JHOP December 2013 by The Oncology Pharmacist

DECEMBER 2013 VOL 3 I NO 4

JOURNAL OF

HEMATOLOGY ONCOLOGY ™ PHARMACY THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

REVIEW ARTICLE Omacetaxine Mepesuccinate: A Novel mRNA Translation Inhibitor for Drug-Resistant Chronic Myelogenous Leukemia Jacqueline L. Olin, MS, PharmD, BCPS; Sabrina W. Cole, PharmD, BCPS; Amie J. Dirks-Naylor, PhD

ORIGINAL RESEARCH The Impact of Angiotensin II Receptor Blocker Use in Patients with Prostate Cancer Lisa Cerutti, PharmD; Jacob K. Kettle, PharmD, BCOP; Dennis Grauer, PhD

FDA UPDATE Recent Cancer Drugs Approved by the FDA FROM THE LITERATURE Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

CONTINUING EDUCATION Considerations in Multiple Myeloma—Ask the Experts: Beyond Complete Responses

WWW.JHOPONLINE.COM

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIX (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction TM

in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

NOW AVAILABLE

GRANIX is a new option in short-acting G-CSF therapy TM

» FDA approved through the rigorous BLA† process » Teva’s filgrastim, the same compound as GRANIX, was first introduced in Europe in 2008 and is available in 39 countries outside the US‡1

» GRANIX is an option for hospitals and payers to consider when determining health system budgets A unique J-code is expected for GRANIX in January 2014 † ‡

Biologics License Application. As of November 2013.

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. May 2013.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

EDITORIAL BOARD

CO-EDITORS-IN-CHIEF Patrick J. Medina, PharmD, BCOP Associate Professor Department of Pharmacy University of Oklahoma College of Pharmacy Oklahoma City, OK

Val R. Adams, PharmD, BCOP, FCCP Associate Professor, Pharmacy Program Director, PGY2 Specialty Residency Hematology/Oncology University of Kentucky College of Pharmacy Lexington, KY

SECTION EDITORS CLINICAL CONTROVERSIES

Christopher Fausel, PharmD, BCPS, BCOP Clinical Director Oncology Pharmacy Services Indiana University Simon Cancer Center Indianapolis, IN

ORIGINAL RESEARCH

R. Donald Harvey, PharmD, FCCP, BCPS, BCOP Assistant Professor, Hematology/Medical Oncology Department of Hematology/Medical Oncology Director, Phase 1 Unit Winship Cancer Institute Emory University, Atlanta, GA

REVIEW ARTICLES

Scott Soefje, PharmD, BCOP Associate Director, Oncology Pharmacy Smilow Cancer Hospital at Yale-New Haven Yale-New Haven Hospital New Haven, CT

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

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

FROM THE LITERATURE

Robert J. Ignoffo, PharmD, FASHP, FCSHP Professor of Pharmacy, College of Pharmacy Touro Universityâ&#x20AC;&#x201C;California Mare Island, Vallejo, CA

EDITORS-AT-LARGE Joseph Bubalo, PharmD, BCPS, BCOP Assistant Professor of Medicine Oncology Clinical Specialist and Oncology Lead OHSU Hospital and Clinics Portland, OR

Steve Stricker, PharmD, MS, BCOP Assistant Professor of Pharmacy Practice Samford University McWhorter School of Pharmacy Birmingham, AL

Sandra Cuellar, PharmD, BCOP Director Oncology Specialty Residency University of Illinois at Chicago Medical Center Chicago, IL

John M. Valgus, PharmD, BCOP, CPP Hematology/Oncology Senior Clinical Pharmacy Specialist University of North Carolina Hospitals and Clinics Chapel Hill, NC

Sachin Shah, PharmD, BCOP Associate Professor Texas Tech University Health Sciences Center Dallas, TX

Daisy Yang, PharmD, BCOP Clinical Pharmacy Specialist University of Texas M. D. Anderson Cancer Center Houston, TX

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December 2013

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PUBLISHING STAFF

Senior Vice President, Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Publishers Russell Hennessy rhennessy@the-lynx-group.com Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon

DECEMBER 2013 JOURNAL OF

HEMATOLOGY ONCOLOGY PHARMACY™ THE PEER-REVIEWED FORUM FOR ONCOLOGY PHARMACY PRACTICE

TABLE OF CONTENTS REVIEW ARTICLE

112 Omacetaxine Mepesuccinate: A Novel mRNA Translation Inhibitor for

Production Manager Stephanie Laudien

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 Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore

Drug-Resistant Chronic Myelogenous Leukemia Jacqueline L. Olin, MS, PharmD, BCPS; Sabrina W. Cole, PharmD, BCPS; Amie J. Dirks-Naylor, PhD

FDA UPDATE 122 Recent Cancer Drugs Approved by the FDA ORIGINAL RESEARCH

128 The Impact of Angiotensin II Receptor Blocker Use in Patients with

Prostate Cancer Lisa Cerutti, PharmD; Jacob K. Kettle, PharmD, BCOP; Dennis Grauer, PhD FROM THE LITERATURE

135 Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

Director, Quality Control Barbara Marino

Quality Control Assistant Theresa Salerno

CONTINUING EDUCATION

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

With commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP

140 Considerations in Multiple Myeloma—Ask the Experts: Beyond Complete Responses

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Jackie Luma Deanna Martinez IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications 1249 South River Road – Ste 202A Cranbury, NJ 08512 Phone: 732-656-7935 • Fax: 732-656-7938

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MISSION STATEMENT

The Journal of Hematology Oncology Pharmacy is an independent, peer-reviewed journal founded in 2011 to provide hematology and oncology pharmacy practitioners and other healthcare professionals with high-quality peer-reviewed information relevant to hematologic and oncologic conditions to help them optimize drug therapy for patients. Journal of Hematology Oncology Pharmacy™, ISSN 2164-1153 (print); ISSN 2164-1161 (online), is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2013 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Hematology Oncology Pharmacy™ logo is a trademark of Green Hill 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. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Hematology Oncology Pharmacy™, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: JHOP@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Hematology Oncology Pharmacy™ do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in Journal of Hematology Oncology Pharmacy™ should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director.

Journal of Hematology Oncology Pharmacy

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December 2013

Vol 3, No 4

Now enrolling Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial. Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

To learn more about this study, please visit www.ClinicalTrials.gov.

NCT#01889186 Reference: ClinicalTrials.gov.

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REVIEW ARTICLE

Omacetaxine Mepesuccinate: A Novel mRNA Translation Inhibitor for Drug-Resistant Chronic Myelogenous Leukemia Jacqueline L. Olin, MS, PharmD, BCPS; Sabrina W. Cole, PharmD, BCPS; Amie J. Dirks-Naylor, PhD Background: Chronic myelogenous leukemia (CML) is a hematopoietic stem-cell disorder that accounts for nearly 15% of all adult leukemias diagnosed annually in the United States. Although the first-line medical treatment for CML remains tyrosine kinase inhibitors (TKIs), resistance and intolerance to these agents have led to interest in alternative agents for the treatment of CML. Omacetaxine, a first-in-class cephalotaxine with a novel mechanism of action, is an mRNA translation inhibitor. Objective: To discuss the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of omacetaxine, as well as to consider its place in therapy. Discussion: Omacetaxine is approved for the treatment of patients with CML in chronic or accelerated phase with resistance and/or intolerance to 2 or more TKIs. The majority (>60%) of patients with chronic-phase CML in phase 2 clinical trials receiving omacetaxine achieved complete hematologic response, extending the patientsâ&#x20AC;&#x2122; time in the chronic phase. In addition, more than 20% of patients in those studies experienced major cytogenetic response. The most common adverse effects associated with the administration of omacetaxine in clinical trials were hematologic abnormalities, infection, diarrhea, and nausea. Although most of the toxicities were of mild-to-moderate severity, 1 death was attributed to unresolved pancytopenia associated with omacetaxine. The recommended induction dose of omacetaxine is 1.25 mg/m2, administered subcutaneously twice daily for 14 consecutive days every 28 days, with the cycle repeated every 28 days until a hematologic response is achieved. A maintenance dose of 1.25 mg/m2 is administered for 7 consecutive days every 28 days of the 28-day cycle for the duration of clinical benefit. Conclusion: Although guidelines suggest that omacetaxine is a reasonable treatment option J Hematol Oncol Pharm. 2013;3(4):112-120. for patients with BCR-ABL mutations, its place in therapy remains unclear, given the paucity of comparative data. Despite limited data, omacetaxine offers a potential treatment advantage to www.JHOPonline.com Disclosures are at end of text patients with CML and TKI resistance or disease relapse. The extent and management of hematologic toxicity associated with omacetaxine warrants further study.

hronic myelogenous leukemia (CML) is a hematopoietic stem-cell disorder resulting from the formation of the Philadelphia (Ph) chromosome, which is the reciprocal translocation of chromosomes 9 (Abelson murine leukemia; ABL) and 22 (breakpoint cluster region; BCR).1,2 The resulting BCR-ABL fusion gene leads to enhanced activity of tyrosine kinase enzymes and reduced apoptosis of granulocytes.2 CML accounts for nearly 15% of adult leukemias in the United States.1 In 2013, an estimated 5920 new cases of CML will be diagnosed, with 610 deaths expected.3 High-dose radiation is the only known risk factor for CML, and no genetic predisposition has been identified.2

The clinical course of CML has 3 distinct phases, with the majority of patients presenting in the chronic phase (CP).1 As cellular differentiation becomes more impaired, CML progresses into the accelerated phase (AP) and the blast crisis (BC) phase. In BC-CML, â&#x2030;Ľ20% of cells in the peripheral blood or bone marrow are blasts, and the disease is aggressive and acute. Untreated CP-CML progresses to advanced phases within 3 to 5 years.1 For most patients with CML, the initial treatment options can be one of the tyrosine kinase inhibitors (TKIs), including imatinib, nilotinib, or dasatinib; hematopoietic stem-cell transplantation; or enroll-

Dr Olin is Associate Professor of Pharmacy; Dr Cole is Assistant Professor of Pharmacy; and Dr Dirks-Naylor is Associate Professor, Wingate University School of Pharmacy, Wingate, NC.

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Vol 3, No 4

Omacetaxine for Drug-Resistant CML

ment in a clinical trial.1 Patients receiving a TKI who have partial to no cytogenetic response or cytogenetic relapse are candidates for therapy with an alternative TKI, other than imatinib.1 Resistance to first-line TKI treatment and a scarcity of therapeutic alternatives have led to the research and approval of 3 additional agents in 2012 for the treatment of CML, including bosutinib, omacetaxine mepesuccinate, and ponatinib (Table 1).4-6 However, in October 2013, the US Food and Drug Administration (FDA) temporarily suspended the marketing of ponatinib because of safety concerns related to increased frequency of blood clots.7 Omacetaxine, a first-in-class cephalotaxine, was approved by the FDA in 2012 for use in patients with CP-CML or AP-CML with resistance and/or intolerance to ≥2 TKIs.5 Omacetaxine mepesuccinate was approved according to the orphan drug process. The safety and efficacy of omacetaxine and its place in therapy are the topics of this review, which involves a thorough discussion of the pharmacology, pharmacokinetics, clinical efficacy, indications for use, safety profile, and dosing and administration considerations of omacetaxine.

Pharmacology Omacetaxine is an alkaloid compound derived from Cephalotaxus harringtonia, an evergreen tree that is native to Japan.8 Omacetaxine is an mRNA translation inhibitor. Specifically, omacetaxine inhibits the initial step in translation elongation by binding to the A site on the ribosome and preventing proper positioning of the incoming aminoacyl-tRNA, thereby preventing formation of the peptide bond by peptidyl transferase.9 Because omacetaxine does not target the ABL-kinase domain of BCR-ABL for its mechanism of action, it is an effective cytotoxic agent in wild-type BCR-ABL and in T315I-mutated BCR-ABL–expressing cells in vitro and in vivo.10 The rationale for using translation inhibitors as a therapeutic option stems from the reports of significantly elevated rates of translation in a variety of cancers, including CML, which has been found to contribute to the development and progression of the disease.11-13 The increased translation of short-lived mRNAs encode essential proteins involved in cell proliferation and survival.14 These short-lived mRNAs have guanine/cytosine–rich 5' untranslated regions with complex 3-dimensional structures compared with longer-lived mRNAs where the 5' untranslated regions are short and unstructured.14 In CML, the constitutively active BCR-ABL tyrosine kinase stimulates the phosphoinositide-3-kinase/ Akt/mammalian target of rapamycin (mTOR)-sig-

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naling pathways. mTOR can stimulate translation by regulating the assembly and the activity of eukaryotic initiation factor 4F (eIF4F). eIF4F preferentially recognizes and translates short-lived mRNAs, including the proto-oncoproteins cyclin D1 and c-Myc, prosurvival proteins, as well as angiogenic proteins, such as vascular endothelial growth factor, fibroblast growth factor, and matrix metalloproteinase.13 C-Myc is a transcription factor that regulates the expression of even more genes involved in the cell cycle, transcription, translation, and protein folding.15

The preferential reduction in translation of these short-lived mRNAs, resulting in apoptosis, is thought to be an important underlying mechanism in the therapeutic effect of omacetaxine on myeloid leukemia cells. By inhibiting translation, omacetaxine has been shown to reduce the protein levels of BCR-ABL, as well as several of the short-lived proteins previously mentioned.10,16 The preferential reduction in translation of these short-lived mRNAs, resulting in apoptosis, is thought to be an important underlying mechanism in the therapeutic effect of omacetaxine on myeloid leukemia cells. CML is a disease originating from pluripotent BCRABL–positive hematopoietic stem cells.17 This subset of stem cells harboring the Ph chromosome, referred to as leukemia-initiating cells (LICs), is responsible for driving tumorigenesis and maintenance of the disease, at least in CP-CML. The expansion of mature myeloid cells in the bone marrow and peripheral blood originates from the LIC population. Evidence suggests that as the disease progresses, granulocyte macrophage progenitors can become a second population of LICs.17 TKIs, such as imatinib, are effective at killing the more differentiated myeloid cells, but not the LICs.16,17 Therefore, in patients with CML, even in those with complete molecular remission, the disease most often relapses if the use of TKIs is discontinued.18 Unlike TKIs, omacetaxine is cytotoxic to the mature myeloid cells, as well as to the LICs and, therefore, is a likely contributing mechanism to its clinical effectiveness.10,16 The mechanisms explaining the differential cytotoxic effects of TKIs and omacetaxine on LICs have not been elucidated. However, in addition to a generalized difference in the gene-expression profile between imatinib and omacetaxine,19 several specific hypotheses exist. First, the cytotoxic effects of omacetaxine on LICs

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Table 1 N ew Agents Approved in 2012 for the Treatment of Patients with CML Drug

Bosutinib

Omacetaxine

Ponatiniba

Brand name

Bosulif4

Synribo5

Iclusig6

Drug class

Second-generation TKI

mRNA translation inhibitor

Third-generation TKI

FDA indication

CP-, AP-, or BC-CML with CP- or AP-CML with resistance resistance or intolerance to or intolerance to ≥2 TKIs previous therapy

CP-, AP-, or BC-CML, or Ph+ ALL with resistance or intolerance to previous TKI therapy

Active against BCRABL kinase domain mutation T315I

Yes

In October 2013, marketing of ponatinib was temporarily suspended because of safety concerns related to increased frequency of blood clots. AP indicates accelerated phase; BC, blast crisis (phase); CML, chronic myelogenous leukemia; CP, chronic phase; FDA, US Food and Drug Administration; Ph+ ALL, Philadelphia chromosome–positive acute lymphoblastic leukemia; TKI, tyrosine kinase inhibitor.

may involve the downregulation of cytokine receptors.20 Various cytokines have been shown to protect LICs from the action of TKIs via the activation of prosurvival mitogenic-signaling pathways.20 Omacetaxine has been shown to decrease the expression of the common beta-subunit c of the cytokine receptors for interleukin-3, interleukin-5, and granulocyte-macrophage colony-stimulating factor, which renders LICs insensitive to the prosurvival effects of these cytokines.20 Second, the differential effects of these 2 drug classes (ie, omacetaxine and TKIs) may theoretically involve omacetaxine-induced downregulation of beta-catenin, a short-lived proto-oncoprotein that is central to the Wnt signaling pathway.21 The expression of beta-catenin has been shown to be essential for the survival of LICs in mice with CML that are insensitive to TKIs.22

Beta-catenin has proved to be central to the survival and renewal of LICs. Omacetaxine has been reported to decrease the expression of beta-catenin in myeloma cell lines; however, it is not yet known if omacetaxine exerts the same effect on LICs. Furthermore, it has been shown that the self-renewal of LICs is dependent on beta-catenin expression; therefore, LIC self-renewal is impaired in beta-catenin–conditional null mice, mice that lack expression of beta-catenin predominantly in the hematopoietic system.23 In addition, mice exhibited increased resistance to developing CML when transplanted with betacatenin –/– BCR-ABL–expressing bone marrow cells.23 Therefore, beta-catenin has proved to be central

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to the survival and renewal of LICs. Omacetaxine has been reported to decrease the expression of beta-catenin in myeloma cell lines; however, it is not yet known if omacetaxine exerts the same effect on LICs.21 Clearly, further research is needed to identify mechanisms that explain the disparity between the cytotoxic effects of TKIs and omacetaxine’s effect on LICs.

Pharmacokinetics Clinical pharmacokinetic data after 11 days of the administration of subcutaneous omacetaxine suggest that peak drug concentrations are evident at 30 to 35 minutes after administration.5,24 The absolute bioavailability of omacetaxine is unknown. Higher mean Cmax concentrations were observed on day 11 compared with day 1, which may suggest drug accumulation.25 Omacetaxine has a steady-state volume of distribution of 141 L ± 93.4 L.5 As much as 50% or less of omacetaxine binds to plasma proteins.5 Omacetaxine is hydrolyzed by esterases to 2 inactive metabolites: 4'-desmethylhomoharringtonine (4'-DMHHT) and cephalotaxine. The primary elimination route of omacetaxine is unknown, with excretion of omacetaxine, 4'-DMHHT, and cephalotaxine comprising 12% to 15%, 4% to 5%, and 0.07% to 0.14%, respectively, of the administered dose.24 The half-lives of omacetaxine and of 4'-DMHHT are 7 and 16 hours, respectively.24 The pharmacokinetics of omacetaxine have not been determined in patients with renal or hepatic impairment.5 With respect to potential drug interactions, omacetaxine is not a substrate or inhibitor of CYP450 enzymes; its potential for enzyme induction is not known.5 Omacetaxine is a P-glycoprotein substrate.

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Table 2 Response Criteria Reported in Studies of Patients with CML Complete hematologic response

Normalization of peripheral blood counts Leukocyte count <10 × 109/L Platelet count <450 × 109/L No evidence of immature cells in peripheral blood No palpable splenomegaly

Complete cytogenetic response

No Ph+ metaphases

Partial cytogenetic response

1%-35% Ph+ metaphases

Major cytogenetic response

0%-35% Ph+ metaphases (complete cytogenetic response + partial cytogenetic response)

Complete molecular response

No detectable BCR-ABL mRNA

CML indicates chronic myelogenous leukemia; Ph+, Philadelphia chromosome–positive. Source: National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®): chronic myelogenous leukemia. Version 2.2014. November 1, 2013. www.nccn.org/ professionals/physician_gls/pdf/cml.pdf.

Experience with omacetaxine so far has not identified any clinically relevant drug interactions.5

Clinical Trials The Cephalotaxus harringtonia (homoharringtonine) compound has been studied in leukemias since the 1970s.26 In several clinical trials of patients with CP-CML between 1997 and 2003, participants who received homoharringtonine with interferon-alpha and/or cytarabine achieved complete hematologic responses of more than 80% and major cytogenetic responses (MCyRs) ranging from 17% to 84%.26 Around the time of these clinical trials of patients with CP-CML, imatinib was approved (ie, in 2001) and was quickly established as first-line therapy for patients with CML. Further development of homoharringtonine had been delayed until recent interest in its potential role for CML in the setting of TKI failures. At this time, to our knowledge, clinical data on omacetaxine in the posthomoharringtonine era are primarily available as 1 case series,27 2 published phase 2 studies,28,29 1 letter to the editor,30 and study updates in abstract form. The disease response criteria used in these studies were consistent with published guidelines on CML (Table 2).1 A report of 8 patients with CP-CML resistant to imatinib describes the use of omacetaxine in patients with CP-CML and the T315I mutation.27 Of these 8 patients, 4 had received nilotinib or dasatinib, and 5 were in hematologic relapse at baseline. The patients had been withdrawn from previous therapy for a median of 2 months (range, 1-9 months). Omacetaxine was administered with an induction course of 1.25 mg/m2

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subcutaneously twice daily for 14 days of every 28 days until hematologic response was achieved. Maintenance therapy included the same regimen but reduced to 5 to 7 days every 28 days. A median of 4 cycles was necessary to reduce the T315I/ABL ratio to below 1%. Complete hematologic response was achieved or maintained in 5 patients, and complete cytogenetic response (CCyR) was achieved in 3 patients. In 2 patients, the T315I mutation became undetectable, but BCR-ABL transcripts were still elevated. The 2 patients were rechallenged with nilotinib for a median of 12 months, and 1 patient obtained CCyR.27 A multicenter phase 2 study was performed to evaluate the use of omacetaxine in patients with CP-CML and the T315I mutation who had failed 1 or more TKIs.28 Of the patients, 62 had discontinued other CML therapies for at least 2 weeks before starting treatment with omacetaxine. Omacetaxine was administered with an induction course of 1.25 mg/m2 subcutaneously twice daily for 14 days of every 28 days until hematologic response was achieved. Maintenance therapy with the same regimen was decreased to 7 days of every 28 days. The primary efficacy end points were the proportion of patients achieving complete hematologic response and MCyR. All patients (median age, 56 years) had previously received imatinib, with 18 (29%) patients having achieved MCyR. A total of 46 (74%) patients had failed treatment with 2 or more TKIs.28 At baseline, 15 (24%) patients were in complete hematologic response. A median of 7 treatment cycles (range, 1-41 cycles) were administered, and 28 (45%) patients discontinued therapy as a result of disease progression or lack of response.

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Table 3 S elected Studies of Omacetaxine Efficacy in Patients with CML Study

CML phase

Total patients, N

Patients with Patients with CHR, N (%) MCyR, N (%)

Patients with CCyR, N (%)

Nicolini FE, et al (2010)27

Chronic

5 (63)

3 (38)

2 patients resumed nilotinib therapy

Cortes J, et al (2012)28

Chronic

48 (77)

14 (23)

10 (16)

7.7-month median PFS

Cortes J, et al (2013)29

Chronic

31 (67)

10 (22)

2 (4)

7-month median PFS

Nicolini FE, et al (2013)30

Accelerated

10 (24)

16-month median OS (95% CI, 8.2-24.6 months)

Comments

CHR indicates complete hematologic response; CCyR, complete cytogenetic response; CI, confidence interval; CML, chronic myelogenous leukemia; MCyR, major cytogenetic response; NR, not reported; OS, overall survival; PFS, progression-free survival.

Efficacy response rates are shown in Table 3. Complete hematologic response was achieved with a median of 1 cycle (range, 1-5) and a duration of 9.1 months (range, 2-46+ months). The median progression-free survival was 7.7 months (95% confidence interval [CI], 5.8-11 months). Of 46 evaluable patients, 17 (37%) had a 50% to 100% reduction from baseline of the T315I-mutated clone.28 The first-generation TKIs have not demonstrated activity against the T315I mutation.

Among patients not in complete hematologic response at baseline, 61% achieved complete hematologic response. A total of 10 patients achieved MCyR. The median follow-up time was 19.1 months. Although studies of omacetaxine in patients with CML and the T315I mutation show a potential promising treatment option in patients whose disease is resistant to other therapies, omacetaxine has not been approved by the FDA specifically for patients with the mutation. A validated assay for the evaluation of T315I mutation status is necessary. The safety and efficacy of omacetaxine in 46 patients with CP-CML that is resistant or intolerant to 2 or more TKIs were evaluated in a phase 2 clinical trial.29 The investigators defined resistance as progressive leukocytosis or lack of complete hematologic response, CCyR, or MCyR at 12, 24, or 52 weeks, respectively. Omacetaxine was administered with the identical induction and maintenance regimen used in the previously described phase 2 trial.28 The primary end point for this trial was the number of patients

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achieving complete hematologic response for 8 weeks or MCyR.29 The patientsâ&#x20AC;&#x2122; median time since CML diagnosis was 6.2 years. All patients had received imatinib, and 85% of the patients had received 2 or more TKIs. At baseline, 17% of patients were in complete hematologic response. Patients received a median of 4.5 treatment cycles (range, 1-36 cycles). Among patients not in complete hematologic response at baseline, 61% achieved complete hematologic response. A total of 10 patients achieved MCyR. The median follow-up time was 19.1 months (range, 0.3-35.3 months); the investigators estimated the median overall survival (OS) to be 30.1 months (95% CI, 20.3 months-not reached). Of note, mutational analyses of the BCR-ABL kinase domain were performed in 33 patients with the most common mutations, F395V (N = 4) and V299L (N = 3).29 Omacetaxine was also evaluated in 41 patients with AP-CML who had been enrolled in the CML202 and CML-203 studies.30 The investigators defined AP-CML in consistency with the National Comprehensive Cancer Network (NCCN) Clinical Practice GuidelinesÂŽ Version 2.2014.1 Omacetaxine was administered using the identical regimen described in the phase 2 clinical trials.28,29 All patients had failed 2 TKIs, and 59% of the patients failed 3 TKIs. The reasons for TKI failure included disease resistance, intolerance, or resistance to one TKI and intolerance to another TKI in 88%, 7%, and 5% of patients, respectively. Two patients had received stem-cell transplantation. In the AP-CML setting, patients received a median of 2 treatment cycles (range, 1-29 cycles). In total, 11 (27%) patients achieved major hematologic response with a median duration of 9 months (95% CI, 3.6-14.1 months). Minor cytogenetic response was

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Table 4 Incidence of Selected Most Frequent Grade 3 or 4 Adverse Events in Phase 2 Studies of Omacetaxine Disease phase Chronic-phase CML27

Chronic-phase CML28

N (%)

Thrombocytopenia

27 (49)

47 (76)

25 (54)

Anemia

20 (36)

24 (39)

15 (33)

Neutropenia

10 (18)

27 (44)

22 (48)

Pancytopenia

13 (21)

8 (17)

Leukopenia

11 (18)

9 (20)

Lymphopenia

10 (16)

Bone marrow failure

Febrile neutropenia

9 (16)

7 (15)

Infection

11 (20)

5 (8)

8 (17)

Fatigue

5 (9)

3 (5)

2 (4)

Diarrhea

4 (7)

1 (2)

Nausea

2 (4)

1 (2)

Pyrexia

1 (2)

Arthralgia

1 (2)

Myalgia

1 (2)

Acute-phase CML Adverse event

Hematologic

Nonhematologic

CML indicates chronic myelogenous leukemia; NR, not reported.

observed in 15% of patients, but MCyR and CCyR were not achieved.30 Various analyses of clinical data that led to the FDA approval of omacetaxine for patients with CML are available in abstract form, and additional data are on file with the manufacturer. A subset of the phase 2 study data evaluating the use of omacetaxine in patients with CP-CML categorized them by TKI resistance, which included 69 patients who never achieved or who lost response to 2 or more TKIs, 7 patients with disease intolerant to the drugs, and 5 patients with disease resistant and intolerant of them.31 After treatment with omacetaxine, 19%, 29%, and 20% of the patients with resistance, intolerance, and resistance plus intolerance, respectively, achieved MCyR. Of note, the median OS times were 33.9 months and 25 months in the resistance patients and resistance and intolerance patients, respectively. OS had not yet been reached in the intolerance subset.30

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Safety and Tolerability The most common adverse events associated with omacetaxine were primarily hematologic abnormalities, infection, diarrhea, nausea, fatigue, and asthenia. Grade 3 or 4 adverse reactions most frequently reported in the phase 2 studies with omacetaxine are summarized in Table 4. In the phase 2 study of omacetaxine in patients with CP-CML and T315I mutations, therapy was generally well tolerated.28 Blood count nadir occurred within 2 to 3 weeks after the first dose of the cycle, with recovery at 1 to 3 weeks later. Thrombocytopenia and neutropenia were the most common reasons for treatment delay, with dose delays occurring most frequently after cycles 2 and 3. Filgrastim and erythropoietin-stimulating agents were administered to 13% and 21% of patients, respectively. Hematologic adverse events were managed by reducing the number of days that omacetaxine was administered in subsequent cycles, which decreased the

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incidence of grade 3 or 4 toxicities by 10% to 20%.28 Erythema from injection-site reactions was reported in 21%28 and 17%29 of patients in these phase 2 trials. In 1 of the phase 2 trials, 6 deaths occurred during the study or 30 days after the study’s completion.29 The investigators rated 1 of these deaths as probably related to omacetaxine, because the patient had pancytopenia that never resolved.29

When omacetaxine was evaluated in patients with AP-CML, hematologic toxicities were reported in 78% of patients, necessitating the administration of granulocyte-stimulating factors, erythropoietin, red blood cells, and platelet transfusions in 5%, 17%, 76%, and 59% of the patients, respectively. The safety of omacetaxine was evaluated in 21 patients with advanced hematologic malignancies or solid tumors.24 A total of 13 (62%) patients received 1 cycle of omacetaxine 1.25 mg/m2 subcutaneously twice daily for 14 days, and 2 patients completed at least 2 cycles. No patients discontinued therapy as a result of toxicity. The most common adverse events were hematologically related, with 17 patients experiencing at least 1 grade 3 or 4 event. Of the serious adverse events, the most common were thrombocytopenia (48%) and neutropenia (33%).24 When omacetaxine was evaluated in patients with AP-CML, hematologic toxicities were reported in 78% of patients, necessitating the administration of granulocyte-stimulating factors, erythropoietin, red blood cells, and platelet transfusions in 5%, 17%, 76%, and 59% of the patients, respectively.30 The most common nonhematologic toxicities in this setting included infection, diarrhea, fatigue, and asthenia.30 In addition to these toxicities, omacetaxine may induce alterations in glycemic control. One patient developed hyperosmolar nonketotic hyperglycemia.5 It is recommended to closely monitor for grade 3 or 4 hyperglycemia, especially in patients with diabetes or those with risk factors for diabetes.1 Patients with uncontrolled diabetes should have their blood glucose optimized before starting omacetaxine therapy.5

Dosing Recommendations Omacetaxine is indicated for induction and maintenance therapy in the management of patients with CP-CML or AP-CML.5 For induction, omacetaxine is

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administered as 1.25 mg/m2 subcutaneously twice daily for 14 consecutive days every 28 days. The 28-day cycle is repeated every 28 days until patients achieve a hematologic response. After induction, a maintenance dose (1.25 mg/m2) is administered subcutaneously twice daily for 7 consecutive days every 28 days of the 28-day cycle, continuing until patients no longer experience clinical benefit from the treatment. While short intravenous infusions were administered in phase 1 clinical trials with omacetaxine, dose-limiting and life-threatening cases of hypotension and tachycardia were observed.24,26 Subcutaneous dosing of omacetaxine has been shown to decrease these adverse effects.24 Weekly monitoring of complete blood count is recommended during induction and during initial maintenance cycles of omacetaxine, and then every 2 weeks or as otherwise indicated.5 Hematologic toxicities, such as neutropenia (absolute neutrophil count <0.5 × 109/L) or thrombocytopenia (platelet count <50 × 109/L), warrant the delay of a treatment cycle with omacetaxine or the reduction in the number of doses during the cycle.1,5 The studies of omacetaxine therapy did not include patients with renal or hepatic impairment; therefore, dosing recommendations in these patient populations are not available. Although the primary elimination route of omacetaxine is not known, metabolites comprise <15% of the administered dose.5 Therefore, dose adjustments in renal impairment may not be necessary. Omacetaxine should be prepared and administered by a healthcare provider, which would entail patient visits to a clinic or a hospital.5 Delay in therapy can occur if infusion centers are not open for weekends or extended hours. There is a short time period of stability once omacetaxine has been prepared: 12 hours at room temperature and 24 hours if refrigerated.5

Place in Therapy Omacetaxine offers an alternative treatment for patients with CML. The NCCN Clinical Practice Guidelines® for the treatment of CML suggest omacetaxine as a treatment option for patients who cannot tolerate TKI therapy or who have experienced disease progression secondary to resistance with the treatment of at least 2 TKIs.1 Omacetaxine is acknowledged in these guidelines as a treatment option for patients with several mutations, including T315I, T315A, F317L/V/ I/C, Y253H, E255K/V, F359V/C/I, and V299L.1 Any other mutation is also an indication for treatment with omacetaxine.1 In the case of T315I mutations, ponatinib had been designated as preferred over omacetaxine.1 The

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safety and efficacy of ponatinib were evaluated in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial, which included patients resistant to or intolerant of other TKIs, or those with T315I mutation.1,32 In 64 patients with CP-CML and T315I mutation, 70% achieved MCyR. Major hematologic responses were also observed in patients with BC-CML or AP-CML and T315I mutation.32 Ponatinibâ&#x20AC;&#x2122;s prescribing information contains a black box warning about the potential for the development of arterial thrombosis or hepatotoxicity with this drug.6 Omacetaxine may provide an alternative for patients susceptible to those conditions, especially given the recent suspension of ponatinib marketing by the FDA,7 as noted earlier. Bosutinib, a second-generation TKI, was approved by the FDA for all phases of patients with CML resistant or intolerant to previous TKI therapy. Its approval was based on an analysis of 118 patients with CP-CML who had received imatinib and had developed resistance or intolerance to it, and had also received dasatinib and/or nilotinib.33 In this heavily pretreated population, treatment with bosutinib for a median of 28.5 months led to rates of 32% MCyR and 73% complete hematologic response. Adverse effects were primarily grades 1 and 2 diarrhea, vomiting, and rash.33 These results suggest a very modest improvement in efficacy and a more tolerable safety profile compared with omacetaxine; however, these 2 agents have not been compared directly. Omacetaxine may provide a non-TKI alternative therapy to bosutinib. National guideline recommendations for omacetaxine are based on data in very limited numbers of patients, as a result of the relative rarity of CML and the urgency to provide therapeutic alternatives for a disease with limited cure potential. Omacetaxine is indicated for CP-CML and AP-CML; however, full data on patients with AP-CML are not available. Published peer-reviewed data supporting omacetaxine efficacy in patients with specific BCR-ABL kinase domain mutations, or comparative data with other therapeutic alternatives are also lacking. In addition, pharmacoeconomic and quality-of-life analyses are lacking. Although treatment with omacetaxine extends complete hematologic response in more than 60% of patients, it is still not clear whether its risks outweigh its benefits. There may be an OS benefit with omacetaxine, but the overall quality-of-life benefit has not been established. In the majority of patients, adverse events have been of mild-to-moderate severity; more clinical experience with omacetaxine will help to bet-

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ter elucidate its safety profile and will help to target which patients will benefit most from this therapy, with minimal risk. Another consideration for providers and payers is the cost of omacetaxine. Experts in CML drugs, including the investigators of omacetaxine studies, published an open editorial to drug manufacturers discussing the cost of cancer drugs and the debate about healthcare costs.34 The cost of omacetaxine is specifically cited in the editorial as $28,000 for an induction cycle and $14,000 for the course of maintenance. If a patient requires only 1 induction cycle, the annual cost becomes $182,000 ($28,000 induction plus $154,000 maintenance); most patients in the clinical trials reported required multiple induction cycles, which would be even more than $182,000 annually. In the open editorial, bosutinib is quoted at an annual cost of $118,000.34 Additional costs that are not considered in this calculation include costs for administration time, hospital or clinic charges, and costs that are involved with supportive care measures, such as transfusions or colony-stimulating factors. Clearly, more research is necessary to determine the clinical and cost benefits of omacetaxine.

These results suggest a very modest improvement in efficacy and a more tolerable safety profile compared with omacetaxine; however, these 2 agents have not been compared directly. Omacetaxine may provide a non-TKI alternative therapy to bosutinib. Conclusion Omacetaxine, the first-in-class mRNA translation inhibitor, offers a therapeutic alternative to TKIs, with a novel mechanism of action, for the treatment of patients with drug-resistant CML. The majority of adverse reactions reported in clinical trials with this drug include hematologic abnormalities, infection, diarrhea, and nausea, and they were mild to moderate in severity in patients with CP-CML. Omacetaxine provides another treatment option for patients who are resistant to or intolerant to first-line TKIs, but its place in therapy compared with bosutinib or ponatinib is not known. Many questions remain concerning its niches in therapy, adverse effect profile, and overall benefit. n Continued

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Author Disclosure Statement Dr Olin, Dr Cole, and Dr Dirks-Naylor reported no conflicts of interest.

References

1. National Comprehensive Cancer Network. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®): chronic myelogenous leukemia. Version 2.2014. November 1, 2013. www.nccn.org/profes sionals/physician_gls/pdf/cml.pdf. Accessed November 25, 2013. 2. Druker BJ, Lee SJ. Chronic myelogenous leukemia. In: DeVita VT, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011:1962-1972. 3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11-30. 4. Bosulif (bosutinib) tablets [prescribing information]. New York, NY: Pfizer Laboratories; September 2013. 5. Synribo (omacetaxine mepesuccinate) for injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc; October 2012. 6. Iclusig (ponatinib) tablets [prescribing information]. Cambridge, MA: ARIAD Pharmaceuticals, Inc; December 2012. 7. US Food and Drug Administration. FDA drug safety communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales. November 5, 2013. Updated November 12, 2013. www.fda.gov/Drugs/ DrugSafety/ucm373040.htm. Accessed November 25, 2013. 8. Chen Y, Peng C, Sullivan C, et al. Novel therapeutic agents against cancer stem cells of chronic myeloid leukemia. Anticancer Agents Med Chem. 2010;10:111-115. 9. Gürel G, Blaha G, Moore PB, Steitz TA. U2504 determines the species specificity of the A-site cleft antibiotics: the structures of tiamulin, homoharringtonine, and bruceantin bound to the ribosome. J Mol Biol. 2009;389:146-156. 10. Chen Y, Hu Y, Michaels S, et al. Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice. Leukemia. 2009;23:1446-1454. 11. Dong Z, Zhang JT. Initiation factor eIF3 and regulation of mRNA translation, cell growth, and cancer. Crit Rev Oncol Hematol. 2006;59:169-180. 12. De Benedetti A, Graff JR. eIF-4E expression and its role in malignancies and metastases. Oncogene. 2004;23:3189-3199. 13. Yin JY, Dong Z, Liu ZQ, Zhang JT. Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments. Biosci Rep. 2011;31:1-15. 14. Robert F, Carrier M, Rawe S, et al. Altering chemosensitivity by modulating translation elongation. PLoS One. 2009;4:e5428. 15. Menssen A, Hermeking H. Characterization of the c-MYC-regulated transcriptome by SAGE: identification and analysis of c-MYC target genes. Proc Natl Acad Sci U S A. 2002;99:6274-6279. 16. Wetzler M, Segal D. Omacetaxine as an anticancer therapeutic: what is old is new again. Curr Pharm Des. 2011;17:59-64. 17. Stuart SA, Minami Y, Wang JY. The CML stem cell: evolution of the progenitor. Cell Cycle. 2009;8:1338-1343. 18. Rousselot P, Huguet F, Rea D, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109:58-60.

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19. Kulkarni H, Göring HH, Diego V, et al. Association of differential gene expression with imatinib mesylate and omacetaxine mepesuccinate toxicity in lymphoblastoid cell lines. BMC Med Genomics. 2012;5:37. 20. Klag T, Härtel N, Erben P, et al. Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common β-subunit c of cytokine receptors. Leukemia. 2012;26:1321-1328. 21. Kuroda J, Kamitsuji Y, Kimura S, et al. Anti-myeloma effect of homoharringtonine with concomitant targeting of the myeloma-promoting molecules, Mcl-1, XIAP, and beta-catenin. Int J Hematol. 2008;87:507-515. 22. Hu Y, Chen Y, Douglas L, Li S. Beta-catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia. 2009;23:109-116. 23. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528-541. 24. Nemunaitis J, Mita A, Stephenson J, et al. Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors. Cancer Chemother Pharmacol. 2013;71:35-41. 25. ChemGenex Pharmaceuticals, Inc. Briefing book. Oncology Drugs Advisory Committee Meeting NDA 22-374: Omapro (omacetaxine mepesuccinate). www. fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/onco logicdrugsadvisorycommittee/ucm199562.pdf. Accessed August 28, 2013. 26. Quintás-Cardama A, Kantarjian H, Cortes J. Homoharringtonine, omacetaxine mepesuccinate, and chronic myeloid leukemia circa 2009. Cancer. 2009;115:5382-5393. 27. Nicolini FE, Chomel JC, Roy L, et al. The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge. Clin Lymphoma Myeloma Leuk. 2010;10:394-399. 28. Cortes J, Lipton JH, Rea D, et al; for the Omacetaxine 202 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012;120:2573-2580. 29. Cortes J, Digumarti R, Parikh PM, et al; for the Omacetaxine 203 Study Group. Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronicphase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors. Am J Hematol. 2013;88:350-354. 30. Nicolini FE, Khoury HJ, Akard L, et al. Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. Haematologica. 2013;98:e78-e79. 31. Akard LP, Kantarjian H, Nicolini FE, et al. Omacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia (CML) in patients resistant, intolerant, or both to two or more tyrosine-kinase inhibitors (TKIs). J Clin Oncol. 2012;30(15 suppl). Abstract 6596. 32. Cortes JE, Kim DW, Pinilla-Ibarz J, et al; for the PACE Study Group. A pivotal phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib, or with the T315I BCR-ABL mutation: 12-month follow-up of the PACE trial. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 163. 33. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403-3412. 34. 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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FDA UPDATE

Recent Cancer Drugs Approved by the FDA

he US Food and Drug Administration (FDA) approved many new cancer drugs and several new indications for previously approved drugs in 2013, as well as the first 2 drugs designated as “breakthrough therapy.” Breakthrough therapy designation will expedite drug development for serious or life-threatening conditions and their approval pro-

Gilotrif for Metastatic NSCLC with EGFR Mutations, Concurrent with a Companion Diagnostic Test The FDA approved the tyrosine kinase inhibitor afatinib (Gilotrif; Boehringer Ingelheim Pharmaceuticals) on July 12, 2013, for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) who have the epidermal growth factor receptor (EGFR) gene mutations exon 19 deletions or exon 21 L858R substitution. The FDA approved afatinib under its priority review program, which offers an expedited review for drugs that provide safe and effective therapy when no good alternatives exist or for drugs that provide significant therapeutic improvement over available agents. Afatinib was approved concurrently with a companion diagnostic, the therascreen EGFR RGQ PCR Kit (manufactured by QIAGEN Manchester, United Kingdom), that identifies patients with the EGFR mutations. These types of mutations occur in approximately 10% of NSCLC tumors, and the majority of these mutations are either exon 19 deletions or exon 21 L858R substitution. Afatinib’s safety and efficacy were established in a clinical study of 345 patients with metastatic NSCLC plus EGFR mutations. Patients were randomized to afatinib or to chemotherapy with pemetrexed and cisplatin. Progression-free survival (PFS) was 4.2 months longer in the group that received afatinib than in the chemotherapy group. No significant difference in overall survival (OS) was seen between the 2 treatment arms. The common side effects reported with afatinib include diarrhea, skin breakouts that resemble acne, dry skin, pruritus, inflammation of the mouth, paronychia, decreased appetite and weight, cystitis, nose bleed, runny nose, fever, eye inflammation, and hypokalemia. Serious side effects include diarrhea that can result in kidney failure and severe dehydration, severe rash, lung inflammation, and liver toxicity. The FDA’s approval of the therascreen EGFR RGQ PCR Kit was based on data from the safety and efficacy clinical study that was used for the approval of afatinib. Tumor samples from patients with NSCLC plus mutations helped to validate the test’s benefit in detecting EGFR mutations in this patient population.

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cess. To be designated as a breakthrough therapy, the drug has to have preliminary clinical evidence that demonstrates that this medication provides substantial improvement on at least 1 clinically significant end point relative to available therapies. The following briefs describe some of the cancer drugs most recently approved by the FDA.

Abraxane Indicated for Metastatic Pancreatic Cancer The FDA approved a new indication for paclitaxel protein-bound particles for injectable suspension, albumin-bound (Abraxane; Celgene) on September 6, 2013, for the treatment of patients with metastatic pancreatic cancer. Removal of the pancreas by surgery is the only curative option in pancreatic cancer, but this option is no longer useful by the time this type of cancer is diagnosed, when the cancer has metastasized. Paclitaxel protein-bound is a chemotherapy agent that has shown to slow certain types of tumors. This approval was based on a clinical trial with 861 patients who were randomized to paclitaxel protein-bound plus gemcitabine or to gemcitabine alone. The OS in patients receiving the combination therapy was an average of 1.8 months longer than in patients receiving gemcitabine alone. In addition, PFS was also, on average, 1.8 months longer with the addition of paclitaxel protein-bound to gemcitabine than in patients receiving only gemcitabine. The common side effects with paclitaxel protein-bound include neutropenia, thrombocytopenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, fever, vomiting, rash, and dehydration. The most severe effects in this trial were fever, dehydration, pneumonia, and vomiting. Paclitaxel protein-bound was already approved for the treatment of breast cancer and NSCLC. Perjeta for Neoadjuvant Breast Cancer Therapy The FDA granted accelerated approval to pertuzumab (Perjeta; Genentech) on September 30, 2013, as part of a treatment regimen for the neoadjuvant setting for patients with HER2-positive early-stage breast cancer. This is the first approval of a drug for the neoadjuvant treatment of patients with breast cancer. Pertuzumab received FDA approval in 2012 for the treatment of patients with advanced or metastatic HER2positive breast cancer. This new indication is for patients with HER2-positive, locally advanced, inflammatory or early-stage breast cancer (ie, tumor size of >2 cm in diameter or with positive lymph nodes) who are at high risk for

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FDA UPDATE

recurrence, of having their cancer metastasize, or who are at high risk of dying from breast cancer. Pertuzumab is indicated for use in combination with trastuzumab and other chemotherapy before surgery and, depending on the treatment regimen used, may be followed by chemotherapy after surgery. After surgery, patients should continue to receive trastuzumab to complete 1 year of treatment. This approval opens a new path for the FDA to approve therapies for early-stage breast cancer. In May 2012, the FDA issued a guidance about the use of pathologic complete response (pCR) as a new end point to support the accelerated approval of a drug for the neoadjuvant treatment of high-risk, early-stage breast cancer. The accelerated approval of pertuzumab for neoadjuvant treatment is based on a study designed to measure pCR. The study included 417 patients with breast cancer who were randomly assigned to receive 1 of 4 neoadjuvant treatment regimens—trastuzumab plus docetaxel, pertuzumab plus trastuzumab and docetaxel, pertuzumab plus trastuzumab, or pertuzumab plus docetaxel. Approximately 39% of the patients receiving pertuzumab plus trastuzumab and docetaxel achieved pCR compared with nearly 21% of those receiving trastuzumab plus docetaxel. The most common side effects reported with pertuzumab plus trastuzumab and docetaxel were hair loss, diarrhea, nausea, and a decrease in white blood cells. Other significant side effects included decreased cardiac function, infusion-related reactions, hypersensitivity reactions, and anaphylaxis.

Gazyva, First Breakthrough Therapy, Approved for Chronic Lymphocytic Leukemia The FDA approved the monoclonal antibody obinutuzumab (Gazyva; Genentech) on November 1, 2013, for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not previously received treatment for CLL. Obinutuzumab is indicated to be used in combination with chlorambucil. Obinutuzumab, which works by helping immune system cells to attack cancer cells, is the first drug with a “breakthrough therapy” designation to receive FDA approval. Obinutuzumab also has an orphan drug designation, based on the designation of CLL as a rare disease. According to the National Cancer Institute, 15,680 Americans are expected to be diagnosed with CLL in 2013, and 4580 will die from the disease. Obinutuzumab’s approval was based on an open-label multicenter trial of 356 treatment-naïve patients with CLL who were randomized to obinutuzumab in combination with chlorambucil or to chlorambucil alone. The combination of obinutuzumab plus chlorambucil demonstrated a significant, 2-fold improvement in PFS

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compared with chlorambucil alone, for an average of 23 months with the combination versus 11.1 months in the monotherapy cohort. The most common adverse events in patients receiving obinutuzumab were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and fever. Gazyva was approved with a boxed warning regarding the risk for hepatitis B virus reactivation and progressive multifocal leukoencephalopathy, a rare brain disorder.

Imbruvica, Second Breakthrough Therapy for MCL A few days after the first cancer drug with a breakthrough therapy designation was approved by the FDA, the second drug with such a designation—ibrutinib (Imbruvica; Pharmacyclics)—received an accelerated FDA approval on November 13, 2013, for the treatment of patients with mantle-cell lymphoma (MCL), a rare form of non-Hodgkin lymphoma (NHL). MCL represents approximately 6% of all cases of NHL in the United States. This aggressive type of cancer is usually diagnosed when it has already spread to the lymph nodes, bone marrow, and other organs. Ibrutinib is an oral Bruton’s tyrosine kinase inhibitor that blocks the activity of malignant B-cells. Ibrutinib is indicated for patients with MCL who have received at least 1 previous therapy with bortezomib or with lenalidomide, the only 2 other drugs approved by the FDA for the treatment of patients with MCL. Ibrutinib was approved under the FDA’s priority review path, and has received an orphan drug designation, by demonstrating its safety and efficacy in the treatment of MCL, a rare disease. The FDA’s accelerated approval of ibrutinib for MCL was based on a multicenter, single-arm trial of 111 patients who were previously treated for MCL; they received ibrutinib therapy daily until their disease progressed or their side effects became intolerable. The results showed an overall response rate of 65.8% (95% confidence interval, 56.274.5); of these, 17% of the patients achieved complete response and 49% achieved partial response. The median duration of response was 17.5 months. The trial did not demonstrate an improvement in OS or in symptoms. The most common side effects reported in patients receiving ibrutinib included thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and reduced appetite. Other clinically significant side effects include bleeding, infections, kidney problems, and the risk for developing other types of cancers. Overall, 10 patients discontinued treatment because of adverse events, and 14% of the patients had dose reduction in the trial. n

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For appropriate patients receiving highly emetogenic chemotherapy,

Prevention of CINV With Triple Therapya Starts on Cycle 1, Day 1 EMEND® (fosaprepitant dimeglumine) for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information

• EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. • Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. • EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Selected Important Safety Information (continued)

• Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. • Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied. • There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. • Coadministration of EMEND® (fosaprepitant dimeglumine) for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle. Triple Therapy=EMEND for Injection, a 5-HT 3 antagonist, and a corticosteroid. CINV=chemotherapy-induced nausea and vomiting.

emendforinjection.com

Please see the adjacent Brief Summary of the Prescribing Information.

Major oncology professional society guidelines recommend first-line use of a regimen including EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid1–3,b

Receive your complimentary copy of guidelines for antiemetic treatment.

Scan this QR code or visit emendforinjection.com. Selected Important Safety Information (continued)

• The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. • Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. • In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). • In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusionsite reactions included infusion-site erythema, infusionsite pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis.

Selected Important Safety Information (continued)

• In clinical trials, EMEND for Injection increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND for Injection should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND for Injection. EMEND® (aprepitant) increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND for Injection 115 mg. b

Based on the Category 2A level of evidence and consensus. Category 2A is based upon lower-level evidence, there is uniform National Comprehensive Cancer Network ® consensus that the intervention is appropriate.2

References: 1. Basch E, Prestrud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29(31):4189–4198. 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) Version 1.2013. Antiemesis. www.nccn.org/professionals/physician_ gls/pdf/antiemesis.pdf. Published December 6, 2012. Accessed July 15, 2013. 3. Irwin MM, Lee J, Rodgers C, et al. Putting Evidence Into Practice: Improving Oncology Patient Outcomes. Chemotherapy-Induced Nausea and Vomiting Resource. Pittsburgh, PA: Oncology Nursing Society; 2012.

INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting Chronic continuous administration is not recommended [see Warnings and Precautions]. CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. Brief Summary of the Prescribing Information for

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction 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 clinical practice. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of ≥1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

EMEND® (fosaprepitant dimeglumine) for Injection Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0–24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as ↑, decrease as ↓, no change as ↔): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC ↑ 1.8-fold on Day 1 and AUC ↔ on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC ↑ 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC ↑ 2.3-fold on Day 1 and ↑ 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC ↑ 25% on Day 4, AUC ↓ 19% on Day 8, and AUC ↓ 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC ↑ 1.5-fold A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant. CYP2C9 substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcg•hr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, 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 EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcg•hr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it

produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant. Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For more detailed information, please read the Prescribing Information. Rx only

ORIGINAL RESEARCH

The Impact of Angiotensin II Receptor Blocker Use in Patients with Prostate Cancer Lisa Cerutti, PharmD; Jacob K. Kettle, PharmD, BCOP; Dennis Grauer, PhD Background: Numerous treatment options are available for prostate cancer, but this type of cancer remains a prevalent disease, with significant morbidity and mortality. Therefore, the investigation of alternative therapeutic approaches remains essential. Previous studies have suggested that the use of angiotensin II receptor blockers (ARBs) may favorably affect the prostate cancer disease course. Objective: To provide preliminary comparative human data on the effect of ARB use on the course of prostate cancer from the time of diagnosis. Methods: This study was a retrospective, single-center, cohort analysis of 48 adult patients with newly diagnosed prostate cancer. All patients received therapy for prostate cancer. The patients were divided into a control group (ie, no previous ARB exposure; N = 24) or an ARB treatment group (N = 24). Median follow-up time was 44.8 months. The groups were similar at baseline, including cancer stage, Gleason score, and prostate-specific antigen (PSA) level. The primary outcome measure was progression-free survival (PFS). Secondary measures included the analysis of PSA levels over time and overall survival (OS). Results: At the end of 4 years after the diagnosis of prostate cancer among the 48 patients, PFS was 79.2% in the control group compared with 62.5% in the ARB group (P = .34). Similarly, J Hematol Oncol Pharm. no significant difference was seen in OS or in PSA levels at any follow-up interval, with all trends 2013;3(4):128-132. favoring the control group. www.JHOPonline.com Disclosures are at end of text Conclusion: This investigation did not demonstrate any positive alteration in the disease course of prostate cancer when patients were receiving ARB therapy at the time of diagnosis.

rostate cancer is the most common cancer in men, with an estimated 238,590 new cases diagnosed in 2013 and 29,720 deaths.1 Despite an increase in the early detection of prostate cancer during the late twentieth century, prostate cancer remains the second leading cause of cancer death in men.1,2 Although generally slow to progress, prostate cancer can lead to significant increases in morbidity, and currently available treatment options may result in considerable reductions in a patientâ&#x20AC;&#x2122;s quality of life during treatment.3 As a result, the investigation of alternative treatment strategies remains a valuable endeavor. In 2003 and 2005, a research group from the Department of Urology at the Yokohama City University Graduate School of Medicine in Japan published 2 studies suggesting that the angiotensin II receptor blockers (ARBs) class of antihypertensive medications may show promise as a treatment for prostate cancer.4,5 In the initial study, Uemura and colleagues demonstrated that angiotensin II type 1 (AT1) receptors are

expressed in higher amounts in cancerous prostate tissue compared with normal prostate tissue.4 Because the binding of angiotensin II to these receptors was shown to activate the proliferation of prostate cancer cells, it was suggested that ARBs could potentially inhibit cancer-cell proliferation through the suppression of this pathway and other tumor growthâ&#x20AC;&#x201C;signaling cascades.4 Initial testing in a mouse model demonstrated that the oral administration of an ARB inhibited the growth of prostate cancer cell tumors in androgen-dependent and androgen-independent cells.4 Subsequently, the same research group demonstrated in a small clinical study of 23 patients that the administration of the ARB candesartan resulted in declining prostate-specific antigen (PSA) values for 8 (34.8%) patients with advanced hormone-refractory prostate cancer at the conclusion of a 4-month study period.5 Although there was no control group for comparison, these results supported the early preclinical findings in their previous study.4 If the inhibition of AT1 use suppresses prostate tumor

Dr Cerutti is PACT Clinical Pharmacist, Department of Pharmacy, VA Eastern Kansas Health Care System, Leavenworth, KS; Dr Kettle is Oncology Clinical Pharmacy Specialist, Department of Pharmacy, University of Missouri Health Care, Columbia, MO; Dr Grauer is Associate Professor and Graduate Director, University of Kansas School of Pharmacy, Lawrence, KS.

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Table 1 D efinitions for Treatment Groups Group

Explanation

Definition

Control group

No ARB exposure after prostate cancer diagnosis

No prescriptions filled for any ARB at any time after the diagnosis of prostate cancer

ARB groupa

ARB exposure after prostate cancer diagnosis

≥1 prescriptions for any ARB filled within 6 months of a prostate cancer diagnosis, and a documented refill of the medication within 6 months of the original fill

ARBs included candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan alone or as part of a combination agent with another antihypertensive agent.

ARB indicates angiotensin II receptor blocker.

growth, as postulated by Uemura and colleagues,4,5 then theoretically, ARB therapy could positively impact the disease course of prostate cancer. The purpose of this study is to provide preliminary comparative human data on the effect of ARB use on the course of prostate cancer from the time of diagnosis.

Methods Study Design and Patient Population This study was a retrospective, single-center, cohort analysis consisting of men aged ≥18 years at a metropolitan hospital who were diagnosed with prostate cancer between 2001 and 2010. Patients were excluded if they received a diagnosis of any malignancy other than prostate cancer during the study period, or if they had insufficient data for analysis in the available medical records. Qualifying patients were divided into 2 groups based on a review of medication history and the exposure to ARB therapy: 24 patients were enrolled in the control group (ie, no ARB exposure) and 24 in the ARB group (Table 1). Because a significant disparity in size between the control and ARB groups was anticipated, it was planned to utilize a computerized random number generator to select an equivalent population size from all identified control group patients to be compared with the ARB group in the final analysis. Data and Statistical Analysis The primary outcome measure was progression-free survival (PFS) at 4 years from the time of prostate cancer diagnosis. For this analysis, disease progression was defined as any increase in PSA over baseline. Secondary outcomes included mean PSA levels at 6-month intervals from the time of diagnosis and overall survival (OS). A priori power calculations indicated that 25 patients in each group would be needed to meet 80% power for

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Figure 1 Selection of Study Patients Prostate cancer diagnosis from 2001-2010 3541 No history of ARB therapy 3448

History of ARB therapy 103

Inclusion and exclusion criteria applied

119

Random selection Control: 24

ARB therapy: 24

ARB indicates angiotensin II receptor blocker.

the primary outcome. Bivariate results were compared using the χ2-test or the student’s t-test when appropriate. In addition, logistic regression analysis was used to predict PFS, controlling for significant covariates such as age, ARB exposure, and prostate cancer therapy. For all statistical tests, a P value ≤.05 was noted as significant.

Results Demographics After applying the inclusion and exclusion criteria, a total of 48 patients were included in the final data analysis (Figure 1). The patient groups were similar in terms of cancer stage at diagnosis, Gleason score, baseline PSA, and exposure to 5-alpha reductase inhibitors (Table 2). Significant differences were noted between the groups with regard to mean age at diagnosis (60.3 years in the

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Table 2 D emographics and Clinical Characteristics of the Research Population Control group (N = 24)

ARB group (N = 24)

P value

Stage I, N

—

Stage II, N

—

Stage III, N

—

Stage IV, N

—

Average Gleason score at diagnosis

6.46

6.58

.575

Baseline PSA, ng/mL

9.7

8.7

.75

Patients with exposure to 5-alpha reductase inhibitor, %

8.3

12.5

.575

Mean duration of follow-up, mos

47.5

.27

Average age at diagnosis, yrs

60.3

69.5

<.001

Pulmonary disease, %

29.17

12.5

.162

Hepatic disease, %

8.33

4.17

.575

Renal disease, %

8.33

29.17

.057

Cardiovascular disease, %

12.5

.004

Diabetes, %

29.17

.002

Prostatectomy, %

20.8

.035

Hormonal therapy, %

20.8

29.2

.515

Radiation therapy, %

37.5

45.8

.568

Chemotherapy, %

Clinical characteristics Median cancer stage (I-IV) at diagnosis

Patients with concomitant disease states

Patients receiving prostate cancer treatments

ARB indicates angiotensin II receptor blocker; PSA, prostate-specific antigen.

control group vs 69.5 years in the ARB group; P <.001) and frequency of radical prostatectomy (50% in the control group vs 20.8% in the ARB group; P = .035). In addition, there was a higher incidence of diabetes and cardiovascular disease (CVD) in the ARB group compared with the control group.

Primary End Point At the conclusion of the 48-month study period, PFS in the control group was 79.2% compared with 62.5% in the ARB group (P = .34). The numerical advantage seen in the control group was maintained throughout the study period (Figure 2). To control for differences between the patient groups, a multinomial logistic regression analysis was performed,

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with PFS as the dependent variable. The factor in the model was ARB exposure, and covariates were age at diagnosis, CVD, diabetes, and prostatectomy. The only significant factor or covariate was ARB exposure.

Secondary End Points Although the 2 study groups were statistically identical at baseline, the ARB group consistently maintained a higher mean PSA level compared with the control group at each time point from 6 months through 48 months (Figure 3). The difference between these groups nearly reached statistical significance at 18 months (P = .05), but at no point was the standard threshold crossed. OS showed a numerically, but not statistically, significant advantage

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Figure 2 Overall Survival in the ARB Group Compared with the Control Group 100%

Overall survival, %

in the control group compared with the ARB group (91.7% vs 83.3%, respectively; P = .66). Of the 4 total deaths that occurred during the study period, 3 were in the ARB group and 1 was in the control group. A rising PSA level was noted at the time of death for each of the patients in the ARB group who had died. Conversely, the level of PSA was steady at the time of death for the 1 patient from the control group who died. The cause of death for that patient was not determined in this study.

Control ARB

95%

PSA, ng/mL

90% Discussion In contrast to the earlier studies by Uemura and colleagues,4,5 data from the current study do not support the theory of a potentially beneficial impact of ARBs 85% on the disease course of prostate cancer. Although this 0 6 12 18 24 30 36 42 48 concept appears plausible in those previous reports,4,5 Months after diagnosis ARB exposure did not appear to translate into any advantageous effects when compared with a control group ARB indicates angiotensin II receptor blocker. in the present study. Of all of the end points that were examined in our study, no data were found to suggest a cancer-related Figure 3 Median Prostate-Specific Antigen in the ARB Group benefit to ARBs in patients with newly diagnosed prosCompared with the Control Group tate cancer. Although the sample size of this study was not sufficiently powered to meet statistical significance, 12 the consistent trends favoring the control group suggest Control it is very unlikely that an underlying advantage associ10 ARB ated with ARB therapy was masked. In addition, the potential relationship between 8 ARBs and prostate cancer has been investigated from the perspective of the impact of ARB therapy on the 6 incidence rate of the disease. Sipahi and colleagues conducted a meta-analysis of more than 93,000 pa4 tients from 8 trials to assess whether ARBs affect cancer incidence.6 The investigators reported a trend to2 ward an increased incidence of prostate cancer among patients receiving ARBs compared with the controls 0 (1.7% vs 1.3%, respectively; P = .076).6 0 6 12 18 24 30 36 42 48 The ARB Trialists Collaboration study conducted a Months after diagnosis sizable meta-analysis involving 15 large clinical trials with a total of 138,769 participants.7 The investigators ARB indicates angiotensin II receptor blocker; PSA, prostate-specific antigen. found that the overall incidence of prostate cancer was virtually equivalent between the ARB treatment group and the controls. Although these studies focused on tectomy were unexpected findings. The potential comdisease occurrence rather than on disease response, the plications that could be introduced by discrepancies results are nonetheless consistent with our analysis in within baseline characteristics were accounted for by showing that ARBs do not provide any beneficial impact completing the logistic regression model. In retrospect, on the course of prostate cancer. the utilization of matching or other patient selection In our present study, the higher percentage of patechniques might have resulted in more appropriate tients with CVD and renal dysfunction in the ARB comparison groups. Considering our results, however, group was anticipated, because both disease states are it is not anticipated that this would have altered our indications for the use of ARBs. Differences between conclusions. the study groups in patient age and history of prostaPatient adherence to treatment provides another

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potential confounder in our study. Although utilization of other more reliable measures would have been preferable, pharmacy refill records were the best of the available options to assess compliance, considering the retrospective nature of the study. There were 2 notable differences between our study and the pilot study that was conducted by Uemura and colleagues.4 First, the drug used in the in vivo studies conducted by this group was candesartan, whereas our study investigated all ARB agents to capture a significant patient population. Because of an institutional formulary, losartan was the most frequently used medication in our study.

It is critical to emphasize that the findings from this research should not be taken to suggest that the use of ARBs in patients with prostate cancer should be avoided. Given the results and limitations of our trial, it certainly remains reasonable to initiate or to continue ARB therapy in a patient with prostate cancer for its established therapeutic benefits in comorbid conditions, such as CVD and diabetes mellitus. Although Uemura and colleagues did not suggest that one ARB would act differently from another in regard to antineoplastic activity, the medications in the ARB class vary from one another in terms of metabolism, volume of distribution, protein binding, and half-life of elimination, despite sharing the same antihypertensive mechanism. Candesartan exhibits stronger and irreversible binding at the AT1 receptor, which distinguishes it from losartan and many of the other ARB agents.8

Limitations The extent to which these pharmacologic differences impact prostate cancer cells is unknown. Unfortunately, the small sample size within our study prohibited a comparison between various ARBs. Second, our study investigated patients with newly diagnosed prostate cancer, whereas the human studies conducted by Uemura and colleagues were limited to hormone-refractory prostate cancer. Given the various mutations that occur within the

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cancer over time, it is conceivable that newly diagnosed prostate cancer may respond differently to a therapeutic intervention than androgen-independent disease.

Conclusion The results from this investigation failed to demonstrate any positive alteration in the disease course of prostate cancer when patients were receiving concomitant therapy with an ARB at the time of diagnosis. This finding is unfortunate, given the large potential positive impact of treating prostate cancer with a class of medications that is very well tolerated compared with the current treatment modalities. It is critical to emphasize that the findings from this research should not be taken to suggest that the use of ARBs in patients with prostate cancer should be avoided. Given the results and limitations of our trial, it certainly remains reasonable to initiate or to continue ARB therapy in a patient with prostate cancer for its established therapeutic benefits in comorbid conditions, such as CVD and diabetes mellitus. n Acknowledgments The authors would like to thank R. Spencer Schaefer, PharmD, and Allyce Schenk, PharmD, BCPS, for their assistance with data extraction. Author Disclosure Statement Dr Cerutti and Dr Grauer reported no conflicts of interest; Dr Kettle served on an advisory board for Genentech after the initial writing of the manuscript.

References

1. American Cancer Society. Cancer facts and figures 2013. 2013. www.cancer.org/ acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845. pdf. Accessed May 2, 2013. 2. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer surveillance series: interpreting trends in prostate cancerâ&#x20AC;&#x201D;part I: evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst. 1999;91:1017-1024. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelineÂŽ): prostate cancer. Version 1.2014. November 27, 2013. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed November 28, 2013. 4. Uemura H, Ishiguro H, Nakaigawa N, et al. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cancer Ther. 2003;2:1139-1147. 5. Uemura H, Hasumi H, Kawahara T, et al. Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer. Int J Clin Oncol. 2005;10:405-410. 6. Sipahi I, Debanne SM, Rowland DY, et al. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010;11:627-636. 7. ARB Trialists Collaboration. Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138,769 individuals. J Hypertens. 2011;29:623-635. 8. Meredith P. Comparative ARB pharmacology. Br J Cardiol. 2010;17(suppl 2):s3-s5.

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VISIT THE NEW ONLINE RESOURCE FOR NURSES AND THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Quality care is everyone’s business.” Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Nurse Practitioner, Multiple Myeloma Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Value-BasedCare IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

Call for Papers The Journal of Hematology Oncology Pharmacy is the nation’s first peer-reviewed clinical journal for oncology pharmacists. As pharmacy practice and research become integral to improving both the clinical care of cancer patients as well as expanding the research literature in contemporary oncology pharmacy, new avenues are necessary to ensure this information gets disseminated to the profession. Launched in March 2011, the Journal of Hematology Oncology Pharmacy provides a new venue for the publication of peer-reviewed, high-quality pharmacy reviews and original research to help oncology pharmacy practitioners and other hematology oncology professionals optimize drug therapy for patients with cancer. Readers are invited to submit articles addressing new research, clinical, and practice management issues in oncology pharmacy. All articles will undergo a blind peer-review process, and acceptance is based on that review.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical • Basic science • Translational • Practice-based • Case reports • Case series

• New drug classes • Disease states • Basic science • Pharmacology • Pathways and the drugs targeting them

CLINICAL CONTROVERSIES

PRACTICAL ISSUES IN PHARMACY MANAGEMENT

• Point and counterpoint • Roundtable discussions • “How I treat”

• Logistics • Economics • Practice-influencing issues

COMMENTARIES

LETTERS TO THE EDITOR

Manuscripts should follow the Author Guidelines at www.JHOPonline.com. For more information, call 732-992-1536.

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FROM THE LITERATURE

Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy With Commentaries by Robert J. Ignoffo, PharmD, FASHP, FCSHP Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy, College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA

nP D-1

Inhibitor Lambrolizumab Is Safe, Shows Durable Responses in Patients with Advanced Melanoma

BACKGROUND: Lambrolizumab (previously known as MK-3475) is a humanized monoclonal immunoglobulin G4 antibody that blocks the programmed death-1 (PD-1) receptor and reactivates an immune response to the cancer cells. The PD-1 receptor limits the body’s immune response against cancer. Researchers have set out to investigate the safety and antitumor activity of 3 dosing regimens of lambrolizumab in a cohort of patients with advanced melanoma. METHODS: This multi-institutional, international, phase 1 expansion study included 135 patients with advanced melanoma. Some of the patients enrolled had received treatment with the checkpoint inhibitor ipilimumab and some had not received such treatment. All patients were administered the intravenous PD-1 inhibitor lambrolizumab at 10-mg/kg dosing every 2 or 3 weeks or 2-mg/kg dosing every 3 weeks. Tumor responses were assessed every 12 weeks. RESULTS: The confirmed response rate across the 3 dose cohorts was 38% (95% confidence interval [CI], 2544), with the highest confirmed response rate observed in the patients receiving the 10-mg/kg dose of lambrolizumab every 2 weeks (52%; 95% CI, 38-66). Previous therapy with ipilimumab did not affect the response to lambrolizumab. The response rate among patients who were previously treated with ipilimumab was 38% (95% CI, 23-55) compared with 37% (95% CI, 26-49) among those who had not received treatment previously. Response rates were durable in the majority of patients who had experienced response at a median follow-up of 11 months; 81% of patients with a response were still continuing treatment as of March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. The most common adverse events reported with lambrolizumab in this study were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. Drugrelated adverse events of any grade were reported by 79% of the patients, with grade 3 or 4 adverse events reported by 13%. The highest incidence of overall treatment-relat-

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ed adverse events was seen among patients receiving the lambrolizumab dose of 10 mg/kg every 2 weeks compared with patients receiving the 10-mg/kg dose every 3 weeks and those receiving 2 mg/kg every 3 weeks (23% vs 4% and 9%, respectively). Source: Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti–PD-1) in melanoma. N Engl J Med. 2013;369:134-144. COMMENTARY BY ROBERT J. IGNOFFO

In this phase 1 study by Hamid and colleagues, lambrolizumab given in a dose of 10 mg/kg intravenously every 2 weeks showed the highest response rate (52% as measured by Response Evaluation Criteria in Solid Tumors, and 57% as measured by an immune-mediated response) in patients with metastatic melanoma. Of the 52 responders, 42 were still receiving the drug at the time of response analysis. Twelve patients achieved a complete response. It is notable that responses were similar in the patients who had received previous ipilimumab therapy. The majority of responses were seen after the first imaging at 12 weeks, but several more responses were seen subsequently. At 11 months of follow-up, the median duration of response had not been reached. Only 10 responders had discontinued therapy at 11 months of follow-up; 5 of these were a result of grade 3 or 4 toxicity. Other common adverse effects included diarrhea, hypothyroidism, rash and pruritus, and fatigue. This degree of toxicity is reasonable for monoclonal antibody therapy. The US Food and Drug Administration designated lambrolizumab (MK-3475) as a breakthrough therapy for the treatment of patients with advanced melanoma. In a similar phase 1 study of nivolumab and ipilimumab in advanced melanoma, Wolchok and colleagues (Wolchok JD, et al. N Engl J Med. 2013;369:122-133) reported that nivolumab, another PD-1 inhibitor, combined with the cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitor ipilimumab, was no more toxic than either agent given alone. In addition, Wolchok and colleagues

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also found that at the maximum tolerated dose, 53% of patients with advanced, treatment-resistant melanoma had objective tumor responses, with tumor regression of at least 80% in every patient who had a response. These studies suggest that combination antibody therapy against PD-1 and CTLA-4 may offer an exciting new approach to treating tumors that are dependent on these tumor signaling receptor proteins.

was found in OS between the 2 treatment arms for the overall study population or for PSA doubling time subsets. These findings demonstrate that faster PSA doubling time is associated with a shorter BMFS in this patient population. Denosumab significantly increased BMFS time and time to first bone metastasis in the overall study population, and the drug has shown the greatest treatment effects in men who are at high risk for disease progression.

enosumab Improves Bone Metastasis–Free D Survival in Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Source: Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis–free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31:3800-3806.

BACKGROUND: In a recently reported phase 3 trial of men with nonmetastatic castration-resistant prostate cancer (CRPC) and high risk for disease progression based on baseline prostate-specific antigen (PSA) ≥8 ng/mL and/or PSA doubling time of 10 months or less, denosumab—an anti-RANK ligand monoclonal antibody—significantly increased bone metastasis–free survival (BMFS) and delayed time to first metastasis, but did not improve overall survival (OS) or progression-free survival compared with placebo. In a new exploratory analysis of the study, researchers evaluated the relationship between PSA doubling time and BMFS, time to first bone metastasis, and OS in recipients of denosumab and placebo. METHODS: This randomized, phase 3, double-blind, placebo-controlled study included 1432 men with nonmetastatic CRPC. The patients were randomized in a 1:1 ratio to monthly subcutaneous denosumab 120 mg or to placebo. The time of survival without bone metastasis was analyzed according to PSA doubling times of ≤10 months, ≤6 months, and ≤4 months. At baseline, median PSA was 12.3 ng/mL, PSA doubling time was 5.1 months, and doubling duration time was 47.1 months. RESULTS: An analysis of the placebo arm demonstrated a shorter BMFS time as PSA doubling time decreased to less than 8 months. Compared with placebo, treatment with denosumab was associated with median BMFS increases of 6 months (28.4 months vs 22.6 months, respectively; hazard ratio [HR], 0.84) in patients with a PSA doubling time of ≤10 months, 7.2 months (25.9 months vs 18.7 months; HR, 0.77) among patients with a PSA doubling time of ≤6 months, and 7.5 months (25.8 months vs 18.3 months; HR, 0.71) in patients with a doubling time of ≤4 months. The median time to first bone metastasis was significantly reduced with denosumab in patients with a PSA doubling time of ≤6 months (26.5 months vs 22.1 months, respectively; HR, 0.80) and ≤4 months (26.4 months vs 18.5 months; HR, 0.71). No difference

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In this study, denosumab was shown to effectively delay the onset of first bone metastases and to increase bone metastases disease-free survival in patients with high-risk prostate cancer, with the best outcomes observed in patients with a PSA doubling time of <6 months. In other studies, denosumab has also been shown to be more effective than zoledronic acid in preventing further skeletal-related events in prostate cancer metastatic to bone, and both drugs are approved by the US Food and Drug Administration (FDA) for this indication. Unfortunately, the beneficial effects of denosumab have not translated into either increased OS or improved control of bone pain, and, as a result, the FDA has not approved the drug for the prevention of bone metastases in patients with high-risk prostate cancer. The FDA was also concerned about the expected long-term use of denosumab in the setting of preventive treatment and the risk of serious toxicities, especially osteonecrosis of the jaw. The most important finding in the study by Smith and colleagues is that a short PSA doubling time was strongly associated with shorter BMFS. This is the first study to show this relationship, and it suggests that new strategies should be investigated that combine rational therapeutics with personalized medicine to treat advanced prostate cancer. The role of denosumab in this setting remains in doubt until it can demonstrate substantially better survival outcomes, improved quality of life, or a safer toxicity profile with long-term use. n

emcitabine Increases Survival for Patients G with Resected Pancreatic Cancer

BACKGROUND: The prognosis for patients with pancreatic cancer is poor, even for patients with surgi-

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FROM THE LITERATURE

cally resectable tumors. Gemcitabine (Gemzar) is the standard chemotherapy for advanced pancreatic cancer. Despite the lack of a clear consensus, gemcitabine has also become the mainstay of adjuvant treatment for this deadly disease, even though its effects on survival after surgery have not been demonstrated. Now, findings from the extended follow-up of the CharitĂŠ Onkologie 001 (CONKO-001) trial of patients with pancreatic cancer who underwent surgery provides support for the use of gemcitabine in the adjuvant setting. METHODS: CONKO-001 was a multicenter, openlabel, parallel-group, randomized, phase 3 trial that compared gemcitabine with observation alone in the adjuvant setting in 368 adults who had undergone complete, curative-intent resection of pancreatic cancer at 88 medical centers in Germany and Austria. In the intent-to-treat analysis, the investigators randomized 354 eligible patients to adjuvant gemcitabine (N = 179) or to observation alone (N = 175). Gemcitabine was administered at 1 g/m2 on days 1, 8, and 15 every 4 weeks for 6 months. The enrollment period ran from July 1998 to December 2004, and the follow-up period ended September 2012. During a median follow-up of 11 years, pancreatic cancer recurred in 308 patientsâ&#x20AC;&#x201D;145 in the gemcitabine group and 163 in the observation group. The primary end point was disease-free survival (DFS). The secondary end points included overall survival (OS). RESULTS: The results show that the median DFS was significantly greater with gemcitabine than with observation alone (13.4 months vs 6.7 months, respectively). Furthermore, the rates of DFS were significantly better with gemcitabine than with observation at 5 years (16.6% vs 7.0%, respectively) and 10 years (14.3% vs 5.8%, respectively). At the end of the follow-up, 316 of the 354 (89.3%) patients had died. The median OS was 22.8 months in the gemcitabine group versus 20.2 months in the observation group. The difference in OS between the 2 groups was significant. OS in the gemcitabine group at 5 years was 20.7% versus 10.4% in the observation group, and at 10 years was 12.2% versus 7.7%, respectively. These treatment benefits occurred across all subgroups of patients, regardless of tumor stage and nodal status at the time of resection. These findings are likely to be representative of general clinical practice in other countries, because CONKO-001 was a community-based trial that involved academic centers and community-based oncologists without uniform standards for surgery. Source: Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer. The CONKO-001 randomized trial. JAMA. 2013;310:1473-1481.

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COMMENTARY BY ROBERT J. IGNOFFO

This large, randomized phase 3 study showed that adjuvant gemcitabine compared with observation doubled the OS rate at 5-year follow-up and increased OS by 58% at year 10, which was a 25% improvement in the risk of mortality. This study establishes gemcitabine as one of the mainstay agents in the adjuvant treatment of pancreatic cancer. According to Sinn and colleagues, who recently reported on the long-term survival (>5 years) of patients with pancreatic cancer (Sinn M, et al. J Surg Oncol. 2013;108:398-402), the benefit of adjuvant gemcitabine was seen regardless of surgical margin outcomes. In the 54 patients (median age, 60.5 years) who were classified as long-term survivors, 53 had a confirmed histologic diagnosis of adenocarcinoma of the pancreas. Furthermore, the researchers also confirmed that the long-term survival rate was 15% at 11.3 years of follow-up. Sinn and colleagues were unable to detect any new biologic tumor markers associated with long-term survival. Although the study by Oettle and colleagues showed the benefit of gemcitabine in the adjuvant setting, pancreatic cancer remains a complex disease and requires further research to determine if other therapies will improve long-term survival in this poor-prognosis cancer. n

L ong-Term Treatment with Cetuximab Linked to Early Tumor Shrinkage in Patients with Colorectal Cancer

BACKGROUND: Although colorectal tumors with a mutation in the KRAS gene generally do not benefit from epidermal growth factor receptor (EGFR)targeted therapy such as cetuximab, there are no current biomarkers to select patients who are more likely to respond to EGFR therapy. In a new study, researchers analyzed data from 2 trials to determine if early tumor shrinkage was associated with longterm outcomes in patients with colorectal cancer receiving first-line treatment with cetuximab. METHODS: The researchers combined data from the Cetuximab Combined with Irinotecan in FirstLine Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer (OPUS) trials that accrued patients between 2004 and 2006. CRYSTAL was a randomized, open-label, multicenter, phase 3 trial comparing

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FROM THE LITERATURE

fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI alone. OPUS was a randomized, open-label, multicenter, phase 2 trial comparing fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) plus cetuximab with FOLFOX-4 alone. The analysis included 1289 patients whose tumors could be analyzed for KRAS mutation status. Patients were followed for a median of 45 months and 32 months in the CRYSTAL and OPUS trials, respectively. Response was assessed every 8 weeks until disease progression or withdrawal. RESULTS: Both trials showed that a more robust tumor response at 8 weeks after the start of therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild-type tumors. The researchers determined that early tumor shrinkage of 20% or more could identify patients who were receiving chemotherapy plus cetuximab with longer PFS and OS. In the CRYSTAL and OPUS trials, respectively, the cutoff value of early tumor shrinkage of ≥20% versus <20% for median PFS was 14.1 months versus 7.3 months and 11.9 months versus 5.7 months, and median survival was 30 months versus 18.6 months and 26 months versus 15.7 months. The interaction between early tumor shrinkage and the treatment group (with cetuximab) was significantly associated with PFS (P = .027 and P = .004 for CRYSTAL and OPUS data, respectively), but not for survival (P = .573 and P = .546, respectively). These results suggest that tumor shrinkage can be used as a prognostic biomarker. Source: Piessevaux H, Buyse M, Schlichting M, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764-3775.

COMMENTARY BY ROBERT J. IGNOFFO

This study uses a biometric model to calculate response to treatment and to compare early tumor shrinkage with a threshold of >20% at 8 weeks in patients with wild-type or mutated KRAS who were receiving cetuximab therapy. The theory is that rapid tumor response equates to greater drug sensitivity, especially in patients with a sensitive biomarker. Thus, patients with a >20% rapid tumor shrinkage is predictive of a better PFS. In contrast, patients who had <20% tumor shrinkage have a worse prognosis, suggesting that there was no benefit with the addition of cetuximab to chemotherapy. This study provides the clinician with a rational decision-making option based on a tumor biologic response (ie, rapid responders vs poor or slow responders), with the latter being switched to an alternative chemotherapy regimen. In an accompanying editorial, Oxnard and Schwartz state that the study suggests that a patient’s “response phenotype” can help guide treatment strategy (Oxnard GR, Schwartz LH. J Clin Oncol. 2013;31:3739-3741). Using a biologic response that can be accurately measured, as was done by Piessevaux and colleagues, can be a predictive marker for survival. Oxnard and Schwartz describe other biometric approaches for non–small-cell lung and esophageal cancers that use other methods for biologic response rather than the traditional objective response criteria. Oxnard and Schwartz also suggest that the work of Piessevaux and colleagues lends evidence that a biologic agent can cause tumor shrinkage as opposed to the older idea that these therapies are static in their antitumor effects. In summary, biometric methodologies that measure a response phenotype may expand our strategies for treating cancer.

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

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NEW FOR 2014! Principles in Value and Market Access Educational Session for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.

CONTINUING EDUCATION 6th Annual

DECEMBER 2013 • VOLUME 6 • NUMBER 5

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Beyond Complete Responses Publishing Staff Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto

LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this 6th annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this fifth issue, experts from the University of California, San Francisco answer questions related to the management of patients with MM who achieve complete responses. Sincerely, Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Associate Director, Content Strategy & Development John Welz 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 Maldonado Anthony Trevean Digital Programmer Michael Amundsen

FACULTY Jeffrey Wolf, MD Clinical Professor Department of Medicine Director, Myeloma Program University of California, San Francisco San Francisco, CA

Amy Marsala, NP Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Rebecca Young, PharmD, BCOP Clinical Pharmacist UCSF Medical Center Assistant Clinical Professor UCSF School of Pharmacy San Francisco, CA

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Supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company.

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This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC.

Office Coordinator Robert Sorensen Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Onyx Pharmaceuticals and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.0 contact hour. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this application-based activity provides for 1.0 contact hour (0.1 CEU) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-026-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss existing and emerging therapeutic options for patients with newly diagnosed or relapsed/refractory MM and how to tailor therapy for individual patients • Describe the pharmacokinetics and pharmacodynamics of nov-

el agents when integrating these agents into treatment regimens for MM • Evaluate adverse event management strategies for patients with MM receiving novel therapies and multidrug regimens

Rebecca Young, PharmD, BCOP, has nothing to disclose. She does intend to discuss either non–FDA-approved or investigational use for the following products/devices: investigation of carfilzomib in newly diagnosed MM.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for any agent discussed in this program should be inferred.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months. Planners’ and Managers’ Disclosures Dana Delibovi, Medical Writer, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use for any products/devices. William J. Wong, MD, MLI Reviewer, has nothing to disclose. Bobbie Perrin, RN, OCN, MLI Reviewer, has nothing to disclose. Shelly Chun, PharmD, MLI Reviewer, has nothing to disclose. Faculty Disclosures Sagar Lonial, MD, is on the advisory board for and is a consultant to Bristol-Myers Squibb, Celgene Corporation, Millennium: The Takeda Oncology Company, Novartis, Onyx Pharmaceuticals, and sanofi-aventis. He does not intend to discuss any non–FDAapproved or investigational use of any products/devices. Jeffrey Wolf, MD, is on the speaker’s bureau for Amgen, Celgene Corporation, Millennium: The Takeda Oncology Company, and Onyx Pharmaceuticals. He does intend to discuss either non–FDAapproved or investigational use for the following products/devices: MLN9708 and frontline carfilzomib. Amy Marsala, NP, has nothing to disclose. She does not intend to discuss non–FDA-approved or investigational use of any products/devices.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13008E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. For pharmacists, Medical Learning Institute Inc will report your participation in this educational activity to the NABP only if you provide your NABP e-Profile number and date of birth. For more information regarding this process or to get your NABP e-Profile number, go to www.mycpemonitor.net. Estimated time to complete activity: 1.0 hour Date of initial release: December 12, 2013 Valid for CME/CPE/CE credit through: December 12, 2014 SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

The Significance of Achieving Complete Response in Multiple Myeloma Jeffrey Wolf, MD

Clinical Professor, Department of Medicine Director, Myeloma Program University of California, San Francisco

Introduction Complete response (CR) is an extremely important goal of therapy for patients with multiple myeloma (MM). In this article, Jeffrey Wolf, MD, discusses recent data and consensus on the role of newer combination regimens in achieving and maintaining this endpoint, as well as the strong association of CR with survival outcomes, and the individualization of therapy for promoting optimal patient outcomes.

Which regimens are showing the greatest promise in terms of CR for newly diagnosed patients with MM? Today, the consensus in academic oncology is that triplet therapies are optimal for induction therapy; this approach is being adopted by more and more community oncologists as well. Commonly used triplet regimens with a robust evidence base in the transplant-eligible population include lenalidomide/bortezomib/dexamethasone (RVD) and cyclophosphamide/bortezomib/dexamethasone (CyBorD).1-3 These regimens provide high rates of very good partial re-

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sponse or better (≥VGPR), including high rates of CR.2,3 In a phase 1/2 study by Richardson and colleagues, the CR/near-complete response (nCR) rate was 57% in newly diagnosed patients treated with RVD, in phase 2 and before proceeding to autologous stem cell transplantation (ASCT).2 In a phase 2 study by Reeder and colleagues, treatment with 4 cycles of CyBorD in newly diagnosed patients led to CR/nCR and VGPR rates of 46% and 71%, respectively.3 Two additional frontline 3-drug regimens are also showing promise, both of which include novel proteasome inhibitors. The first of these is carfilzomib/ lenalidomide/low-dose dexamethasone (CRd). In a phase 1/2 trial by Jakubowiak and colleagues, after a median of 22 cycles and a median follow-up of 25 months (during which only 7 of 53 patients underwent ASCT), 87% of those treated with CRd achieved ≥VGPR, including 64% who achieved CR.4 The second regimen is MLN9708 combined with lenalidomide and dexamethasone. Richardson and colleagues recently reported early phase 1/2 trial results (after a median of 6 cycles in phase 1 and a single cycle in phase 2), which showed that treatment with this triplet produced ≥VGPR in 9 of 19 patients with newly diagnosed MM.5 Clinicians await more mature data from these studies as well as from randomized, controlled, phase 3 trials enrolling larger cohorts of patients. RVD is under investigation in phase 3 trials designed to compare its efficacy with or without transplant, to determine whether this regimen produces deep enough responses to warrant delay of ASCT to first progression.6,7 Results from these trials will attempt to address the following controversial question: Will regimens that include novel, targeted drugs be effective enough to shift the current paradigm from early transplantation (just after induction) to delayed transplantation (at first relapse)?

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Figure. 12-year PFS and OS rates by depth of response after induction and ASCT (N=344).13

Survival parameter

40 35

Patients (%)

Table. Association Between Post-ASCT Response and Median EFS and OS (N=632)15

28 22

15 10

11 8

5 0

0 CR

nCR

VGPR

nCR (months)

PR (months)

nCR vs PR, P value

EFS

<.00001

.07

.01

.04

ASCT indicates autologous stem cell transplantation; CR, complete response; EFS, event-free survival; nCR, near-complete response; NR, not reached; OS, overall survival; PR, partial response.

PFS

CR (months)

Differences in median survival between CR versus nCR, CR versus VGPR, and CR versus PR were statistically signiﬁcant in favor of CR (P≤.01). ASCT indicates autologous stem cell transplantation; CR, complete response; nCR, near-complete response; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; VGPR, very good partial response.

For the population of patients not eligible for transplant, we are free to use melphalan as part of an induction regimen. Beyond that, there is no longer a marked difference in approach between transplant-eligible and -ineligible patients. The distinction between the groups has been blurred by the increasing use of the same regimens in both settings. However, we now tend to use melphalan less often in older, transplant-ineligible patients. We may tailor regimens a bit when treating elderly patients or those whose performance status renders them too vulnerable for transplant.8 For example, we have used a dose-adjusted regimen of RVD in which lenalidomide is given at 15 mg (instead of at the usual 25-mg dose), bortezomib is given weekly instead of twice weekly, and dexamethasone is reduced from 40 mg to 20 mg. In frail or otherwise compromised older patients, clinicians in both academic and community settings may elect to use a doublet instead of a triplet regimen. Lenalidomide plus low-dose dexamethasone is a 2-drug regimen with a strong evidence base in older patients.9 If a patient has a high-risk cytogenetic abnormality, such as translocation 4;14 or deletion 17p,10,11 we tend to use bortezomib plus dexamethasone, as long as there is no special concern regarding bortezomib-induced neurotoxicity.

As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Should CR always be the goal of antimyeloma therapy, or is ≥VGPR a sufficient goal? There is no question that the goal of treatment should be CR. Granted, some data have suggested that achievement of ≥VGPR in transplant-eligible patients is a robust indicator of prognosis.12 However, the observation that VGPR is “sufficient” in many patients does not entail that VGPR is a “good enough” goal. As our therapies improve and we move closer to making myeloma a curable disease, we must absolutely strive for CR. Right now, we have a small number of patients with MM who have achieved CR and are essentially cured. Some of the patients treated at our center who underwent ASCT in the 1990s have not relapsed. We are curing a small population, and we are going to cure more in time. To make this happen, the goal out of the gate must be CR. Major studies supply evidence for the value of CR. A retrospective, multicenter evaluation of 344 patients by Martinez-Lopez and colleagues assessed the long-term prognostic significance of response in MM after transplantation; pa-

tients were treated between 1989 and 1999.13 Both overall survival (OS) and progression-free survival were significantly prolonged in patients who attained CR after transplantation compared with those who attained nCR, VGPR, and partial response (PR). At 12 years of follow-up, the percentage of patients who survived was highest among the group that achieved CR (Figure).13 After 17 years, OS plateaued in all groups, but at a three-fold higher rate in patients who attained CR posttransplant versus those who achieved nCR/VGPR/PR at ASCT (35% vs 11%, respectively). Similar results were observed in an analysis of data from the prospective Grupo Español de Mieloma 2000 trial.14 In patients who achieved CR after ASCT, both event-free survival (EFS) and OS were significantly longer than in patients achieving nCR. The nCR group, in turn, had significantly longer OS (but not EFS) than those who achieved only PR (Table).14 In this trial, posttransplantation response was markedly influenced by pretransplantation response, underscoring the importance of aiming for CR from the start of treatment. Data from important trials of antimyeloma therapy—VISTA; Total Therapy 2, 3, and 5; and an older trial evaluating vincristine/doxorubicin/dexamethasone—showed a directly proportional relationship between CR and survival.15-18 For instance, in the phase 3 VISTA trial, which compared bortezomib/melphalan/prednisone versus melphalan plus prednisone alone in a nontransplant population, attaining CR was associated with a significantly longer time to progression and OS.15 These findings support the strategy of continuing therapy in transplant-ineligible patients until CR. Although there will always be concern regarding the tolerability of drug treatment, on the whole, current regimens are fairly tolerable. Specifically, we now have oral immunomodulators and can administer bortezomib by subcutaneous (SC) injection, which reduces the risk of peripheral neuropathy.19 The SC route is quickly becoming the standard of care in terms of bortezomib administration. We can also offer patients improved supportive care. Taken together, all of these factors enable us to offer highly effective therapies for longer periods of time. Does a patient’s age have an impact on how aggressively you strive for CR? Achieving CR is especially important in younger patients with MM. If we fail to produce a cure or a very long remission in these individuals, they will die of the disease well before their time. Young patients in nCR, VGPR, or PR after several induction cycles are the ones we generally take to ASCT sooner rather than later. We feel that they need to be consolidated to try to get them to CR. In some cases, we may also switch the induction regimen (eg, from CyBorD to RVD or vice versa), add a drug to a doublet regimen, or use other strategies to improve reponse. The point is that we make every effort to produce CR, working to support patients through any toxicities associated with more aggressive treatments. In many older patients, CR should also be the goal. The reality for this age group, however, is that frailty, comorbidities, and lower performance status may make it more difficult to push as hard.8 These patients may not tolerate the treatments or doses often required to attain CR. Sometimes, we must accept the fact that VGPR is the most that can be achieved without risking quality of life and severe cytopenias or infections. We also must remember that every patient, regardless of age, is unique and complex. A few patients achieve CR and never need treatment again. Others achieve CR and sustain it with single-agent maintenance therapy. Still others, typically with high-risk cytogenetics, may achieve CR, but the remission is short-lived; these patients require skillful selection of second-line and salvage therapies to keep new clones from growing out and causing progression.

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CONSIDERATIONS IN MULTIPLE MYELOMA

Nursing Strategies for Improved Outcomes in Multiple Myeloma Amy Marsala, NP

Nurse Practitioner UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

Introduction Although the benefits seen with newer multidrug regimens have significantly improved clinical outcomes, patients with multiple myeloma (MM) are often challenged by the development of adverse events (AEs) that may impact quality of life (QoL) and lead to delays or discontinuation of treatment. In this article, Amy Marsala, NP, discusses nursing strategies for preventing and managing these events in the era of novel agents, and how consideration of patient-related factors contributes to effective individualized care.

How do patient preferences and limitations affect the choice of agents or regimens used in the treatment of MM? Multiple factors can influence treatment selection for patients with MM. Two of the most important factors are high-risk cytogenetics and prior response to treatment, including length of progression-free survival, how well therapy was tolerated, and whether the patient is still experiencing lingering toxicites.1,2 From a patient perspective, choice of treatment may also be influenced by mode of administration and toxicity profiles of various therapies and the type of maintenance follow-up that is required.2,3 In patients who are older or who have complex comorbidities, treatment tolerability is often an issue. For such individuals, dosing and schedule adjustments may be necessary to reduce the likelihood of exacerbating existing conditions such as peripheral neuropathy (PN), myelosuppression, or thromboembolic complications.3 For many of our patients, travel time to the clinic, access to transportation, and degree of caregiver dependence may impact medication adherence and influence treatment decisions. Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, as well as alkylating agents, such as melphalan and cyclophosphamide, have the advantage of being administered orally. In the outpatient setting, oral regimens offer greater convenience and consequently reduce certain barriers to adherence compared with regimens requiring attendance at the clinic for injections or infusions. Both lenalidomide and pomalidomide are typically dosed once daily on days 1 to 21 of repeated 28-day cycles.4,5 Melphalan and cyclophosphamide can be dosed weekly, which reduces daily pill burden.6,7 While daily dosing of agents can also lead to compliance issues, especially if complicated medication schedules or high pill burdens are involved, most patients still prefer oral administration over more invasive and lengthy intravenous (IV) administration. The first-in-class proteasome inhibitor bortezomib is available as either an IV infusion or a subcutaneous (SC) injection.8 SC bortezomib has become the preferred route at our center and requires less maintenance than IV bortezomib or the next-generation proteasome inhibitor, carfilzomib, which is typically administered as an IV infusion on 2 consecutive days for 3 weeks of a 4-week schedule.8,9 While total time of carfilzomib infusion is 2 to 10 minutes,9 medication preparation involving vein access and pre- and post-hydration results in a longer amount of chair time than IV bortezomib. The extra time and energy needed for IV treatments may be a deterrent for some patients, especially those who have remained in the workforce, are caring for young children, or must rely heavily on caregivers for transportation and support. Treatment-related toxicities impact the frequency and duration of clinical follow-up. Complete blood counts and chemistry panels are routinely drawn

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once weekly for patients receiving SC or IV medications, and less frequently for those receiving oral therapies.10 For patients with more aggressive MM or those with therapy-related hemodynamic instability, additional follow-up, including laboratory tests and possible blood or platelet transfusions, are often required if dose adjustments cannot be made without compromising disease control.10 Patients with relapsed/refractory MM are typically treated with combination regimens that include IMiDs, proteasome inhibitors, and/or alkylators plus dexamethasone.3 In this setting, the potential for cumulative toxicities must take precedence over patient preferences related to time commitments and routes of administration. To the best of their ability, clinicians should balance their efforts to minimize toxicities that are particularly distressing or which compromise QoL with maintaining control of the disease. How can chemotherapy-induced nausea and vomiting (CINV) be managed in patients receiving combination therapy? In the outpatient setting, the routine use of antiemetics has been reasonably effective in the management of CINV. Fortunately, novel antimyeloma agents are typically associated with lower rates of nausea and vomiting than older chemotherapeutic drugs used several decades ago. For example, bortezomib and lenalidomide are classified as having minimal emetogenic potential (<10% of patients experience emesis when antiemetics are not given).11 In fact, a recent cross-sectional cohort study reported that patients who had been treated for the previous 12 months with bortezomib, lenalidomide, and lower-dose alkylating agents reported symptoms of CINV as the least of all therapy-related toxicities.2 Similarly, carfilzomib and pomalidomide have demonstrated low to minimal emetogenic risk, especially when administered with dexamethasone.5,9 Some patients may be at increased risk for experiencing CINV. Female patients, those of younger age (<50 years), patients who are low regular alcohol users (<1 ounce per day), and those with a history of prior CINV all have elevated risk.11 Management of CINV should be approached similarly to management of pain, with an emphasis on prevention prior to onset of symptoms.10,11 It is important for clinicians to be mindful not only of acute CINV, which occurs 0 to 24 hours postchemotherapy, but delayed and breakthrough CINV as well, which may occur several days after chemotherapy, necessitating further antiemetic intervention.11 In accordance with antiemesis guidelines from the National Comprehensive Cancer Network, patients receiving chemotherapy with low risk of emetogenic potential should be treated prior to therapy with 1 or more antiemetic agents (Table).12 For patients who are at higher risk for CINV, 2 agents can be used. The concomitant use of dexamethasone to treat MM has also been effective as prophylaxis and treatment of nausea, although steroid use has its own toxicity profile that requires additional considerations.10 For patients with recurrent or unremitting CINV, or for patients receiving high-dose myeloablative therapies, including cy-

Table. Antiemetics for Patients Receiving IV Chemotherapy with Low Emetogenic Potential12 Metoclopramide 10-40 mg PO or IV (and then either every 4 or 6 hours as needed) or Dexamethasone 12 mg PO or IV daily or Prochlorperazine 10 mg PO or IV (and then every 6 hours as needed [maximum 40 mg/day]) Âą lorazepam, 0.5-2 mg PO or IV every 4 or 6 hours as needed Âą H2 blocker or proton pump inhibitor IV indicates intravenous; PO, by mouth.

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Figure. Treatable contributing factors for cancer-related fatigue.14 Activity level

Malnutrition

Sleep disorders

Pain

Cancer-related fatigue

Emotional distress

• Depression • Anxiety

Noncancer comorbidities

Anemia

• Endocrine dysfunction (hypothyroidism) • Infection • Cardiac dysfunction • Pulmonary dysfunction • Renal dysfunction • Hepatic dysfunction • Neurologic dysfunction

Reprinted with permission.

clophosphamide >1500 mg or IV melphalan 200 mg/m2 while undergoing transplantation, more potent medications may be necessary. Palonosetron, a nextgeneration serotonin subtype-3 receptor antagonist, aprepitant, a neurokinin-1 receptor antagonist, and olanzapine, an antipsychotic, can be given prophylactically and during treatment, but may require more complex management.12 Clinical implications of CINV include an increased risk for malnutrition, dehydration (and subsequent electrolyte imbalances), and weakness, which can ultimately affect organ function.13 The social health impact of chronic CINV hinders patient participation in social and public events, decreases energy and mood, and may worsen overall performance status. Patients should be assessed during every follow-up visit for the presence and severity of CINV and its interference with QoL. They should be encouraged to eat foods that offer the greatest appeal and to prepare smaller, more frequent meals or snacks to minimize weight loss. Treatment of underlying gastrointestinal disturbances, such as gastrointestinal reflux, abdominal bloating and cramping, or bowel movement irregularities is also important. In addition, adjusting the dose of current antiemetics, switching to antiemetics of a different class, and adding additional therapies are viable approaches to ameliorate symptoms. What can be done to address chronic fatigue? Chronic fatigue continues to pose a great challenge for most patients undergoing active antimyeloma therapy.14 The multifactorial and complex nature of fatigue demands comprehensive management of chronic anemia and pain, physical deconditioning, emotional stress, depression, and sleep disturbances.15 Nurses play a critical role in screening patients to identify modifiable causes of fatigue and implementing interventions to improve health outcomes (Figure).14 Chronic fatigue is often compounded by chronic anemia, which can be secondary to therapy or may be due to the disease itself or comorbid conditions. Treatment-induced myelosuppression may require dose adjustments or even discontinuation of therapy if anemia is severe (hemoglobin <8 g/dL).16 Cautionary supplemental use of injectable erythropoiesis-stimulating agents, such as epoetin alfa weekly or darbepoetin alfa weekly or every 3 weeks, has been recommended for those with chemotherapy-related severe anemia, with the goal of raising hemoglobin to 10 mg/dL.16 For anemia and/or fatigue related to iron deficiency or general malnutrition, counseling patients on diet modifications may also improve overall energy. Another cause of fatigue is the likelihood for decreased activity due to chron-

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ic pain in patients with myeloma-related bone disease. Approximately 85% of patients with MM have or will develop lytic bone lesions or fractures, which inhibit daily activities and decrease functional status.2,17 Therefore, effective pain management through adequate disease control and the use of pain medications prescribed at the lowest effective doses is imperative. Procedural kyphoplasty for eligible patients and adjunctive use of bisphosphonates to manage bone pain and prevent new fracture and lesions are also recommended.17 Localized radiation therapy may also be implemented to palliate specific bone sites and soft tissue pains with the goal of alleviating pain and enabling increased physical activity.17 Fatigue is also compounded by generalized muscle atrophy and physical deconditioning, which occurs in approximately 50% of patients during active treatment.15 Considerable research has demonstrated that patients who participate in low to moderate physical activities on a routine basis of 3 to 4 times per week can decrease their overall fatigue as well as improve their sleep quality, mood, and functional status.15 Coordinating care with cancer exercise specialists or assisting patients to create modified exercise programs and resistance activities should be explored. Engaging in as much physical activity as patients can comfortably tolerate is critical to enhancing energy and improving QoL. In our clinic, we routinely monitor patients for their ability and motivation to be active and make recommendations accordingly. Facilitating periodic discussions with patients about their mood and perception of functional status as it corresponds with the ability to enjoy life should be practiced. Antidepressants such as paroxetine, bupropion, or fluoxetine can be given to augment mood, although for some patients these agents may increase sedation and alter sleep patterns.14 Research on the use of psycho-stimulants including methylphenidate and modafinil are inconclusive, but these agents have been shown to provide enhanced mood and energy for select patients, although they may cause other undesirable AEs.14 Medications such as lorazepam or clonazepam may reduce anxiety and promote sleep; these agents may also alleviate CINV.12 We also encourage patients to seek out formal support groups, spiritual resources, pet therapy, and the help of family and friends as valuable resources during and after treatment. ♦ References

1. Munshi NC, Anderson KC, Bergsagel L, et al; on behalf of the International Myeloma

Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117:4696-4700. 2. Jordan K, Proskorovsky I, Lewis P, et al. Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer. 2013 Oct 13. [Epub ahead of print]. 3. Castelli R, Gualtierotti R, Orofino N, et al. Current and emerging treatment options for patients with relapsed myeloma. Clinical Medicine Insights: Oncology. 2013;7:209-219. 4. Revlimid [package insert]. Summit, NJ: Celgene Corporation. November 2013. 5. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013. 6. Alkeran Tablet [package insert]. Rockville, MD: ApoPharma USA, Inc. June 2011. 7. Cytoxan Tablets [package insert]. Princeton, NJ: Bristol-Myers Squibb. September 2005. 8. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc. 2012. 9. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc. July 2012. 10. Polovich M, Whitford JM, Olsen M (eds). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society, 2009. 11. Navari RM. Management of chemotherapy-induced nausea and vomiting: focus on newer agents and new uses for older agents. Drugs. 2013;73:249-262. 12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Antiemesis. Version 1.2013. http://www.nccn.org/ professionals/physician_gls/PDF/antiemesis.pdf. Accessed November 25, 2013. 13. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. 14. Carroll JK, Kohli S, Mustian KM, et al. Pharmacologic treatment of cancer-related fatigue. Oncologist. 2007;12(suppl 1):43-51. 15. Coleman EA, Goodwin JA, Coon SK, et al. Fatigue, sleep, pain, mood and performance status in patients with multiple myeloma. Cancer Nurs. 2011;34:219-227. 16. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression associated with novel therapies in patients with multiple myeloma: consensus statement of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 17. Terpos E, Moulopoulos LA, Dimopoulos MA. Advances in imaging and the management of myeloma bone disease. J Clin Oncol. 2011;29:1907-1915.

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Pharmacologic Perspectives on Novel Therapies in Multiple Myeloma Rebecca Young, PharmD, BCOP

Clinical Pharmacist, UCSF Medical Center Assistant Clinical Professor, UCSF School of Pharmacy San Francisco, CA

Introduction The development and approval of more effective drugs have led to better complete response (CR) rates and prolonged survival in multiple myeloma (MM). When choosing among these novel therapies, it is essential to consider factors such as pharmacologic profiles and dosing requirements to promote individualized care. In this article, Rebecca Young, PharmD, BCOP, discusses recent advances in the management of myeloma, including novel agents being incorporated into combination regimens and the role of bisphosphonates for improving patient outcomes.

How are newer frontline regimens improving outcomes in patients with MM? Survival of patients with MM has dramatically improved in recent years, as initial treatment has shifted from conventional chemotherapy to incorporation of novel therapies such as immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was the first novel IMiD to demonstrate clinical benefit in MM. A phase 3 randomized trial demonstrated significantly higher response rates in newly diagnosed patients who received thalidomide plus dexamethasone, compared with dexamethasone alone (63% vs 41%, respectively; P=.0017).1 Lenalidomide, a potent analogue of thalidomide with an improved toxicity profile—including lower rates of neurotoxicity—exerts a unique dual mechanism of action comprising both tumoricidal and immunomodulatory effects.2 Lenalidomide plus low-dose dexamethasone (Rd) has been associated with improved short-term overall survival (OS) with less toxicity compared with the historical standard of lenalidomide plus high-dose dexamethasone (RD). Newly diagnosed patients with MM were studied in an open-label noninferiority trial of lenalidomide 25 mg on days 1 to 21, plus either high-dose dexamethasone (40 mg on days 1-4, 9-12, and 17-20), or low-dose dexamethasone (40 mg on days 1, 8, 15, and 22). Interim analysis at 1 year showed that OS was higher with Rd than with RD (96% vs 87%; P=.0002). Low-dose dexamethasone was also better tolerated than high-dose dexamethasone, with less incidence of grade 3/4 toxicities within the first 4 months of treatment (35% vs 52%, respectively; P=.0001).3 Bortezomib, the first-in-class reversible proteasome inhibitor, has also transformed outcomes for patients with MM. Bortezomib-based therapy has been shown to improve survival in patients with translocation 4;14, a high-risk cytogenetic feature that typically confers poorer prognosis.4 Combination therapy with melphalan and prednisone plus either thalidomide or bortezomib has been shown to be effective in patients not eligible for transplant, producing significantly improved CR rates, time to progression, and OS.5,6 In the phase 3 randomized IFM 2005-01 trial, the combination of bortezomib plus dexamethasone (VD) demonstrated significantly higher rates of postinduction CR/near-complete response (nCR) (14.8% vs 6.4%), very good partial response ([VGPR] 37.7% vs 15.1%), and overall response rate ([ORR] 78.5% vs 62.8%) compared with vincristine/doxorubicin/dexamethasone (VAD) in transplant-eligible patients with MM. After a median follow-up of 32.2 months, progression-free survival (PFS) was slightly higher, though not statistically significant, with the VD regimen compared with the VAD regimen (36 months vs 29.7 months; P=.064).7 In a phase 2 clinical trial, cyclophosphamide/bortezomib/dexamethasone

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(CyBorD) as frontline therapy in 33 newly diagnosed patients with MM produced an ORR of 88% by intention-to-treat analysis. Patients received oral cyclophosphamide 300 mg/m2 (days 1, 8, 15, and 22), intravenous (IV) bortezomib 1.3 mg/m2 (twice weekly; days 1, 4, 8, and 11), and oral dexamethasone 40 mg (days 1-4, 9-12, and 17-20) every 28 days for 4 cycles. For those completing all 4 cycles of treatment (n=28), the ORR was 98% (including 71% in ≥VGPR and 46% CR/nCR).8 Despite the high response rates noted above, the investigators modified the treatment schedule for an additional 30 patients in an effort to decrease toxicity and treatment delays. Additional patients received the same weekly dose of cyclophosphamide, but were given once-weekly bortezomib 1.5 mg/m2 (days 1, 8, 15, and 22), and weekly dexamethasone in cycles 3 and 4. Although patients who received twice-weekly bortezomib had higher baseline advanced-stage disease, weekly bortezomib produced similar responses with less grade 3/4 toxicity. Fewer dose reductions of bortezomib and dexamethasone were required with once-weekly bortezomib, and rates of peripheral neuropathy (PN) were the same despite higher total bortezomib dose per cycle in the once-weekly versus the twice-weekly schedule (6.0 mg/m2 vs 5.2 mg/m2).9 A phase 1/2, multicenter trial by Richardson and colleagues was the first prospective study of lenalidomide/bortezomib/dexamethasone as treatment for patients with newly diagnosed MM (N=66).10 The phase 2 study portion established a maximum planned treatment dose of lenalidomide 25 mg (days 1-14), bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), and dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12) given every 3 weeks. In the phase 2 population, the partial response rate was 100%, with 74% of patients achieving ≥VGPR. Primary toxicities included PN (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3. No treatment-related mortality was observed. What do pharmacists need to know about carfilzomib and pomalidomide? Carfilzomib, a next-generation epoxyketone-based proteasome inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of patients with MM who have received at least 2 prior therapies, including bortezomib and an IMiD, and have demonstrated disease progression on or within 60 days of the completion of their last therapy.11 Two advantages that carfilzomib has over bortezomib are its ability to provide a more durable, irreversible inhibition of the proteasome, and its association with a lower incidence of PN. These characteristics and others are highlighted in the comparison of bortezomib and carfilzomib found in Table 1.12,13 Initial dose of carfilzomib is 20 mg/m2 on 2 consecutive days each week for 3 weeks (days 1, 2, 8, 9, 15, and 16) of a 28-day cycle. The dose should be increased on cycle 2 and subsequent cycles to 27 mg/m2.12 Doses should be capped at a body surface area of 2.2 m2. Higher doses and alternative infusion strategies are currently under investigation. Carfilzomib is a substrate of P-glycoprotein, and weakly inhibits cytochrome (CYP) 3A4 and P-glycoprotein.12,13 Carfilzomib received accelerated approval by the FDA in July 2012 based on Table 1. Comparison of Proteasome Inhibitors Approved for MM12,13 Chemical structure Inhibition type Administration route Cytochrome metabolism Half-life (minutes)

Bortezomib

Carfilzomib

Boronic acid

Epoxyketone

Reversible

Irreversible

IV/SC

3A4, 2C19

Minimal

110

<30

IV indicates intravenous; MM, multiple myeloma; SC, subcutaneous.

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Table 2. Recommended Dosing of Bisphosphonates for Prevention of SREs27,28 Clearance Creatinine (mL/min)

Zoledronic Acid (mg)a

Pamidronate (mg) 90 IV over at least 2 hours

>60

50-60

3.5

40-49

3.3

30-39

<30

Avoid use

30-90b IV over 4-6 hours

All doses infused IV over 15 minutes. In absence of formal guidelines, clinicians may consider reduced doses given over an extended interval of 4-6 hours based on individual patient risk assessment. IV indicates intravenous; SREs, skeletal-related events. b

results of a phase 2, open-label, single-arm trial that enrolled 266 heavily pretreated patients (≥2 prior therapies) with relapsed and/or refractory MM. Among the efficacy population (n=257), median duration of treatment was 3 months, and ORR was 23.7%.11,14 The efficacy of carfilzomib in frontline regimens for newly diagnosed patients with MM is the focus of ongoing investigation. Carfilzomib in combination with lenalidomide and dexamethasone as initial therapy has been evaluated in 2 phase 1/2 single-arm trials.15,16 Results from these studies have led to this combination being listed as a category 2A treatment option in the National Comprehensive Cancer Network guidelines for myeloma.17 Similar to bortezomib, no significant changes in pharmacokinetics in renally impaired patients have been observed with carfilzomib.14-16 In patients with high tumor burden, clinicians should monitor for signs/symptoms of tumor lysis syndrome. Prehydration with a minimum of 250 to 500 mL during cycle 1 of carfilzomib is recommended, and should be continued on subsequent cycles if necessary. Infusion reactions may occur immediately or within 24 hours of carfilzomib administration. Premedication with dexamethasone 4 mg to reduce the incidence and severity of infusion reactions is recommended during cycle 1, during escalation cycles, and as needed with subsequent cycles. Bone marrow suppression, especially thrombocytopenia, is a toxicity frequently observed with carfilzomib use. Other rare, but serious toxicities associated with this agent include cardiovascular complications (development or worsening of congestive heart failure, pulmonary edema, decreased left ventricular ejection fraction), pulmonary complications, and hepatotoxicity.18

Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Pomalidomide, a next-generation oral immunomodulatory agent, is also approved by the FDA for the treatment of patients who have received at least 2 prior therapies, including bortezomib and an IMiD, and who have demonstrated disease progression on or within 60 days of therapy completion.19 In general, IMiDs suppress production of various cytokines that support tumor cell growth, alter bone marrow microenvironment, as well as inhibit angiogenesis. Pomalidomide is 10fold more potent than lenalidomide and up to 15,000 times more potent than thalidomide in inhibiting tumor necrosis factor-α.20 The recommended starting dose of pomalidomide is 4 mg once daily orally on days 1 to 21 of repeated 28-day cycles until disease progression.21 This agent is primarily metabolized by CYP3A4 and CYP1A2, and is a substrate for P-glycoprotein. Pomalidomide and its metabolites are excreted renally.21 Use of this agent should be avoided in patients with serum creatinine >3 mg/dL due to lack of safety data. A multicenter, randomized, open-label, phase 3 trial compared the efficacy and safety of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone in patients with MM who were refractory to both lenalidomide and bortezomib (N=455).22 At interim analysis (median follow-up, 4.2 months), PFS was significantly longer in patients who received pomalidomide and low-dose dexamethasone (3.6 months vs 1.9 months; P<.0001) compared

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with high-dose dexamethasone. Regimens containing pomalidomide and carfilzomib are promising. For example, interim results of a phase 1/2 trial evaluating a combination of carfilzomib/pomalidomide/low-dose dexamethasone in 32 heavily pretreated patients with relapsed and/or refractory MM suggest that this regimen is well tolerated with high response rates, even in patients with poorrisk cytogenetics such as deletion 17p.23 Pomalidomide is associated with a relatively low risk of PN compared with other IMiDs.13 Common grade 3/4 toxicities associated with the use of this agent include myelosuppression, fatigue, and infections.21 Pomalidomide should be administered on an empty stomach, and is only available through the Celgene Risk Evaluation and Mitigation Strategy program to prevent its administration during pregnancy, due to the risk of embryo-fetal toxicity. As with other IMiDs, the risk of thromboembolism is increased with administration of pomalidomide, requiring the need for thromboprophylaxis.21 What is the role of bisphosphonates in managing myeloma-related bone disease? Osteolytic bone disease, a common complication of myeloma, affects approximately 85% of patients at diagnosis.17 Bisphosphonates exert their effects by inhibiting osteoclast recruitment and maturation, and inducing osteoclast apoptosis. IV zoledronic acid and pamidronate, as well as oral clodronate (available outside of the United States) are the only agents approved for the treatment of myeloma-related bone disease.17 All patients with myeloma-related bone lesions at the time of diagnosis should be started on bisphosphonate therapy, repeated every 3 to 4 weeks, concurrently with induction chemotherapy. Use of bisphosphonates in asymptomatic (smoldering) or stage I disease is debatable. A recent Cochrane meta-analysis of 20 randomized controlled trials concluded that adding bisphosphonates to the treatment of MM reduced vertebral fractures and pain; the duration of therapy was typically 2 years.24 Subset data for patients receiving zoledronic acid for longer than 2 years demonstrated a continued reduction in skeletal-related events (SREs) and prolonged OS. Currently, it is unclear if patients will continue to benefit from bisphosphonate therapy after they achieve a CR. Use beyond 2 years is dependent on the patient’s response to therapy, as well as the physician's discretion. If bisphosphonate therapy is stopped after 2 years, it should be resumed at disease progression.25 Whether zoledronic acid is superior to pamidronate in preventing myeloma-related bone disease remains to be determined. The Cochrane meta-analysis reported that zoledronic acid is the only bisphosphonate to demonstrate superior OS compared with placebo in a randomized study.24 In a randomized, doubleblind, multicenter trial, zoledronic acid was found to be as effective as pamidronate in reducing pain, incidence of SREs, and delaying time to first SRE.26 Overall, zoledronic acid and pamidronate are equally well tolerated.27,28 Possible toxicities include bone pain, gastrointestinal disturbances, fatigue, fever, renal impairment, and hypocalcemia. Providers should monitor for renal dysfunction, and adjust doses appropriately. Standard and recommended dose adjustments are shown in Table 2.27,28 Osteonecrosis of the jaw (ONJ) is a rare but serious complication associated with prolonged bisphosphonate therapy. This event occurs more often with zoledronic acid than with pamidronate therapy.29 Preventive measures such as completing dental work-up prior to the start of bisphosphonates, waiting 6 to 8 weeks after invasive dental procedures prior to starting bisphosphonates, and maintaining good oral hygiene have been shown to decrease the incidence of ONJ.30 ♦ References

1. Rajkumar SV, Blood E, Vesole D, et al. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431-436. 2. Dimopoulos MA, Terpos E. Lenalidomide: an update on evidence from clinical trials. Blood Rev. 2010;24(suppl 1):S21-S26). 3. Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised control trial. Lancet Oncol. 2010;11:29-37. 4. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improves outcome of patients t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 5. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalana and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696.

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CONSIDERATIONS IN MULTIPLE MYELOMA

6. 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;28:2259-2266. 7. Harousseau JL, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. 8. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 9. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 10. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116; 679-686. 11. US Food and Drug Administration. Announcements. FDA approves Kyprolis for some patients with multiple myeloma. July 20, 2012. www.fda.gov/newsevents/newsroom/pressannouncements/ucm312920.htm. Accessed December 1, 2013. 12. Jain S, Diefenbach C, Zain J, et al. Emerging role of carfilzomib in treatment of relapsed and refractory lymphoid neoplasms and multiple myeloma. Core Evid. 2011;6:43-57. 13. El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. Am J Clin Oncol. 2013 Aug 7. [Epub ahead of print]. 14. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX-171003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120: 2817-2825. 15. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood. 2012;120:1801-1809. 16. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of carfilzomib, lenalidomide, and dexamethasone (CRd) in newly diagnosed multiple myeloma (MM) patients. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 732. 17. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in

Oncology (NCCN Guidelines®). Multiple Myeloma, V2. 2014. www.nccn.org. Accessed November 24, 2013. 18. Kyprolis [package insert]. South San Francisco, CA: Onyx Pharmaceuticals, Inc. July 2012. 19. US Food and Drug Administration. Announcements. FDA approves Pomalyst for advanced multiple myeloma. February 8, 2013. www.fda.gov/newsevents/newsroom/pressannouncements/ ucm338895.htm. Accessed December 5, 2013. 20. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163:380-386. 21. Pomalyst [package insert]. Summit, NJ: Celgene Corporation. February 2013. 22. Dimopoulos MA, Lacy MQ, Moreau P, et al. Pomalidomide in combination with low-dose dexamethasone: demonstrates a significant progression free survival and overall survival advantage, in relapsed/refractory MM: a phase 3, multicenter, randomized, open-label study. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 6. 23. Shah JJ, Stadtmauer EA, Abonour R, et al. A multi-center phase I/II trial of carfilzomib and pomalidomide with dexamethasone (Car-Pom-d) in patients with relapsed/refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 74. 24. Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev. 2012;5:CD003188. 25. Terpos E, Roodman GD, Dimopoulos MA. Optimal use of bisphosphonates in patients with multiple myeloma. Blood. 2013;121:3325-3328. 26. Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer. 2003; 98:1735-1744. 27. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. May 2012. 28. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp. September 2013. 29. Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134:620-623. 30. Dimopoulos MA, Kastritis E, Bamia C, et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventative measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol. 2009;20:117-120.

The Significance of Achieving Complete Response in Multiple Myeloma Continued from page 142 Newer technologies, notably genomic sequencing and testing after CR for minimal residual disease, hold the promise of enhancing our predictions of each patient’s clinical course. These technologies may also improve our ability to choose drugs and to determine when maintenance is warranted. The result will be greater personalization of care and a better chance at CR for more patients with MM. ♦ References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Multiple Myeloma. Version 2.2013. http://www.nccn.org. Accessed June 2, 2013. 2. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116: 679-686. 3. Reeder CB, Reece DE, Kukreti V, et al. Cyclosphosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 4. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(15 suppl):Abstract 8543. 5. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(15 suppl):Abstract 8033. 6. Randomized trial of lenalidomide, bortezomib, dexamethasone vs high-dose treatment with SCT in MM patients up to age 65 (DFCI 10-106). NCT01208662. http://www.clinicaltrials. gov/ct2/show/NCT01208662?term=RVD&rank=9. Accessed November 22, 2013. 7. Study comparing conventional dose combination RVD to high-dose treatment with ASCT in the initial myeloma up to 65 years (IFM/DFCI2009). NCT01191060. http://www.clinicaltrials. gov/ct2/show/NCT01191060?term=RVD&rank=2. Accessed November 22, 2013. 8. Palumbo A, Bringhen S, Ludwig H, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011; 118:4519-4529.

9. Rajkumar SV, Jacobus S, Callander NS, et al; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 10. Cavo M, Tacchetti P, Patriarca F, et al; GIMEMA Italian Myeloma Network. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 11. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2012;119:940-948. 12. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009; 27:5720-5726. 13. Martinez-Lopez J, Blade J, Mateos M-V, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011;118:529-534. 14. Laheurta JJ, Mateos MV, Martinez-López J, et al. Influence of pre- and post-transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol. 2008; 26:5775-5782. 15. Harousseau J-L, Palumbo A, Richardson P, et al. Superior outcomes associated with complete response: analysis of the phase III VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 2778. 16. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer. 2008;113: 355-359. 17. Usmani SZ, Waheed S, Van Rhee F, et al. Total Therapy 5 (TT5) for newly diagnosed highrisk multiple myeloma (HRMM): comparison with predecessor trials Total Therapy 3a and 3b (TT3 a/b). J Clin Oncol (ASCO Annual Meeting Abstracts). 2013;31(15 suppl):Abstract 8539. 18. Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant. 2001;27:1037-1043. 19. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12:431-440.

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What if you could use the body’s own T cells to combat Lung Cancer? With Immuno-Oncology it may be possible. Current approaches to lung cancer treatment include radiation, surgery and chemotherapy/targeted therapy, all of which are intended to target the tumor. Through our ongoing clinical program, BMS is investigating an entirely new way to treat lung cancer by targeting the immune system. Our research is focused on transforming the way tumor cells and the immune system communicate, including checkpoint pathways; we hope to find new ways to stop lung cancer from evading the immune system, thereby restoring the body’s natural ability to fight it. If you’re interested in learning more about BMS investigational studies in lung cancer, including a list of study sites, please visit BMS Study Connect to search for lung cancer studies near you. http://www.bms.com/studyconnect/Pages/Home.aspx

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