 10 years of tamoxifen prolongs survival PROSTATE CANCER. . . . . . . . . . 35 Patient lack of knowledge increases unnecessary treatment DRUG THERAPY . . . . . . . . . . . . . Sorafenib effective in metastatic thyroid cancer

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DRUG UPDATE . . . . . . . . . . . . . . Xofigo for metastatic CRPC

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PAYERS’ PERSPECTIVE. . . . . . . 39 Cancer care in 2013: hope, reality, and a call to action


The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.


In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,544 per 3.5-mg vial as of July 2013 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE on the next page of this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.


FDA Update Mekinist and Dabrafenib Approved for Advanced Melanoma with BRAF Mutations

On May 29, 2013, the US Food and Drug Administration (FDA) approved 2 targeted oral therapies for patients with melanoma. The 2 therapies were both developed by Glaxo­SmithKline

and are targeting similar, but not the same, populations of patients with melanoma and a BRAF mutation. Both drugs were approved concurrently with the FDA approval of a companion diagnostic assay THxID BRAF (manufactured by bioMérieux) for the detection of BRAF B:7”V600E and BRAF V600K mutations.

Trametinib (Mekinist tablet) was approved for the treatment of patients with metastatic or unresectable melanoma and the BRAF V600E and BRAF V600K mutation who have not been previously treated with a BRAF inhibitor therapy. The recommended dosage for trametinib is 2 mg orally until disease progression or unacceptable

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306 All rights reserved. Printed in USA

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WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

toxicity, to be taken ≥1 hour before or 2 hours after a meal. The FDA’s approval of trametinib was based on a demonstrated improvement in progression-free survival (PFS) in a multicenter, international, open-label, active-controlled trial with 322 patients with stage IIIc or stage IV melanoma with either BRAF V600E and BRAF V600K mutation. Patients with >1 previous chemotherapy regimen or those who received BRAF or MEK inhibitors were excluded from the trial. The patients were randomized in a 2:1 ratio to oral trametinib 2 mg daily or to intravenous chemotherapy with dacarbazine or paclitaxel every 3 weeks. Overall, 51 (47%) patients in the chemotherapy arm received trametinib at the time of disease progression. The median PFS was 4.8 months in the trametinib arm versus 1.5 months in the chemotherapy arm (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.34-0.65; P <.001). Objective response rates were 22% with trametinib and 8% with chemotherapy. Data for overall survival (OS) were not mature. In a single-arm trial of 40 patients with unresectable or metastatic melanoma and BRAF V600E or BRAF V600K mutation who had received previous BRAF inhibition therapy, the administration of trametinib showed no evidence of antitumor activity (ie, no response) in these patients. The most common (≥20) adverse events (AEs) reported with trametinib were rash, diarrhea, and lymphedema. Serious AEs included cardiomyopathy, retinal pigment epithelial detachment, retinal vein occlusion, interstitial lung disease, and serious skin reactions. Dabrafenib (Tafinlar capsule) was approved for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation. Dabrafenib is not approved for patients with wild-type BRAF melanoma (ie, without BRAF mutation); in those patients it could potentially lead to tumor promotion. The recommended dosage is 150 mg twice daily until disease progression or until unacceptable toxicity. Dabrafenib should be taken ≥1 hour before or 2 hours after a meal. The presence of BRAF V600E mutation must be confirmed before prescribing dabrafenib, which could potentially promote tumor growth in patients with wild-type melanoma. The approval was based on a multicenter, international, open-label, randomized, active-controlled trial of 250 patients with treatment-naïve unresectable stage III or stage IV melanoma. A total of 28 patients in the Continued on page 38

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August 2013 VOL. 6

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Special Issue


Payers’ Perspectives in Oncology

The Peer-Reviewed Forum For Real-world Evidence in Benefit Design™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Directors, Client Services Joseph Beck Ron Gordon Projects Manager John Welz Senior Production Manager Lynn Hamilton The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonato Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications 1249 South River Road, Suite 202A Cranbury, NJ 08512 Phone: 732-992-1880

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

VOL. 6

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FDA UPDATE Mekinist and dabrafenib for advanced melanoma with BRAF mutations More….. HEALTH ECONOMICS 1 in 5 patients with cancer in financial distress Eliminating copay increases mammography rates Can we afford progress in oncology? Use of costly diagnostics for lung cancer surveillance rising More…..

breast cancer 10 years of tamoxifen prolongs life in ER-positive breast cancer PROSTATE CANCER Patient misinformation ups unnecessary treatment More….. DRUG THERAPY Sorafenib effective in metastatic thyroid cancer More….. PAYERS’ PERSPECTIVE Cancer care in 2013: hope, reality, and a call to action

EMERGING THERAPIES Cancer drug pipeline is bustling More….. LUNG CANCER Dabrafenib shows promise for stage IV NSCLC

DRUG UPDATE Xofigo new option for patients with metastatic prostate cancer

EDITORIAL BOARD Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy Philadelphia

J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine

Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Medical Lead, Specialty & Payer Strategy Medical Affairs, Pfizer, Inc, PA Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Diana Brixner, RPh, PhD Institute, Washington, DC Professor & Chair, Dept. of Pharmacotherapy Robert W. Dubois, MD, PhD PATIENT ADVOCACY Executive Director, Outcomes Research Chief Science Officer William E. Fassett, BSPharm, MBA, Center, Director of Outcomes Personalized PhD, FAPhA National Pharmaceutical Council Health Care Program, University of Utah, Professor of Pharmacy Law & Ethics Washington, DC Salt Lake City Aging and Wellness Dept. of Pharmacotherapy, College of Jack E. Fincham, PhD, RPh Eric G. Tangalos, MD, FACP, AGSF Pharmacy Washington State University Joseph Couto, PharmD, MBA Professor of Pharmacy, School of Pharmacy Professor of Medicine Spokane, WA Clinical Program Manager University of Missouri, Kansas City, MO Mayo Clinic, Rochester, MN Cigna Corporation, Bloomfield, CT Mike Pucci Walid F. Gellad, MD, MPH CANCER RESEARCH Sr VP, Commercial Operations and Steve Miff, PhD Assistant Professor of Medicine Al B. Benson III, MD, FACP, FASCO Business Development, PhytoChem Senior Vice President University of Pittsburgh, Staff Physician, Professor of Medicine, Associate Director Pharmaceuticals VHA, Inc., Irving, TX Pittsburgh VA Medical Center, Adjunct for Clinical Investigations Lake Gaston, NC Scientist, RAND Health Christopher (Chris) P. Molineaux Robert H. Lurie Comprehensive Cancer Personalized medicine President, Pennsylvania BIO Paul Pomerantz, MBA Center Northwestern University, IL Amalia M. Issa, PhD, MPH Malvern, PA CEO, American Society of Past Chair, NCCN Board of Directors Director, Program in Personalized Anesthesiologists Terri S. Moore, PhD, RPh, MBA Samuel M. Silver, MD, PhD, FASCO Medicine & Targeted Therapeutics Park Ridge, IL Senior Manager, Product Development Professor of Internal Medicine, Hematology/ URAC, Washington, DC University of the Sciences, Philadelphia J. Warren Salmon, PhD Oncology PHARMACOECONOMICs Professor of Health Policy & Kavita V. Nair, PhD Assistant Dean for Research, Associate Josh Feldstein Administration, School of Public Health Associate Professor, School of Pharmacy Director, Faculty Group Practice President & CEO, CAVA, The Center for University of Illinois at Chicago University of Colorado at Denver, CO University of Michigan Medical School Applied Value Analysis, Norwalk, CT Raymond L. Singer, MD, MMM, CPE, Gary M. Owens, MD EMPLOYERS Jeff Jianfei Guo, BPharm, MS, PhD FACS President, Gary Owens Associates Arthur F. Shinn, PharmD, FASCP Professor of Pharmacoeconomics & Chief, Division of Cardiothoracic Surgery Glen Mills, PA President, Managed Pharmacy Pharmacoepidemiology, College of Vice Chair, Department of Surgery for Consultants, LLC, Lake Worth, FL Andrew M. Peterson, PharmD, PhD Pharmacy, Univ of Cincinnati Medical Quality & Patient Safety and Outreach Dean, Mayes School of Healthcare F. Randy Vogenberg, RPh, PhD Center, OH Lehigh Valley Health Network, PA Business and Policy, Associate Professor, Principal, Institute for Integrated Grant D. Lawless, RPh, MD, FACP RESEARCH & DEVELOPMENT University of the Sciences, Philadelphia Healthcare, Greenville, SC Assoc. Prof. and Director, Healthcare Frank Casty, MD, FACP Sarah A. Priddy, PhD ENDOCRINOLOGY Decision Analysis, Dept. of Clinical Chief Medical Officer Director, Competitive Health Analytics James V. Felicetta, MD Pharmacy Senior VP, Clinical Development Humana, Louisville, KY Chairman, Dept. of Medicine Pharmaceutical Economics and Policy Medical Science Carl T. Hayden Veterans Affairs Timothy S. Regan, BPharm, RPh, CPh Univ. of Southern California, Los Angeles Endo Pharmaceuticals, Chadds Ford, PA Medical Center, Phoenix, AZ Executive Director, Strategic Accounts PHARMACY BENEFIT DESIGN Michael F. Murphy, MD, PhD Xcenda, Palm Harbor, FL Quang Nguyen, DO, FACP, FACE Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer and Scientific Medical Director, Las Vegas Endocrinology Vincent J. Willey, PharmD Chief Medical Officer, Predictive Officer, Worldwide Clinical Trials Adjunct Associate Professor, Endocrinology Associate Professor, School of Pharmacy Health, Phoenix, AZ King of Prussia, PA Touro University Nevada University of the Sciences, Philadelphia Teresa DeLuca, MD, MBA SPECIALTY PHARMACY EPIDEMIOLOGY Research Paul Wilson Chief Medical Officer–Pharmacy Atheer A. Kaddis, PharmD Joshua N. Liberman, PhD Senior VP, Health Consumer Insights and Magellan Health Services Senior Vice President Executive Director, Research, Analytics, Blue Bell, PA Sales and Business Development Leslie S. Fish, PharmD Development & Dissemination David W. Wright, MPH Diplomat Specialty Pharmacy, Flint, MI Vice President of Clinical Programs Sutter Health, Concord, CA President, Institute for Interactive Patient Fallon Community Health Plan, MA James T. Kenney, Jr, RPh, MBA GOVERNMENT Care, Bethesda, MD Pharmacy Operations Manager John Hornberger, MD, MS Kevin B. “Kip” Piper, MA, FACHE health & value promotion Harvard Pilgrim Health Care Cedar Associates, LLC President, Health Results Group, LLC Craig Deligdish, MD Wellesley, MA CHP/PCOR Adjunct Associate Washington, DC Hematologist/Oncologist Menlo Park, CA Michael Kleinrock HEALTH INFORMATION TECHNOLOGY Oncology Resource Networks, Orlando, FL Michael S. Jacobs, RPh Director, Research Development Kelly Huang, PhD Thomas G. McCarter, MD, FACP IMS Institute for Healthcare Informatics MSJ Associates, Sandy Springs, GA President, HealthTronics, Inc. Chief Clinical Officer Collegeville, PA Matthew Mitchell, PharmD, MBA Austin, TX Executive Health Resources, PA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT HEALTH OUTCOMES RESEARCH

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo­metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the im­provement of healthcare. This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and edi­torial queries, please contact: editorial@engagehc.com; tel: 732-992-1892; fax: 732-992-1881 POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

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Health Economics

Nearly 1 in 5 Patients with Cancer Reports Financial Distress But most don’t discuss cost with their oncologist By Audrey Andrews Chicago, IL—Financial distress is prevalent among insured patients with cancer, and although most patients state a desire to talk to their physicians about costs, this discussion rarely occurs, according to a study conducted at Duke University Medical Center, Durham, NC. Of the 300 insured patients with cancer included in this study, 17% reported “high” or “overwhelming” financial distress, and only 25% of this group discussed costs with their physicians. “Financial distress increases the burden of living with cancer. Even insured patients may experience considerable financial distress, but little has been known about whether patients want to include cost discussions in treatment decision-making,” said S. Yousuf Zafar, MD, MHS, Assistant Professor, Division of Medical Oncology, De­ partment of Internal Medicine, Duke University Medical Center, who presented the study results at ASCO 2013. Nearly 50% of patients with cancer dip into their savings to pay for cancer treatment, according to other research by Dr Zafar and colleagues (Oncologist. 2013;18:381-390). Other researchers have shown that patients with a cancer

diagnosis are 2.6 times more likely to file for bankruptcy than patients without cancer (Ramsey S, et al. Health Aff [Millwood]. 2013;32:1143-1152). The researchers conducted a crosssectional study of 300 insured adults who were treated for at least 1 month for solid tumors. Participants were surveyed in person and were asked about financial distress (via a validated 10-point scale), out-of-pocket costs, discussions about costs with their doctor, and about decision-making.

“We found a ‘disconnect’ between a desire to talk about cost and actual­ly having this discussion.” —S. Yousuf Zafar, MD, MHS “We wanted to answer 3 questions,” Dr Zafar said. “Do patients want to discuss costs? Do they want cost to be included in treatment decision-making? And, if these discussions occur, do they result in decreased costs?” The patients’ mean age was 60 years; 53% were male, 72% had at least a high school education, and 66% were mar-

ried. The median household income was $60,000. Of the patients, 55% had private insurance and 36% had Medicare. Colorectal cancer was the most common diagnosis, followed by breast, lung, and pancreaticobiliary cancers; 78% of patients had advanced disease. A Lot of Stress, Little Conversation High or overwhelming financial distress was reported by 17% of patients. Approximately 50% of all respondents expressed a desire to talk about cost with their oncologist, but only 19% actually engaged in a cost discussion. Of the 17% of patients with the highest financial distress, only 25% had these discussions. “We found a ‘disconnect’ between a desire to talk about cost and actual­ ly having this discussion,” Dr Zafar observed. Barriers to Cost Discussions The investigators explored the barriers to discussions about cost, and found that 50% of patients did not talk about cost because they had “no difficulties” with cost, approximately 35% hesitated because they wanted “the best care,” and 20% said that cost was “not my doctor’s job,” or “my doctor can’t help.” Overall, 10% of patients

ASCO President Highlights Bridges to Conquer... strengthen future generations of leaders and providers, and (3) the vision for a rapid learning system in oncology. These 3 issues “belong squarely on our personal and professional radar screens,” she said. Disparity in Access to Care Gaps in connecting proven treatments and preventive measures with underserved populations are linked to increased mortality from cancer and more suffering as a result of later disease stages at initial presentation. These gaps occur in various parts of the United States, and not just in lowand middle-income countries, said Dr Swain. The 48 million uninsured Americans—and those joining the Medicaid rolls—are all part of this picture. One area of concern is the wide variability in Medicaid programs. “On the plus side, a recent study showed that in states where Medicaid programs have been expanded to cover more individuals, there has been a reduction in overall mortality,” she said. “While this is an encouraging sign for the general population, cancer-specific outcomes for patients covered by Med-

6

icaid have been associated with no better outcomes than for those who are uninsured.”

“Not only did the program help patients avoid the pain and suffering associated with aggressive treatment of late-stage illness, it saved millions of dollars in treatment costs.” —Sandra M. Swain, MD A key predictor of whether an adult will survive cancer is income. This outcome gap is largely a result of differences in access to care. One innovative effort to bridge equity gaps is a screening program for colon cancer that is available to every citizen in Delaware. The program’s success is exemplified by screening rates in blacks, which rose from 48% to 74%. The

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reported that they had talked to someone other than their physician about cost, and 10% said they were “embarrassed” to bring up the topic. “The fact that many patients said they wanted the best care, regardless of cost, carries the implication that patients link cost to quality, and if they broach the topic of cost, they may receive lesser quality care,” Dr Zafar suggested. The cohort was evenly split regarding their desire to include cost in decision-making; 21% wanted to “always take cost into account.” Of the 19% of patients who reported having cost discussions with their oncologist, 57% said these discussions resulted in decreased expenses for them. In an exploratory analysis of the study, white race and a high level of distress were significantly associated with the likelihood of discussing costs. The majority of patients who actually have cost discussions find them helpful, which indicates that there are “false barriers” to these discussions, Dr Zafar said. “We need to at least identify patients at greatest risk for financial distress. We may not have all the answers, but broaching the topic can go a long way.” n

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number of blacks presenting with regional and distant colorectal cancer was reduced by 39%. The decline in mortality rates for blacks was 42%, bringing it closer to that of whites. “Not only did the program help patients avoid the pain and suffering associated with aggressive treatment of latestage illness, it saved millions of dollars in treatment costs,” said Dr Swain. Although advances in vaccines and screening large populations for breast cancer and cervical cancer have been made, many of these methods are not available globally. And even if the cancer is diagnosed, there are wide gaps in the availability of affordable treatments. In response to the global cancer crisis, ASCO has started a program called ASCO International, which aims to increase support for existing programs and to invest in new programs aimed at global cancer control. One important strategy will be to use digital resources (ie, virtual meetings and mentoring) “to knit the world closer together.” Supporting the Next Generation of Leaders and Providers Supporting the next generation of

clinical cancer researchers is a priority, said Dr Swain. Although 98% of past winners of ASCO’s Young Investigator Award and Career Development Award programs are still involved in cancer research, donations to support the program are declining, an unwelcome occurrence at a time when federal research dollars are dwindling. ASCO is continuing its successful and popular Leadership Development Program in an effort to develop the next generation of leaders, but potential shortfalls in practicing oncologists are a concern. “Will we be able to meet the projected increase in cancer cases? To better understand and monitor these trends, ASCO has established a workforce information system,” she said. The number of oncologists aged ≥64 years is growing rapidly, and outnumbers those aged <40 years. Furthermore, only 3% of oncology fellows are black and 8% are Hispanic. To address disparities in which populations receive access to cancer care, a diverse professional workforce is necessary. n

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Health Economics

Off-Label Drug Use in Oncology Accounts for 18%... The study identified 42,634 patients with multiple myeloma or with metastatic breast, ovarian, lung, colon, or prostate cancer during that period in the SEER database. FDA drug approvals and their dates were identified; if the claim was within 1 year before the FDA approval date, it was categorized as NCCN compendia–supported. If the claim was made after the FDA approval date, it was categorized as FDA-approved. The researchers also determined which of the drugs were ever approved. The Medicare reimbursement rate was calculated for the most common regimen and dosing, and was not adjusted for inflation. The following numbers of unapproved anticancer agents used in the 7 common tumor types were: 20 in breast cancer, 8 in colon cancer, 8 in lung cancer, 18 in multiple myeloma, 28 in ovarian cancer, 33 in prostate cancer, and 13 in uterine cancer. Overall, 55% of patients received an on-label drug only, meaning that 45% of patients received a drug that was neither FDA-indicated nor compendia-supported. A strong variability was evident by tumor type: patients with multiple myeloma were most likely (80%) to receive an off-label drug and patients with colon cancer were least likely (10%). This pattern was consistent across the 10-year period. Of the drugs with no FDA indication for the specific tumor type, 70% were endorsed by compendia and 30% were not. The mean number of claims for drugs with no FDA indication or compendia support averaged 11 per patient overall. “The bulk of unapproved drugs are, however, compendia approved, and this is reassuring, because we think the compendia are appropriate,” Dr Hershman noted. Approximately 50% of the compendia-supported drugs were eventually approved by the FDA for that indication, but those that were not FDA-approved were not deleted from the compendia, she added.

Cost of Off-Label Use: $150 Million in This Cohort A breakdown of the cost according to appropriate use revealed nearly $150 million in reimbursement for drugs that were neither FDA-indicated nor compendia-supported (Table). Most of the cost for off-label use was for the treatment of multiple myeloma and prostate cancer.

“Of $850 million spent on drugs in this cohort, $150 million was for drugs only supported by compendia, and $150 million was for unapproved indications.” —Dawn L. Hershman, MD, MS “So, of $850 million spent on drugs in this cohort, $150 million was for drugs only supported by compendia, and $150 million was for unapproved indications,” Dr Hershman concluded, adding that the cost of drugs has increased substantially in the past 5 years, and thus the actual costs would be much greater. She cited data from another recent study (Conti RM, et al. J Clin Oncol. 2013;31:1134-1139) that detailed which patent-protected chemotherapy agents were the most likely to be used in­ appropriately. Conti and colleagues showed that off-label use (neither FDA-indicated nor NCCN compendia–endorsed) was greatest for rituximab (Rituxan) and gemcitabine (Gemzar; approximately 40%), and for bevacizumab (Avastin; approximately 25%). The least inappropriate use was for trastuzumab (Herceptin), for which

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Table Cancer Drug Use and Associated Costs for 42,634 Patients, 1998-2008 Drug use status

Cost, $ (%)

FDA-indicated drug for the actual use

531.8 million (64)

Compendia-supported drug

144.7 million (18)

Off-label use

149.5 million (18)

FDA indicates US Food and Drug Administration. essentially no inappropriate use was documented, and for pemetrexed (Alimta; <10%). The estimated national spending on these common, patent-protected drugs was $12 billion, of which $2.5 billion was for off-label use and NCCN compendia–unsupported use, according to the study by Conti and colleagues. While acknowledging limitations to the study that pertain to the use of billing codes, estimates of cost, and other factors, Dr Hershman commented, “We didn’t think we would find any unapproved use of drugs. We thought regulations were in place to stop that.” The Good, the Bad, and the Ugly Monika K. Krzyzanowska, MD, MPH, Director, Quality Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, discussed the study, noting that some off-label use is not completely “inappropriate” but may exist in terms of a different admin-

“Greater scrutiny of off-label use is needed, especially for diseases or drugs with a high prevalence of this, for expensive drugs....” —Monika K. Krzyzanowska, MD, MPH istration schedule, or in a different context for the same disease. In some cases, of course, the drug is used for a disease in which it has not been well studied.

Bevacizumab is a good example of this, Dr Krzyzanowska said. She noted that “this matters,” because there can be “bad” consequences, such as a negative impact on trial accrual and undue financial costs, or “ugly” consequences, such as harm to the patient. Of course, some consequences are “good,” such as drug access for patients with rare diseases and the promotion of innovation, Dr Krzyzanowska said. She said that Dr Hershman’s study confirms previous research showing that off-label prescribing is common in oncology and varies by disease, although a substantial proportion of off-label use is supported by the NCCN compendia. Several questions remain to be answered, including: • Is compendium-compliant use of drugs appropriate? • What is the impact of off-label prescribing on patients (ie, benefit and toxicity)? • What is the motivation for off-label prescribing? • How can the cost of off-label therapy best be estimated? • What is the incidence of off-label use in oral chemotherapy? • How would molecular profiling impact off-label prescribing? Clearly, Dr Krzyzanowska suggested, oncologists are not “choosing wisely” in all circumstances. “Greater scrutiny of off-label use is needed,” she pointed out, “especially for diseases or drugs with a high prevalence of this, for expensive drugs, and for situations where the benefit is likely small and the risk of toxicity substantial.” n

Do Financial Incentives Drive Physician Behavior? By Caroline Helwick Chicago, IL—It may come as no surprise that financial incentives can influence the behavior of physicians and the actions of healthcare systems. Elena B. Elkin, PhD, MPH, Health Outcomes Research Group, Memorial Sloan-Kettering Cancer Center, New York, discussed this topic at ASCO 2013. VOL. 6

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Although the association between incentives and behavior is often maligned, policymakers use it to their advantage, Dr Elkin pointed out. “When we find providers acting in ways that may be undesirable— referral to physician-owned facilities, prescribing influenced by drug reimbursement—we find public out-

rage. But, at the same time, we see policymakers wanting to capitalize on the incentives that are related to behavior, linking doctor payments to performance and income to quality of care,” she noted. The medical literature suggests that incentives can influence behavior. For example, a shift in the reimbursement

policy favoring office-based endoscopy over hospital-based endoscopy led to more office-based procedures for bladder lesions. When Medicare chemotherapy reimbursements were reduced for the treatment of metastatic cancer, the receipt of any chemother­ apy versus no chemotherapy did not change, but the use of more expensive

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Health Economics Do Financial Incentives Drive Physician... Continued from page 7 regimens increased. The decline in reimbursement for androgen-deprivation therapy led to a decrease in the utilization of this modality, but its appropriate use did not change. “Utilization patterns often track with changes in reimbursement,” Dr Elkin said.

“With patient-centered care becoming so important, we can consider providing decision support tools for patients that would facilitate informed, shared decisionmaking between patients and physicians.”

for-profit hospitals, which was primarily driven by the use of brachytherapy. “The bottom line is, in planning treatment, does the breast cancer treatment team have the patient’s best interest in mind, or are they thinking about which option will be the most profitable for them and their institu-

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we directly link reimbursement to the value of the service provided. Finally, with patient-centered care becoming so important, we can consider providing decision support tools for patients that would facilitate informed, shared decision-making between patients and physicians.” n

A Critical Connection Between B-Cell Signaling and the Tumor Microenvironment* Until recently, research of B-cell malignancies has been focused primarily on the B cell itself.1 However, new insights have revealed that there are important interactions between the B cell and the extracellular microenvironment that are dependent on intracellular signaling pathways mediated by various kinases including Bruton’s tyrosine kinase (BTK).2,3 These interactions suggest an important role in B-cell homing, adhesion, and migration.4,5 Further elucidation of these processes could change how we view and approach B-cell malignancies.

—Elena B. Elkin, PhD, MPH

Lack of Evidence: Brachytherapy for Breast Cancer Among the newer options for adjuvant radiotherapy in breast cancer are whole breast irradiation and partial breast irradiation, such as external beam radiotherapy and brachytherapy. Randomized controlled trials comparing these approaches are ongoing; meanwhile, dissemination of the new technologies has been rapid. In the absence of clinical trial data and evidence regarding patient selection, the American Society for Radiation Oncology (ASTRO) developed guidelines based mainly on observational and nonrandomized trial data to define patient groups who are and are not suitable for partial breast irradiation and patients in whom partial breast irradiation should be used with caution. In 2002, the US Food and Drug Administration approved an accelerated partial breast irradiation device, balloon brachytherapy (MammoSite), and its use sharply increased in all patient groups, even among patients deemed unsuitable for it (Hattangadi JA, et al. J Natl Cancer Inst. 2012;104:2941). By the end of 2007, 2.6% of patients receiving radiotherapy had MammoSite, and 65.8% of them were classified as cautionary or unsuitable. By ASTRO criteria, MammoSite was used by 5% of suitable patients, 3.4% of cautionary patients, and by 1.6% of unsuitable patients. In a study presented at the meeting (see article on page 11), Sen and colleagues showed greater use of brachytherapy in women aged ≥66 years at for-profit hospitals (20.2%) versus at nonprofit hospitals (15.2%). In women aged ≥80 years, there was greater use of any radiotherapy at

tion, and does this vary according to provider incentives?” Dr Elkin asked. She added, “We need to understand incentives and monitor their effects on utilization and cost and health outcomes. We can also consider changing incentives, suchS:7”as is being done with value-based insurance, where

BTK signaling pathways and the microenvironment*† FDC BCR TLR T cell MyD88

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*

Pharmacyclics, Inc., and Janssen Biotech, Inc., are currently investigating BTK in search of insights that could improve the lives of patients with B-cell malignancies. Visit us at www.BCellSignals.com.

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Health Economics

Mammography Screening Rates Enhanced by Copay Elimination By Wayne Kuznar

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—Jeffrey M. Peppercorn, MD, MPH

For the present study, Dr Peppercorn and his colleagues used claims data for screening mammography between 1999 and 2009 from the National Rural Electric Cooperative Association (NRECA) database, an organization that insures more than 100,000 electrical workers and their families nationwide. The researchers focused on women aged 40 to 64 years who had no history of invasive breast cancer or noninvasive ductal carcinoma in situ. The study’s overarching goals were to review screening rates and to determine the effect of removing coinsurance for screening mammography on the use of mammography screening for a mostly rural population. More than 20,000 women had annual insurance through NRECA. There was a rise in annual mammography screening utilization from 38.1% to 49.5% during the study period. Similarly, biennial mammography screening utilization climbed from 57.2% to 68.1% during the 10-year study period. Of note, in 2006, the NRECA unveiled a well woman examination that eliminated copays, coinsurance, and deductibles for screening mammography for women aged ≥40 years. As a result of the elimination of the copay, screening rates jumped significantly. The percentage of women who at least elected to have biennial screening rose from 60.9% in 2006 to 68.8% in 2007. The absolute difference in screening by age ranged from 5.3% for women aged 40 to 45 years to 10% for women aged 60 to 64 years. Given the findings to date, the researchers are continuing to review the financial and nonfinancial obstacles to screening, as well as the perceptions of current screening guidance. n

NF-κB

B-Cell Homing Cells in the microenvironment secrete chemoattractant factors to promote the homing of B cells to lymphoid tissue.14 These factors act via signaling pathways involving BTK and other kinases.4,15

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Normal and malignant B cells rely on multiple prosurvival pathways to avoid apoptosis.6-9 In B-cell malignancies, microenvironmental cues may inappropriately initiate signaling cascades through several kinases, including BTK, driving uncontrolled growth and survival of malignant B cells.5,10-13

“Despite the benefits of screening, we also know that not all patients are getting screened.” AE/AS

CD79A CD79B

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getting screened,” Dr Peppercorn said. Lower screening rates are found in places such as rural North Carolina, where a 2004 study showed that only 58% of women had a screening mammography over the past 3 years, and a sizable 24% had never had screening mammography. A 2008 study reported annual mammography screenings for only 57.9% of women from rural Pennsylvania.

AD

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He and his colleagues evaluated the rates of annual screening mammography utilization and biennial screening mammography utilization in women in rural US regions. “Despite the benefits of screening, we also know that not all patients are

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The upregulation and increased migration of B cells may lead to retention of malignant cells in proliferative environments and the promotion of chemoresistance.16-18 BTK is an essential mediator of multiple adhesion and migration processes.4

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References: 1. Burger JA. Nurture versus nature: the microenvironment in chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2011;2011:96-103. 2. Kil LP, de Bruijn MJW, van Hulst JA, Langerak AW, Yuvaraj S, Hendriks RW. Bruton’s tyrosine kinase mediated signaling enhances leukemogenesis in a mouse model for chronic lymphocytic leukemia. Am J Blood Res. 2013;3:71-83. 3. Pighi C, Gu T-L, Dalai I, et al. Phospho-proteomic analysis of mantle cell lymphoma cells suggests a pro-survival role of B-cell receptor signaling. Cell Oncol (Dordr). 2011;34:141-153. 4. de Gorter DJJ, Beuling EA, Kersseboom R, et al. Bruton’s tyrosine kinase and phospholipase C2 mediate chemokine-controlled B cell migration and homing. Immunity. 2007;26:93-104. 5. Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F. The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood. 2009;114:3367-3375. 6. Woyach JA, Johnson AJ, Byrd JC. The B-cell receptor signaling pathway as a therapeutic target in CLL. Blood. 2012;120:1175-1184. 7. Rauch M, Tussiwand R, Bosco N, Rolink AG. Crucial role for BAFF-BAFF-R signaling in the survival and maintenance of mature B cells. PLoS One. 2009;4:e5456. 8. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol. 2007;85:471-475. 9. Grumont RJ, Rourke IJ, O’Reilly LA, et al. B lymphocytes differentially use the Rel and nuclear factor B1 (NF-B1) transcription factors to regulate cell cycle progression and apoptosis in quiescent and mitogen-activated cells. J Exp Med. 1998;187:663-674. 10. Nishio M, Endo T, Tsukada N, et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1. Blood. 2005;106:1012-1020. 11. Wiestner A. Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia. Blood. 2012;120:4684-4691. 12. Herishanu Y, Pérez-Galán P, Liu D, et al. The lymph node microenvironment promotes B-cell receptor signaling, NF-B activation, and tumor proliferation in chronic lymphocytic leukemia. Blood. 2011;117:563-574. 13. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463:88-92. 14. Okada T, Ngo VN, Ekland EH, et al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med. 2002;196:65-75. 15. Burger JA, Burger M, Kipps TJ. Chronic lymphocytic leukemia B cells express functional CXCR4 chemokine receptors that mediate spontaneous migration beneath bone marrow stromal cells. Blood. 1999;94:3658-3667. 16. Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009;113:4604-4613. 17. Binsky I, Lantner F, Grabovsky V, et al. TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent manner. J Immunol. 2010;184:4761-4769. 18. Kurtova AV, Balakrishnan K, Chen R, et al. Diverse marrow stromal cells protect CLL cells from spontaneous and drug-induced apoptosis: development of a reliable and reproducible system to assess stromal cell adhesion-mediated drug resistance. Blood. 2009;114:4441-4450.

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at Duke Cancer Institute, Durham, NC. A significant number of middle-aged women who live in rural locales do not pursue even biennial breast cancer screening, and cost may play a role, according to insurance claims data Dr S:7” Peppercorn presented at ASCO 2013.

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Chicago, IL—Removing copays may help boost mammography screening rates for all age-groups above age 40 years. One insurer found a significant increase in screening rates with the removal of a copay, said Jeffrey M. Peppercorn, MD, MPH, Medical Oncologist

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Health Economics

Can We Afford to Make Progress in Cancer Care? The economics of drug development By Caroline Helwick Chicago, IL—The rapid advances in cancer treatment, especially in personalized medicine, are occurring at an enormous financial cost to the healthcare system. “If we really want to make progress in an economically viable way, we must spend as much time on the economics of drug development as on the basic science,” said Kevin A. Schulman, MD, MBA, Director, Center for Clinical and Genetic Economics, and Director, Health Sector Management Program of the Fuqua School of Business, Duke University, Durham, NC, who spoke about the cost of oncology drugs at an educational session at ASCO 2013. “There is no quick fix. We must rethink the entire pharmaceutical development process,” said Dr Schulman. Growth in healthcare spending has slowed; for the first time ever, the spending on pharmaceuticals has declined. But money spent on drugs is shifting from blockbuster products to targeted biologics; within the specialty pharmacy category, spending on drugs actually increased by 18% in 2012, he reported. The current business model for drug development is unsustainable. The traditional business model is based on manufacturers producing a few high-profit blockbuster drugs that are marketed broadly, but this does not translate to the era of personalized medicine, which requires novel drugs targeted to a vastly smaller population of patients with specific molecular profiles. Spread across a much smaller market, the cost per patient is enormous. “Of $250 billion spent on prescrip-

tion drugs, $100 billion is spent on biologics,” Dr Schulman said. “The idea that one such pharmaceutical product will cost $100,000 per patient is bad enough, but many patients receive a whole inventory of novel agents in multiple combinations. How many dollars’ worth of expensive therapies does 1 colorectal patient, for example, use in just 1 course of treatment? And look at chronic myelogenous leukemia, where there are different products for different genetic mutations and resistance patterns.” This raises the question, Dr Schulman asked, “How will we bring multiple new products forward for smaller and smaller cohorts? What we are seeing are products with tremendously high prices, available to a restricted number of patients.” Economic Reforms to Lower Drug Costs Society cannot label new oncology drugs as too expensive without first understanding why the costs are so high, Dr Schulman suggested. Out-of-pocket costs to the manufacturer can be hundreds of millions of dollars, with no guarantee that a new compound will prove effective. Approximately 80% of molecules fail to make it to market—and the figure is closer to 90% in oncology. The probability of market entry for a cancer drug, in fact, has been calculated at 7.2%. “The cost of these failures is borne by the rest of the molecules that do make it to market. If a compound fails early, the cost is fairly modest. But if a biologic fails on a 1000-person phase 3 trial, it’s incredibly expensive,” he

said, noting that an experimental cholesterol-lowering drug that failed to win approval after phase 3 testing cost Pfizer $800 million. Financial returns are critical to pharmaceutical companies, which promise a cash flow to Wall Street and a return to their shareholders. The more difficult it is to bring a new compound to market, the higher the price

“If we really want to make progress in an economically viable way, we must spend as much time on the economics of drug development as on the basic science….There is no quick fix. We must rethink the entire pharmaceutical development process.” —Kevin A. Schulman, MD, MBA required to meet the needs of investors will be. Increasing the size of a company’s portfolio would allow manufacturers to spread revenue over multiple products and reduce the pressure on individual products to bear the entirety of the company’s returns, Dr Schulman maintained. “We should think of a way for manufacturers to get access to capital but restrict the returns to innovators— [that is,] firms that use this capital as a way of lowering cost of drugs that get to market,” he suggested. “By reducing the cost of drug development, we would reduce the barrier to entry for

new and competitive firms. This could ignite price competition, and that would help us out.” Transforming Clinical Research in Drug Development Transformation of the clinical development enterprise can begin by “reimagining” the roles and the responsibilities of patients and clinicians in the realm of clinical research, as well as the roles of institutions and principal investigators, Dr Schulman further suggested. Data collection in clinical trials must become more compatible with the way that technology is being used in medicine. “We have gone from paper-based systems to electronic medical records to smartphones and tablets. Why are we not using this to change how we conduct research?” he asked. Optimal application of technology could certainly shorten the decades-long clinical trial process, Dr Schulman suggested. Patients should also become empowered to better navigate the clinical trials system themselves, to share in decision-making, and to reduce the clinical burden of collecting the information needed for enrollment. Finally, it would help to better understand the demand for new drugs by patients, that is, the “behavioral economics,” Dr Schulman said. “Why do patients believe that 1 week of life is worth extraordinary amounts of money? It is critical to understand the disconnect between the public anger over high prices for products with modest benefits and the demand that our patients have for hope.” n

Variations in Cancer Treatment Raise Average Cost of Care by $25,000 per Patient By Wayne Kuznar Chicago, IL—Inappropriate deviation from evidence-based standards of care for cancer raises costs in excess of $25,000 per patient, stated Arlene A. Forastiere, MD, Senior Vice President of Medical Affairs at eviti, Inc, Philadelphia, PA, in a poster presented at the 2013 American Society of Clinical Oncology annual meeting. In Dr Forastiere’s review of oncology treatment plans for 2544 patients, approximately 25% of the patients

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had treatment plans that did not conform to evidence-based standards. The finding “is an argument for decision support tools that are used at the point of care,” noted Dr Forastiere. “We can’t change this if we’re always at the back end.” Eviti is an independent health in­for­ mation technology company that reviews treatment plans for commercial payers. For this study, treatment plans for all cancer types were reviewed from

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March 2009 to March 2012 for adherence to national guideline recommendations. The cost difference between the proposed treatment and the expected treatment (when the treatment was nonadherent or not a medically justified deviation) was calculated. For prospective reviews, “we had discussions with oncologists to see if there was some patient-specific factor to justify a deviation. If that wasn’t the case, if in our conversation with the

doctor the treatment was changed to a recommended drug, we calculated the exact cost related to what the doctor initially wanted to do versus what they changed the treatment to,” Dr Forastiere observed. In retrospective situations in which no justification for a treatment could be identified, the lowest-cost evidence-based treatment that yielded a comparable outcome was used as the comparator. Average wholesale pric-

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Health Economics Variations in Cancer Treatment Raise Average Cost of... Continued from page 10 ing was used for chemotherapy and for supportive drugs. Medicare pricing was used for radiation therapy. Some of the major deviations in drug use were growth factor overutilization (in particular, the overuse of white blood cell growth factor), the use of combination therapies that have not been shown to be beneficial or indicated, more cycles of chemotherapy than are recommended in an adjuvant setting, and the use of drugs that are not approved for a particular indication, according to Dr Forastiere. For radiation, the overutilization of technologies, such as image-guided radiation or intensity-modulated radiation, could qualify as deviations. Of the 2544 patients included in this analysis, 730 (28.7%) had “unjustified”

“If you consider that 1 in 4 [patients] is likely getting some treatment that is inappropriate, multiply that by $25,000, and you’re talking about billions of dollars. That $25,000 is a very conservative number, because it’s just first-order savings.” —Arlene A. Forastiere, MD

non–evidence-based treatment plans. The mean per-patient excess cost for unjustified deviations was $25,579. With an expected annual incidence of 2500 new cancer cases per 1 million

commercially insured lives, 1875 patients would receive chemotherapy or radiation therapy as part of their treatment. With a 28.7% rate of in­appropriate deviations from evidence-based stan-

dards of care, 538 patients would receive treatment outside of these standards, and the overspending in this group would be >$13 million, based on a $25,000 cost per patient, according to Dr Forastiere. She concluded, “Another way of looking at it, which is even more striking, is that we know that there are 1.6 million new cases of cancer diagnosed per year in the [United States] currently. If you consider that 1 in 4 [patients] is likely getting some treatment that is inappropriate, multiply that by $25,000, and you’re talking about billions of dollars. That $25,000 is a very conservative number, because it’s just first-order savings. It doesn’t include hospitalizations as a result of overtreatment or complications.” n

Assessing the Value of New, Costly Radiation Therapies in Older Patients with Breast Cancer

See also page 34

By Caroline Helwick Chicago, IL—For-profit hospitals are more likely than their nonprofit counterparts to treat elderly patients with breast cancer with an expensive form of radiotherapy—despite lacking evidence of its benefit, researchers from the Yale Cancer Outcomes, Public Policy and Effectiveness Research Center reported at ASCO 2013. “We wanted to evaluate how hospital ownership affects the adoption of technology,” said Sounok Sen, BSE, MD, Yale School of Medicine, New Haven, CT. “We found that Medicare beneficiaries receiving breast-conserving surgery at for-profit hospitals disproportionately received brachytherapy….While brachytherapy has been rapidly adopted, it costs twice as much as external beam radiotherapy and is reimbursed more substantially,” Dr Sen pointed out. “While the long-term risks and benefits of brachytherapy are still being defined,” he added, “payers may want to reconsider the wisdom of reimbursement policies that promote the rapid adoption of newer and unproven cancer therapies without incorporating rigorous assessments.” Although for-profit and nonprofit hospitals may have financial incentives, “for-profit providers may have additional incentives to fulfill their fiduciary responsibilities and their mission to shareholders,” Dr Sen suggested. “This may affect the pattern of care as it relates to the adoption of VOL. 6

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new or higher-margin technology.” “The literature has suggested that financial gain exerts a powerful influence on the individual and the institution,” he added. Radiotherapy a “Salient Example” Dr Sen and colleagues evaluated the use of brachytherapy, a new radiotherapy modality in breast cancer, against recent evidence indicating that radiotherapy of any form is not always necessary in some patient subsets.

“Payers may want to reconsider the wisdom of reimbursement policies that promote the rapid adoption of newer and unproven cancer therapies.” —Sounok Sen, BSE, MD Specifically, the Cancer and Leu­ kemia Group B (CALGB) 9343 trial showed that in women aged ≥70 years with low-risk breast cancer, external beam radiotherapy did not improve overall survival or disease-free survival at 10 years, although it did reduce local or regional recurrences. The guidelines now therefore state that radiotherapy can safely be eliminated in this population. New radiotherapy modalities— spe-

Table Brachytherapy Use, by Patient Age and Hospital Type Age of patients with breast cancer

For-profit hospitals, %

Nonprofit hospitals, %

All ages

14.8

10.9

66-79 yrs

15.6

12.0

≥80 yrs (P <.05)

12.4

8.0

cifically brachytherapy—have some advantages over older approaches, including shorter length of treatment and reduced toxicity. Brachytherapy’s efficacy in breast cancer, however, has not been well established, and some studies suggest that the risks are increased with this therapy compared with conventional radiotherapy. The researchers used the Medicare database of women aged 66 years to 94 years who underwent breast-conserving surgery in 2008 and 2009, and determined hospital ownership status by the Medicare Hospital General Information data set. A total of 35,118 women were included (mean age, 74 years; 27% aged ≥80 years) who were treated at 2255 nonprofit hospitals and 420 for-profit hospitals. Adjuvant radiotherapy was administered to 72% of the patients, including brachytherapy in 15.7%. Radiotherapy of any type was more common at for-profit hospitals among women aged ≥80 years. This 22% relative increase in radiotherapy was largely driven by brachytherapy. Brachy­therapy was most common in

all women who were treated at for-profit hospitals compared with nonprofit hospitals (20.2% vs 15.2%, respectively; P <.001), with the greatest difference observed among the elderly (Table). Financial Incentives Influence Use Treatment at a for-profit hospital was associated with an odds ratio of 1.29 for receiving brachytherapy in women aged 66 years to 79 years (P = .04) and of 1.66 in women aged ≥80 years (P = .003). “Women whose surgery was performed at for-profit hospitals were significantly more likely to receive any radiation, driven by the differential use of newer, less proven brachytherapy,” Dr Sen said. He suggested that for-profit hospitals may have had “financial incentives and fiduciary responsibilities, or a desire to be at the vanguard of care or build market share,…but it is also possible that brachytherapy was chosen to enhance convenience and tolerability for the patient. It’s challenging to delineate the incentives.” n

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Health Economics

Essential Health Benefits, Comparative Effectiveness Research, Payment Models All Play a Role in the ACA Chicago, IL—Although cancer care is not at the front and center of the Affordable Care Act (ACA), oncology experts pointed out significant aspects to monitor as time goes on during a discussion of the topic at ASCO 2013. A key element of the ACA is that the number of covered lives would expand by 38 million people by 2022 through the individual coverage mandate. The majority of the expansion will be through the Medicaid program and the establishment of health insurance exchanges, which, starting in October 2013, will offer an insurance option for individuals and families who are unemployed, work for small businesses, or are not offered insurance through their employer. Premium and cost-sharing subsidies are available for individuals who are less able to afford insurance coverage. ACA Action Plans The ACA is designed to encourage innovation through comparative effectiveness research (CER), alternative payment models, and accountable care organizations. One oncology expert, William Charles Penley, MD, Medical Oncologist, Tennessee Oncology, Nashville, spelled out some of the ACA’s action plans: • Prohibit discrimination based on sex or preexisting condition • Eliminate annual limits on coverage • Prohibit dropping or limiting coverage because of choosing to participate in clinical trials for cancer or for other life-threatening diseases • Offer tax credits for people with income 100% to 400% above the federal poverty level • Set up a health insurance market-­­ place. So far under the ACA, 32 million Medicare beneficiaries have used a free preventive service; 50,000 uninsured individuals with preexisting conditions have gained health insurace; and 3.6 million Medicare beneficiaries have saved $2.1 billion on prescription drugs (www.whitehouse. gov/healthreform). “Regarding the ACA, there’s not a lot written in the law specifically about cancer care. However, for example, we know that based on the patient bill of rights, cancer survivors can’t be denied coverage because [cancer is] a preexisting illness,” Dr Penley said.

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Photo by © ASCO/Silas Crews 2013

By Wayne Kuznar

“There’s not a lot written in the law specifically about cancer care. However, for example, we know that based on the patient bill of rights, cancer survivors can’t be denied coverage because [cancer is] a preexisting illness.” —William Charles Penley, MD

Additional ACA components of relevance to oncology include: • Children with cancer cannot be denied coverage because of a preexisting condition • Medicare Part D “donut hole” is reduced and will eventually be eliminated •  Lifetime coverage limits will be eliminated by 2014 • Coverage cannot be rescinded •  Access to preventive services is increased. ASCO’s Priorities Dr Penley, who serves on several ASCO committees, said that although it does not have an ACA task force, ASCO has committees that are dedicated to working on the care of patients with cancer, especially in the way of a robust quality program. He mentioned the Quality Oncology Practice Initiative (QOPI) and its 300,000 patient data sets. “CancerLinQ will take QOPI to the next level with real-time data for a prototype,” Dr Penley said. ASCO has also developed its “Guiding Principles of Payment Reform,” which advocates:

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• Every patient having access to high-­ quality, high-value, evidence-based care • Protecting patients’ needs and wishes through shared decision-making with physicians • Further developing and upholding the practice standards for the medical profession •  Supporting systemwide reforms and improvements that keep pace with the evolution of the healthcare system. “ASCO’s priorities are to address disparities—offer quality cancer care for all, that is, affordable care with no barriers to insurance coverage and no geographic barrier to high-quality cancer care. We also want to define value as it pertains to cancer care delivery,” Dr Penley said. He concluded that the “ACA is complex legislation. Its full impact is yet to be realized. There are few oncology-specific components. In the meantime, ASCO’s focus is on quality, value, access to care, and innovation to serve patients and oncologists well.” Medicaid Expansion Steven K. Stranne, MD, JD, Shareholder, Polsinelli PC, a law firm in Washington, DC, participated in the discussion. He said that the focus of recent legislation, including the ACA, is multifaceted, including expanding access to care, offering patient safeguards and prevention, enhancing CER, innovation and bending the cost curve, and promoting quality. Medicaid expansion under Medicare refers to extending eligibility for most nonelderly adults aged <65 years with income below 138% of the federal poverty level, with a 100% federal match until 2017 and with a 90% match in 2020 and after. One major concern is the adequacy of Medicaid coverage, said Dr Stranne. “ACA relies heavily on Medicaid to expand access to coverage, although some stakeholders worry about the adequacy of coverage and reimbursement under Medicaid,” he noted. Dr Stranne stated that the medical literature suggests that clinical outcomes for Medicaid enrollees with life-threatening diseases, such as cancer, may not be better than for the uninsured. Essential Health Benefits Defining the essential health benefits helps to establish the minimal

level of coverage under the state health insurance exchanges. “The vision when this law was passed was that the Department of Health and Human Services and the Centers for Medicare & Medicaid Services [CMS] would offer great specificity on patient safeguards, such as minimum coverage, through essential health benefits. Yet, administration and CMS’ overarching concern is to avoid raising premiums. Therefore, there’s limited specificity in the definition of essential health benefits,” Dr Stranne said.

“Administration and CMS’ overarching concern is to avoid raising premiums. Therefore, there’s limited specificity in the definition of essential health benefits.” —Steven K. Stranne, MD, JD

Of note, there is a clinical trials safeguard in the essential health benefits. Coverage is required for routine costs of clinical trials. Also, there are safeguards for prescription drug access, although they are not the same as under Medicare Part D. CER Gets a Nod Dr Stranne noted how there is a new infusion of federal funding devoted to CER. There is a linkage to this type of research and to efforts to reduce the cost of care, he said. “CER is viewed by policymakers as a way to fill gaps in scientific evidence used to guide prescribers to high-value, cost-effective options,” Dr Stranne said. “CER advocates see the opportunity for dramatic savings in the future based on linking CER results with coverage policies and reimbursement incentives.” Payment Models The Center for Medicare & Medicaid Innovation tests and implements new payment models for healthcare delivery. Its authority is “extremely” broad, according to Dr Stranne, meaning that it can test and expand the use of innovative approaches to reimbursement under Medicare without further action by Congress. n

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™. Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages. To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.


POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors. Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia. Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide

were excluded from studies and may be at higher risk of hypersensitivity. Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.


WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction. • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established. Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044a


Health Economics

Use of High-Cost Diagnostic Tests for Lung Cancer Surveillance Rising

See also pages 29-34

By Wayne Kuznar Chicago, IL—The use of costly diagnostic imaging of uncertain value is increasing rapidly for patients with localized non–small-cell lung cancer (NSCLC), according to data from the

Surveillance, Epidemiology and End Results (SEER)-Medicare database. Frequent surveillance imaging was found for white patients and for those with higher socioeconomic status, de-

spite lack of evidence for its value and its high cost, said Jason D. Wright, MD, Assistant Clinical Professor of Gyne­cologic Oncology, Columbia Uni-­ ver­sity, New York, at ASCO 2013.

Computed tomography (CT) screening of high-risk individuals has led to an increase in the diagnosis and treatment of early-stage tumors, which is then followed by surveillance. “Despite

T:7”

This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment. • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)]. POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)]. Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)]. 1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily. 500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436. 5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported. 5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal). 2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.


Health Economics the increasing number of cancer survivors, there are little evidence-based data to guide surveillance strategies,” said Dr Wright. Guidelines from the National Comprehensive Cancer Network suggest continued surveillance after tumor diagnosis, including a CT scan every 6 to 12 months, and then annu­ally. Positron emission tomography (PET) and magnetic resonance imaging (MRI) are not

routinely indicat­ed. Lacking evidence, most of these recommendations are based on expert opinion, he noted. For patients in remission, the goals of surveillance are to detect recurrent disease and second primary tumors, and to facilitate access to care for other chronic diseases. “The goal of the analysis was to capture testing for patients without recurrent disease,” Dr Wright said.

This study evaluated records from the SEER-Medicare database of patients with stage I or stage II NSCLC who underwent curative surgical resection from 2000 to 2007. Three periods after cancer-directed surgery (6-18 months, 18-30 months, and 30-42 months) were examined. A separate analysis was performed to examine high-intensity surveillance, defined as at least 1 advanced

imaging test (ie, CT, MRI, or PET) during each surveillance period. The 6 to 18 months postsurgery use of high-cost chest CT climbed from 48% in 2000 to 78% in 2007 and PET use increased from 2% to 23%, whereas the use of chest radiography and bone scanning decreased over time. Similar trends were noted for the other 2 surveillance periods. MRI was used infrequently throughout the study. Continued on page 18

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease. Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

(continued)

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(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

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Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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Health Economics Use of High-Cost Diagnostic Tests for Lung Cancer... Continued from page 17 “The average cost of surveillance testing during period 1 increased from $397 in 2000 to a peak of $1080 in 2005, and then decreased slightly to $878 in 2007,” said Dr Wright. “Similar trends were noted for subsequent surveillance periods.” Among 5269 patients who were included in the analysis of high-intensity

“The average cost of surveillance testing during period 1 increased from $397 in 2000 to a peak of $1080 in 2005, and then decreased slightly to $878 in 2007. Similar trends were noted for subsequent surveillance periods.” —Jason D. Wright, MD T:7”

Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

surveillance, 21.0% diagnosed in 2000 had at least 1 high-cost surveillance test annually; this increased to 47.7% in patients who were diagnosed in 2006. In addition, patients with high socioeconomic status were more likely to undergo annual surveillance imaging; Hispanics and older patients were less likely to undergo testing. n

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea General disorders and administration site conditions

Cardiac Disorders

(continued)

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n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period. Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). 7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided. Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and

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Urinary tract infection

Hypercalcemia

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constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)


Health Economics Routine Surveillance CT Costly, Unnecessary in Lymphoma in Remission By Caroline Helwick Chicago, IL—Routine surveillance imaging is of little value in patients with diffuse large B-cell lymphoma (DLBCL) or classical Hodgkin lymphoma who are in remission, researchers from 2 institutions reported. “DLBCL is clinically aggressive but potentially curable, even after re-

lapse,” said Carrie A. Thompson, MD, Hematology Division, Mayo Clinic, Rochester, MN. “However, the optimal follow-up strategy is not clear.” The National Comprehensive Cancer Network recommends a surveillance computed tomography (CT) scan every 3 months to 6 months for 5 years

posttreatment. Dr Thompson’s study enrolled 644 patients with DLBCL; 537 of them entered posttreatment observation. Of these, 20% (109) relapsed. Of the 100 patients who were evaluable, 62 presented earlier than the planned follow-up visit because of symptoms. Overall, 87% of patients

had at least 1 feature indicative of relapse. Of the 38 patients whose relapse was detected at a planned visit, only 12 had the relapse detected solely by a surveillance scan. Only 1.5% of patients had a relapse that would have only been detected by a surveillance CT scan while in remission, Dr Thompson said.

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“No data support the use of routine surveillance CT scans in clinical practice in classical Hodgkin lymphoma and diffuse large B-cell lymphoma in remissions. I think we must reeducate ourselves as clinicians.”

diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN.

—Leo I. Gordon, MD

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation. POMALYST REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

“Routine surveillance scans posttherapy add little to the detection of DLBCL,” Dr Thompson said. A second study presented at ASCO 2013 included 241 patients with lymphoma: 164 had surveillance CT and 77 had clinical surveillance only. Patients who relapsed in the clinical surveillance group had an average of 17.6 scans per relapse compared with 123.8 scans in the imaging group, resulting in additional costs of $593,698 per relapse. At a median follow-up of approximately 4 years, there were 5 (3.8%) deaths in the imaging group and 4 (5.3%) in the clinical surveillance group, yielding a similar overall survival rate. “We don’t feel that the potential risks and costs, without overall survival benefit or any other clinical benefit, justify the practice” of routine imaging in patients with lymphoma, said Sai Ravi Pingali, MD, of the Medical College of Wisconsin Affiliated Hospitals, who conducted the study. Leo I. Gordon, MD, Abby and John Friend Professor of Oncology Research, Northwestern University Feinberg Medical School, Chicago, IL, said that a physical examination can detect most relapses: the cost of an office visit is relatively inexpensive and does not expose patients to radiation, whereas 1 scan costs approximately $5000 and involves radiation exposure. “We can at least say that no data support the use of routine surveillance CT scans in clinical practice in classical Hodgkin lymphoma and diffuse large B-cell lymphoma in remissions. I think we must reeducate ourselves as clinicians,” Dr Gordon said. n

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Poor Adherence to Oral Cancer Drugs a Growing Concern By Wayne Kuznar Chicago, IL—The number of oral oncolytic drugs has increased dramatically, but despite increased convenience, there is growing concern regarding adherence, said Winson Y. Cheung, MD, MPH, Assistant Professor, University of British Columbia Division of Medical Oncology, Vancouver, at a session on adherence at ASCO 2013. “Oral drugs shift the onus of treatment adherence from healthcare providers to patients,” Dr Cheung said. Cancers at more tumor sites are being treated with oral therapy, and the duration of therapy is lengthening. Adherence is an issue not only with antineoplastic drugs but also with nononcology drugs, he said. In one study of 169 patients with chronic myelogenous leukemia (CML), only 14% were 100% adherent to a daily regimen of imatinib (Gleevec) over a 3-month period. Although 91% of the prescribed doses were taken, 71% of the patients took less than the dose prescribed, and 15% took more. Suboptimal responses were more likely in patients with a higher mean percentage of missed doses. Treatment response is related to adherence, noted Dawn L. Hershman, MD, MS, Associate Professor of Medicine and Epidemiology, Columbia University Medical Center, New York. In chronic-phase CML, nonadherence to imatinib adversely affected event-free survival: the 5-year event-free survival rates were 76.7% in adherent patients and 59.8% in nonadherent patients. Predictors of Nonadherence Predictors of treatment discontinu-

ation or nonadherence have been identified. Among women with earlystage breast cancer, those aged <40 years had the highest risk of discontinuation of endocrine therapy. Age ≥65 years and the presence of comorbidities were other factors associated

“Asking patients about adherence detects 50% of nonadherence.” —Dawn L. Hershman, MD, MS with increased rates of discontinuation. Approximately 33% of women with early-stage breast cancer discontinued aromatase inhibitor therapy within 2 years because of an adverse effect; the rate of discontinuation because of musculoskeletal symptoms was 24.3%. Higher prescription copayments also predict nonpersistence with aromatase inhibitor therapy. Focusing on patients at the highest risk of discontinuation is an effective use of resources, Dr Hershman said. Other factors that predict cancer drug discontinuation are being single, being nonwhite, and therapy not being administered by an oncologist, said Dr Hershman. Strategies to Improve Adherence Improving adherence requires a multifaceted approach that relies on several strategies: • Patients should be encouraged to call with questions about their regimen • The regimen should be as simple as possible

• The consequences of missing doses should be explained to the patient. Involving family members and significant others can aid adherence. Simply “asking patients about adherence detects 50% of nonadherence,” she said. Technology may be a helpful resource for improving adherence. Phone consultation and daily text messaging reminders increased adherence to imatinib from 79.3% to 98.2% in a study of patients with chronic-phase CML. Texting reminders twice a week for 3 years also reduced the rate of discontinuation of anastrozole (Arimidex).

“There is evidence to suggest that the reduction of out-of-pocket expenses improves medication adherence across clinical conditions….Reducing copayments can potentially improve adherence for large numbers of geographically diverse patients.” —Winson Y. Cheung, MD, MPH Dedicated nurse managers assigned to patients at high risk for nonadherence, as well as collaborative care models are other potential solutions, said Dr Cheung. Pharmacist-led interventions are also effective, especially in the setting of polypharmacy. “There is evidence to suggest that the reduction of out-of-pocket expenses improves medication adherence

across clinical conditions,” Dr Cheung said. “Compared with other effective interventions that are relatively complex and resource intensive, reducing copayments can potentially improve adherence for large numbers of geographically diverse patients.” “Overadherence” “Overadherence” is an emerging concern in oncology, because patients sometimes believe that “more is better.” It is often overlooked, because most research has focused on underadherence, but the transition to oral oncolytics requires attention from providers and researchers to this new phenomenon. Pharmacy Channel Matters In a retrospective cohort analysis, Michael E. Stokes, MPH, of United BioSource Corporation, Montreal, Quebec, and colleagues found that patients with cancer whose prescriptions were provided by the specialty pharmacy were more likely to be adherent to their oral oncolytic agents than patients who filled their prescriptions through the traditional retail channel. Among 46,521 patients identified from claims databases who were prescribed either oral erlotinib (Tarceva), imatinib, or capecitabine (Xeloda), the rates of discontinuation of the initial prescription were higher among patients who filled prescriptions at traditional retail compared with those who received their medications via the specialty pharmacy for all 3 agents examined (erlotinib, 2.3% vs 0.1%; imatinib, 1.6% vs 0.1%; capecitabine, 1.9% vs 0.3%; P <.001 for all). n

Two Surveys Confirm Drug Shortages Are a Persistent Problem, Increasing Costs By Caroline Helwick Chicago, IL—Recent surveys of hematologists/oncologists show that drug shortages persist, that oncologists are adapting in ways that often raise the cost of cancer care, and that most oncologists have no guidance to aid their decision-making. A survey of 250 physicians showed that 83% of physicians encountered shortages of curative and palliative chemotherapy agents between March and September 2012. Many physicians reported that shortages affected the quali-

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ty and cost of patient care, because physicians were forced to substitute more expensive drugs for cheaper generics. “Drug shortages are affecting the treatment of curable malignancies. We don’t know the extent to which adaptations forced by these shortages led to adverse clinical outcomes for patients,” said Keerthi Gogineni, MD, MSHP, Medical Oncologist, Abramson Cancer Center, University of Pennsylvania, Philadelphia, at ASCO 2013. Shortages have also interfered with

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patient participation in clinical trials, Dr Gogineni added. “We were surprised by the large number of oncologists who had to make changes in how they care for patients due to drug shortages,” she said. “Unfortunately, cancer drug shortages are likely to persist, but doctors are adapting to this new reality as best they can. We need more uniform guidance to ensure that the modifications in treatment are being made in the most educated and ethical way.”

The survey was distributed to 455 US oncologists and hematologists; 250 members responded, and 214 surveys were analyzed. Approximately 66% of respondents practiced in community-based private settings, and 33% practiced in academic settings. The data reflect drug shortage experiences from March 2012 to March 2013. Shortages were most frequently reported for leucovorin, liposomal doxorubicin, 5-fluorouracil (5-FU), bleomycin, and cytarabine.

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AN 8-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

â&#x201E;˘

The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer CareTM, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will explore a specific topic to be considered when developing value-based strategies. IN MULTIPLE MYELOMA

Value-BasedCare FEBRUARY 2013



Â&#x2122;

1st IN A SERIES

Treating Newly Diagnosed Multiple Myeloma: Data on Safety, EfďŹ cacy, and Dosing Regimens

Topics to include: Safety and Efficacy of Front-Line Treatment Assessing the Value of Complete Response Pharmacoeconomic Analysis of Treatment Options Therapeutic Decision Making Based on Cytogenetics Assessing the Value of Progression-Free Survival Data Safety and Efficacy of Therapies in the Relapsed Setting Using Alternate Routes of Drug Administration Cost-Effective Use of Imaging Techniques

Introduction The therapeutic paradigm for multiple myeloma (MM) continues to evolve, due to advances in our understanding of the molecular and genetic basis of the disease.1 Newly diagnosed patients typically undergo multidrug therapy that includes novel, targeted agents, often followed by consolidation with autologous stem cell transplantation (ASCT) and maintenance therapy.1,2 This therapeutic model has altered the value equation in newly diagnosed MM, because survival and life quality have increased along with cost of treatment.1 Enhanced survival, through the use of novel therapies, requires us to balance both short- and long-term outcomes. Over its clinical course, MM has one of the highest direct costs of any cancer.1 For example, in a 2007 analysis, the direct costs associated with a course of treatment with a novel agent plus a steroid (taking into account the drugs themselves, as well as prophylaxis and management of toxicities) ranged from approximately $47,000 to $72,000.1,3 Simple assessment of cost, however, is not sufďŹ cient, because value comprises not only expenses but also outcome over the increasingly prolonged survival time for MM. For example, in the VISTA trial (N=682), newly diagnosed, transplant-ineligible patients who were randomized to either triple therapy with bortezomib/melphalan/prednisone (VMP) or double therapy with melphalan/prednisone (MP) were followed for life quality over nine 6-week cycles.4 The study found that, through cycle 4, health-related quality of life (HRQoL) was lower with VMP than with MP, due to decreased treatment tolerability. However, from cycle 5 through the end of therapy, HRQoL with VMP was not compromised relative to MP, and recovered to the point where HRQoL was comparable for the 2 treatments.4 This investigation also demonstrated the link between antimyeloma efďŹ cacy and HRQoL. Among responders to therapy, HRQoL increased from the time of response to the end of treatment.4 Responders were more common in the VMP group than in the MP group in this trial, in which response rates were 71% and 35%, respectively (P<.001).5 In addition, 5-year overall survival (OS) was prolonged with VMP versus MP,6 another beneďŹ t to consider in the value equation. Pharmacoeconomic analysis of initial treatment with melphalan/prednisone/lenalidomide (MPR) followed by lenalidomide maintenance (MPR-R) reported that this regimen, although more expensive than MPR or MP without maintenance, yielded greater cost-effectiveness.7 Although MPR-R increased progression-free survival (PFS) compared with regimens without maintenance, no This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

beneďŹ t in OS has yet been reported with MPR-R, so the observation of cost-effectiveness remains provisional.7 In todayâ&#x20AC;&#x2122;s healthcare environment, when evidence changes the value equation, it changes practice. Therefore, it is critical to be aware of current and emerging data on the tolerability and efďŹ cacy of novel agents, which will inďŹ&#x201A;uence therapeutic strategies. Tolerability: The Role of Optimized Dosing and Novel Drugs For newly diagnosed MM, current recommendations for care typically include the use of bortezomib, lenalidomide, or thalidomide in multidrug regimens, either for pre-ASCT induction or, in transplant-ineligible patients, as an initial course of therapy.2 All

OVERVIEW The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care, is to provide our readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-ef                   topic to be considered when developing value-based                           newly diagnosed MM.

STAKEHOLDERSâ&#x20AC;&#x2122; PERSPECTIVES Assessing the Value of Novel Therapies for Multiple Myeloma ............................................. 5 By William J. Cardarelli, PharmD Atrius Health, Harvard Vanguard Medical Associates

Clinical and Economic Challenges in the Treatment of Multiple Myeloma........................ 6 By Kevin B. Knopf MD, MPH California PaciďŹ c Medical Center

An ofďŹ cial publication of

TO VIEW THE SERIES ONLINE PLEASE LOG ON TO:

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Health Economics

Two Surveys Confirm Drug Shortages Are a Persistent...

Costly Substitutions Nearly 60% of physicians substituted more expensive agents when cheaper generics were not available. This included substituting levoleucovorin (Fusilev) for leucovorin, capecitabine (Xeloda) for 5-FU, and nab-paclitaxel (Abraxane) for paclitaxel (Taxol). “This is adding to healthcare costs,” Dr Gogineni emphasized. Levoleucovorin costs approximately 30 times more than leucovorin, and capecitabine costs approximately 140 times more than 5-FU for a 1-cycle treatment for colon cancer. There are

“Cancer drug shortages are likely to persist....We need more uniform guidance to ensure that the modifications in treatment are being made in the most educated and ethical way.” —Keerthi Gogineni, MD, MSHP

Oncologists’ Survey: Only Small Improvements Reported The American Society of Clinical Oncology (ASCO) also surveyed its members in October 2012 (N = 390), and again in April 2013 (N = 462), to assess the impact of shortages during those 6 months and to determine whether recent legislative and regu-

latory efforts to address the problem are working. The results of the second survey suggest that chemotherapy drug shortages eased slightly, but oncologists still needed to substitute drugs. Moreover, respondents expressed a growing concern regarding the shortage of drugs used in supportive care, such as antiemetics, pain medications, and basic intravenous fluids and electrolytes, reported Richard L. Schilsky, MD, Chief Medical Officer of ASCO. The most frequently reported substitutions are levoleucovorin for leucovorin (cited by 38% of respondents giving examples) and capecitabine for 5-FU (reported by 12% of respondents), similar to what Dr Gogenini found in her survey. “The cost implications of these [substitutions] are significant,” Dr Schilsky noted. In addition to critical chemotherapy substitutions, other substitutions included oral formulations for intravenous drugs in nearly 12 drugs. In supportive care, the substitutions included ganciclovir for acyclovir, diphenoxylate/atropine for atropine, and methylprednisolone and prednisone for dexamethasone. The 2013 survey also showed that: • 59% of the respondents were aware of ongoing drug shortages in their community versus 70% of respondents in the October 2012 survey • More than 40% of respondents said that drug shortages have not been resolved • 17% of respondents said the situation is worse now, 16% said the situation is unchanged, and 9% said some shortages improved and others worsened

•  Of respondents in both surveys, 37% had no institutional policy for drug allocation during a shortage. The Cancer and Leukemia Group B (CALGB) clinical trials group reported that 23 study protocols have been affected by drug shortages, Dr Schil-

Photo by ©ASCO/Todd Buchanan 2013

also the “hidden costs” in terms of additional hours spent by staff trying to manage these shortages, she said.

Photo by ©ASCO/Todd Buchanan 2013

Treatment Altered in More than 80% of Patients The respondents were asked about the impact of drug shortages over the previous 6 months. In response, 94% reported that their patients’ treatments had been affected, and 83% were unable to provide standard chemotherapy for their patients. Approximately 13% of respondents said that shortages had prevented patient enrollment in clinical trials or had suspended participation. The physicians adapted to shortages in various ways, including changing the treatment regimen (78%), substituting drugs partially through therapy (77%), delaying treatment (43%), “rationing” treatment to certain patients (37%), omitting doses (29%), reducing doses (20%), and referring patients to other practices (17%). Most (70%) providers indicated that they lacked institutional guidelines or committees to advise them on these difficult treatment decisions; academic physicians had more help. Clinical trial participation was somehow affected in 11% of instances.

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“Permanent solutions will require enhancing the business model of generic drug manufacturing.” —Richard L. Schilsky, MD

sky said. The CALGB is delaying registration of new patients, borrowing drugs from neighboring institutions, substituting alternative drugs, and omitting drugs that are currently in short supply. Dr Schilsky said that although the US Food and Drug Administration has stopgap measures in place to ease the situation, “permanent solutions will require enhancing the business model of generic drug manufacturing.” n

Causes of Hospital Readmissions of Patients with Cancer Annual cost of rehospitalization is approximately $16 billion By Wayne Kuznar Chicago, IL—Hospitalizations and readmissions add substantial costs to healthcare. The annual cost of 30-day hospital readmissions in the United States is estimated to be $16 billion. In addition, bundled payment models may eliminate additional payment for readmissions in a specified period after discharge. Several poster presentations at ASCO 2013 explored factors associated with readmission or unplanned hospitalizations in patients with cancer.

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Risk Factors Cancer site, Medicare severity diagnosis-related group (MS-DRG), admission status, length of stay, and payer status are significantly associated with readmission in patients with gynecologic cancer, found Kristy K. Ward, MD, Gynecologic Oncology Fellow, Department of Reproductive Medicine, University of California, San Diego Moores Cancer Center, La Jolla. Dr Ward and colleagues queried the database of the University

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HealthSystem Consortium (with 217 academic medical centers) to identify readmissions among patients with gynecologic cancer. For each risk factor found to be independently associated with readmission, the low-risk group was scored 0 and the high-risk group was scored 1. A risk of readmission score was created using findings from the multivariate analysis. The overall readmission rate for patients with gynecologic cancer was

4.5%. Vulvar cancer, medical MSDRG, urgent or emergent admission, length of stay of >4 days, and coverage by a public payer were each independently associated with readmission. The probability of readmission rose significantly with increasing risk score. Patients with a risk of readmission score of 0 or 1 have a readmission rate of 3.9% compared with 10.7% for patients with a risk of readmission score of >1. “Just 2 of these risk factors put

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Health Economics Causes of Hospital Readmissions... Continued from page 22 you at greater risk of readmission than the general population,” according to Dr Ward. “The risk of readmission score may be used to determine which patients you would expect to be readmitted; then you could allocate your resources better toward those patients.”

Utilization Project, common cancer hospitalizations in New York State in 2009 were identified and 30-day readmissions were assessed. From 21,945 index admissions for cancer surgery, the overall readmission rate was 9.3%, with 11.2% readmissions in nonteaching hospitals and 8.6% in teaching hospitals (P <.001).

“Our hypothesis is that academic hospitals are more likely to have clinical protocols, and that may reduce readmission rates.” —Nina A. Bickell, MD

“Just 2 of these risk factors put you at greater risk of readmission than the general population.”

At Amgen, biologic medicines are rooted in

—Kristy K. Ward, MD

Unplanned Hospitalization High hospital admission rates among patients with gastrointestinal (GI) cancer are driven by unplanned hospitalization and are potentially preventable, according to researchers from M.D. Anderson Cancer Center, Houston. They used Texas Cancer Registry and Medicare claims data for in-hospital admissions from 30,199 patients with GI cancer aged >66 years. The rate of unplanned hospitalization was 58%, and 77% of these hospitalizations occurred within the first year of the cancer diagnosis. The top 5 reasons for unplanned hospitalization were volume depletion, congestive heart failure, pneumonia, urinary tract infection, and septicemia. These are “diagnoses that are considered potentially preventable and should be a focus for intervention,” noted Joanna-Grace M. Manzano, MD, M.D. Anderson Cancer Center, Houston. On multivariate analysis, unplanned hospitalization was more likely among patients with esophageal cancer (relative risk [RR], 1.16), gastric cancer (RR, 1.07), pancreatic cancer (RR, 1.04), and rectal cancer (RR, 1.03). Patients with regional and distant diseases were at higher risk for unplanned hospitalization (RR, 1.14 and 1.13, respectively). Having ≥1 unplanned hospitalization was associated with poorer survival. Of the entire cohort, 14% had ≥3 unplanned hospitalizations, which amounted to 49% of the unplanned hospitalizations. Academic versus Nonacademic Hospitals Readmission after an index hospitalization for cancer surgery is higher in nonteaching hospitals than in teaching hospitals, found Nina A. Bickell, MD, Codirector, Center for Health Equity and Community Engaged Research, Mount Sinai, NY, and colleagues. As part of the Healthcare Cost and VOL. 6

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Being male, undergoing surgery at a nonteaching hospital, black race, and certain comorbidities increased a patient’s risk of 30-day readmission for a preventable cause. “Our hypothesis is that academic hospitals are more likely to have clinical protocols, and that may reduce readmission rates,” said Dr Bickell. n

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Robust quality control and a reliable supply are every bit as important as scientific innovation. For more than 30 years, Amgen has poured commitment, passion, and a drive for perfection into every medicine we make. So you can turn to Amgen for the biologic medicines that matter so much to your patients’ treatment…for generations to come. To learn more about Amgen’s commitment to consistent quality and reliable supply, visit biotechnologybyamgen.com ©2013 Amgen Inc. All rights reserved. 73979-R1-V1

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Emerging Therapies

Cancer Drug Pipeline Is Bustling... Melanoma Program, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, noted that these findings “will ultimately be practice-changing.” A new class of immunotherapy agents blocks programmed death-1 (PD-1) and its ligand (PD-L1) and helps T-cells attack the tumor. In an expanded phase 1 trial of the PD-1 inhibitor nivolumab in 107 heavily pretreated patients, the median overall survival (OS) approached 17 months. In combination with ipilimumab (Yervoy) in another phase 1 study, nivolumab led to deep, rapid, and durable responses. With concurrent treatment, 53% of patients responded and 17% achieved a complete response (CR); the estimated 1-year OS with this regimen was 82% (see article on page 26). Lambrolizumab is another anti– PD-1 antibody that recently received a Breakthrough Therapy designation from the US Food and Drug Administration (FDA). Lambrolizumab was evaluated in an open-label study of 135 patients; 52% of the patients receiving the optimal dose responded, with a median PFS exceeding 7 months. Lambrolizumab is currently being studied in patients with melanoma, non–small-cell lung cancer (NSCLC), breast cancer, head and neck cancer, and bladder cancer. A global phase 2 study of the drug in patients with ipilimumab-refractory advanced melanoma will enroll 510 patients (see article on page 26). Talimogene laherparepvec (T-VEC) was the first oncolytic virus to show benefit in patients with advanced melanoma in the phase 3 OPTiM trial. Of the 436 patients, those receiving T-VEC injections had more durable responses compared with patients receiving granulocyte-macrophage colony-stimulating factor and significantly longer time (8.2 months vs 2.9 months, respectively) to treatment failure (see article on page 26). Melanoma experts suggested that the best use of this novel drug may be in combination with another immunomodulating agent. Whether the oncolytic virus will pan out remains to be seen, but melanoma experts are betting on the success of the anti–PD-1 and anti–PD-L1 agents. According to Walter J. Urba, MD, PhD, Providence Cancer Center, Portland, OR, these novel drugs “are certainly going to change the state of the care of patients with melanoma.” Lung Cancer Ganetespib. In a phase 2b/3 study, the novel second-generation heat

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shock protein (HSP) 90 inhibitor ganetespib improved survival as second-line therapy in patients with advanced-stage NSCLC, a benefit that was more apparent in patients who were diagnosed >6 months before treatment. Improvements in OS and PFS were seen when ganetespib was used in combination with docetaxel (Taxotere). Lead investigator Suresh S. Ramalingam, MD, Winship Cancer Institute of Emory University, Atlanta, GA, said that HSP inhibitors are molecular chaperones for several key cellular oncogenic proteins, and that inhibiting HSP90 may stall tumor development and progression. In the trial known as GALAXY-1, 252 patients with adenocarcinoma were randomized to ganet­ espib/docetaxel or to docetaxel alone. The median PFS was 4.5 months in the combination arm and 3.2 months in the docetaxel monotherapy arm, with a hazard ratio (HR) of 0.84 (P = .038). OS was 9.8 months versus 7.4 months (HR, 0.82; P = .082). Patients who were enrolled >6 months from being diagnosed derived the most benefit—with PFS of 5.4 months with ganetespib/docetaxel versus 3.4 months with docetaxel alone (P = .041); OS was 10.7 months versus 6.4 months, respectively (P = .093). Improved survival with ganetespib was not related to endothelial growth factor receptor (EGFR) or to KRAS mutational status. Ninteda­nib. A phase 3 study demonstrated an improvement in PFS when ninteda­nib, a triple angiokinase inhibitor, was added to docetaxel in the second-line setting compared with docetaxel alone in patients with NSCLC. Nintedanib targets 3 tyrosine kinases—fibroblast growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor, according to Martin Reck, MD, PhD, of Grosshansdorf Hospital, Germany. In the LUME-Lung 1 study, 1314 patients with NSCLC whose disease progressed after first-line chemotherapy were randomized to nintedanib/ docetaxel or to docetaxel alone. The median PFS was 3.4 months in the combination arm and 2.7 months in the monotherapy arm (HR, 0.79; P = .019). The median OS was 10.1 months in the nintedanib/docetaxel arm versus 9.1 months in the docetaxel arm, a nonsignificant difference. The greatest improvement in median OS was in patients with adenocarcinoma, whose time to study treatment was <9 months since the start of first-line treatment—10.9 months versus 7.9 months (HR, 0.75; P = .073). In pa-

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tients with an adenocarcinoma histology, median OS was significantly improved with nintedanib/docetaxel versus docetaxel alone (12.6 months vs 10.3 months, respectively), a 17% reduction in risk (P = .035). Ovarian Cancer A retrospective analysis of a phase 2 study of olaparib, a poly ADP ribose polymerase (PARP) inhibitor, demonstrated an improvement in PFS as maintenance therapy for women with advanced platinum-sensitive ovarian cancer. The stratification of data by BRCA1 or BRCA2 mutation status showed that olaparib is most likely to benefit patients with BRCA1 or BRCA2 mutations, said Jonathan A. Lederman, MD, BSc, of University College, London. In women with BRCA mutation, PFS was 11.2 months with olaparib versus 4.3 months with placebo (P <.001). There was a “strong trend” for improvement in median OS with olaparib compared with placebo in patients with BRCA mutations (34.9 months vs 31.9 months, respectively; P <.208). A pivotal phase 3 trial is planned. Renal-Cell Carcinoma The anti–PD-L1 antibody MPDL3280A produced durable responses in a phase 1 study of patients with renal-cell carcinoma (RCC). PD-L1 is believed to be “abhorrently expressed in both primary and metastatic renal-cell carcinoma,” said lead investigator Daniel C. Cho, MD, Beth Israel Deaconess Medical Center, Boston, MA. This dose-finding study of patients with multiple tumor types included 53 patients with RCC (mostly clearcell histology). Patients received MPDL3280A intravenously 3 times weekly at various doses. No treatment-­­ related deaths or dose-limiting toxicities were reported in the patients with RCC. The overall response rate (ORR) among all tumor types was 21%, and an additional 16% of patients achieved stable disease for ≥24 weeks. The ORR was 13% in patients with RCC and 32% of patients achieved stable disease. The 24-week PFS in the patients with RCC was 53%. Responses were higher among patients expressing the PD-L1 receptor than in PD-L1–negative patients. CRs occurred only in the PD-L1–positive group. Leukemia The novel anti-CD20 agent obinutu­ zumab added to standard chemotherapy improved the response rate and the PFS of patients with chronic lymphocytic leukemia (CLL) and comorbidities compared with chlorambucil (Leu-

keran) alone in the phase 3 clinical trial CLL11, reported Valentin Goede, MD, of the University of Cologne, Germany. Based on these data, the FDA has granted obinutuzumab priority review status. Obinutuzumab is a type 2 antibody with stronger binding to the B-cell compared with rituximab, which increases direct cell death. The CLL11 study enrolled 590 adults with treatment-naïve CLL and comorbidities and/or impaired kidney function. The median investigator-assessed PFS improved from 10.9 months with chlorambucil chemotherapy alone to 23 months with the addition of obinutuzumab to chemotherapy (P <.001). Obinutuzumab/ chlorambucil resulted in an 86% reduction in the risk of disease progression or death compared with chlorambucil alone (P <.001). CRs were achieved by 22.2% of the combination arm and in none of the patients in the chlorambucil arm. A third arm—rituximab/chlorambucil —also had improved PFS (median, 16.7 months) compared with chemotherapy alone, and approximately 8% of patients in the rituximab plus chlor­ ambucil group had a CR. The risk reduction of disease progression or death with rituximab/chlorambucil was 68% compared with chlorambucil alone. At 1 year, PFS was 84% with obinutuzumab, 63% with rituximab, and 27% with chlorambucil alone. OS data were not mature after 14 months of follow-up. Lymphoma Idelalisib. In early-phase trials of patients with non-Hodgkin lymphoma (NHL), this novel agent targeting the PI3K pathway (which fuels the growth and survival of B-cell and Tcell malignancies) turned in impressive results as a single agent and in combination with standard therapy. Idelalisib was combined with standard therapy in a phase 1 study of 78 previously treated patients with indolent NHL, producing response rates of 78%, with 26% CRs, reported John P. Leonard, MD, of Weill Cornell Medical College, New York. At the discretion of the treating physician, patients received idelalisib in combination with rituximab (Rituxan), bendamustine (Treanda), or rituximab/bendamustine. Patients were treated for 6 cycles, and responders could continue idelalisib therapy for a total of 48 weeks. The median PFS has not been reached; at 24 months, 62.5% of patients are still in remission. Single-agent activity of idelalisib was confirmed in another phase 1

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Cancer Drug Pipeline Is Bustling... study, with a 48% response rate, rising to 67% among optimally dosed patients (≥100 mg twice daily). In patients with mantle-cell lymphoma, single-agent idelalisib showed activity in phase 1 studies, but it appeared especially beneficial in combination with other agents. In a phase 1 study of 33 patients reported by Nina D. Wagner-Johnston, MD, of Washington University, St Louis, MO, the combination of idelalisib and everolimus (Afinitor), bortezomib (Velcade), or bendamustine/rituximab yielded an impressive 49% ORR, with 12% CRs. In the bendamustine/rituximab arm, 100% of patients responded, but this population was not heavily pretreated, unlike the other 2 arms, Dr Wagner-Johnston pointed out. The median PFS was 8 months and tolerability was good, although elevations in liver enzymes were seen. Phase 3 trials of this PI3K inhibitor are under way. The Bruton’s tyrosine kinase inhibitor ibrutinib, which has received

Breakthrough Therapy designation from the FDA, was evaluated in combination with rituximab plus chemotherapy (R-CHOP) in a small phase 1/2 study of 33 treatment-naïve patients with NHL, reported Anas Younes, MD, of the University of Texas M.D. Anderson Cancer Center, Houston. The combination produced an ORR of 100%, including 67% CRs. Although ibrutinib shows promising results in lymphoma, researchers are still debating whether it will best be used as a single agent or in combination with other drugs. Multiple Myeloma The final results of the phase 1 study of the oral proteasome inhibitor ixazomib, better known as MLN9708, were reported by Shaji K. Kumar, MD, Mayo Clinic, Rochester, MN. The study included 32 heavily pretreated patients in the dose-escalation phase, and 31 patients in the expansion cohort (who received the maximum tolerated dose). Of 50 evaluable patients,

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18% responded to monotherapy, increasing to 26% among optimally dosed patients. “Some responses have been long-lasting, beyond 10 cycles of therapy,” Dr Kumar reported. The drug is known to be less neurotoxic than current therapies. The overall rate of peripheral neuropathy was 20%, with grade ≥3 in 1 patient only. The data continue to accumulate for novel monoclonal antibodies in patients with myeloma. “For the first time, monoclonal antibodies are appearing to make a difference in the treatment of multiple myeloma patients,” said Mehdi Hamadani, MD, MBBS, of West Virginia University, Morgantown. In a phase 1/2 study of elotuzumab plus lenalidomide (Revlimid)/dexamethasone (Decadron), the ORR among 98 heavily pretreated patients was 84%, rising to 92% in patients receiving elotuzumab 10 mg/kg. Median PFS was 33 months in this optimally dosed cohort. “Historically, treatment with lenalidomide plus

high-dose dexamethasone (no elo­ tuzumab) resulted in an objective response rate of about 60% and median time to progression of about 11 months in 2 randomized phase 3 studies with similar patient populations,” noted lead investigator Sagar Lonial, MD, of Emory University, Atlanta, GA. Elotuzumab is being studied in 2 phase 3 trials: in the frontline setting in the ELOQUENT-1 trial and in relapsed/refractory disease in the ELOQUENT-2 trial. Daratumumab is being studied in a phase 1/2 study of 32 heavily pretreated patients with relapsed and/or refractory multiple myeloma that produced clinical benefit in nearly 70% of patients. At 18-week follow-up, median PFS has not been reached. The histone deacetylase inhibitor quisinostat, given in combination with bortezomib and dexamethasone in patients with relapsed myeloma, produced an 87.5% ORR in a phase 1b dose-escalation study involving 18 patients. n

Pazopanib: First Positive Maintenance Trial in Ovarian Cancer A multikinase inhibitor delays relapse in advanced disease Chicago, IL—Previous trials of maintenance therapy for patients with ovarian cancer have failed to show improved survival. A study presented at ASCO 2013 is the first successful phase 3 trial in this setting, showing that the targeted therapy pazopanib (Votrient) extended progression-free survival (PFS) by a median of 5.6 months in women with ovarian cancer. Women who were enrolled in the trial were free of the disease after the initial treatment with surgery and chemotherapy. “Pazopanib maintenance therapy prolongs the time the patient has control over the disease versus the time the disease controls the patient’s life. Pazopanib might be a valuable option for treatment of stages II to IV ovarian cancer,” stated lead investigator Andreas Du Bois, MD, Director, Department of Gynecology and Gy­ necologic Oncology, at Kliniken Essen Mitte, Germany. Although patients with ovarian cancer typically respond to initial therapy with surgery and chemotherapy, the relapse rate for this type of cancer is approximately 75%. The rationale for maintenance therapy is to VOL. 6

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“Pazopanib maintenance therapy prolongs the time the patient has control over the disease versus the time the disease controls the patient’s life. Pazopanib might be a valuable option for treatment of stages II to IV ovarian cancer.”

keep patients in remission, but results of studies to date have been disappointing. Given the cost and the added toxicity of maintenance therapy, demonstrating improved survival with an agent is important for its approval. Pazopanib is an oral multikinase inhibitor that is approved by the US Food and Drug Administration for the treatment of renal-cell carcinoma and soft-tissue sarcoma. Medication side effects reported in the current trial were class-specific to angiogenesis inhibitors: hypertension, elevated liver enzymes, neutropenia, and diarrhea.

—Andreas Du Bois, MD Most Patients Had Advanced Disease This phase 3 multicenter trial included 940 patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancers. Trial eligibility criteria included stage II to IV disease, but most patients had stage III or IV ovarian cancer. Participants were randomized in a 1:1 ratio to receive 800 mg of pazopanib orally once daily or placebo for up to 2 years after standard surgery and chemotherapy. The median time to disease progression was 17.9 months for the paz­opanib group compared with 12.3 months for the placebo group, representing a 5.6-

month advantage for patients receiving the targeted therapy, for a 24% reduction in the risk of recurrence or of death. At 24 months, however, no significant difference in overall survival was observed. Longer follow-up is needed to see if there is an overall survival benefit. “There is currently no standard of care for maintenance therapy. Evidence continues to mount that targeting angiogenesis is important in ovarian cancer. The bottom line from several studies is that targeting angiogenesis is effective in ovarian cancer. These results show that pazopanib extends PFS as maintenance therapy, similar to the results of previous trials of bevacizumab,” said Carol Aghajanian, MD, Chief, Gynecologic Medical Oncology Service, Memorial Sloan-Kettering Cancer Center, New York. “This large trial shows us that targeting multiple molecular cancer drivers can have a substantial impact on this cancer’s ability to grow,” Dr Aghajanian said. “This study offers a real-world example of how the precision medicine era of cancer research is paying off in areas where no alternate approved drugs exist.” n

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Melanoma

Growth Factors Boost Ipilimumab’s Activity Investigators presented new data showing a way to boost the alreadypotent response to ipilimumab (Yervoy) by the addition of granulocyte macrophage colony-stimulating factor (GM-CSF) in a phase 2 study that showed improved overall survival (OS) with the combination versus with ipilimumab alone. “Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” said F. Stephen Hodi, Jr, MD, Director of the Melanoma Center at Dana-Farber Cancer Institute, Boston, at a press briefing. GM-CSF works within the immune system by enhancing granulocytes and macrophages, while the antibody ipilimumab “takes the brakes off” immune blockade, allowing the body to fight the tumor itself, Dr Hodi said. ECOG 1608 randomly assigned 245 patients with previously treated metastatic melanoma to receive ipi­ limumab and maintenance treatment, or the same plus the growth factor sargramostim (Leukine). The addition of GM-CSF to ipilimumab significantly improved OS from a median of 12.7 months with ipilimumab alone to 17.5 months, which was a 36% reduction in mortality. Tolerability was better with the combination than with the single agent. “With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Dr Hodi suggested. Lynn Mara Schuchter, MD, Program Leader of the Melanoma Program at Abramson Cancer Center, University of Pennsylvania, Philadelphia, commented that because both of these drugs are approved, physicians could start using this combination immediately, although she questioned whether third-party payers would reimburse for the growth factors. New Class of Anti–PD-1 Blockade Agents May Be a Blockbuster A new class of immunotherapeutic agents blocks the programmed death1 (PD-1) and PD-1 ligand and helps keep T-cells primed and ready to attack tumor cells. This class of agents is poised to again change the standard of care of patients with melanoma, according to melanoma experts. Interest in these agents is so great that an entire clinical science symposium was devoted to the drug class at ASCO.

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Long-term follow-up of an expanded phase 1 trial of the PD-1 inhibitor nivolumab in heavily pretreated patients with melanoma showed median OS approaching 17 months, with a very favorable toxicity profile, reported Mario Sznol, MD, Professor of Medical Oncology, Melanoma Pro­ gram, Yale Cancer Center, New Haven, CT. In this study of 107 patients who received nivolumab, response rates reached 41% among patients receiving optimal doses, and median OS was 20 months; responses were prompt and averaged 24 months. “We are in an era of remarkable advances for melanoma,” he said. “Median survival with vemurafenib is 16 months. For ipilimumab it is similar. But here, with nivolumab, it’s 16.8 months, and the median duration of response of 2 years is one of the highest numbers I have seen.”

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade.” —F. Stephen Hodi, Jr, MD

Antoni Ribas, MD, of the University of California, Los Angeles, presented data for lambrolizumab, the anti– PD-1 agent that recently received “breakthrough therapy” status by the US Food and Drug Administration. He discussed preliminary results of an ongoing phase 1b expansion trial at the Clinical Science Symposium on anti–PD-1. Lambrolizumab was administered every 2 or 3 weeks until disease pro-

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gression or unacceptable toxicity. Of the 294 enrolled patients with melanoma, 179 did not receive ipilimumab and 115 patients were pretreated with ipilimumab. As of December 2012, the median response duration has not been reached. “We found that efficacy and safety were similar in ipilimu­ mab-naïve patients and those who had received prior treatment with ipilimumab,” Dr Ribas noted. Dual Blockade with PD-1 Packs Bigger Punch Combining the CTLA-4–blocking antibody ipilimumab and the PD-1 blocker nivolumab achieved deep, rapid, and durable tumor responses in a phase 1 study that was presented by Jedd D. Wolchok, MD, PhD, an oncologist at Memorial Sloan-Kettering Cancer Center, NY, and was published online simultaneously (Wolchok JD, et al. N Engl J Med. 2013;369:122-133. 2013 Jun 2. Epub ahead of print). Of the 86 patients, 53 received concurrent therapy with the 2 agents, and 33 received sequential therapy (ie, they previously received ipilimumab and were now receiving nivolumab every 2 weeks for up to 48 doses). The results were impressive. Among the 53 patients receiving concurrent treatment, 53% had an objective response, with all patients showing tumor reduction of ≥80%, including 18% who achieved a complete response. After a median follow-up of 13 months, 90% of responders were still stable. The estimated 1-year survival rate with this regimen was 82%. “The proportion of patients with a rapidly declining tumor burden is reminiscent of responses to targeted pathway inhibitors, yet the durability of these responses maintains consistency with the long-lasting nature of immunotherapy in prior studies,” Dr Wolchok said at the Clinical Science Symposium on anti–PD-1. Walter J. Urba, MD, PhD, Director of Cancer Research at the Providence Cancer Center in Oregon, predicted that PD-1 blockade is “certainly going to change the state of the care of patients with melanoma once again.” Harnessing an Oncolytic Virus The cancer-killing virus talimogene laherparepvec (T-VEC) is the first oncolytic virus to produce benefits in patients with melanoma. T-VEC directly kills tumor cells and elicits a host response that targets distant metastases as well, said Howard L. Kaufman, MD, Director of the Rush University Cancer Center, Chicago.

The phase 3 OPTiM trial randomized 436 patients with advanced melanoma to intratumoral injections of T-VEC or to subcutaneous GM-CSF injections. T-VEC significantly improves responses ≥6 months compared with GM-CSF (16.3% vs 2.1%; P <.001), meeting the study’s end point.

Photo by ©ASCO/Scott Morgan 2013

Immunotherapies Take Center Stage in Melanoma

“We are in an era of remarkable advances for melanoma. With nivolumab… the median duration of response of 2 years is one of the highest numbers I have seen.” —Mario Sznol, MD

Median time to treatment failure with T-VEC was 8.2 months versus 2.9 months with GM-CSF, a 58% reduction in progression (P <.001). In the interim analysis, the median OS was 23.3 months with T-VEC and 19.0 months with GM-CSF. The treatment was also very well tolerated, he said. Kim A. Margolin, MD, of the Seattle Cancer Care Alliance, commented that because GM-CSF is not a standard treatment for metastatic melanoma, it may not be a good comparator for the novel therapy. She suggested that the best use of T-VEC may be in combination with another immune mediator, such as ipilimumab. Arlene H. Sharpe, MD, PhD, Co­ director of the Harvard Institute of Translational Immunology at Harvard Medical School, commented that “Tar­ geting immunoinhibitory pathways is providing a new strategy for immunotherapy….There are synergies among inhibitory pathways. Co-blockade enables better rescue of exhausted T-cells and therapeutic efficacy than blockade of a single inhibitory pathway.” n

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Personalized Medicine

Two Genetic Tests Can Prevent Overtreatment of Early Prostate Cancer Oncotype DX prostate cancer test and Prolaris will compete for market share By Phoebe Starr Chicago, IL—The management of patients with prostate cancer will be advanced by 2 new genetic tests—Oncotype DX prostate cancer test and Prolaris. Both tests generate a score that can be used to analyze biopsy specimens of men with low-risk prostate cancer (ie, Gleason score ≤6) to determine if they are truly “low risk” and appropriate for watchful waiting, or if they harbor higher-risk genes and need immediate treatment. These tests, although expensive, have the potential to prevent overtreatment and the associated costs, and to improve decision-making and risk assessment. Studies presented at the 2013 Ameri­ can Society of Clinical Oncology meeting focused on the 2 tests, which experts believe will compete with each other for market share. Oncotype DX for Prostate Cancer Expecting FDA Approval Launched by Genomic Health on May 18, 2013, the Oncotype DX prostate cancer test is similar to the Oncotype DX breast cancer and colon cancer tests widely used in the United States. The Oncotype DX prostate cancer test measures the expression of 17 genes in a prostate tissue specimen that

can predict the aggressive level of prostate cancer by generating a genomic prostate score ranging from 0 to 100. H. Jeffrey Lawrence, MD, Senior Director of Medical Affairs, Genomic Health, Redwood City, CA, presented data showing that the expression patterns that predict prostate cancer aggressiveness are similar in tumor tissue and in normal prostate tissue.

These genetic tests, although expensive, have the potential to prevent overtreatment of prostate cancer and reduce the associated costs. The genomic prostate score derived from tumor-based gene-expression patterns in the tumor was also associated with clinical recurrence when assessed in adjacent normal prostate tissue, but the strength of the association was less robust than in the tumor. The genes associated with the strong­ est predictive value of the genomic prostate score in normal tissue were those representing stromal response and androgen signaling.

A validation study of the Oncotype DX prostate cancer test was presented at the 2013 meeting of the American Urological Association by Peter Carroll, MD, Professor and Chair, Department of Urology, University of California, San Francisco. The test significantly predicted disease aggressiveness (P = .002) beyond clinical factors that included prostate-specific antigen level and Gleason score. The test is estimated to cost approximately $3800. Genomic Health is in the process of building a dossier of evidence for insurers. Based on Genomic Health’s strong track record with the breast and colon cancer Oncotype DX assays, the company expects the US Food and Drug Administration (FDA) to grant approval to the prostate test. Prolaris Approved by FDA Prolaris, manufactured by Myriad Genetics, is approved by the FDA for use in low-risk men with a Gleason score of 6, and for patients postprostatectomy who are at high risk for prostate cancer recurrence. Prolaris, which has been available for several months, costs approximately $3400. The assay generates a cell cycle progression (CCP) score based on the av-

erage RNA expression of 31 CCP genes that are normalized by the average expression of 15 housekeeping genes as quantitated by reverse transcriptase polymerase chain reaction. Jack M. Cuzick, PhD, Director, Wolfson Institute of Preventive Medicine, University of London, United Kingdom, presented a retrospective review of 5 studies of the Prolaris test showing that the test-generated CCP score was able to predict prostate cancer outcomes in multiple patient cohorts and in diverse clinical settings. In a statement issued before the meeting, Dr Cuzick said, “Clinical data show that PROLARIS predicts prostate cancer outcome in multiple patient cohorts and in diverse clinical settings. PROLARIS provides independent information beyond clinicopathologic variables and accurately differentiates aggressive prostate cancer from indolent cancer based on real oncologic outcomes.” A similar distribution of CCP scores was found in all 5 studies, showing its utility in different settings. The CCP score was a significant predictor of disease outcome. However, the 5 studies were not randomized; therefore, the results should be interpreted with caution, Dr Cuzick said. n

Strategies to Overcome the Challenges of Personalized Medicine Chicago, IL—The use of molecular profiling to guide treatment decisions is envisioned as a critical new strategy in cancer therapy, but for patients to reap the benefits of personalized medicine, sweeping reforms are needed in how genetic information is analyzed and acted upon, said Richard L. Schilsky, MD, Chief Medical Officer, American Society of Clinical Oncology (ASCO), and Chief of Hematology/ Oncology, Department of Medicine, University of Chicago Comprehensive Cancer Center, IL. Dr Schilsky’s talk at ASCO 2013 was titled, “Breaking Down Barriers in the Implementation of Personalized Medicine.” “We have learned that each person’s tumor has a unique molecular profile. This has generated excitement, but dif-

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By Caroline Helwick

“We have learned that each person’s tumor has a unique molecular profile. This has generated excitement, but difficulty as well, with respect to how we understand the unique biology of each tumor and how we act on this to individualize treatment.”

ficulty as well, with respect to how we understand the unique biology of each tumor and how we act on this to individualize treatment,” he noted. Challenges in Personalizing Treatment Implementing a personalized cancer

—Richard L. Schilsky, MD medicine program requires (1) adequate tumor tissue available for molecular profiling; (2) a standardized, high-quality laboratory for molecular profiling to ensure the accuracy, reliability, and timeliness of test results; (3) identification of tumor “targetable” molecular aberrations; and (4) the availabil-

ity of a targeted agent known to inhibit the activity of the molecular aberration. There are problems inherent in all of these steps. Established guidelines for tissue collection and testing are lacking, while testing facilities are proliferating. “Clinicians are having a hard time figuring out which lab to use, which gives the most reliable results. And there are few established standards for the molecular workup of tumors,” Dr Schilsky said. Dr Schilsky proposed that ASCO and the College of American Pathologists collaborate on developing guidelines for tissue handling and molecular workup. Guidelines established by professional societies will ensure that laboratories across the country meet uniform proficiency standards and produce high-quality results. Continued on page 28

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Health Policy

FDA Expected to Approve Surrogate End Point for Neoadjuvant Breast Cancer Trials New guidance for manufacturers should accelerate drug approvals Chicago, IL—For years, the cancer research community has pushed for the use of surrogate end points in clinical trials as a means of hastening the drug approval process. These efforts will soon bear fruit, with the anticipated release by the US Food and Drug Administration (FDA) of its final guidance to drug manufacturers for accelerated drug approval for neoadjuvant breast cancer therapies. At ASCO 2013, the speakers discussed the potential implications for researchers, providers, and patients. Under the new guidance for the pharmaceutical industry, accelerated approval could be granted based on a surrogate end point that predicts for clinical benefit; such an approval would require subsequent confirmation in a clinical trial. For neoadjuvant breast cancer, this end point would likely be patholog­­ic complete response (pCR) rate. Although achieving a pCR has been associated with superior outcomes in multiple studies, the correlation needs further validation, said Tatiana M. Prowell, MD, Breast Cancer Scientific

Lead, Breast Oncology Group, FDA, and Assistant Professor of Oncology, Johns Hopkins, Baltimore, MD. It is expected that pCR will be the surrogate end point in this setting, but other outcomes have been studied in patients with breast cancer, including tumor response on imaging, measurement of the tumor proliferation marker Ki-67, preoperative endocrine prognostic index, and residual cancer burden after treatment. Faster Drug Approval to Most Benefit High-Risk Patients The traditional drug approval process averages 10 to 15 years. The goal of accelerated approval is to provide early access to effective drugs and to provide incentives for developing drugs for particular breast cancer subtypes with unmet needs. Under the new approval process, a single trial or a short-duration trial would be appropriate for accelerated approval, and a simultaneous longer trial would be conducted to support “regular” approval, according to the speakers at a session at the ASCO

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By Caroline Helwick

Moving clinical trials from adjuvant to the neoadjuvant setting can yield important information about drugs that are under evaluation and should identify active agents faster. —Angela DeMichele, MD, MSCE

meeting entitled “Pushing the Limits of Upfront Care and Drug Devel­ opment: Neoadjuvant Opportuni­ ties in Breast Cancer.” The use of pCR to support accelerated approval is appropriate “for highly promising drugs and high-risk patient populations,” Dr Prowell maintained. Session Chair Angela DeMichele, MD, MSCE, Co-Program Leader, Breast Cancer Program, Abramson Cancer Center, University of Penn­

sylvania, Philadelphia, noted that there is a “fertile environment” for new drug development in the neoadjuvant breast cancer treatment setting, because the many benefits of neoadjuvant therapy are now established. Moving clinical trials from adjuvant to the neoadjuvant setting can yield important information about drugs that are under evaluation, such as the ability of pharmacodynamic markers to provide in vivo evidence of biologic effects. But most important, this should identify active agents faster, which serves patients, Dr DeMichele said. She emphasized that surrogate markers must be robust (ie, reproducible and standardized), and their correlation with the true end point, such as overall survival, must be more than a simple “correlation.” In this case, pCR must be strictly defined as the elimination of all invasive and noninvasive disease in the breast and lymph nodes, rather than a “looser” definition. Its relationship with the final end point can only be assured through long-term follow-up of patients. n

Strategies to Overcome the Challenges of Personalized... But there will still be the problem of the increasing complexity of molecular diagnoses, he added. “The problem is, the harder you look, the more you will find,” Dr Schilsky said. “We are moving from individual mutations to multiplex assays of mutations of interest to whole genome and whole exome sequencing.” Then, there is the problem of using the information that is obtained. Physicians need standardized decision support tools so that they can understand the mutational profiles identified on these tests and how to apply the information in treatment. “For the oncologist, the challenge is understanding what mutations are clinically ‘actionable’ and which are not—which can be acted on and which ignored, and what treatment may be the best match for the molecular profile of the tumor,” Dr Schilsky said. Drug access is also a big problem. The test result will most likely suggest that the best course of action involves the off-label use of an available agent or an experimental drug that can only

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be accessed through a clinical trial or from the manufacturer. National Registry Dr Schilsky proposed the establishment of a national registry in which baseline and outcomes data could be aggregated. This would be a way to make sense of the genetic information on a grand scale and to move personalized medicine forward on the individual level. The registry would record information about molecular test results, clinical decisions that are made based on the genetic information, and patient outcome. “My Cancer Genome, which was developed at Vanderbilt, is very useful. It collates all the available medical literature to inform the doctor as to whether an aberration in a particular tumor might be clinically meaningful. But the problem is that it’s collated from the literature, and it’s about what might work. It does not include the actual outcomes for that particular approach, for that particular aberration, in that particular patient,” he said.

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National Pharmacy Exchange Dr Schilsky’s solution to the problem of access to cancer drugs is a national pharmacy exchange that contains targeted agents against common mutations, as well as the treatments administered and their outcomes. This national pharmacy exchange would work in this way: • The patient is enrolled into the national registry • The physician submits a validated test result from a certified laboratory, along with a request for the matched drug • The formulary committee reviews the request against predetermined guidelines; if approved, the pharmacy dispenses the drug • The patient receives the drug and the clinical outcomes are entered into the registry. “For this to work, all stakeholders must participate,” Dr Schilsky emphasized. “Private insurers and the Centers for Medicare & Medicaid Services must agree to reimburse for the treatment cost.”

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Such a system would benefit patients, who would receive a matched targeted agent; physicians, because they would receive guidance, treatment recommendations, and access to drugs for their patients; the pharmaceutical industry, because companies would obtain data on drug use and outcomes to inform their research and development, as well as the life cycle management for their drugs; insurers, because they would receive data to inform coverage decisions (eg, off-label use); and regulators, such as the US Food and Drug Administration, because they would receive real-world outcomes and safety data. Only 5% of patients participate in clinical trials, and it is becoming clear that drugs will need to be evaluated outside of this traditional framework, Dr Schilsky said. “There are too few patients, too many molecular subtypes, too many drugs to study, and not enough time or money. We must find alternative ways to learn about patients.” n

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Lung Cancer

Dabrafenib Shows Promising Results in Patients with Stage IV NSCLC Chicago, IL—In an interim analysis of a single-arm phase 2 study, the BRAF kinase inhibitor dabrafenib (Tafinlar), which was recently approved for the treatment of melanoma, has demonstrated very good efficacy in the treatment of stage IV non–small-cell lung cancer (NSCLC) with the BRAF V600E mutation in patients whose disease progressed after chemotherapy, reported David Planchard, MD, PhD, of the Department of Medical Oncology, Institut Gustave-Roussy, Villejuif Cedex, France, at ASCO 2013. The safety profile of dabrafenib was consistent with previous studies of this medication in patients with melanoma, said Dr Planchard. BRAF mutations are found in <2% of patients with NSCLC, and V600E accounts for approximately 50% of these mutations. The phase 2 study continues to recruit patients with stage IV NSCLC with the BRAF V600E mutation who have undergone ≥1 unsuccessful chemotherapy treatments. The study consists of 2 stages: if the first 20 patients (stage 1) have measurable progress with the use of dabrafenib, then

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At the most recent data analysis, 48% of patients were still taking dabrafenib and 52% had discontinued treatment. A durable partial response was reported in 2 patients who have been taking dabrafenib for more than 1 year. —David Planchard, MD, PhD study investigators add 20 more patients (stage 2). If results are encour-

aging, 20 patients with stage IV NSCLC who had not previously received treatment would become part of an expansion group. Patients in the trial were administered 150 mg of dabrafenib twice daily until disease progression. The primary end point was overall response rate (ORR). The results were presented for 25 patients, including 20 patients who were evaluable for efficacy. The ORR, which was defined as complete and partial responses plus stable disease, was 60%. A partial response rate was detected in 40% of the patients, and disease stability was realized in 20% of the patients. The disease advanced in 30% of patients. At the most recent data analysis, 48% of patients were still taking da­ brafenib and 52% had discontinued treatment. A durable partial response was reported in 2 patients who have been taking dabrafenib for more than 1 year. Overall, 24 (96%) patients had an adverse event (AE); 11 (44%) had grade 3 AEs. Most (92%) AEs were related to study treatment; 2 AEs were related to study treatment discontinu-

ation. In addition, AEs in 5 (20%) patients led to dose reduction, and 10 (40%) patients had AEs that resulted in dose interruption. The most common AEs were fatigue (40%), reduced appetite (32%), rash (24%), nausea (24%), dry skin (20%), and diarrhea (20%). A total of 10 (40%) patients had serious AEs. Of those, 2 patients had squamous-cell carcinoma. To date, the trial only included a white patient population, Dr Plan­ chard noted. New participants will include an Asian population to help analyze dabrafenib treatment across different races. As the trial goes forward, it will enroll first-line patients as well, he said. The durability of responses still needs to be determined, and the data on progression-free survival are immature. The results of the study demonstrate that BRAF V600E is “an actionable target beyond melanoma,” said Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, who was not involved in the study. n

Afatinib Doubles Progression-Free Survival Compared with Chemotherapy in Patients with Lung Cancer Chicago, IL—Data presented at ASCO 2013 from the phase 3 clinical trial, known as LUX-Lung 6, show that Asian patients with epidermal growth factor receptor (EGFR) or ErbB1 mutation–positive advanced non–smallcell lung cancer (NSCLC) who were treated with first-line afatinib (Gilo­ trif) had a doubling in progression-free survival (PFS) compared with treatment with standard chemotherapy with gemcitabine and cisplatin. A few weeks after the release of the data at the meeting, the US Food and Drug Administration (FDA) approved afatinib for the first-line treatment of patients with nonmetastatic NSCLC and EGFR exon 19 deletions or exon 21 substitution mutations, as detected by a companion diagnostic test approved by the FDA concomitantly with afatinib. The data were released in a poster presented by Yi-Long Wu, MD, of the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China. Afatinib targets the enVOL. 6

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tire ErbB/HER family of receptors, including EGFR and ErbB1 and ErbB2. The LUX-Lung 6 study is the larg­ est prospective trial of patients with NSCLC plus EGFR mutations. The study included 664 patients from China, the Republic of Korea, and Thailand with advanced NSCLC and EGFR mutation who were randomized in a 2:1 ratio to first-line treatment with oral afatinib 40 mg daily or to intravenous gemcitabine 75 mg/m2 plus cisplatin 1000 mg/m2 every 21 days for up to 6 cycles. The median PFS was 11.0 months in patients randomized to afatinib compared with 5.6 months in patients randomized to chemotherapy (hazard ratio [HR], 0.28; P <.001). These PFS findings were consistent across all subgroups. Median PFS results from the investigator review were similar—13.7 months with afatinib versus 5.6 months with chemotherapy (HR, 0.26; P <.001). Patients in the afatinib arm also had a significantly higher objective response rate compared with those re-

ceiving chemotherapy (66.9% vs 23.0%, respectively; P <.001) and a significantly higher disease control rate (92.6% vs 76.2%; P <.001). Approximately 47% of patients receiving afatinib are currently alive and progression free after 1 year of treatment compared with 2% of the patients who received chemotherapy.

“Significantly more patients had symptom improvement with afatinib for the prespecified symptoms of cough, dyspnea, and pain.” —Yi-Long Wu, MD The safety profile was as expected in both treatment arms, and consistent with previous studies, according to Dr Wu. The most common grade 3 adverse events (AEs) associated with afatinib were EGFR-mediated events (ie, diarrhea, rash, and stomatitis/mucosi-

tis). Nausea and vomiting, bone marrow suppression, and fatigue were more frequent with chemotherapy. The discontinuation rate resulting from AEs was 5.9% with afatinib and 39.8% with chemotherapy. Patient-reported outcomes were evaluated as secondary end points of LUX-Lung 6. “Significantly more patients had symptom improvement with afatinib for the prespecified symptoms of cough [P = .003], dyspnea [P <.001], and pain [P = .003],” said Dr Wu. Health-related quality of life (QOL) was measured using the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire, which evaluated global health status/QOL (ie, overall well-being) in addition to physical, cognitive, role, social, and emotional functioning. Based on a review of these 6 measurements, afatinib-treated patients had improvements in global health–related QOL and physical, role, and social functioning compared with chemotherapy (P <.05).­—WK n

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For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac

imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.


Kyprolis™ (carfilzomib) for Injection is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma. • Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria. References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391. 2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

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

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243 September 2012


Lung Cancer

Current Treatment of Advanced NSCLC Requires Testing for Driver Mutations By Wayne Kuznar Chicago, IL—Advances in the treatment of non–small-cell lung cancer (NSCLC) to date have focused on mutations in the epidermal growth factor receptor (EGFR) gene, sensitivity to

various oncologic agents, the effects of chemotherapy versus single drug on quality of life, and oncologic drug development, said Paul A. Bunn, Jr, MD, James Dudley Chair in Cancer

Research, University of Colorado Denver, at ASCO 2013. Years ago, the selection of patients for treatment was based on clinical features. Today, histology must be

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information. INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified. DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%. Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 2 Dosing Dosing Dosing Dosing (27 mg/m ): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid. Give an additional 250  mL  to 500  mL of intravenous  fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2. Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• • •

• Non-Hematologic Toxicity Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • congestive heart failure; • decreased left ventricular function; • or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

32

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• • •

Recommended Action Withhold dose. If fully recovered before next scheduled dose, continue at same dose level. If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. Recommended Action Withhold until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline. • Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. • After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

part of the mix, Dr Bunn said. “In the molecular era, we have to consider patients of almost any performance status [for treatment]. We have to do a special test to determine whether they

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function. • Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If not attributable to KYPROLIS, restart at the dose used prior to the event. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician. • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. • Withhold until resolved or returned to baseline. Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. a

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2  mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29  mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs.  DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2  to 5  minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The  reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50  mL 5% Dextrose Injection, USP intravenous bag. 6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3. Table 3: Stability of Reconstituted KYPROLIS

Fatigue Anemia Fatigue Nausea Anemia Thromboc Nausea Dyspnea Thrombocy Diarrhea Dyspnea Pyrexia Diarrhea Upper resp Pyrexia Headache Upper resp Cough Headache Blood crea Cough Lymphope Blood crea Edema pe Lymphopen Vomiting Edema per Constipati Vomiting Neutropen Constipatio Back pain Neutropeni Insomnia Back pain Chills Insomnia Arthralgia Chills Muscle sp Arthralgia Hypertens Muscle spa Asthenia Hypertensio Hypokalem Asthenia Hypomagn Hypokalem Leukopeni Hypomagn Pain in ext Leukopenia Pneumoni Pain in extr Aspartate Pneumonia Dizzinessa Aspartate Hypoesthe Dizziness Anorexia Hypoesthes Pain Anorexia Hyperglyce Pain Chest wall Hyperglyce Hypercalce Chest wall Hypophosp Hypercalce Hyponatre Hypophosp a National Can Hyponatrem

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WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade  4 events, and 1  death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in <  1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day  8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration]. Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

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yocardial ation. New unction or ents (e.g., in 7% of Grade 3 or enefit/risk ass III and normalities at greater sion (PAH) han 1% of ROLIS for to restart ulmonary 3 dyspnea d manage seline [see tions were lgia, facial tightness, stration of severity of to contact mor Lysis <  1% of d to be at ee Dosage y. Interrupt KYPROLIS cycle and ma, 36% of following nuation of treatment nistration]. have been

Lung Cancer have oncogene changes,” he said. A major breakthrough was the 2004 discovery of mutations in the EGFR gene. These mutations alter the aden­osine triphosphate (ATP)-binding pocket, allowing ATP to bind. “The tyrosine kinase inhibitors [TKIs] imatinib [Gleevec], erlotinib [Tarceva], and gefitinib [Iressa] bind and outcompete ATP for the binding pocket, so ATP can’t bind, and there’s

no signal,” Dr Bunn said. Clinical trials emphasize the importance of mutation testing if TKI therapy is to be selected over chemotherapy for firstline treatment of advanced NSCLC. In the Iressa Pan-Asia Study, in the group with EGFR mutations, gefitinib showed response in 71% of patients compared with 47% with chemotherapy. In patients without the mutation, the response was 23% with chemo-

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other reported (<  1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other KYPROLIS is appropriate. Monitororliver enzymes frequentlyAfter [seeresolution, Dosage and Administration and liver abnormalities until resolved returned to baseline. consider if restarting Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause harmand when administeredand to a KYPROLIS is appropriate. Monitor liver enzymes frequently [see fetal Dosage Administration pregnant woman based on its mechanism of action and findings in animals. There are no adequate Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered toand a well‑controlled womenofusing Carfilzomib caused toxicity pregnant womanstudies based inonpregnant its mechanism actionKYPROLIS. and findings in animals. Thereembryo‑fetal are no adequate andin pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of If this drug is used during if thebecoming patient becomes while taking thisKYPROLIS. drug, the reproductive potential shouldpregnancy, be advised or to avoid pregnantpregnant while being treated with should be apprised of the potential to thebecomes fetus [seepregnant Use in Specific Populations]. Ifpatient this drug is used during pregnancy, or ifhazard the patient while taking this drug, the ADVERSE REACTIONS: following adverse are discussed greater detail in other sections patient should be apprised The of the potential hazardreactions to the fetus [see Use ininSpecific Populations]. of the labeling: ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] of the labeling: • Pulmonary Hypertension [see Warnings and Precautions] • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Complications [see Warningsand andPrecautions] Precautions] • Pulmonary Hypertension [see Warnings • Infusion Reactions [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Thrombocytopenia [see Warnings andand Precautions] • Tumor Lysis Syndrome [see Warnings Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings • Thrombocytopenia [see Warnings and Precautions] and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical diarrhea, and pyrexia. Clinical Trials Safety Experience. clinical trials are conducted trials of patients with multiple myeloma were fatigue, anemia, Because nausea, thrombocytopenia, dyspnea, under widely adverseSafety reaction rates observed in the clinical clinical trials a drug cannot diarrhea, and varying pyrexia.conditions, Clinical Trials Experience. Because trials ofare conducted be directly with ratesadverse in the clinical another in drug, and may notofreflect rates under widelycompared varying conditions, reactiontrials ratesofobserved the clinical trials a drugthe cannot observed medical practice. A total 526 patients relapsed and/or myeloma be directlyincompared with rates in theof clinical trials with of another drug, andrefractory may not multiple reflect the rates received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myelomaof four treatment cycles with a median cumulative KYPROLIS dose of Patients 993.4 mg. Deaths due to of all received KYPROLIS as monotherapy or with pre‑dose dexamethasone. received a median causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not cardiac disorder), failure 4 patients (multi‑organ hepatic failure,cardiac renal failure), attributed to diseaseend‑organ progression wereincardiac in 5 patients (acutefailure, coronary syndrome, arrest, infectiondisorder), in 4 patients (sepsis, tractfailure, bacterial infection), dyspnea and cardiac end‑organ failurepneumonia, in 4 patientsrespiratory (multi‑organ hepatic failure, renal failure), intracranial in 1 patient each, andrespiratory 1 patient tract found bacterial dead of unknown Serious infection in hemorrhage 4 patients (sepsis, pneumonia, infection),causes. dyspnea and adverse reactions were reported in 45% patients. mostfound common adversecauses. reactions were intracranial hemorrhage in 1 patient each, and 1 The patient deadserious of unknown Serious pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse adverse reactions were reported in 45% patients. The most common serious adverse reactions were reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, andand acute renal congestive failure (1% reactions leading to discontinuation of KYPROLIS occurred in 15% of patients included each).failure Adverse reactions at a rateincreased of 10% orblood greater are presented in Table 4. failure (1% heart (2%), cardiacoccurring arrest, dyspnea, creatinine, and acute renal TableAdverse 4: Incidence of occurring Adverse Reactions in ≥ 10% of Multiple Myeloma each). reactions at a rate of Occurring 10% or greater are presented in Table 4. Patients Treated with KYPROLIS Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS Patients (N = 526) [n (%)] Patients (N = 526) Grade 3 Grade 4 All [n (%)] a Events Events Event Grades Grade 3 Grade 4 All a Fatigue 292 (55.5) 38 (7.2) 2 (0.4) Events Events Event Grades Anemia 246(55.5) (46.8) 111 (21.1) Fatigue 292 38 (7.2) 27 (1.3) (0.4) Nausea 236 (44.9) 7 (1.3) 0 Anemia 246 (46.8) 111 (21.1) 7 (1.3) Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Nausea 236 (44.9) 7 (1.3) 0 Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Diarrhea 172 (32.7) (0.8) (0.2)b Dyspnea 182 (34.6) 254(4.8) 11(0.2) Pyrexia 160 (30.4) (0.4) Diarrhea 172 (32.7) 47 (1.3) (0.8) 12(0.2) Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) Headache 145 (27.6) 7 (1.3) Upper respiratory tract infection 149 (28.3) 17 (3.2) 00 Cough 137 (26.0) 1 (0.2) Headache 145 (27.6) 7 (1.3) 00 Blood creatinine increased 127 (24.1) 13 (2.5) 1 0(0.2) Cough 137 (26.0) 1 (0.2) Lymphopenia 126(24.1) (24.0) 84 (16.0) 11 (2.1) Blood creatinine increased 127 13 (2.5) 1 (0.2) Edema peripheral 126(24.0) (24.0) 3 (0.6) 0 Lymphopenia 126 84 (16.0) 11 (2.1) Vomiting 117(24.0) (22.2) 5 (1.0) Edema peripheral 126 3 (0.6) 00 Constipation 110(22.2) (20.9) (0.2) Vomiting 117 51(1.0) 00 Neutropenia 109(20.9) (20.7) 50 (9.5) 4 0(0.8) Constipation 110 1 (0.2) Back pain 106(20.7) (20.2) 15(9.5) (2.9) 0 Neutropenia 109 50 4 (0.8) Insomnia 94(20.2) (17.9) 0 Back pain 106 15 (2.9) 00 Chills 84(17.9) (16.0) 1 0(0.2) Insomnia 94 00 Arthralgia 83 (15.8) Chills 84 (16.0) 17 (1.3) (0.2) 00 Muscle spasms 76 (14.4) 2 (0.4) Arthralgia 83 (15.8) 7 (1.3) 00 Hypertension 75 (14.3) 15 (2.9) 2 0(0.4) Muscle spasms 76 (14.4) 2 (0.4) Asthenia 73 (13.9) 12 (2.3) (0.2) Hypertension 75 (14.3) 15 (2.9) 21(0.4) Hypokalemia 72 (13.7) 14 (2.7) Asthenia 73 (13.9) 12 (2.3) 13 (0.6) (0.2) Hypomagnesemia 71 (13.5) (0.4) 0 Hypokalemia 72 (13.7) 142(2.7) 3 (0.6) Leukopenia 71 (13.5) 27 (5.1) 1 0(0.2) Hypomagnesemia 71 (13.5) 2 (0.4) Pain in extremity 70 (13.3) 0 Leukopenia 71 (13.5) 277 (1.3) (5.1) 1 (0.2) Pneumonia 67 (12.7) 52 (9.9) 3 (0.6) Pain in extremity 70 (13.3) 7 (1.3) 0 b Aspartate aminotransferase increased 66(12.7) (12.5) 15(9.9) (2.9) 1 (0.2)b Pneumonia 67 52 3 (0.6) Dizzinessaminotransferase increased 66(12.5) (12.5) (1.0) (0.2) Aspartate 66 155(2.9) 11(0.2) Hypoesthesia 64(12.5) (12.2) 0 Dizziness 66 53 (0.6) (1.0) 1 (0.2) Anorexia 63 (12.0) 1 (0.2) Hypoesthesia 64 (12.2) 3 (0.6) 00 Pain 63 (12.0) 12 (2.3) Anorexia 63 (12.0) 1 (0.2) 00 Hyperglycemia 62 (11.8) 16 (3.0) 3 (0.6) Pain 63 (12.0) 12 (2.3) 0 Chest wall pain 60(11.8) (11.4) 3 (0.6) 0 Hyperglycemia 62 16 (3.0) 3 (0.6) Hypercalcemia 58(11.4) (11.0) 13 (2.5) 8 0(1.5) Chest wall pain 60 3 (0.6) Hypophosphatemia 55(11.0) (10.5) 24 (4.6) Hypercalcemia 58 13 (2.5) 83 (0.6) (1.5) Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) One event was Grade 5 severity. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. b One event was Grade 5 severity. a

b

therapy and 1% with gefitinib. Patients with an EGFR mutation who received gefitinib as a single oral drug had better progression-free survival (PFS) than with chemotherapy with carboplatin/paclitaxel. “The opposite was true for patients that did not have EGFR mutation,” Dr Bunn said. In patients with no mutation, chemotherapy was better, although the quality of life was not as

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%)Renal and renal failure (9%), which were mostly Description of Selected Adverse Drug Reactions. Events: The most common renal Grade or Grade  2 in increase severity. inGrade  renal adverse in 6% of were patients and adverse1 reactions were blood 3 creatinine (24%) reactions and renal occurred failure (9%), which mostly Grade 4 events occurred in 1%. Grade  Discontinuations due to reactions increasedoccurred blood creatinine andpatients acute renal Grade  1 or Grade  2 in severity. 3 renal adverse in 6% of and failure were 1%occurred each. Ininone death occurred concurrent and and worsening renal Grade 4 events 1%.patient, Discontinuations due towith increased bloodsepsis creatinine acute renal function [see1% Dosage Administration]. Peripheral Peripheral neuropathy (including failure were each.and In one patient, death occurred Neuropathy: with concurrent sepsis and worsening renal all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (includingof patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious and treatment discontinuation in <  1%. Withhold or discontinue treatment as peripheral neuropathy events occurred in < 1% of patients, which resulted in doserecommended [see reduction in < 1% Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% and treatment discontinuation in <  1%. Withhold or discontinue treatment as recommended [see of patients. antiviralHerpes prophylaxis patients Herpes who have a history of herpes infection. Dosage and Consider Administration]. Virusfor Infection: zoster reactivation waszoster reported in 2% INTERACTIONS: Carfilzomib is primarily metabolized peptidase and epoxide hydrolase ofDRUG patients. Consider antiviral prophylaxis for patients who have via a history of herpes zoster infection. activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase concomitant of cytochrome P450 profile inhibitors and inducers. is not expected activities, andadministration as a result, the pharmacokinetic of carfilzomib is Carfilzomib unlikely to be affected by to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected IN SPECIFIC Pregnancysection Category toUSE influence exposure ofPOPULATIONS: other drugs [seePregnancy. Clinical Pharmacology of fullDPI].[see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while can cause when administered to a pregnant woman. being treatedfetal withharm KYPROLIS. Based on its mechanism of action andCarfilzomib findings incaused animals,embryo‑fetal KYPROLIS toxicity in pregnant doses that to were lower than in patients receiving the recommended can cause fetal harmrabbits when at administered a pregnant woman. Carfilzomib caused embryo‑fetal dose. IfinKYPROLIS used at during if thethan patient becomes pregnant taking this toxicity pregnant israbbits dosespregnancy, that wereorlower in patients receiving thewhile recommended drug, IftheKYPROLIS patient should be during apprised of the potential hazard to the fetus. Carfilzomib was administered dose. is used pregnancy, or if the patient becomes pregnant while taking this intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered 2 mg/kg/daytoinpregnant rats andrats 0.2,and 0.4,rabbits and 0.8 mg/kg/day in of rabbits. Carfilzomib was not teratogenic intravenously during the period organogenesis at doses of 0.5, 1, and any dose tested. there increase inin pre‑implantation losswas at ≥not 0.4teratogenic mg/kg/day 2atmg/kg/day in rats In andrabbits, 0.2, 0.4, andwas 0.8anmg/kg/day rabbits. Carfilzomib in Inearly resorptions andan post‑implantation loss and a decrease fetalmg/kg/day weight at atand anyan increase dose tested. rabbits, there was increase in pre‑implantation loss at ≥in0.4 the maternally toxic dose of 0.8  mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at 2 approximately respectively, of the in humans of 27inmg/m the maternally 20% toxic and dose40%, of 0.8  mg/kg/day. Therecommended doses of 0.4 dose and 0.8 mg/kg/day rabbitsbased are on body surface Mothers.ofIt the is not known whether approximately 20%area. and Nursing 40%, respectively, recommended doseKYPROLIS in humansisofexcreted 27 mg/min2 human based milk. Since manyarea. drugsNursing are excreted in human milkknown and because the potential for serious on body surface Mothers. It is not whetherofKYPROLIS is excreted in adverse human reactions nursing infants KYPROLIS, a decision be made discontinue nursing milk. Sinceinmany drugs are from excreted in human milk andshould because of thewhether potentialto for serious adverse or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing The safety the anddrug, effectiveness KYPROLIS pediatric ofpatients have not mother. been established. orUse. to discontinue taking intoofaccount the in importance the drug to the Pediatric Geriatric Use. Inand studies of KYPROLIS were no observed in safety Use. The safety effectiveness of there KYPROLIS in clinically pediatricsignificant patients differences have not been established. and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal patients with The normal renal function and and safety those with mild, moderate, and severe Impairment. pharmacokinetics of KYPROLIS were evaluated in a renal Phaseimpairment 2 trial in and patients chronic dialysis. Onand average, patients were treated for usingimpairment KYPROLIS patients with on normal renal function those with mild, moderate, and25.5 cycles severe renal 2 2 doses of 15 mg/m on Cycle 1, 20 mg/m on Cycle 2, and 27 mg/m on Cycles  3 and beyond. and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS 2 The pharmacokinetics safety of KYPROLIS by the renal doses of 15 mg/m2 onand Cycle 1, 20 mg/m2 on were Cyclenot 2, influenced and 27 mg/m on degree Cycles of3 baseline and beyond. impairment, including and the patients dialysis. were Since not dialysis clearance of KYPROLIS concentrations The pharmacokinetics safety ofon KYPROLIS influenced by the degree of baseline renal has not been studied,thethepatients drug should be administered the dialysis procedure [see Clinical impairment, including on dialysis. Since dialysisafter clearance of KYPROLIS concentrations Pharmacology section of PI].should Hepatic efficacyprocedure and pharmacokinetics has not been studied, thefull drug be Impairment. administered The aftersafety, the dialysis [see Clinical of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics offollowing laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper New York Class III and IV heart failure were eligible Impairment. limit of normal Patients (ULN) andwith bilirubin ≥ 2 Heart × ULNAssociation [see Clinical Pharmacology section of full PI].not Cardiac for the clinicalPatients trials. Safety in this population has not been Impairment. with New York Heart Association Classevaluated. III and IV heart failure were not eligible OVERDOSAGE: There is no known specific has antidote for KYPROLIS for the clinical trials. Safety in this population not been evaluated. overdosage. In the event of an overdosage, monitor and specific provide antidote appropriate OVERDOSAGE: Theretheis patient no known for supportive KYPROLIS care. overdosage. In the event of an NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. overdosage, monitor the patient and provide appropriate supportive care. Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. in vitro chromosomal test inconducted peripheralwith bloodcarfilzomib. lymphocytes. Carfilzomib not mutagenic Carcinogenicity studiesaberration have not been Carfilzomib waswas clastogenic in the the chromosomal in vitro bacterial reverse test mutation (Ames) blood test and was not clastogenic thenot in vivo mouse ininvitro aberration in peripheral lymphocytes. Carfilzomibinwas mutagenic micronucleus assay. Fertility studies have not inbeen No inbone the marrow in vitro bacterial reverse mutation (Ames) testwith and carfilzomib was not clastogenic the conducted. in vivo mouse rat and monkey toxicity effects on reproductive tissues were noted during 28‑day repeat‑dose bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity or Pharmacology. studies or in 6‑monthMonkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg 2 experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) bolus intravenous administration carfilzomib ≥ 2 mg/kg/dose in rats and 2  mg/kg/dose experienced hypotension, increasedofheart rate, andatincreased serum levels of troponin‑T. The repeatedin monkeys using dosing schedulesof similar to those clinically resulted that were bolus intravenous administration carfilzomib at ≥used 2 mg/kg/dose in rats inandmortalities 2  mg/kg/dose in due to toxicities occurring in the similar cardiovascular failure, resulted cardiac in fibrosis, pericardial fluid monkeys using dosing schedules to those (cardiac used clinically mortalities that were accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal systems. The dose of 2 mg/kg/dose in rats dysfunction), is approximately the recommended dose in humans (glomerulonephropathy, tubular necrosis, andhalf pulmonary (hemorrhage/inflammation) 2 of 27 mg/m based body surface area.isThe dose of 2 mg/kg/dose in monkeys dose is approximately systems. The dose of 2onmg/kg/dose in rats approximately half the recommended in humans the recommended dosearea. in humans based body surfaceinarea. ofequivalent 27 mg/mto2 based on body surface The dose of on 2 mg/kg/dose monkeys is approximately PATIENT COUNSELING INFORMATION: Discuss the following with patients equivalent to the recommended dose in humans based on body surface area. prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: may cause dizziness, dropofinthe blood Advisepatients patientsthat not KYPROLIS to drive or fever, chills, fatigue, rigors, chest pain, fainting, cough, orand/or swelling feet pressure. or legs. Advise operate machinery they experience of these Advise patients they may experience may cause fatigue, ifdizziness, fainting,any and/or dropsymptoms. in blood pressure. Advisethat patients not to drive or shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within operate machinery if they experience any of these symptoms. Advise patients that they may experience a day of dosing. Advise patients to contact theirwith physicians if they shortness of breath. shortness of breath (dyspnea) during treatment KYPROLIS. Thisexperience most commonly occurs within patientsAdvise to avoid dehydration, since patients receiving KYPROLIS therapy may experience aCounsel day of dosing. patients to contact their physicians if they experience shortness of breath. vomitingpatients and/or to diarrhea. Instruct patients seek medical if they experience symptoms Counsel avoid dehydration, since topatients receivingadvice KYPROLIS therapy may experience of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms contraceptive measures to prevent pregnancy treatment with KYPROLIS. Advise the ofeffective dizziness, lightheadedness, or fainting spells. Counselduring females of reproductive potential to use patient that if she becomes pregnant duringpregnancy treatment,during to contact her physician immediately. Advise effective contraceptive measures to prevent treatment with KYPROLIS. Advise the patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise breastfeeding afterKYPROLIS treatment,treatment advise herwhile to discuss theorappropriate timing her wishes physician. Advise patients not to take pregnant breastfeeding. If awith patient to restart patients to discuss with theiradvise physician medication they are timing currently prior to starting breastfeeding after treatment, her toany discuss the appropriate withtaking her physician. Advise treatment KYPROLIS, or prior to starting new medication(s) during treatment with toKYPROLIS. patients to with discuss with their physician any any medication they are currently taking prior starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 South San Francisco, CA 94080 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

good as for patients with mutations who received the oral drug, he added. At least 6 other trials have shown that in patients with an EGFR mutation, an oral TKI was associated with superior response, with a doubling of PFS compared with platinum-based doublet chemotherapy, Dr Bunn said. Crossover prevented detecting a difference between treatments in overall survival, “but the hazard ratio always favored the TKI,” as did convenience and reduced toxicity.

“Routine testing for additional genetic alterations will become standard in the future. Fortunately, the costs of next-generation sequencing and other biomarker tests are decreasing, while reliability and turn-around times are improving.” —Paul A. Bunn, Jr, MD He added that, based on findings, the question becomes, “when do you stop these treatments?” For patients with a driver mutation whose tumors progress after an initial response to a TKI, “would it be better to keep the patient on the TKI, because all the cells still have the sensitizing mutation…or should you immediately stop and switch to chemotherapy?” Preliminary data suggest no difference between giving platinum-based doublet chemotherapy immediately at progression and continuing the TKI, but the “TKI would be preferred because of convenience and toxicity,” Dr Bunn said. “In our practice, if the patients are asymptomatic, they’re continued on the TKI.” Secondary mutations in a single metastasis may develop, and some cancers may progress in a single site, while other sites are still responding to the TKI. In this case, continuing the TKI while adding local radiation produces a PFS superior to switching to chemotherapy, said Dr Bunn. Where Is Treatment Headed? Cancer cells may undergo a second mutation in the ATP binding pocket of the intracellular portion of the receptor, resulting in the ATP outcompeting the TKI. This type of resistance has been reported for imatinib, erlotinib, and crizotinib. Approximately 50% to 60% of patients with an EGFR mutation who are receiving a TKI have a second mutation, and other paContinued on page 34

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Breast Cancer

New Data Confirm Benefits of 10 Years Tamoxifen See also pages 9,11 versus 5 Years in Patients with ER-Positive Breast Cancer Chicago, IL—Updated data confirm that 10 years of adjuvant tamoxifen is superior to 5 years in reducing the rates of late recurrence and death in women with estrogen receptor (ER)-­ positive breast cancer, reported Richard G. Gray, MA, MSc, Professor of Medical Statistics, University of Oxford, United Kingdom. Previously, 5 years of treatment with tamoxifen had been shown to reduce breast cancer mortality by approximately 33% over 15 years. At ASCO 2013, Mr Gray presented data from a study known as Adjuvant Tamoxifen Treatment—To Offer More? (aTTom), which demonstrated an additional 25% reduction in cancer recurrence and death rates from year 10 onward in women treated with tamoxifen for 10 years compared with for 5 years. These results complement and confirm the results from the recently released and published study known as ATLAS (Adjuvant Tamoxifen: Longer Against Shorter; Davies C, et al. Lancet. 2013;381:805-816). In the aTTom study, 6953 women in the United Kingdom who had been taking tamoxifen for 5 years were randomized to continuing treatment for

Photo by ©ASCO/Silas Crews 2013

By Wayne Kuznar

“Treatment allocation had little effect on either recurrence rates or death rates from 5 to 9 years after diagnosis, but the benefit of longer treatment became evident in the second decade after diagnosis.” —Richard G. Gray, MA, MSc an additional 5 years or to stopping treatment. Approximately 75% of the women assigned to continue tamoxifen had done so for 5 extra years. Treatment with tamoxifen for 10 years compared with 5 years reduced cancer recurrence by 15% (P = .003). The rate of deaths from breast cancer was reduced by 12% with 10 years of treatment with tamoxifen relative to 5 years (P = .06). “Treatment allocation had little effect on either recurrence rates or death rates from 5 to 9 years after diagnosis, but the benefit of longer treatment be-

came evident in the second decade after diagnosis,” said Mr Gray. The relative reduction in the risk of death with 10 years of tamoxifen therapy increased to 21% in years 10 to 14 after diagnosis, and to 25% by 15 years of follow-up and later. No significant differences were seen in death without recurrence or allcause mortality rates between the 2 groups, although a significant improvement (P = .016) in overall survival emerged from 10 years onward of tamoxifen therapy. Extending the use of tamoxifen approximately doubled the risk of developing endometrial cancer (from 1.3% to 2.9%) and of death from endometrial cancer (from 0.6% to 1.1%), but the net clinical benefit favored 10 years of treatment, he said. Compared with no tamoxifen treatment, 10 years of tamoxifen therapy reduces the rate of breast cancer death by approximately 33% in the first 10 years after diagnosis and by 50% subsequently, said Mr Gray. The benefit of tamoxifen as shown in the aTTom study may be even greater than what was reported, because 60% of enrolled patients had an unknown ER status. An estimated 15% of patients likely had

ER-negative disease and did not benefit from treatment with tamoxifen. These findings complement and confirm the results from the ATLAS study. The combined data from the aTTom and ATLAS studies, which included data from >17,000 patients, show a significant 15% reduction in breast cancer mortality overall (P = .001) and an additional 25% reduction in breast cancer mortality 10 years and beyond after 10 years compared with 5 years of treatment with tamoxifen (P = .004). Together, the results of the aTTom and ATLAS trials constitute “proof beyond reasonable doubt” that continuing tamoxifen beyond 5 years reduces the risk of late breast cancer recurrence and reduces breast cancer mortality, said Mr Gray. Late relapses remain a concern in patients with ER-positive breast cancer, even with the introduction of effective early therapies, said Ann H. Partridge, MD, MPH, Medical Oncologist, Dana-Farber Cancer Institute, Boston, and extended treatment with tamoxifen appears to reduce the risk of late relapses. In the aTTom and the ATLAS studies, extending tamoxifen primarily reduced the risk of breast cancer recurrences starting after year 7. n

Lung Cancer Current Treatment of Advanced... Continued from page 33 tients have other oncogenic drivers. These include mutations in HER2, BRAF, and PI3KCA; rearrangements in ROS and RET; and amplifications in MET and FGFR1. Preliminary results in patients with ROS fusions treated with crizotinib suggest that response rates and PFS may be similar to those with TKIs in patients with EGFR mutations, or with crizotinib in patients with ALK fusions, said Dr Bunn.

“These data suggest that routine testing for additional genetic alterations will become standard.” —Paul A. Bunn, Jr, MD “These data suggest that routine testing for additional genetic alterations will become standard in the future,” he said. “Fortunately, the costs of next-generation sequencing and other biomarker tests are decreasing, while reliability and turn-

34

around times are improving. The future is also likely to see combinations of targeted therapies, since single agents produce few complete responses and no cures.” Second- and third-generation TKIs have been designed to outcompete ATP for binding pockets. In patients with acquired resistance to a TKI, second-generation TKIs have not been able to produce high response rates when used alone. The newly approved afatinib (Gilotrif) is a second-generation TKI that in combination with cetuximab (Erbitux) was associated with a 50% response rate in patients whose disease progressed after treatment with a first-generation TKI. Several second-generation ALK inhibitors are in phase 1 or phase 2 trials, including LKD378, AP26113, and CH5424802. Overall response rates in these trials are 56% to 94%. “In addition, responses in patients with central nervous system metastases are reported with all 3 of these agents,” Dr Bunn said. n

American health & drug benefits

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Crizotinib Superior to Standard Chemo­therapy in ALK-Positive Lung Cancer Crizotinib, an inhibitor of the anaplastic lymphoma kinase (ALK) gene, has shown significant response rates in patients with advanced non– small-cell lung cancer (NSCLC) and the ALK rearrangement. A new study compared the response rates of standard chemotherapy with crizotinib in patients with ALK-positive advanced NSCLC (Shaw AT, et al. N Engl J Med. 2013;368:2385-2394). This phase 3, open-label clinical trial included 374 patients with locally advanced or metastatic ALKpositive NSCLC who had previously received 1 platinum-based regimen. The patients were randomized in a 1:1 ratio to oral crizotinib 250 mg twice daily or to intravenous chemotherapy with pemetrexed or with docetaxel every 3 weeks. The patients receiving chemotherapy whose disease progressed were allowed to cross over to receive crizotinib as a

separate study. The study primary end point was progression-free survival (PFS). The median PFS was 7.7 months with crizotinib versus 3.0 months with chemotherapy. The response rates were 65% (95% CI, 58-72) with crizotinib versus 20% with chemotherapy (P <.001). At the time of the data cutoff, the median follow-up for overall survival was similar between the 2 groups: 12.2 months in the crizotinib group and 12.1 months in the chemotherapy group. Overall, 58 patients receiving crizotinib continued therapy beyond the predefined period of progression compared with 17 of the patients receiving chemotherapy, and the therapy duration was also longer with crizotinib than with chemotherapy—a median of 15.9 weeks versus a median of 6.9 weeks, respectively. n

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Prostate Cancer

Lack of Knowledge Prevents Men with Early-Stage Prostate Cancer from Choosing Active Surveillance By Wayne Kuznar Chicago, IL—A lack of awareness of active surveillance prevents more men with early-stage prostate cancer from choosing this option, according to a study funded by the Centers for Disease Control and Prevention (CDC), which showed that African-American men are more influenced by convenience than Caucasian men in their choice of treatment. Spouses and significant others are also influential in the decision, and they tend to be less enthusiastic about active surveillance than the men who have prostate cancer. The study was presented in a poster session by Theresa W. Gillespie, PhD, MA, Associate Professor, Departments of Surgery and of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA. The CDC estimates that approximately 50% of men diagnosed with prostate cancer remain asymptomatic and do not require treatment; yet, approximately 90% of these men receive surgery or radiation. African-American men have been reported to receive aggressive therapy significantly less

often than Caucasians, although prostate tumors in African-American men are often at higher risk for poor outcomes, raising questions about health disparities in treatment selection.

“Somewhere in the discussion, active surveillance has to be mentioned. There may be a real opportunity to take the time for a comprehensive discussion of treatment options.” —Theresa W. Gillespie, PhD, MA “The CDC was particularly interested in knowing why people don’t choose active surveillance more, and what might be some of the differential predictors or variables that could lead to more informed decisionmaking about active surveillance,” said Dr Gillespie.

Of the 214 men and 188 significant others who participated in the 5center study, 63% were African American. All participants completed quantitative questionnaires before attending focus group sessions. There were 27 focus groups for the men and 27 for their significant others. A total of 57.6% of African-American men reported that convenience influenced their treatment choice compared with 30.8% of Caucasian men (P = .004). After adjusting for education, comorbidities, insurance, age, health literacy, distance to treatment center, willingness to travel, income, and numeracy score, African-American men were nearly 3 times more likely to be influenced by convenience (odds ratio, 2.84) than Caucasians. Rural residence, however, did not affect decision-making. “Convenience might mean that men would not choose surgery because of the after effects; they would be inconvenienced if they are incontinent, for example,” said Dr Gillespie. Significant others tend to value treatment efficacy more than side effects.

Lack of awareness of active surveillance as a treatment option and no designated provider to present active surveillance as a viable choice were identified as key reasons for not choosing it. The focus groups showed that physician treatment discussions tend to be limited to the physicians’ specialty. “The urologist didn’t talk about it because he’s usually talking about surgery. Radiation oncologists don’t talk about it because they usually talk about external beam [radiation therapy] or brachytherapy,” she said. “No one has skin in the game in terms of active surveillance.” Patients and spouses also wanted feedback from patients who had been through the various treatments, Dr Gillespie said. “Somewhere in the discussion, active surveillance has to be mentioned,” she said. “There may be a real opportunity to take the time for a comprehensive discussion of treatment options, because in early-stage prostate cancer, you don’t have to choose what you’re going to do immediately.” n

See also page 40 New Analysis Confirms Radium Ra-223 Prolongs Survival in Patients with Metastatic CRPC, Regardless of Previous Docetaxel Therapy Status Chicago, IL—Results of a new subgroup analysis of the ALSYMPCA study that were presented at ASCO 2013 showed that radium Ra-223 dichloride (Xofigo) significantly prolongs overall survival (OS) and has a highly favorable safety profile in patients with metastatic castration-resistant prostate cancer (CRPC), regardless of whether they had previously received docetaxel therapy. The main results of ALSYMPCA had been released previously, showing that in the overall study population of men with metastatic CRPC, Ra-223 improved median OS and delayed the time to a first skeletal-related adverse event compared with best standard of care. Based on the main results, the US Food and Drug Administration approved Ra-223 on May 15, 2013, for the treatment of patients with metastatic CRPC that has spread to the bone but not to other organs (see also article on page 40). The ALSYMPCA trial was a phase VOL. 6

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3, randomized, double-blind, placebo-controlled study of Ra-223 dichloride plus best standard of care compared with placebo plus best standard of care in 921 patients with late-stage CRPC with bone metastases. Results of the New Analysis Nicholas J. Vogelzang, MD, Executive Medical Director, Associate Chair, Developmental Therapeutics and Genitourinary Committees, US Oncology Research, Houston, TX, and Comprehensive Cancer Centers of Nevada, Las Vegas, presented the results of a prespecified subgroup analysis of patients in ALSYMPCA in a poster session. Of the 921 randomized patients included in the analysis, 395 patients had no previous treatment with docetaxel, and 526 had received previous docetaxel. The median OS favored Ra-223 in both patient groups compared with standard of care: median OS in patients with no previous docetaxel was

16.1 months in patients who received Ra-223 versus 11.5 months with best standard of care (hazard ratio [HR],

The safety profile of Ra-223 was very favorable. Overall, there was a low incidence of myelosuppression in the docetaxel subgroups, but patients who had received previous docetaxel had a significantly higher rate of grade 3 and grade 4 bone marrow suppression with Ra-223 versus placebo. —Nicholas J. Vogelzang, MD

0.745; P = .039). In patients with previous docetaxel therapy, the median OS

was 14.4 months versus 11.4 months, respectively (HR, 0.71; P = .003). The safety profile of Ra-223 in patients with CRPC that has metastasized to the bone was very favorable. Overall, there was a low incidence of myelosuppression in the docetaxel subgroups, reported Dr Vogelzang, but patients who had received previous docetaxel had a significantly higher rate of grade 3 and grade 4 bone marrow suppression with Ra223 versus placebo (9% vs 3%, respectively; P = .01). The total incidence of grade 3 or grade 4 thrombocytopenia was significantly higher in patients with previous docetaxel use than in patients who have not received docetaxel (7% vs 2%, respectively; P = .001). No significant difference was found in the incidence of anemia or neutropenia between the docetaxel-receiving subgroups, or between the Ra-223 and placebo groups within each docetaxel-­related subgroup.—WK n

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Drug Therapy

Sorafenib Effective in Metastatic Differentiated Thyroid Cancer By Audrey Andrews

Photo by © ASCO/Rodney White 2013

Chicago, IL—Sorafenib (Nexavar) has become the first drug in years to prove effective in the treatment of differentiated thyroid cancer (DTC) that has become resistant to radioactive iodine, according to phase 3 study results that were reported at the ASCO 2013 meeting. DTC is the most common subtype of thyroid cancer, and its incidence is rising. DTC is rarely fatal, although up to 15% of patients become resistant to the current standard of care, radioactive iodine, and can die from the malignancy. For this group, there has never been an effective treatment, said Marcia S. Brose, MD, PhD, Assistant Professor of Otorhinolaryngology, Head and Neck Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. “We have had no effective drugs for these patients for many years, so it is very exciting to have an oral drug that halts cancer growth for several months,” Dr Brose said at a press briefing. “This is the first time we have

See also page 38

“We have had no effective drugs for these patients for many years, so it is very exciting to have an oral drug that halts cancer growth for several months. This is the first time we have had a systemic treatment that can help them.” —Marcia S. Brose, MD, PhD had a systemic treatment that can help them.”

Remission Prolonged by 5 Months The 89-center Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial enrolled 417 patients who had become resistant to radioactive iodine. Patients were randomly assigned to sorafenib 400 mg twice daily or to placebo. On disease progression, the placebo recipients could cross over to receive sorafenib. The median progression-free survival was 10.8 months in the sorafenib arm versus 5.8 months in the placebo arm, for a 42% reduction in mortality that was highly significant (P <.001). The median overall survival has not been reached in either arm, but a difference is unlikely to emerge, because 70% of patients have crossed over to receive active treatment, Dr Brose said. Responses were observed in 12.2% of patients in the sorafenib arm versus in 0.5% of patients in the placebo arm. Stable disease was achieved by 42% of the patients receiving sorafenib, re-

flecting a disease control rate of 54% with the drug compared with 34% with placebo. New Standard of Care? Commenting on this study at the plenary session, Ezra Cohen, MD, Associate Professor of Medicine, University of Chicago, IL, commented, “These patients finally have options.” Dr Cohen was enthusiastic about the data, but he reminded oncologists that “not all iodine-refractory patients need treatment.” He noted that 25% of placebo recipients did not progress during the trial, and in reality, most patients with radioactive iodine–refractory disease are asymptomatic. Dr Cohen said that the choice to use sorafenib should be based on the presence of symptoms, as well as on the location and growth rate of the disease. He also noted that DTC that becomes refractory to vascular endothelial growth factor receptor inhibitors, such as sorafenib, “is an emerging entity that needs to be addressed.” n

Bevacizumab an Effective New Treatment Option for Relapsed Cervical Cancer First targeted therapy to prolong survival in this setting By Wayne Kuznar Chicago, IL—Adding bevacizumab (Avastin) to standard chemotherapy improves overall survival (OS) in women with metastatic or relapsed cervical cancer, representing the first instance in which a targeted therapy has significantly prolonged OS in this patient population. This phase 3 randomized clinical trial showed a near 4-month improvement in survival by adding bevaciz­ umab to either paclitaxel (Taxol) plus cisplatin (Platinol) or to paclitaxel plus topotecan (Hycamtin), said Krishnansu S. Tewari, MD, Professor of Obstetrics and Gynecology, University of Cali­ fornia, Irvine, at ASCO 2013. Few options currently exist for women with relapsed cervical cancer. Cisplatin plus paclitaxel is the standard of care, but it extends survival by ≤12 months. Acquired drug resistance to cisplatin plus paclitaxel or to platinum-based chemoradiation renders these treatments less effec-

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tive for recurrence, leading to poor outcomes, said Dr Tewari. Because angiogenesis appears to play an active role in cervical carcinogenesis and its progression, an antiangiogenesis therapy, such as bevaciz­ umab, was a logical option to study in patients with relapsed or advanced disease, he said. The National Cancer Institute– funded study included 452 women with recurrent or metastatic cervical cancer who were randomized to 1 of 4 arms—treatment with paclitaxel plus cisplatin, paclitaxel plus cisplatin plus bevacizumab, paclitaxel plus topotecan, or paclitaxel plus topotecan plus beva­cizumab. Patients could not have received previous chemotherapy for a recurrence. There was no significant difference in OS between the 2 chemotherapy arms. Progression-free survival was improved from a mean 5.9 months with chemotherapy alone to 8.2 months with the addition of bevaciz­umab. The

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response rate was significantly higher with bevacizumab plus chemotherapy compared with chemotherapy alone (48% vs 36%, respectively; P = .0078). Most notable, median OS was 17.0 months in the arms that received bevacizumab versus 13.3 months for those that received chemotherapy without bevacizumab—a 29% reduction in the risk of death (P = .0035). The 3.7-month OS improvement “is clinically meaningful in a population of patients that doesn’t respond to chemotherapy very well,” said Dr Tewari.

“I’m hoping that the data are strong enough to allow this drug to be approved for this indication, and I do believe ultimately that it will change practice.” —Krishnansu S. Tewari, MD There were 4 fatal adverse events each with bevacizumab and with chemotherapy alone. “No new side effects were identified with bevacizumab,” he emphasized. Gastrointestinal fistula

occurred in 7 (3%) bevacizumab-treated patients and in none of the patients receiving chemotherapy alone. “This is a recognized complication of this drug,” Dr Tewari added. Grade ≥2 hypertension was a complication in 54 (25%) of the patients in the bevacizumab group and in 4 (2%) in the group that received chemotherapy alone, but no patients withdrew from the study because of hypertension. Health-related quality of life, as measured by the Functional As­ sessment of Cancer Therapy for cervical cancer index, was marginally worse, a maximum of 2.95 points, in the bevacizumab group versus the group that received only chemotherapy. (The score on this index ranges from 0 to 116 points, with a clinically meaningful change being 4 to 5 points.) “I’m hoping that the data are strong enough to allow this drug to be approved for this indication, and I do believe ultimately that it will change practice,” said Dr Tewari. The finding may open the door to testing other antiangiogenesis drugs in the setting of advanced cervical cancer, he suggested. n

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Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

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Drug Therapy

Experts Debate Value of Bevacizumab in Newly Diagnosed Glioblastoma

See also page 36

Mekinist and Dabrafenib... Continued from page 4 dacarbazine arm received dabrafenib when their disease progressed. The median PFS was 5.1 months with dabrafenib versus 2.7 months in the dacarbazine arm (HR, 0.33; 95% CI, 0.20-0.54; P <.001). The objective response rates were 52% with da­ brafenib, which included 3% complete response, versus 17% with dacarbazine (P <.001). The median response duration was approximately 5 months in both arms. OS was not significantly different. The most common (≥20%) AEs with dabrafenib included hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. Serious AEs involved new primary skin cancer, including cutaneous squamous-cell carcinoma, new primary melanoma,

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“Molecular profiling studies may uncover tumor subsets that identify patients benefiting from first-line bevacizumab, but until this subgroup has been defined, these results do not support the use of bevacizumab for newly diagnosed glioblastoma.”

groups by MGMT promoter methylation and 9-gene signature, patients with methylated status benefited from bevacizumab. In the MGMT methylation group, the median OS was 23.2 months versus 14.3 months for patients with MGMT unmethylated status (P <.001), and the median PFS was 14.1 months versus 8.2 months, respectively (P <.001). The patients with MGMT promoter methylation and a favorable 9-gene signature showed a strong trend toward a worse outcome with bevacizumab, especially for OS. “There was no definable group with an overall survival benefit with bevacizumab,” Dr Gilbert said. “In

—Mark R. Gilbert, MD zumab arm (per study design). The coprimary end points were OS and PFS, with statistically significant P values of .046 for OS and .004 for PFS. After a median follow-up of 20.5 months, the median OS was 15.7 months with bevacizumab versus 16.1 months with standard therapy (hazard ratio [HR], 1.13; P = .021), and the median PFS was 10.7 months versus 7.3 months, respectively (HR, 0.79; P = .007). In a prespecified analysis of sub-

and keratoacanthomas; febrile drug reactions requiring hospitalization; hyperglycemia; and uveitis/iritis. Dabrafenib was approved with a medication guide informing patients of these serious risks.

Lenalidomide Receives New Indication for MantleCell Lymphoma

On June 5, 2013, the US Food and Drug Administration (FDA) approved lenalidomide capsules (Revlimid; Celgene Cor­poration) for the treatment of patients with mantle-cell lymphoma whose disease has relapsed or progressed after 2 previous therapies, one of which included bortezomib (Velcade). The FDA approved the new indication for lenalidomide based a singlearm, multicenter clinical trial of 134 patients (median age, 67 years) with

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Photo by ©ASCO/Scott Morgan 2013

Chicago, IL—At a plenary session of ASCO 2013, investigators of the phase 3 Radiation Therapy Oncology Group (RTOG) 0825 trial reported that bevacizumab (Avastin) did not improve overall survival (OS) in patients with newly diagnosed glioblastoma, but it did extend progression-free survival (PFS). Mark R. Gilbert, MD, Professor and Deputy Chairman, Department of Neuro-Oncology, University of Texas M.D. Anderson Cancer Center, Houston, said that although bevacizumab is beneficial in patients with recurrent disease, when added to standard of care, it did not improve OS and, therefore, the study failed to meet its prespecified target. “Molecular profiling studies may uncover tumor subsets that identify patients benefiting from first-line bevacizumab, but until this subgroup has been defined, these results do not support the use of bevacizumab for newly diagnosed glioblastoma,” Dr Gilbert said. The RTOG 0825 trial evaluated the use of first-line or early bevacizumab therapy in 637 patients with newly diagnosed glioblastoma who received chemoradiation therapy plus temozolomide and placebo (ie, standard of care) or chemoradiation therapy plus temozolomide and bevacizumab 10 mg/kg every 2 weeks. At disease progression, 41% of patients in the control arm crossed over to the bevaci-

Photo by ©ASCO/Scott Morgan 2013

By Audrey Andrews for the comparable AVAglio study. The median OS was 17 months in each arm, and the median PFS was 10.6 months with bevacizumab versus 6.2 months with standard care (P <.001). Of note, unlike the RTOG 0825 trial, health-­ related quality of life improved in the AVAglio study with bevacizumab. Howard A. Fine, MD, Deputy Director, New York University Cancer Institute, NY, who was the discussant at the session, remained optimistic about the role of bevacizumab in patients with glioblastoma, noting, “Despite these new data demonstrating its limitations, bevacizumab represents the single most important

“Despite these new data demonstrating its limitations, bevacizumab represents the single most important therapeutic agent in glioblastoma multiforme since temozolomide. Ongoing and future trials will better define how and when it should be optimally used in these patients.” —Howard A. Fine, MD

addition, symptom burden, neurocognitive function, and quality-of-life data show an overall decline over time on first-line bevacizumab.” Similar findings were also reported

therapeutic agent in glioblastoma multiforme since temozolomide. Ongoing and future trials will better define how and when it should be optimally used in these patients.” n

mantle-cell lymphoma. All of the patients previously received treatment with bortezomib, and 60% of the 134 patients had disease that was refractory to bortezomib therapy. Overall, the patients received a median of 4 previous therapies for mantle-cell lymphoma; 61% of the patients had mantle-cell lymphoma for at least 3 years. The efficacy end points were overall response rate (ORR) and duration of response. The ORR was defined as the proportion of patients whose best response was complete response (CR), CR unconfirmed, or partial response (PR). The ORR was 26% (95% confidence interval [CI], 18.4-33.9) among the 133 evaluable patients, CR or CR unconfirmed was achieved by 9 (7%) patients, and 25 (19%) patients achieved a PR. The median duration of response of the patients who achieved

any response was 16.6 months (95% CI, 7.7-26.7). The median duration of therapy was 95 days, and 58% of the patients received ≥3 cycles of therapy. Overall, 19% of the patients discontinued treatment because of adverse events. The most common (≥5%) grade 3 to 4 adverse reactions were neutropenia, thrombocytopenia, anemia, pneumonia, leukopenia, fatigue, febrile neutropenia, dyspnea, and diarrhea. The recommended oral dose and schedule for lenalidomide is 25 mg once daily on day 1 through day 21 of a 28-day cycle. Lenalidomide should be taken at approximately the same time daily, with no regard to food. In addition, as part of this new supplemental indication, the FDA also approved a new 20-mg capsule strength of lenalidomide. n

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Payers’ Perspective

Cancer Care in 2013: Hope, Reality, and a Call to Action By Gary M. Owens, MD, Gary Owens Associates, Glen Mills, PA

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he cost of cancer care is an issue of major importance to payers in 2013. There are more than 12.5 million people living with cancer in the United States today, and that number is rising.1 According to a recent study published in the Journal of the National Cancer Institute and supported by the National Institutes of Health, “Based on growth and aging of the U.S. population, medical expenditures for cancer in the year 2020 are projected to reach at least $158 billion (in 2010 dollars)—an increase of 27 percent over 2010,”2,3 the authors project. The authors go on to state that if newly developed tools for cancer diagnosis, treatment, and follow-up continue to be more expensive, medical expenditures for cancer could reach as high as $207 billion by 2020, which represents a growth of 67% over 2010 costs, and is, by all accounts, considered unsustainable.2 Payers are of course concerned about the rising costs of care for patients with cancer, but it is not only payers who are concerned about these cost trends. In a recent article published in Blood, 100 leukemia experts concluded, “Pricing of cancer and other drugs involves complex societal and political issues which demand immediate attention, and which will need to consider many factors and involve many constituencies….We propose to begin the dialogue by organizing regular meetings, involving all

It is essential that all stakeholders begin to work collaboratively to develop and promote new systems of care, new models of drug development, and new payment methodologies for oncology. parties concerned, to address the reasons behind high cancer drug prices and offer solutions to reduce them.”4 Impressive Drug Developments This special issue is focused on cancer care and highlights critical issues presented at the 2013 ASCO annual meeting, including the cost of care, utilization trends, and new therapies for a variety of cancers. The number of novel therapies currently in the pipeline for

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the treatment of cancer is impressive, as described in the article summarizing key drugs in late-stage development or those in early development that have shown promising results or chart new directions in drug therapy. For example, there is a new MEK inhibitor being developed for melanoma that shows great promise for the treatment of metastatic ocular melanoma—a difficult-to-treat cancer. We further learn about a new class of immunotherapeutic agents that block the programmed death (PD)-1 and its ligand (PD-L1) that facilitate T-cell tumor destruction. We also learn about novel developments for the treatment of various hematologic malignancies, including lymphoma, leukemia, and multiple myeloma. Similarly, there are exciting new compounds that are in development for the treatment of solid organ tumors, including lung and ovarian cancers. Inefficient System of Care Delivery However, these exciting developments that promise hope and improved outcomes for many patients with cancer are being contrasted with the stark reality that our system of cancer care delivery is in need of significant change. For example, data presented from a study by eviti show that more than 25% of patients included in that study had treatment plans that did not conform to evidence-based cancer care. In addition, inappropriate deviations from the standards of care for cancer cost more than $25,000 per patient, based on that study. Clearly, these types of treatment patterns cannot be ignored. The presenter concluded that, “Decision support tools that are used at the point of care can help avoid overspending.” Furthermore, an evaluation of the Surveillance, Epidemiology and End Results (SEER)-Medicare database revealed that 18% of the spending on cancer drugs is for off-label use, meaning that many drugs prescribed for patients with cancer are used off-label and are also not endorsed by the National Comprehensive Cancer Network compendia for that purpose. In yet another article we find out the use of costly diagnostic imaging of uncertain value is increasing rapidly for patients with localized, non–smallcell lung cancer, according to data from the SEER-Medicare database. Kevin A. Schulman, MD, MBA, com-

mented that, “If we really want to make progress in an economically viable way, we must spend as much time on the economics of drug development as on the basic science.” Cancer affects approximately 3% to 4% of a health plan’s population, yet the current cost of caring for those patients exceeds 10% of total medical costs, and those costs are growing rapidly. Recent and ongoing developments in cancer care show promise to improve outcomes and quality of life; in many cases, cancer is becoming a chronic illness, joining diabetes and heart disease as one of the top drivers of medical costs in the US healthcare system. The articles in this special issue highlight these contrasts. We learn about many new developments and advances in therapy, but those advances are contrasted by many reports of inefficiencies in the system that will need to be addressed to temper the current cost trend that is associated with caring for the growing number of patients with cancer at all stages—from diagnosis to survivorship and end-of-life care. A Call to Action Therefore, all stakeholders—including payers, providers, drug developers, employers, and patients— will need to join together to embark on a meaningful dialogue about these issues, including the proper use of guidelines and pathways, improving delivery systems and reducing waste, and adhering to therapy. It is essential that all stakeholders begin to work collaboratively to develop and promote new systems of care, new models of drug development, and new payment methodologies for oncology. Without such initiatives, the burden of cancer care will continue to grow at an unsustainable rate and access to cancer care will remain a serious concern. n References

1. American Cancer Society. Cancer prevalence: how many people have cancer? Revised October 23, 2012. www.cancer.org/cancer/cancerbasics/cancer-prev alence. Accessed August 8, 2013. 2. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128. 3. NIH News. Cancer costs projected to reach at least $158 billion in 2020. January 12, 2011. www.nih.gov/news/ health/jan2011/nci-12.htm. Accessed August 8, 2013. 4. Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121:4439-4442.

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Drug Update Xofigo (Radium Ra 223 Dichloride): The First Alpha Particle–Emitting Radioactive Agent for the Treatment of Castration-Resistant Prostate Cancer with Symptomatic Bone Metastases By Lisa A. Raedler, PhD, RPh

P

rostate cancer is the second leading cause of cancer-related death in the United States among men and the most frequently diagnosed cancer in American males. Among patients with metastatic prostate cancer, up to approximately 90% have bone metastases.1 The median survival after the diagnosis of bone metastasis associated with prostate cancer is approximately 3 years.2 Bone metastases have serious and debilitating clinical consequences, including pain that requires opioids and/or radiotherapy, hypercalcemia, pathologic fracture, spinal cord compression, and nerve root compression.3 Prostate cancer places a significant burden on the US healthcare system. Using Surveillance, Epidemiology and End Results (SEER) data, Stokes and colleagues estimated the survival of men aged ≥65 years who were diagnosed with prostate cancer between the calendar years of 1991 and 2002.4 The medical cost data were obtained from the SEER-Medicare database and were estimated during specific phases of cancer care. These cost estimates were then combined with survival data to determine the total lifetime costs and the prostate cancer– related lifetime costs. The model estimated total lifetime medical costs of approximately $110,500 per patient (in 2004 US dollars).4 The prostate cancer–related costs made up approximately 31% of the total costs, or more than $34,000 per patient.4 Patients with prostate cancer and bone metastases utilize an inordinate amount of healthcare resources. A retrospective, observational study using health insurance claims data for episodes of care from September 2002 to June 2011 demonstrated that, among patients with prostate cancer, the cost of a skeletal-related event ranged from approximately $11,700 for an outpatient episode to more than $54,000 for an inpatient episode.5 Unmet Need in Patients with Prostate Cancer and Bone Metastases According to the National Cancer Institute, in 2013, more than 238,500 men will be diagnosed with prostate cancer and more than 29,700 will die from the disease. More than 2.5 million American men are currently living with prostate cancer.6

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Currently, 4 bone-targeted therapies are available for men with prostate cancer, including zoledronic acid (Zometa), denosumab (Prolia), samarium-153 ethylene diamine tetramethylene phosphonate (EDTMP; Quadramet), and strontium-89 (Metastron). None of these 4 agents has been proved to prolong overall survival (OS) in large phase 3 randomized trials. The 2 radiopharmaceuticals, strontium-89 and samarium-153 EDTMP, are beta-particle emitters. Both were approved by the US Food and Drug Administration (FDA) on the basis of randomized phase 3 clinical trials that demonstrated an improvement in pain in patients with metastatic prostate cancer.7,8

“Radium-223 is the first isotope to show a survival benefit [in advanced prostate cancer]….Now we need to do the studies to know how to best sequence these drugs.” —Daniel P. Petrylak, MD

By contrast, sipuleucel-T (Provenge), abiraterone (Zytiga), and enzalutamide (Xtandi) have demonstrated advantages in OS in patients with metastatic prostate cancer, but these agents do not target disease that has spread to bone and are not indicated specifically for patients with prostate cancer plus bone metastases.9-11 FDA Approves Xofigo for Metastatic CRPC with Bone Metastasis In May 2013, the FDA approved radium Ra 223 dichloride (Xofigo Injection [formerly known as Alpharadin]; Bayer HealthCare Pharmaceuticals) for the treatment of patients with castration-resistant prostate cancer (CRPC) plus symptomatic bone metastases and no known visceral metastatic disease.12 In a prespecified interim analysis, radium Ra 223 dichloride (radium-223) combined with best standard of care demonstrated a significant 3.2-month (hazard ratio, 0.70; 95% confidence interval, 0.55-0.88; P = .00185) improvement in median OS

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compared with placebo plus best standard of care.13 The improvement in OS was supported by a delay in time to the first symptomatic skeletal-related event favoring the radium-223 arm.13 In an interview regarding this new radiopharmaceutical, Daniel P. Petrylak, MD, Director of the Genitourinary Oncology Program at the Yale Cancer Center, New Haven, CT, noted that radium-223 “is the first isotope to show a survival benefit [in advanced prostate cancer]….Now we need to do the studies to know how to best sequence these drugs.”14 The availability of radium-223 offers a novel therapeutic alternative for patients with CRPC and bone metastasis, particularly for those who wish to avoid the side effects of chemotherapy. According to Nicholas J. Vogel­ zang, MD, a genitourinary oncologist at Comprehensive Cancer Centers of Nevada, Las Vegas, “In general, about half of [patients with advanced prostate cancer] say they will not take chemotherapy. For them, [radium-223] is a wonderful option because it suppresses the cancer, controls the pain, and extends their life.”15 According to the drug manufacturer, 6 cycles of treatment with radium223 cost $69,000.16 Mechanism of Action and Pharmacodynamics The active component in Xofigo is the alpha particle–emitting isotope radium-223, which mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The high energy transfer of alpha emitters increases the breaking frequency of double-strand DNA in adjacent cells, leading to an antitumor effect on bone metastases. The alpha particle range from radium-223 dichloride localizes the impact of the drug and limits damage to the surrounding normal tissue.17 In a phase 2 randomized trial that compared radium-223 and placebo, a significant difference was seen in favor of radium-223 in all 5 biomarkers for bone turnover.17 Dosing and Administration The recommended dose and schedule for radium-223 is 50 kBq/kg body weight, which is administered by slow intravenous injection over 1 min-

ute every 4 weeks for a total of 6 injections. The safety and efficacy of radium-223 beyond 6 injections have not been studied.17 No dosage adjustment is necessary in elderly patients. No dose adjustments can be recommended for patients with moderate or severe hepatic impairment because of a lack of clinical data. No dose adjustment can be recommended for patients with severe renal impairment (creatinine clearance <30 mL/min) because of the limited available data.17 ALSYMPCA: A Pivotal Phase 3 Clinical Trial Radium-223 was approved by the FDA based on the results of a single, phase 3 clinical trial—the Alpharadin in Patients with Symptomatic Hormone Refractory Prostate Cancer with Skeletal Metastases (ALSYMPCA) trial—a randomized, multicenter, doubleblind study of more than 800 patients with CRPC and symptomatic bone metastases. Patients were stratified by baseline alkaline phosphatase, bisphosphonate use, and previous docetaxel exposure.17 Trial Design In the ALSYMPCA trial, patients were randomly assigned in a 2:1 ratio to receive radium-223 50 kBq/kg intravenously every 4 weeks for 6 cycles plus best standard of care (N = 541) or to matching placebo plus best standard of care (N = 268). Best standard of care included local external beam radiation therapy [EBRT], corticosteroids, antiandrogens, estrogens, estramustine, or ketoconazole.17 Therapy was continued until unacceptable toxicity or until the initiation of cytotoxic chemotherapy, other systemic radioisotope, hemibody EBRT, or other investigational drugs. The primary efficacy end point was OS. A key secondary efficacy end point was time to first symptomatic skeletal event, which was defined as EBRT to relieve skeletal symptoms, new symptomatic pathologic bone fracture, occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention. There were no scheduled radiographic assessments performed during the study. All patients were to continue androgen-deprivation therapy.17

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Drug Update Patient Population Patient demographics and baseline disease characteristics were balanced between the 2 arms. The patients’ median age was 71 years (range, 44-94 years), with a racial distribution of 94% white, 4% Asian, 2% black, and <1% other. The Eastern Cooperative Oncology Group performance status was 0 to 1 in 86% of patients.17 Overall, 85% of the patients had ≥6 bone scan lesions; of those, 40% had >20 lesions or a superscan. For cancer-related pain, 54% of the patients received opiate pain medications, 44% received nonopiate pain medications, and 2% received no pain medication. Overall, bisphosphonates were used by 41% of patients. More than half (58%) of the patients had previously received docetaxel.17 During the study period, 83% of the patients in the radium-223 arm and 82% of the patients in the placebo arm were also using gonadotropin-releasing hormone agonists; 21% and 34% of patients, respectively, were using concomitant antiandrogens. The use of systemic corticosteroids (41%) and bisphosphonates (40%) was equal between the 2 arms.17 Efficacy The prespecified interim analysis of ALSYMPCA revealed a significant improvement in OS in patients receiving radium-223 plus best standard of care compared with patients receiving placebo plus best standard of care (Figure), with a median OS of 14.0 months with radium-223 versus 11.2 months with placebo, for a difference of 3.2 months (Table 1).13,17 The median duration of treatment was 20 weeks (6 cycles) with radium-223 and 18 weeks (5 cycles) with placebo.17

An updated OS analysis performed before the patient crossover with an additional 214 events yielded findings that confirmed the OS advantage of radium-223 versus placebo, resulting in a median OS of 14.9 months with radium-223 versus 11.3 months with placebo, for a 3.6-month difference (Table 1).17 The survival results were supported by a delay in the time to first symptomatic skeletal event favoring the radium-223 arm. The majority of events consisted of treatment with EBRT to bone metastases.17 Safety Profile The most common (≥10%) adverse reactions in patients receiving radium-223 were nausea, diarrhea, vomiting, and peripheral edema (Table 2).18 Grade 3 or 4 adverse events were reported in 57% of patients receiving radium-223 and in 63% of patients receiving placebo.17 The most common (≥10%) hematologic laboratory abnormalities in patients receiving radium-223 were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia. Grade 3 or 4 lymphocytopenia was reported in 20% of patients receiving radium-223 and in 7% of patients receiving placebo (Table 3).17 Dehydration occurred in 3% of patients receiving radium-223 and in 1% of patients receiving placebo. Treatment discontinuations resulting from adverse events occurred in 17% of patients who received radium-223 and in 21% of patients who received placebo.17 Warnings and Precautions Fluid status. Radium-223 can result in adverse reactions such as diarrhea,

 aplan-Meier Overall Survival Curves from the Phase 3 Clinical Trial Figure K of Radium-223

changes, including osteosarcomas in rats after receiving radium-223, radium-223 may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized ALSYMPCA trial was lower in the radium-223 arm compared with in the placebo arm (<1% vs 2%, respectively). The expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients in the trial.17

Overall Survival of Radium-223 versus Placebo: Interim and Updated Table 1 Analyses from the Phase 3 Trial Radium-223 plus best Placebo plus best standard of care standard of care Interim analysis 541 268 Randomized patients, N 191 (35.3) 123 (45.9) Deaths, N (%) 350 (64.7) 145 (54.1) Censored, N (%) a 14.0 11.2 Median survival, mo (12.1-15.8) (9.0-13.2) (95% CI) .00185 P valueb 0.695 (0.552-0.875) Hazard ratio (95% CI)c Updated analysis Randomized patients, N Deaths, N (%) Censored, N (%) Median survival, moa (95% CI)

614

307

333 (54.2)

195 (63.5)

281 (45.8)

112 (36.5)

14.9

11.3

(13.9-16.1)

(10.4-12.8)

0.695 (0.581-0.832)

c

Hazard ratio (95% CI)

Survival time is calculated as months from date of randomization to date of death from any cause. Patients who are not deceased at time of analysis are censored on the last date a patient was known to be alive or was lost to follow-up. b P value is stratified by total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel. c Hazard ratio adjusted for total alkaline phosphatase, current use of bisphosphonates, and previous use of docetaxel; hazard ratio <1 favors radium-223 dichloride. CI indicates confidence interval. Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013. a

0.7

 dverse Reactions ≥2% Higher with Xofigo than with Placebo in Table 2 A the Phase 3 Trial Xofigo (N = 600) Placebo (N = 301) System/organ class Grades 1-4, Grades 3-4, Grades 1-4, Grades 3-4, preferred term % % % %

0.6

Blood and lymphatic system disorders

0.5

Pancytopenia

0.4

Gastrointestinal disorders

0.3 0.2 0.1

1.0 0.9

Xofigo Placebo

0.8

Probability of survival

nausea, and vomiting, which may result in dehydration. Patients’ oral intake and fluid status should be care­ fully monitored, and patients who display signs or symptoms of dehydration or hypovolemia should be promptly treated.17 Secondary malignant neoplasms. Radium-223 contributes to a patient’s overall long-term cumulative radiation exposure, which may be associated with increased risk of cancer and hereditary defects. Because of its mechanism of action and neoplastic

0.0 0 3 6 9 12 15 18 21 24 27 30 33 36 39

Number of patients at risk

Time, months

Xofigo 614 578 504 369 277 178 105 80 41 18 7 1 0 0 Placebo 307 288 228 157 104 67 39 24 14 7 4 2 1 0

Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

2

1

0

0

Nausea

36

2

35

2

Diarrhea

25

2

15

2

Vomiting

19

2

14

2

10

1

General disorders and administration site conditions Peripheral edema

13

2

Renal and urinary disorders 3 1 1 1 Renal failure and impairment Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

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Drug Update Xofigo (Radium Ra 223 Dichloride): The First... Continued from page 41 Subsequent treatment with cytotox­ ic chemotherapy. In the ALSYMPCA trial, 16% of patients included in the radium-223 cohort and 18% of patients in the placebo cohort received cytotoxic chemotherapy after completion of the study treatments. Adequate safety monitoring and laboratory testing were not performed to assess how patients who were treated with radium-223 will tolerate subsequent cytotoxic chemotherapy.17 Contraception. Because of the potential effects on spermatogenesis that is associated with radiation treatment, men who are sexually active and their female partners of reproductive potential should be advised to use highly effective contraceptives during and for 6 months after completing treatment with radium-223.17 This new therapy is not to be used in women. Bone marrow failure. In the ALSYMPCA trial, 2% of patients in the radium-223 arm had bone marrow failure or ongoing pancytopenia compared with none of the patients receiving placebo. In addition, 2 deaths resulted from bone marrow failure. For 7 of the 13 patients who were treated with radium-223, bone marrow failure was ongoing at the time of death. Among the 13 patients who had bone marrow failure, 54% required blood transfusions. In that study, 4% of patients in the radium-223 arm and 2% of patients in the placebo arm discontinued ther­ apy as a result of bone marrow suppression.17 Myelosuppression. Deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of patients receiving radium-223 compared with in 0.3% of patients receiving placebo. The incidence (2%) of infection-related deaths, serious infections (10%), and febrile neutropenia (<1%) was similar for patients receiving radium-223 and for patients receiving placebo.17 Myelosuppression (ie, thrombocytopenia, neutropenia, pancytopenia, and leukopenia) has been reported in patients treated with radium-223. Complete blood counts were obtained every 4 weeks before each dose. Nadir

 ematologic Reactions ≥10% Higher with Xofigo than with Placebo Table 3 H in the Phase 3 Trial Hematologic Xofigo (N = 600) Placebo (N = 301) laboratory Grades 1-4, Grades 3-4, Grades 1-4, Grades 3-4, abnormalities % % % % Anemia

93

6

88

6

Lymphocytopenia

72

20

53

7

Leukopenia

35

3

10

<1

Thrombocytopenia

31

3

22

<1

18 2 5 <1 Neutropenia Source: Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013.

complete blood counts and bone marrow recovery times were not well characterized in ALSYMPCA.17 In a single-dose phase 1 study of radium-223, neutrophil and platelet count nadirs occurred 2 to 3 weeks after the administration of radium-223 at doses of 1 to 5 times that of the recommended dose. Most patients recovered 6 to 8 weeks after administration.17

Experts suggest that this bone-targeting radiopharmaceutical is a viable treatment option for men with CRPC who have received, or who are ineligible for cytotoxic chemotherapy.

Monitoring. Hematologic evaluation of patients must be performed at baseline and before every dose of radium-223. Absolute neutrophil counts, platelet counts, and hemoglobin levels must meet minimum requirements as specified in the product’s labeling information. If these values do not recover within 6 to 8 weeks after the last administration of radium-223, despite supportive care, treatment should be discontinued.17 Patients with evidence of compro-

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mised bone marrow reserve should be monitored closely and should be provided with supportive-care measures when clinically indicated. Radium-223 should be discontinued in patients who experience life-threatening complications despite supportive care for bone marrow failure.17 The safety and efficacy of concomitant chemotherapy with radium-223 have not been established. Outside of a clinical trial, the concomitant use of radium-223 with chemotherapy is not recommended because of the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, radium-223 should be discontinued.17 Conclusion For patients with advanced prostate cancer and bone metastasis, single-­agent radium-223 offers clinically and statistically significant efficacy benefits, with a favorable tolerability profile and a convenient dosing schedule. Experts suggest that this bone-targeting radiopharmaceutical is a viable treatment option for men with CRPC who have received, or who are ineligible for, or who prefer to delay or to avoid cytotoxic chemotherapy. Combination studies with radium-223 and hormonal agents, immunomodulatory agents, and doce­taxel are pending or are under way to fur-

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ther elucidate the role of radium-223 as a part of the armamentarium for patients with prostate cancer.18 n References

1. Scher HI, Morris MJ, Kelly WK, et al. Prostate cancer clinical trial end points: “RECIST”ing a step backwards. Clin Cancer Res. 2005;11:5223-5232. 2. Coleman RE. Skeletal complications of malignancy. Cancer. 1997;80(8 suppl):1558-1594. 3. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 pt 2):6243S-6249S. 4. Stokes ME, Ishak J, Proskorovsky I, et al. Lifetime economic burden of prostate cancer. BMC Health Serv Res. 2011;11:349. 5. Hagiwara M, Delea TE, Saville MW, Chung K. Healthcare utilization and costs associated with skeletal-related events in prostate cancer patients with bone metastases. Prostate Cancer Prostatic Dis. 2013;16:23-27. 6. National Cancer Institute. Prostate Cancer. www. cancer.gov/cancertopics/types/prostate. Accessed June 13, 2013. 7. Porter AT, McEwan AJ. Strontium-89 as an adjuvant to external beam radiation improves pain relief and delays disease progression in advanced prostate cancer: results of a randomized controlled trial. Semin Oncol. 1993;20(3 suppl 2):38-43. 8. Medical Services Advisory Committee. Samarium-53lexidronam for bone pain due to skeletal metastases. Final assessment report. MSAC application 1016. August 1999. www.msac.gov.au/internet/msac/publishing. nsf/Content/FA4579BED311BC15CA2575AD0082F D8A/$File/1016%20-%20Samarium153lexidronam%20 for%20bone%20pain%20due%20to%20skeletal%20 metastases%20Report.pdf. Accessed June 13, 2013. 9. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 10. de Bono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154. 11. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; 2012. 12. US Food and Drug Administration. Radium Ra 223 dichloride. Updated May 15, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm352393. htm?source=govdelivery. Accessed June 13, 2013. 13. Parker C, Heinrich D, O’Sullivan JM, et al. Overall survival benefit of radium-223 chloride (Alpharadin) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase 3 randomized trial (ALSYMPCA). Eur J Cancer. 2011;47(suppl 2):3. 14. OncLive TV. Dr Petrylak discusses the isotope radium-223. YouTube. February 28, 2012. www.youtube. com/watch?feature=player_detailpage&v=A-jLlybtyeQ. Accessed June 13, 2013. 15. Targeted Communications. Dr Vogelzang reviews ra­dium-223 in metastatic prostate cancer. YouTube. April 22, 2013. www.youtube.com/watch?feature=player_ detailpage&v=1KLLrQuJk_g. Accessed June 13, 2013. 16. Dooren JC. Bayer gets FDA approval for advanced prostate cancer drug. Wall Street Journal. May 15, 2013. http://online.wsj.com/article/SB100014241278873247 67004578485552000140508.html. Accessed June 13, 2013. 17. Xofigo (radium Ra 223 dichloride) injection [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals, Inc; May 2013. 18. Sartor O. Radium-223 (Alpharadin): a novel targeted alpha-emitter for bone-metastatic castrate-resistant prostate cancer. PCRI Insights. May 2012:9-14.

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