TOP May 2014 by The Oncology Pharmacist

May 2014

www.TheOncologyPharmacist.com

Vol 7, No 2

Pharmacoeconomics

Cancer Center Profile

Jefferson School of Pharmacy at Thomas Jefferson University

340B Pricing—Who Wins, Who Loses? Caroline Helwick

“T The staff at the Senior Adult Oncology Center at Thomas Jefferson University Hospital. Front row, left to right: Ginah Nightingale, PharmD, BCOP (Oncology Advanced Practice Pharmacist) and Kristine Swartz, MD (Geriatrician). Back row, left to right: Jillian Brown, RN (Nurse Coordinator); Andrew Chapman, DO, FACP (Co-Director for the Senior Adult Oncology Center, Medical Oncologist); Monica Crawford, MA, RD, LDN (Registered Dietitian); and Carolyn Davis, MSW, LSW (Social Worker).

he Jefferson School of Pharmacy at Thomas Jefferson University was founded in 2008 and offers an innovative doctor of pharmacy program that prepares graduates for interesting and challenging pharmacy practice roles across the healthcare continuum. The faculty comprises accomplished and diverse healthcare leaders, teachers, researchers, and preceptors (practitioners). Collectively, this group offers a broad range of experiences and perspectives, and its members are recognized for leadership in national and international pharmacy and healthcare membership organizations as well as research in pharmaceutics, pharmacology, health outcomes, the clinical sciences, and related fields. Continued on page 22

Conference News

Highlights From the American Association for Cancer Research Annual Meeting Alice Goodman

he American Association for Cancer Research (AACR) held its annual meeting in San Diego, California, April 5-9, 2014. Presentations at this meeting are typically focused on new research in therapeutics and epidemiology. Below are brief reports on some highlights from the AACR annual meeting related to cancer risk

and health-related behaviors. As in the general population, some risk factors are modifiable; these include exercise, diet, maintaining a healthy body weight, and avoiding tobacco. Drinking 4 cups of coffee or more per day appears to offer protection against hepatocellular carcinoma and melanoma.

he 340B pricing program will continue to be modified to improve oversight and compliance, but it is here to stay,” according to Ron Schleif, MBA, BSPharm, cofounder and president of Oncology Reimbursement Management, a consulting firm. Speaking at the Hematology/Oncology Pharmacy Association 10th Annual Conference in New Orleans, Louisiana,

Schleif explained that 340B is intended to stretch limited federal resources for certain entities, and it has garnered near-universal legislative support. In fact, in 2013 both the US House and Senate took steps to broaden the program. “The reason is fairly obvious,” he said. “This is a program that is offered by the government, but it doesn’t cost the government a dime.” Continued on page 10

Side Effects Management

Skin Toxicity With Targeted Agents: Treatment With Antibiotics, Topical Steroids Often Sufficient Wayne Kuznar

eactive management and attention to possible infection is usually sufficient to treat dermatologic toxicities associated with targeted cancer therapies, said Barbara Burtness, MD, professor of medical oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania. With epidermal growth factor receptor (EGFR) inhibitors, treating skin toxicity is preferred over suspending the agent,

because the development of rash is associated with better efficacy and outcome, she said at the 2014 annual meeting of the National Comprehensive Cancer Network. Although rash as a toxicity of EGFR inhibitors may look like acne, it is actually a mixed inflammatory infiltrate with follicular rupture. In general, these infiltrates Continued on page 22

inside Multiple Myeloma . . . . . . . . . . . . . . Monoclonal Antibodies for Multiple Myeloma Side Effects Management . . . . For Cancer-Induced Anemia, ESAs Best Given With IV Iron Leukemias. . . . . . . . . . . . . . . . . . . . . . . . . Molecular Monitoring Can Provide Treatment Guidance in CML

3 8 9

Renal Cancer Angiotensin System Inhibitors Extend Survival in Patients With Metastatic Renal Cell Carcinoma. . . . . Molecular Therapy Beyond Sorafenib in HCC: New Pathways, Targets Being Explored. . . . . . . . . . . . . .

14 15 18

Best Practices . . . . . . . . . . . . . . . . Maximizing Safety of Chemotherapeutic Drugs During Pregnancy

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *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 is a leukocyte growth factor indicated for reduction 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 colonystimulating 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. » 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 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. » 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. February 2014.

Cancer Multiple Center Myeloma Profile

Monoclonal Antibodies for Multiple Myeloma Caroline Helwick

ithin the oncology drug development pipeline, “multiple myeloma is one of the more intriguing spaces,” according to R. Donald Harvey, PharmD, BCOP, who said one reason for his excitement is the emergence of monoclonal antibodies. Harvey, associate professor of hematology/oncology at Emory University

in Atlanta, Georgia, and director of its Phase I Clinical Trials Section, described investigational agents for myeloma and other cancers at the Hematology/ Oncology Pharmacy Association 10th Annual Conference.1 Among the drugs for myeloma are not only better versions of current conventional classes of drugs, but entirely new

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 non-US-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.

classes of agents for this malignancy. Early-phase trials suggest their impact will be huge, he said. “It is odd to treat a disease of antibodies with antibodies,” Harvey said, “but improvements in our understanding of molecular biology and cell surface receptors have led to a number of impressive drug development stories.”

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: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Monoclonal antibody inhibition is still in its early phases with respect to myeloma, but already a number of targets are in focus, including CS1, CD38, CD40, CD138, CD200, CD56, interleukin-6, and BAFF. Besides monoclonal antibodies, he said he is also encouraged by early-phase data on histone deacetylase inhibitors (panobinostat, ricolinostat), a kinesin spindle protein inhibitor (filanesib), and an Akt inhibitor (afuresertib). Targeting CS1 Elotuzumab targets CS1, a cell surface glycoprotein that is highly expressed on more than 95% of myeloma cells. In a myeloma xenograft mouse model, the combination of elotuzumab plus lenalidomide significantly reduced tumor volume, compared with either agent alone, suggesting this drug will work best in combination regimens. In a study of 73 patients, the objective response rate was 82% for the combination, including 12% complete or stringent complete responses.2 Interestingly, elotuzumab displays “saturable receptor occupancy,” likely meaning that with this compound “the more drug you have, the more it knocks itself off the receptor”; therefore, 10 mg/kg is more active than 20 mg/kg. Infusion reactions are not uncommon with elotuzumab, which has led to the recommendation for aggressive premedication. Targeting CD38 Daratumumab targets CD38, a transmembrane glycoprotein and ectoenzyme with high receptor density on myeloma cells. The effects of CD38 inhibition include apoptosis after cross-linking, modulation of enzymatic activation, induction of cell-dependent cytotoxicity, and induction of antibody-dependent cell cytotoxicity. “These things are generally good with respect to cancer but concerning with respect to infusion reactions, and adverse events do occur, including bronchospasm, but it is typically well managed,” Harvey indicated. As a single agent, daratumumab showed strong activity in a phase 1/2 study in which 47% of patients derived benefit, with 66% achieving a minor response or better at doses of 4 mg/kg.3 Due to encouraging results from phase 1 trials, a phase 2 trial has enrolled “at record numbers,” he noted, and the US Food and Drug Administration has granted this agent breakthrough status. SAR650984 is also an anti-CD38 antibody. In a phase 1 dose-escalation trial of Continued on page 5

www.TheOncologyPharmacist.com

May 2014 I VOL 7, NO 2

Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Tulsa, OK

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh Roswell Park Cancer Institute Buffalo, NY

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

Fox Chase Cancer Center Philadelphia, PA

Desert Regional Medical Center Palm Springs, CA

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

ASSOCIATE EDITOR-IN-CHIEF

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

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

David Baribeault, BS, BCOP McKesson Health Solutions Boston, MA

Betty M. Chan, PharmD, BCOP USC/Norris Cancer Hospital Los Angeles, CA

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

David C. Gammon, BSPh

Laura Boehnke Michaud, PharmD, BCOP, FASHP

Jefferson School of Pharmacy Philadelphia, PA

OncologyPharmacist.net Warwick, RI

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

The University of Texas MD Anderson Cancer Center Houston, TX

University of North Carolina Hospitals and Clinics Chapel Hill, NC

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Burt Zweigenhaft, BS

Onco360/OncoMed New York, NY

Marlo Blazer, PharmD, BCOP James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP Maine Center for Cancer Medicine Scarborough, ME

May 2014 I VOL 7, NO 2

Lew Iacovelli, BS, PharmD, BCOP, CPP

Moses H. Cone Health System Greensboro, NC

LeAnn Best Norris, PharmD, BCPS, BCOP South Carolina College of Pharmacy Columbia, SC

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

www.TheOncologyPharmacist.com

Cancer Multiple Center Myeloma Profile

Monoclonal Antibodies for Multiple Myeloma

Continued from page 3

patients who had received a median of 5 prior lines of therapy, 13 patients received the maximum dose ( 10 mg/kg every 2 weeks). The overall response rate was 30.8%, with half of these a complete response.4

we can say that we eradicated all measurable disease in the patient,” he said.

Targeting CD138 Another interesting new drug is a potent antibody-drug conjugate that targets CD138, an antigen highly expressed on myeloma cells. Indatuximab ravtansine (BT062) is designed to deliver the maytansinoid cytotoxic agent DM4 specifically to these CD138-expressing cells. In a phase 1 trial of 21 patients with relapsed/ refractory multiple myeloma, 100% of 15 evaluable patients achieved stable disease or better, and 73% of patients evaluable for efficacy responded to BT062 plus lenalidomide/dexamethasone.5 “I think not only in hematology but in solid tumors as well, we are going to see an explosion in antibody drug conjugates,” he said. Harvey predicted that based on the activity of these monoclonal antibodies, myeloma may someday be treated more as lymphoma is treated, by adding an antibody. “We might someday be giving 5 or 6 drugs for induction, because we will get deep responses this way. And we might be measuring myeloma like we do CLL [chronic lymphocytic leukemia], where

“We might someday be giving 5 or 6 drugs for induction, because we will get deep responses this way. And we might be measuring myeloma like we do CLL, where we can say that we eradicated all measurable disease in the patient.”

until disease progression. Only 2 cases of grade 3 peripheral neuropathy occurred

R. Donald Harvey, PharmD, BCOP

Oral Proteasome Inhibitors In addition to new classes of drugs, conventional classes of agents are becoming even more effective and less toxic. The oral proteasome inhibitor ixazomib (MLN9708) produced a highly impressive 94% response rate (after 4 cycles) when combined with lenalidomide and dexamethasone in treatment-naive patients.6 Sixty-five patients received ixazomib weekly in combination with lenalidomide (25 mg/day) and dexamethasone (40 mg/week), then continued on ixazomib as maintenance therapy

at the recommended phase 2 dose of 2.97 mg/m2. “This is an exciting 3-drug regimen that is fairly well tolerated. Ixazomib is not an ‘oral bortezomib.’ It is different in terms of activity and also toxicity,” he indicated. Another oral proteasome inhibitor in development, oprozomib, is a structural analog of carfilzomib that comes in 2 formulations: powder-in-capsule split dose and once-daily modified-release formulations. The drug’s efficacy seems dependent on proteasome inhibition; more

than 80% inhibition is achieved with 210 mg/day of oprozomib. With oral proteasome inhibitors now becoming available, Harvey suggested that induction approaches will eventually look very different from how they look now. “I think that ultimately,” he predicted, “we will have an all-oral regimen.” l References

1. Harvey RD. Investigational agents in development. Presented at: 10th Annual Conference of the Hematology/Oncology Pharmacy Association; March 26-29, 2014; New Orleans, LA. 2. Lonial S, Jakubowiak AJ, Jagannath S, et al. A phase 2 study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed/ refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 303. 3. Plesner T, Lokhorst H, Gimsing P, et al. Daratumumab, a CD38 monoclonal antibody in patients with multiple myeloma: data from a dose-escalation phase I/II study. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 73. 4. Martin TG III, Strickland SA, Glenn M, et al. SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies: data from a dose-escalation phase I study. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 284. 5. Kelly KR, Chanan-Khan A, Somlo G, et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in Len/Dex-refractory patients. Blood (ASH Annual Meeting Abstracts). 2013;122:Abstract 758. 6. Kumar SK, Berdeja JG, Niesvizky R, et al. A phase 1/2 study of weekly MLN9708, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 332.

Take action: get YOUR cancer center profiled! We are looking to interview oncology pharmacists from cancer centers around the country. It’s an easy process—a short phone interview and you need to submit some photos.

Contact editorial@greenhillhc.com for information.

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May 2014 I VOL 7, NO 2

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May 2014 I VOL 7, NO 2

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Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

n this month’s issue of The Oncology Pharmacist (TOP), we present our coverage of the news from the Hematology/Oncology Pharmacy Association (HOPA) 10th Annual Conference. TOP was there, and we highlight presentations about the 340B drug-pricing program, erythropoiesis-stimulating agents and iron supplementation for patients with cancer- and chemotherapy-induced anemia, the drug development pipeline of “intriguing” monoclonal antibodies to treat multiple myeloma, and the use of chemotherapy in a pregnant patient. Our reader poll (see below) asks about your experience with chemotherapy and pregnant patients. Please visit our website, www.TheOncologyPharmacist.com, and let us know if this is a situation you’ve confronted and, if so, how it was handled. In her presentation at HOPA, Erica Hochard, PharmD, noted that approximately 6000 pregnant women are diagnosed with cancer each year. This number is expected to increase as more women delay childbearing, making this a situation that more of us will see in our practice.

We also present information about skin toxicity with targeted agents and how monitoring molecular response to tyrosine kinase inhibitor therapy for chronic myelogenous leukemia may help guide treatment decisions—this is part of our coverage of the 2014 annual meeting of the National Comprehensive Cancer Network. In addition, this issue provides you with information about some of the news coming out of the 2014 Genitourinary Cancers Symposium and Gastrointestinal Cancers Symposium. Our coverage includes research about hormone therapy and immunotherapy for prostate cancer. Ginah Nightingale, PharmD, BCOP, is the subject of this month’s Cancer Center Profile. Ginah is an assistant professor in the Department of Pharmacy Practice, Jefferson School of Pharmacy at Thomas Jefferson University. She tells us about her own research interests and discusses how she became an oncology pharmacist as well as working with student pharmacists. We encourage you to visit the TOP website and give us your feedback about what you see in print and online. We want to hear from you! l

Reader Poll Have you ever used chemotherapeutic drugs to treat a pregnant patient? o Yes o No ©iStockphoto.com/ValuaVitaly

Go to www.TheOncologyPharmacist.com to answer the question and add your comments.

The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 4 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2014 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered 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, The Oncology Pharmacist®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@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, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® 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.

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Side Effects Management

For Cancer-Induced Anemia, ESAs Best Given With IV Iron Caroline Helwick

bout 50% of cancer patients —90% in some subsets—develop cancer- or chemotherapyrelated anemia.1 For these patients, iron supplementation is a relatively safe and effective way to improve both hemoglobin level and quality of life, and it clearly enhances the effectiveness of erythropoiesis-stimulating agents (ESAs) in patients eligible to receive them, according to David Baribeault, BS, BCOP, clinical advisor for McKesson Health Solutions in the Pharmacy Optimization group.2 Baribeault made a case for intravenous (IV) iron supplementation in patients with cancer- and chemotherapy-induced anemia at the Hematology/Oncology Pharmacy Association 10th Annual Conference. ESAs are effective for anemia related to cancer or chemotherapy—they reduce the need for transfusion and improve quality of life. However, 30% to 50% of patients do not achieve a clinically meaningful hematologic response,1 and restrictions imposed by the US Food and Drug Administration, due to safety concerns, have made ESAs more difficult to use, he said.

mentation with 1 of 6 compounds on the market, the most recently approved being ferric carboxymaltose. The products have minor differences in terms of molecular weight, half-life, ability to be given as total-dose infusion, requirement of test dose, black box warning, and indications. In the future, these compounds will be joined by biosimilars. Assessing Iron Deficiency Iron status can be assessed 4 ways: • Serum iron, which measures iron available for hemoglobin synthesis (reference range, 60-150 µg/dL) • Total iron-binding capacity (TIBC; reference range, 250-435 µg/dL) • Transferrin iron saturation (TSAT), which also measures iron available for hemoglobin synthesis (reference range, 20%-50% in men, 15%-50% in women) • Serum ferritin, which is an indirect measure of total body iron stores (reference range, 20-250 ng/mL in men, 10-120 ng/mL in women). A study by Henry and colleagues demonstrated that TSAT is the best predictor of iron deficiency in anemic cancer

David Baribeault, BS, BCOP

The reasons for nonresponse to ESAs are not clear, though actual or functional iron deficiency or a reduced reserve of stem cells in the bone marrow could be responsible. Even when patients respond, response may not occur for a month or longer. Transfusions are also effective, but they do carry some risk for infection, transfusion-related acute lung injury, and treatment-associated graft-versus-host disease. “Though ESAs and transfusion can be used, we need to think of alternatives,” he said. The best “alternative” is iron supple-

May 2014 I VOL 7, NO 2

patients. In the study, 59% of patients had a TSAT value <20%, even if they had a serum ferritin level >100 ng/mL.1 Only 17% of patients had a serum ferritin level <100 ng/mL, but when ferritin was combined with TSAT, a large proportion of study patients were shown to have iron deficiency, he noted. Adding Iron to ESAs When erythropoietin is used to treat anemia caused by chemotherapy or other factors, functional iron deficiency ensues unless patients are iron-overloaded from prior transfusions. Iron therapy is there-

The reasons for nonresponse to ESAs are not clear, though actual or functional iron deficiency or a reduced reserve of stem cells in the bone marrow could be responsible.

fore important in conjunction with ESAs, as it maximizes erythropoiesis by avoiding absolute and functional iron deficiency. “Recent data indicate response may be improved by IV iron supplementation,” Baribeault stated. A study by Auerbach and colleagues of patients receiving ESAs for chemotherapy-induced anemia showed a significant effect of adding IV iron (iron dextran): a mean change in hemoglobin of +2.5 g/dL over baseline and an improvement of +1.0 g/dL over oral iron.3 Administration by bolus and total-dose infusion was equally effective. In another study by Henry and colleagues, IV sodium ferric gluconate complex (125 mg once a week) produced a significantly greater increase in hemoglobin and hemoglobin response (increase 2 g/dL) than did oral iron supplementation (ferrous sulfate 325 mg three times a day) or no iron.4 The mean increase in hemoglobin was 2.4 g/dL with IV iron, 1.6 g/dL with oral iron, and 1.5 g/dL when no iron was given. A study by Bastit and colleagues showed that the addition of IV iron (sodium ferric gluconate complex in sucrose or iron sucrose) to darbepoetin alfa improved the hematopoietic response rate and reduced the need for transfusions from 20% to 9% over darbepoetin alone.5 In the same journal issue, Pedrazzoli and colleagues showed that patients with chemotherapyrelated anemia and no iron deficiency (ie, replete by TSAT or ferritin levels) also were more likely to respond to darbepoetin when they received IV iron (sodium ferric gluconate).6 “This last study suggests that if you stimulate erythropoiesis, you have to include iron, even in patients who are iron replete,” Baribeault pointed out. l References

1. Henry DH, Dahl NV; on behalf of the Ferrlecit Cancer Study Group. Iron or vitamin B12 deficiency in anemic cancer patients prior to erythropoiesis-stimulating agent therapy. Commun Oncol. 2007;4(2):95-101.

2. Baribeault D. Cancer and chemotherapy-induced anemia: the roles of iron and ESAs. Presented at: 10th Annual Conference of the Hematology/Oncology Pharmacy Association; March 26-29, 2014; New Orleans, LA. 3. Auerbach M, Ballard H, Trout JR, et al. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapyrelated anemia: a multicenter, open-label, randomized trial. J Clin Oncol. 2004;22(7):1301-1307. 4. Henry DH, Dahl NV, Auerbach M, et al. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12(2):231-242. 5. Bastit L, Vandebroek A, Altintas S, et al. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26(10):1611-1618. 6. Pedrazzoli P, Farris A, Del Prete S, et al. Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alfa. J Clin Oncol. 2008;26(10):1619-1625.

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Leukemias Cancer Center Profile

Molecular Monitoring Can Provide Treatment Guidance in CML Wayne Kuznar

onitoring molecular response to tyrosine kinase inhibitor (TKI) therapy for chronic myelogenous leukemia (CML) may help guide the decision to switch therapy and the timing of progression to second- and third-line therapy, said Jerald P. Radich, MD, at the 2014 annual meeting of the National Comprehensive Cancer Network (NCCN). Response rates to TKI therapy in CML are high, and many times these responses can be measured only at the molecular level. The reliance on molecular monitoring as a sensitive measure to monitor response is increasing. Molecular monitoring detects the presence of BCRABL1 mRNA using real-time quantitative polymerase chain reaction. A major molecular response (MMR) is defined as a reduction in BCR-ABL transcript levels of at least 3 logs compared with a standardized baseline obtained from patients with untreated newly diagnosed CML. “The concept of MMR...ended up having profound clinical utility,” said Radich, a member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center and professor of medicine at the University of Washington, Seattle. “It indicates patients who are very stable. Once you reach MMR, unless you discontinue medications, your chance of progressing to accelerated phase or becoming resistant is almost nil.” A BCR-ABL transcript level <10% at 3 months predicts clinical outcome. The 8-year probability of survival after first-line imatinib therapy improved to 93% with a BCR-ABL transcript level 10%, compared with a 57% probability at a level >10%. Similar findings have been obtained with dasatinib and nilotinib. The BCR-ABL transcript level at 3 months can also

predict MMR, he said, with poor achievement of MMR with a BCR-ABL transcript level >10% as opposed to “an outstanding chance of achieving MMR in those who have their disease fall off the cliff in a few months.” When to Switch Therapy The NCCN considers the lack of an MMR at 3 months a treatment failure, at which time it recommends applying a different therapy. “If somebody has had an incomplete exposure to any of the TKIs at a few months, and they’re not at 10%, you can be patient,” Radich said. “But if somebody has been taking their drug religiously for 3 months, and they’re not below 10%, then you have to think [about switching].” The European LeukemiaNet (ELN) recommends waiting until 6 months to determine the need for a change. “The reason is because there are no data that show that early switching has anything to do with changing the natural history of the disease,” he continued. “A fair amount of people who don’t reach 10% by 3 months will progress to accelerated phase or blast crisis by 6 months. So you’ll lose some of those people if you’re too patient.” Up to 200 resistance mutations have been found in CML. Mutational analysis may provide additional information for patients with inadequate response. The NCCN and ELN also recommend mutational analysis when patients lose response, progress to accelerated phase or blast crisis, or experience a 1-log increase in BCR-ABL transcript levels with loss of MMR. Salvage therapy with second-generation TKIs produces a complete cytogenetic response (CCyR) 25% to 50% of the time. Eventual relapse is common in

patients who achieve CCyR with salvage therapy. “You have to think about what’s down the line for them, such as transplantation,” he said. When starting salvage therapy, “3 months of therapy is enough to tell you how people are going to do. If they have a CCyR at 3 months, they do great,” he said, noting that CCyR is the only factor independently associated with event-free and overall survival in patients on second-line TKIs. “If they don’t achieve CCyR, you have to go to plan C. That turns out to be a really convenient time because most unrelated donor searches take around 3 to 4 months,” he explained. Median survival is about 10 months for patients who progress to accelerated phase or blast crisis. Undergoing transplantation is the only option for cure in these patients, with survival rates decreasing from 85% in patients in chronic phase to 40% in accelerated phase to 10% to 20% in blast crisis. “You have to make sure to move these people to more aggressive therapy, and you need to move them there in a timely fashion, not when they’ve blown up to advanced phase disease,” said Radich. About 40% of patients can remain in complete molecular remission for up to 2 years after TKI discontinuation. Stopping TKI therapy after achievement of complete molecular remission should not be attempted outside of a clinical trial, he said. l Reference

Radich JP. Monitoring molecular response to TKI therapy in chronic myelogenous leukemia. Presented at: 2014 Annual Conference of the National Comprehensive Cancer Network; March 13-15, 2014; Hollywood, FL.

Prostate Cancer

Hormone Therapy Poses Health Risks in Patients With Prostate Cancer Alice Goodman

en with prostate cancer are often treated with hormone therapy (androgen deprivation therapy [ADT]), but this treatment can have unpleasant and even harmful side effects, including metabolic abnormalities that lead to diabetes mellitus (DM) and cardiovascular disease (CVD). A new study found that with prolonged exposure to ADT ( 2 years), both DM and CVD are more likely to occur in older men and in men with comorbidities than in younger men. This study should reassure younger men diagnosed with prostate cancer who are prescribed ADT, said lead author Alicia K. Morgans, MD, of the Vanderbilt University School of Medicine, Nashville, Tennessee. However, older men with comorbidities who have a higher risk may want to select a different treatment option, she added. The study assessed the association between duration of exposure to ADT and development of incident DM or CVD in a prospectively surveyed cohort of 3718 survivors diagnosed with local prostate cancer

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and enrolled in the Prostate Cancer Outcomes Study at 6 SEER sites. Of these survivors, 3526 were eligible for the study: 2985 for the DM analysis and 3112 for the CVD analysis.

Older men...who were exposed to ADT for 2 years had the highest risk of developing DM and CVD. Patients were stratified by length of exposure to ADT: no ADT (2033 in the DM analysis and 2112 in the CVD analysis); ADT for <2 years (692 in the DM analysis and 723 in the CVD analysis); or ADT for 2 years (260 in the DM analysis and 277 in the CVD analysis). Development of DM or CVD was estab-

lished by patient report in surveys at baseline, 6 months, and 1-, 2-, 5-, and 15-year time points as well as by death certificate diagnoses. Older men (>76 years for DM and >74 years for CVD) who were exposed to ADT for 2 years had the highest risk of developing DM and CVD. A multivariate analysis identified greater comorbidity burden as being significantly associated with odds of developing DM or CVD versus men with no other comorbidities. Shorter exposure to ADT (<2 years) was not significantly associated with developing either DM or CVD over 15 years of follow-up. The main implication of these findings is that older men with comorbidities who have been taking ADT for 2 years should be monitored for DM and CVD, Morgans said. l Reference

Morgans AK, Fan K-H, Koyama T, et al. Influence of age on incident diabetes (DM) and cardiovascular disease (CVD) among prostate cancer survivors receiving androgen deprivation therapy (ADT). J Clin Oncol. 2014;32(suppl 4):Abstract 31. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, CA.

May 2014 I VOL 7, NO 2

Pharmacoeconomics

340B Pricing—Who Wins, Who Loses? The 340B drug discount program, which is for outpatient (not inpatient) drugs, has grown substantially over the past 5 to 10 years within the disproportionate share hospitals (DSHs) and contract pharmacies, dramatically impacting the cost of expensive products, such as oncology drugs. This, in turn, is impacting the site of care, as more oncology care shifts to the hospital setting as a result, Schleif said. 340B Background The Public Health Service Act of 1992 created 340B to help put limits on prices of outpatient drugs. The program applies to 6 types of hospitals, but primarily DSHs: nonprofit entities with government contracts and a large percentage of low-income patients. DSHs are determined by the percentage of underprivileged inpatients they treat, although the discount applies only to outpatient prescribing. A DSH-adjusted percentage above 11.75% qualifies an entity for a 340B contract.

The 340B price is calculated by taking the average manufacturer’s price and automatically applying a 23.1% discount.

Continued from cover

The program is also available to critical access hospitals, freestanding cancer and children’s hospitals, rural referral centers, and sole community hospitals with government contracts. Who Benefits? A number of stakeholders are strongly impacted by the growth of 340B. Those who benefit most include the DSHs (pharmacy and outpatient clinic), Medicaid, the drug wholesaler or distributor, and the benefits administrator. A negative impact is felt, however, by group purchasing organizations (GPOs; 340B hospitals cannot use a GPO), community practices (which are on the outside looking in), and pharmaceutical manufacturers (who fund the program). The 340B price is calculated by taking the average manufacturer’s price (AMP) and automatically applying a 23.1% discount. This discount is further compounded by the degree the manufacturer has raised the drug price above the consumer price index (CPI). “If, for example, the price is 10% higher than the CPI, that 10% gets added to the 23.1%, and that is the discount that the pharmaceutical company takes,” Schleif explained. “340B pricing is very attractive to providers when compared to other drug acquisition costs,” he said. The Congressional Budget Office analyzed pricing for 130 brand-name products and found the AMP is 30% greater than 340B pricing. “The only thing better than 340B pricing is the price that is given to Veterans Administration hospitals and the Department of Defense’s military treatment facilities,” he noted.

Ron Schleif, MBA, BSPharm

The Growth of DSH and 340B Programs As DSHs have grown exponentially, so has the impact on outpatient cancer drug purchases. Today, about one-third of all hospitals participate in 340B pricing, representing 62% of the outpatient drugs dispensed in hospitals today. “This makes for a significant impact for the hospitals, and for the pharmaceutical companies who are funding this,” he noted. An increase in 340B programs can be expected as a result of Medicaid expansion through the Affordable Care Act. More Contract Pharmacy Arrangements Another area of growth is that of contract pharmacy arrangements within 340B. Drugs (prescription and nonprescription) are dispensed out of the main outpatient or satellite pharmacy, and this can include contract pharmacies that have arrangements with the DSH.

In 2010, contract pharmacies numbered about 2500. This rose to 8400 in 2012 and to more than 12,000 in 2014. This growth has occurred because entities that were once allowed to have only 1 contract pharmacy for its 340B pricing can now engage an unlimited number “to serve its 340B population,” he said. Contract pharmacies give entities a high likelihood of capturing oral prescriptions; therefore, the 340B impact on Medicare Part D drugs will be much greater (and grow faster) than for Part B. “There are now entities with more than 100 contracts with pharmacies, and there are pharmacies with more than 300 contracts,” he indicated. “This growth has dramatically affected the way 340B discounting is being realized. Most of it is happening on the oral side. These pharmacies are dispensing oral drugs to patients who are being treated as outpatients, and hospitals are capturing discounts that they would otherwise forgo.” Pharma Seeking More Control According to Schleif, the pharmaceutical industry has for years sought legislation that focuses on the indigent patient, but 340B benefits all patients seen in the outpatient setting. “This bothers pharma… it’s not what was intended,” he said, “so their focus is to better define these patients and to gain better control of things that lead to the broader diversion of products.” l Reference

Schleif R. 340B price discounts—current and future impact on cancer care delivery. Presented at: 10th Annual Conference of the Hematology/Oncology Pharmacy Association; March 26-29, 2014; New Orleans, LA.

Prostate Cancer

Weight Gain on Hormone Therapy Alice Goodman

ounger, thinner, nondiabetic men were more likely to gain weight on androgen deprivation therapy (ADT) than older men with comorbidities. “This is a new finding. We always thought that older, sicker prostate cancer patients were more likely to gain weight on hormonal therapy, but this study shows something different. At present, we don’t have an explanation for this, but our working theory is that younger men have higher baseline levels of testosterone than older, obese, and diabetic men and the magnitude of testosterone decline on hormone therapy might explain the weight gain,” said lead author Daniel Seible, MD, of the Dana-Farber Cancer Institute, Boston, Massachusetts. The retrospective study assessed weight change among 118 men with nonmetastatic prostate cancer assigned to ADT. The primary end point was

May 2014 I VOL 7, NO 2

weight change 1 year after initiation of ADT. The secondary aim was to identify factors associated with weight gain. Overall, a significant weight gain was found 1 year after starting ADT (P = .0005). Three main risk factors associated with weight gain were: • Younger age: 5.98 lb gained for men younger than age 65 versus 1.3 lb for men older than age 65 • Body mass index (BMI) <30: 4.36 lb gained for those with BMI <30 versus 0.22 lb for men with BMI 30 • Nondiabetic status: 3.43 lb gained versus 0.57 lb for diabetic men Another finding was that the more risk factors a patient had at baseline, the greater the weight gain. In this study, the authors did not measure baseline testosterone levels of subjects, Seible said. l

“We always thought that older, sicker prostate cancer patients were more likely to gain weight on hormonal therapy, but this study shows something different.” Daniel Seible, MD

Reference

Seible DM, Gu X, Hyatt A, et al. Identifying men at greatest risk of weight gain from androgen deprivation therapy. J Clin Oncol. 2014;32 (suppl 4):Abstract 80. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, CA.

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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 sixth 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 second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

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Conference News: AACR Continued from cover

Irregular Menses and Ovarian Cancer The first prospective study to link reproduction to ovarian cancer risk found that a history of irregular menstrual cycles at age 26 predicted the eventual development of aggressive ovarian cancer. In fact, women with irregular menses had as high as a 2-fold increase in the risk of ovarian cancer and a more than 2-fold increase in the risk of ovarian cancer death. These findings are important, said lead author Barbara A. Cohn, PhD, MPH, of the Public Health Institute in Berkeley, California, because by the time most ovarian cancers are detected, they are already symptomatic and aggressive. “These data are the first solid lead we’ve had that has potential for earlier diagnosis. This is an opportunity to identify underlying mechanisms and ways to prevent the 90% of sporadic ovarian cancers that occur without known heritable risk,” she added. “The devil is in the details,” Cohn said. “We defined ‘irregular’ as cycles longer than 35 days or anovulatory menstrual cycles. In other words, these women could not predict when their menses was coming.”

The study enrolled only pregnant women in order to rule out the effect of fertility drugs and infertility on the risk of developing ovarian cancer. As part of the Child Health and Development Studies, 14,403 pregnant women were recruited from 1959 to 1967. At baseline (median age, 26 years), women were asked to characterize their menstrual cycles. Thirteen percent reported irregular menses according to the definition Cohn described. These data were linked to California

Vital Statistics and National Death Index files to detect 103 cases of ovarian cancer, histology, stage, grade, and mortality (there were 65 deaths). Women with irregular cycles had a 37% increased risk of developing ovarian cancer and more than a 2-fold increase in ovarian cancer death due to more latestage disease and more aggressive histology at diagnosis. The risk was greatest for late-stage, high-grade, and serous tumors, Cohn said.

Women with irregular cycles had a 37% increased risk of developing ovarian cancer and more than a 2-fold increase in ovarian cancer death due to more late-stage disease and more aggressive histology at diagnosis.

In the overall analysis, irregular menses was associated with a 2.3 times greater risk of ovarian cancer death (P = .01) and a 3 times greater risk of death from latestage serous ovarian cancer (P = .01). The risk of developing late-stage or high-grade serous ovarian cancer was also significantly increased among women with a history of irregular menses (P = .02 and P = .07, respectively). Although these findings are hypothesis generating, Cohn said that young women with irregular menses might consider taking birth control pills. “Birth control pills seem to be protective and regularize menstrual cycles. Of course, this decision should be made in consultation with a physician, and individual risk factors need to be considered as well,” Cohn noted. l

Reference

Cohn BA, Cirillo PM, Wang ET, et al. Irregular menstruation predicts increased risk of subsequent ovarian cancer death in a prospective cohort, The Child Health and Development Studies. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Abstract LB-277.

Obesity Linked to Poor Outcome in Colorectal Cancer Yet another study points out the dangers of obesity, in this case the relationship of prediagnosis obesity to poor outcomes for people with colorectal cancer. In fact, the presence of prediagnosis obesity trumped high microsatellite instability (MSI), a tumor marker usually associated with better outcomes. “We know that increased body mass index [BMI] is associated with a variety of poor health outcomes, including poor prognosis in survivors of breast and endometrial cancers. One of the clearest associations is with colorectal cancers. The timing of obesity is important, because increased BMI measured before diagnosis is predictive. After diagnosis, BMI is no longer predictive because patients get sick and lose weight,” explained lead author Peter T. Campbell, PhD, director of the Tumor Repository in

the Epidemiology Research Program at the American Cancer Society in Atlanta, Georgia. “This study, to my knowledge, is the first study with sufficient numbers to investigate how these independent risk factors work together to influence survival after a colorectal cancer diagnosis. We found that a high prediagnosis BMI is associated with increased all-cause and colorectal cancer–specific mortality after diagnosis. We also found that high BMI overrides the survival advantage conferred by an MSI-high tumor,” he said. “The take-home message is that BMI is prognostic. At the highest level (BMI >40 kg/m2), colorectal cancer mortality was increased by 48%. This is another reason to maintain lower body weight,” Campbell stated. The study was based on 6763 patients with invasive

“We know that increased body mass index is associated with a variety of poor health outcomes, including poor prognosis in survivors of breast and endometrial cancers. One of the clearest associations is with colorectal cancers." Peter T. Campbell, PhD

May 2014 I VOL 7, NO 2

colorectal cancer who enrolled in the Colon Cancer Family Registry from 1997 to 2008. BMI 2 years prior to diagnosis and at age 20 years and adult weight gain were calculated from self-reports of height and weight. Tumor MSI status was available for 4987 patients. Median follow-up was 5.3 years. For every 5 kg/m2 increase in BMI, there was a 10% increase in all-cause mortality. For patients with MSIhigh and MSI-stable/MSI-low tumors, every 5 kg/m2 increase in BMI increased all-cause mortality by 19% and 8%, respectively. A similar pattern was observed for the association between increased BMI and colorectal cancer–specific mortality as well, with the risk of colorectal cancer– specific mortality increasing by 7% for every 5 kg/m2 increase in BMI. “This study is unique because we looked at the joint impact of BMI and MSI. Obesity removes the net benefit of high MSI,” Campbell emphasized. He and his colleagues are planning to look at the association between prediagnosis obesity and other tumor markers implicated in colorectal cancer survival. The ultimate goal is to investigate the association between obesity and somatic tumor mutations to determine how obesity may drive cancer, he noted. l

Reference

Campbell PT, Newton C, Newcomb PA, et al. Prospective study of body mass index and adult weight change with colorectal cancer survival, overall and by tumor microsatellite instability status. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Abstract LB-276.

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Conference Cancer Center News: Profile AACR Coffee Intake May Reduce Risk of Hepatocellular Carcinoma Increased consumption of coffee was associated with reduced risk of developing hepatocellular carcinoma (HCC), the most common type of liver cancer.1 A significant dose response was observed, noted lead author V. Wendy Setiawan, PhD, of the USC Norris Comprehensive Cancer Center in Los Angeles, California. People who drank between 1 to 3 cups of coffee per day had a 29% reduced risk of HCC, while those who drank 4 or more cups per day had a 42% lower risk. The researchers did not look at the effect of consumption of decaffeinated coffee. “Previous studies showed that coffee lowers the risk of HCC, but these studies were conducted outside of the US. We wanted to examine whether coffee consumption was associated with risk of HCC in multiethnic US populations,” she said. The study was based on a prospective analysis of approximately 180,000 men and women, including 52,548 Japanese Americans, 45,641 Caucasians, 39,097 Latinos, 29,486 African Americans, and 13,118 Native Hawaiians. Data were collected on coffee consumption and other

lifestyle factors, and people were followed for up to 18 years. HCC developed in 498 participants: 171 Japanese Americans, 67 Caucasians, 153 Latinos, 73 African Americans, and 34 Native Hawaiians. The relationship between coffee consumption and lower risk of HCC was independent of ethnicity, gender, body mass index, smoking status, alcohol intake, and diabetes status. Also, in a subset analysis of participants with available hepatitis B and hepatitis C serologic status, the association between coffee consumption and HCC was independent of hepatitis infections.

Setiawan and colleagues plan to study the association between coffee consumption and incidence and mortality with chronic liver diseases across multiethnic groups. A related study showed that increased coffee intake was also associated with reduced risk of melanoma.2 Participants who consumed 4 or more cups of coffee per day had a 20% reduction in the risk of melanoma compared with non-coffee drinkers. No association was observed for decaffeinated coffee. The study analyzed data from the large, prospective NIH-AARP Study. Coffee

The relationship between coffee consumption and lower risk of hepatocellular cancer was independent of ethnicity, gender, body mass index, smoking status, alcohol intake, and diabetes status.

intake was assessed at baseline with a food intake questionnaire. Among 447,357 non-Hispanic whites who were cancer-free at baseline, 2904 developed melanoma during 4,329,044 person-years of follow-up. Respondents were followed from baseline until the date of first skin cancer diagnosis, the date of death, the end of study follow-up, or moving out of a catchment area (whichever occurred first). The analysis was adjusted for multiple potential confounders for melanoma risk in relationship to level of coffee intake. Lead author Erikka Loftfield, MPH, of the National Cancer Institute, said that additional study of caffeine and other coffee constituents is warranted in the prevention of melanoma. l References

1. Setiawan VW, Wilkens LR, Hernandez BY, et al. Coffee intake reduces hepatocellular carcinoma risk: the Multiethnic Cohort. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Abstract LB-281. 2. Loftfield E, Mayne S, Shebl F, et al. Prospective study of coffee drinking and risk of melanoma in the United States. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Abstract LB-280.

Bladder Cancer

The Cancer Genome Atlas: Bladder Cancer Alice Goodman

he Cancer Genome Atlas (TCGA) project now includes a recently reported comprehensive molecular characterization of muscle-invasive urothelial bladder carcinoma (presented January 31, 2014, at the Genitourinary Cancers Symposium and published simultaneously online in Nature).1,2 The hope is that these genetic discoveries will translate to identification and development of new treatments for bladder cancer. New therapies for bladder cancer represent an unmet need. Over the past decade, kidney and prostate cancer therapy has seen an explosion of novel agents, but no new treatment for bladder cancer has been identified since the 1970s. The TCGA findings on muscle-invasive urothelial bladder cancer were presented by Jonathan Rosenberg, MD, Section Chief of the Non-Prostate Program in the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City. The 2 major take-home messages of his presentation were: • The majority of patients with muscle-invasive urothelial bladder carcinoma have actionable mutations that can be targeted in selected populations with either drugs approved by the US Food and Drug Administration or investigational agents. • Epigenetic regulatory genes are frequently altered in this type of bladder cancer, suggesting that

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there may be a different paradigm for therapeutic intervention. Seventy-six percent of tumors had 1 inactivating epigenetic mutation and 41% had 2. More clinical and laboratory research is needed with drugs that target these alterations, such as histone deacetylase inhibitors, DNA methyltransferase inhibitors, and bromodomain inhibitors. These drugs may be useful in subsets of patients, Rosenberg said. Rosenberg and colleagues analyzed DNA from 131 muscle-invasive urothelial bladder cancer tumors and corresponding normal samples (predominantly blood). They determined that bladder cancer was one of the most highly mutated tumor types, with each tumor possessing an average of 302 exonic mutations, 204 segmental alterations in DNA copy number, and 22 large-scale genomic alterations. Thirty-two recurrent significantly mutated genes were identified that appear to be involved in bladder cancer pathogenesis. Some of these genetic abnormalities had not been previously reported in bladder cancer or in other cancers included in the TCGA, he said. Three clusters of abnormalities were identified based on an integrated analysis of both mutations and copy number: a genomic amplification cluster, a p16-deleted cluster, and a p53-mutated cluster. “These clusters suggest that there may be different oncogenic mechanisms involved in the development of muscle-invasive bladder cancer, but we don’t know yet whether any of them are clinically relevant,”

Rosenberg commented. Between mutation and copy number analysis, potential targets were identified in 69% of the tumors, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets in the RTK/MAPK pathway (including ERBB2). Rosenberg said that this work represents progress in bladder cancer, and carefully designed trials are needed to test therapies directed to these potentially actionable genetic aberrations. l

Jonathan Rosenberg, MD

Photo by © ASCO/Todd Buchanan 2014.

References

1. Rosenberg JE, Kim J, Cherniack A, et al. Somatic genomic alterations in urothelial cancer: results of the Cancer Genome Atlas (TCGA) bladder cancer (BC) analysis. J Clin Oncol. 2014;32(suppl 4):Abstract 285. Presented at: 2014 Genitourinary Cancers Symposium; January 30February 1, 2014; San Francisco, CA. 2. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315-322.

May 2014 I VOL 7, NO 2

CONFERENCE News: Conference NEWS: AACR News ESMO Continued from page 13

Exercise for Cancer Survivors Despite the well-known benefits of physical activity for general health and for cancer survivors, only about 1 in 10 of all cancer survivors are doing enough exercise to gain benefits, according to a study reported by Yale investigators. The level of physical activity recommended for cancer survivors by the US Department of Health and Human Services is 150 minutes of moderate-intensity physical exercise, or 75 minutes of vigorous exercise, and 2 sessions of strength training every week. In a large US study of cancer survivors, only 10% met the recommended level of physical activity. Interestingly, survivors who did exercise at the recommended level reported improved quality of life, with less fatigue, improved mental and physical health, and increased satisfaction in social activities and relationships compared with those who did not exercise. One of the study investigators, Melinda

Irwin, PhD, codirector of the Cancer Prevention and Control Research Program at Yale Cancer Center and asso-

was based on the 2010 National Health Interview Survey that included a large sample of more than 19 million cancer

Survivors who did exercise at the recommended level reported improved quality of life, with less fatigue, improved mental and physical health, and increased satisfaction in social activities and relationships compared with those who did not exercise.

is very concerning. We know that exercise not only improves multiple aspects of quality of life, but other studies have shown that it is also associated with lower risk of recurrence and mortality,” Irwin said. “The 10% rate is what we see in the general healthy adult population, so we need to make huge efforts to increase physical activity for everyone.” Senior author of the study, Anees Chagpar, MD, director of the Breast Center at Smilow Cancer Hospital at Yale-New Haven, said that exercise should be a priority for patients and physicians. “Perhaps we as oncologists should be writing more prescriptions for physical activity,” she stated. l Reference

ciate professor at the Yale School of Public Health in New Haven, Connecticut, said most studies of exercise and cancer are in breast cancer survivors. The present study

survivors with more than 10 different types of cancer. “The finding that only 10% of cancer survivors meet physical activity guidelines

Tewari A, Irwin M, Chagpar A. Physical activity is associated with improved quality of life in cancer survivors: a population-based analysis. Presented at: 2014 Annual Meeting of the American Association for Cancer Research; April 5-9, 2014; San Diego, CA. Abstract 5039.

Renal Cancer

Angiotensin System Inhibitors Extend Survival in Patients With Metastatic Renal Cell Carcinoma Phoebe Starr

se of angiotensin system inhibitors (ASIs) improved survival in patients with renal cell carcinoma (RCC) by 9 months compared with patients not taking any of these agents, according to a retrospective pooled analysis of a number of clinical trials presented at the 2014 Genitourinary Cancers Symposium and discussed at a pre-meeting press cast. Survival was further improved if patients were also taking vascular endothelial growth factor (VEGF) receptor–targeted agents. “Based on results of this study, an ASI should be considered for patients with metastatic RCC who require antihypertensive therapy and have no contraindications that preclude their use, especially patients receiving VEGF-targeted treatments. However, it is too early to determine if ASIs should be used for patients with metastatic RCC who do not have coexisting hypertension or another medical condition to warrant ASI treatment,” stated lead author Rana McKay, MD, clinical oncology fellow at the DanaFarber Cancer Institute, Boston, Massachusetts. VEGF is an established target in metastatic RCC, she continued. ASIs include angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. These 2 classes of drugs act on the renin-angiotensin system and are used singly and in combination to treat hypertension as well as other conditions. Recent research suggests that the peptide hormone angiotensin II modulates VEGF-dependent angiogenesis. These data are intriguing and need confirmation in a larger prospective study, stated the authors. The study—the largest retrospective study to date

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evaluating the role of ASIs on outcomes in cancer patients—was based on a database of 4736 patients with metastatic RCC participating in phase 2 and phase 3 clinical trials conducted between 2003 and 2013. ASI use was defined as taking an ASI at baseline or within 30 days of cancer treatment initiation. Baseline hypertension was present in 48% of all patients; 1487 patients were taking an ASI, and 783 were taking other antihypertensive agents. RCC treatments included VEGF-targeted agents such as sunitinib, sorafenib, axitinib, and bevacizumab, an mTOR inhibitor (temsirolimus), and interferon. Overall survival (OS) for patients receiving ASI treatment was 26.68 months versus 17 months for non-ASI users (hazard ratio [HR] 1.213; P <.0009). In patients taking VEGF agents for metastatic RCC, ASI use significantly prolonged OS: 31 months for ASI users versus 21.94 months for nonusers (HR 1.38; P = .0003). Moreover, tumor shrinkage was more likely in patients receiving ASIs. Median progression-free survival was 8.3 months for ASI users versus 6.5 months for nonusers (P = .0042). A subgroup analysis of type of anticancer therapy showed that only concomitant VEGF and ASI use was associated with a significant survival benefit. This association persisted in a multivariate analysis adjusted for a number of cofactors, including age, sex, type of metastatic RCC therapy, presence of bone metastases, and risk groups. This association was not seen with mTOR inhibitors or interferon. “The effect of ASIs on RCC needs to be studied

“Based on results of this study, an ASI should be considered for patients with metastatic RCC who require antihypertensive therapy and have no contraindications that preclude their use, especially patients receiving VEGFtargeted treatments.” Rana McKay, MD

further. For now, results suggest that for patients with metastatic RCC who are hypertensive at baseline, ASIs may be the best choice of antihypertensive therapy,” McKay said. l Reference

McKay RR, Rodriguez GE, Lin X, et al. Impact of angiotensin system inhibitors (ASI) on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): results from a pooled clinical trials database. J Clin Oncol. 2014;32(suppl 4):Abstract 437. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; Orlando, FL.

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Conference Cancer Center News: Profile AACR Jump-Starting Smoking Cessation for Cancer Patients To commemorate the 50th anniversary of the US Surgeon General’s report on the dangers of tobacco, the AACR published a policy statement on tobacco use by cancer patients to coincide with its 2014 annual meeting. Scientific evidence shows that tobacco use in cancer patients leads to poorer outcomes by compromising response to therapy, increasing treatment-related toxicity, increasing the risk of recurrence and second primary tumors, and hastening earlier death. Yet a certain proportion of patients continues to smoke. The policy statement emphasizes the need to integrate evidence-based tobacco-dependence treatment into all healthcare delivery. At the present time,

there is a scarcity of dedicated cessation treatment programs available at oncology practices. The statement emphasizes that the “5 As” program developed by the US Department of Health and Human Services is a proven method of increasing rates of successful quitting. This model relies on the following steps: ASK about tobacco use at every clinic visit; ADVISE to quit; ASSESS interest in quitting; ASSIST by providing counseling and pharmacotherapy; and ARRANGE follow-up. Although the “5 As” model lacks an evidence base for patients with cancer, following this model could be instrumental in helping cancer patients to quit smoking. Surveys of oncologists and other

healthcare providers show that smoking cessation is rarely offered to patients, even though most agree that tobacco affects cancer outcomes and should be part of cancer care. In one survey of members of the International Association for the Study of Lung Cancer, more than 90% of respondents said this was important, yet only 40% discussed medications or provided any type of cessation support. Many respondents indicated the perceived inability to get patients to quit using tobacco as well as patient resistance to intervention programs were the main barriers to offering cessation support. AACR made 2 recommendations: (1) Patients with cancer who use tobacco or who have quit within the past 30 days should be provided with evidence-based

tobacco-cessation assistance, ideally within or associated with the oncology practice; and (2) Tobacco use should be comprehensively and repeatedly documented for all patients so that the confounding effects of tobacco on cancer treatment, disease progression, comorbid events, and survival can be evaluated in clinical trials and in all cancer settings. l

Reference

Toll BA, Brandon TH, Gritz ER, et al; Writing Committee for the AACR Subcommittee on Tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Clin Cancer Res. 2013;19(8):1-8. http://www.aacr.org/ Uploads/DocumentRepository/LegAffairs/Tobacco/ AACRStatement_TobaccoUseCancerPatients_2013_ CCR.pdf. Accessed April 16, 2014.

Renal Cancer

Molecular Therapy Beyond Sorafenib in HCC: New Pathways, Targets Being Explored Wayne Kuznar

any molecularly targeted agents that inhibit different pathways of hepatocarcinogenesis are under clinical development, and novel targets are being assessed in hepatocellular carcinoma (HCC). These efforts were described by Andrew X. Zhu, MD, PhD, at the 2014 Gastrointestinal Cancers Symposium. Sorafenib remains the only systemic agent to improve survival in advanced HCC. It improves median overall survival (OS) in HCC, but median survival is still only about 10 months. Unfortunately, multiple more potent or selective antiangiogenic agents have failed to improve on this outcome. “While we develop new therapies, a concerted and parallel effort must be made to identify and validate biomarkers of response, resistance, and toxicity to better match patients with safe, effective therapies,” said Zhu, director of liver cancer research at Massachusetts General Hospital, Boston. Surpassing sorafenib may require a combination of antiangiogenic agents with cytotoxic chemotherapy or with other molecularly targeted therapies to allow for synergy or additive effects. “Alternatively, it might require moving beyond the antiangiogenesis approach and targeting cell autonomous pathways involved in hepatocarcinogenesis, such as the HGF/c-MET, PI3K/AKT/mTOR, or FGF/FGFR pathways,” he said.

Antiangiogenic Strategies Antiangiogenic agents including pazopanib, lenvatinib, axitinib, and ramu-

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cirumab are in clinical development for treating HCC. Based on phase 2 data, lenvatinib and ramucirumab have advanced to phase 3 evaluation.

Andrew X. Zhu, MD, PhD

Photo by © ASCO/Todd Buchanan 2014.

Although HCCs are highly vascular tumors with increased levels of vascular endothelial growth factor (VEGF), multiple VEGF receptor (VEGFR) inhibitors have failed to improve OS in HCC. This failure has prompted reconsideration of targeting VEGFR in HCC, said Zhu. Future efforts should focus on developing surrogate and predictive markers to identify patients likely to benefit from antiangiogenic treatment. Antiangiogenics are being combined with chemotherapy (sorafenib plus doxorubicin) in late-stage clinical trials, and with targeted therapies (ie, bevacizumab) in early-phase trials.

mTOR Inhibitors mTOR regulates protein translation, angiogenesis, and cell cycle progression in HCC. mTOR inhibitors have been shown to inhibit cell growth and tumor vascularity in HCC cell lines and HCC tumor models. The mTOR inhibitor everolimus failed to extend OS compared with best supportive care in the multicenter EVOLVE-1 trial of 546 patients with advanced HCC. Nevertheless, the preclinical promise of inhibiting the mTOR pathway has led to the development of other mTOR inhibitors, such as temsirolimus and sirolimus, and CC-223, which is a dual inhibitor of TORC1/TORC2. Immune-Based Therapy In the realm of immune-based therapy for HCC, “perhaps the most excitement comes from the inhibitors targeting the checkpoint pathway,” said Zhu. A phase 1 trial has been conducted with tremelimumab, a fully human IgG2 monoclonal antibody that blocks cytotoxic CTLA-4 in hepatitis C virus– related HCC. It generated a modest response rate of 17% and a progression-free survival of approximately 6 months in 17 evaluable patients. It also modulated hepatitis C viral load. The PD-1 inhibitor nivolumab is also entering clinical trials. HGF/c-MET Inhibitors The HGF/c-MET pathway has a significant role in promoting angiogenesis, proliferation, and metastasis in HCC. c-MET inhibitors have shown early

evidence of modest efficacy. Tivantinib, a selective, non-ATP–competitive inhibitor of c-MET, improved time to progression, particularly in patients with tumors with a high MET signature, compared with placebo in a phase 2 study. The median OS in patients with METhigh tumors was 7.2 months with tivantinib versus 3.8 months with placebo. “If you enrich the right population, you may achieve the clinical benefit,” Zhu noted. Cabozantinib, a receptor tyrosine kinase inhibitor of c-MET/VEGFR2, is also in phase 3 evaluation in patients in whom sorafenib has failed or could not be tolerated. It demonstrated antitumor activity in a randomized discontinuation phase 2 study, with a median progression-free survival of 4.2 months. Cancer Stem Cells Novel approaches to targeting cancer stem cells (CSCs) are being explored in multiple cancers, including advanced HCC. Hepatocarcinogenesis and the regulation of CSCs have both been shown to involve the Wnt pathways. OMP-54F28, a fusion protein, targets CSCs, bulk tumor cells, and tumor stromal cells. A phase 1/2 study combining OMP-54F28 and sorafenib for the firstline treatment of advanced HCC is under way. l

Reference

Zhu A. Molecular therapies in hepatocellualar carcinoma beyond sorafenib: alternatives to recent phase III trials failures. Presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.

May 2014 I VOL 7, NO 2

Pancreatic Cancer

Promising Vaccine Combination Identified for Patients With Metastatic Pancreatic Cancer Wayne Kuznar

dual vaccine strategy improved survival more than single vaccination of patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Data from a randomized phase 2 trial were reported by Dung T. Le, MD, at the 2014 Gastrointestinal Cancers Symposium. It is the first randomized study to show improved overall survival for patients with metastatic pancreatic cancer treated with immunotherapy. “This study is just a first step, and we believe we’ll be able to take this approach further,” said Le, assistant professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. The approach used in the study involves 2 distinct immunotherapy platforms. GVAX is an allogeneic whole cell vaccine created from 2 pancreatic cancer cell lines. These cells have been genetically modified to express granulo-

“This study is just a first step, and we believe we’ll be able to take this approach further.” Dung T. Le, MD

cyte-macrophage colony-stimulating factor (GM-CSF). “The advantage of this platform is that using whole cells allows presentation of a wide variety of tumor-associated antigens to the immune system,” said Le. “The GM-CSF serves to attract dendritic cells to the vaccine site that will then pick up the antigens and present them to the immune system, resulting in an activation of tumor-specific T cells.” Low-dose intravenous cyclophosphamide is administered the day before GVAX to inhibit regulatory (suppressive) T cells. The second immunotherapy platform,

CRS-207, is attenuated Listeria monocytogenes engineered to elicit an immune response against mesothelin. Mesothelin is a tumor-associated antigen expressed in a majority of pancreatic cancers. Prior studies have shown that induction of mesothelin-specific T-cell responses is associated with improved survival. The modified strain of Listeria decreases pathogenicity but retains immunogenicity. “Listeria is unique in that it is able to stimulate both innate and adaptive immunity,” she said. “Because it is an intracellular organism, it has access to both class I and class II antigen-processing

Noteworthy Numbers

Lung Cancer In 2010, Dr Thomas Frieden, director of the Centers for Disease Control and Prevention (CDC), chose the 6 original health priorities that he would call “winnable battles.” Tobacco use was one of them. As reported in the CDC’s tobacco overview materials, tobacco use is responsible for 443,000 deaths in the United States each year, including 128,900 deaths attributed to lung cancer.1 Here we will consider some specific lung cancer statistics.

•T he American Cancer Society estimates that there will be approximately 224,210 new cases of lung cancer in the United States in 2014.2

•O f the 2 major types of lung cancer, non– small cell lung cancer is diagnosed in 7 of 8 lung cancer patients, and small cell lung cancer is found in 1 of 8 patients.5

•A mong risk factors for developing lung cancer, cigarette smoking is number 1. Of the more than 7000 chemicals in tobacco smoke, at least 70 are known carcinogens, and smoking causes more than 90% of lung cancers in the United States. The second leading cause is exposure to radon gas, which causes about 20,000 cases of lung cancer annually.3

• I n the Annual Report to the Nation on the Status of Cancer, covering the years 19752010, the National Cancer Institute included a special feature on comorbidities among cancer patients. Reporting on patients with lung, colorectal, breast (female), and prostate cancer, who were age 66 years and older and were Medicare beneficiaries, data show that 30% had at least 1 comorbidity. However, among those with lung cancer, at least 1 comorbidity was found in 52.9% of patients. Diabetes, chronic obstructive pulmonary disease, congestive heart failure, and cerebrovascular disease were the most common comorbidities.6

•A lthough lung cancer accounts for only 14% of all new cancer diagnoses, it is responsible for 27% of all cancer deaths, more than colorectal, breast, pancreatic, and prostate cancers combined. It is the leading cause of cancer death among all ethnicities regardless of gender, and is responsible for almost 2 times as many deaths in women as breast cancer and almost 3 times as many deaths in men as prostate cancer.4

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Sources 1. www.cdc.gov/winnablebattles/Tobacco/. 2. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-celllung-cancer-key-statistics. 3. www.cdc.gov/cancer/lung/basic_info/risk_factors.htm. 4. http://events.lungevity.org/site/PageServer?pagename=v2_AboutLungCancer. 5. www.cancer.gov/cancertopics/wyntk/lung/page4. 6. www.cancer.gov/newscenter/newsfromnci/2013/ReportNationDec2013Release.

pathways and can deliver the encoded antigen directly to the encoded antigen-presenting cell.” The study investigators randomized 90 patients with previously treated, metastatic PDAC in a 2:1 ratio to 2 doses of GVAX and low-dose cyclophosphamide followed by 4 doses of CRS-207 every 3 weeks, or to 6 doses of cyclophosphamide and GVAX every 3 weeks. At a planned interim analysis, the median overall survival on an intentto-treat basis was 6.1 months with the 2-vaccine therapy compared with 3.9 months with GVAX alone (P = .0343). One-year survival was doubled by giving dual immunotherapy compared with single GVAX (24% vs 12%). The study met the early stopping rule for efficacy at this interim analysis, said Le. Among the patients who received at least 3 doses (per protocol analysis), the median survival was 9.7 months in the group randomized to dual vaccine and 4.6 months in those randomized to single vaccination (P = .03). The side effects of the vaccine were relatively mild and resolved quickly, she said. Toxicities included local reactions after GVAX, and transient fevers, rigors, and lymphopenia after CRS-207. “These are exciting results in a poor prognosis cancer. This is a phase 2 study, but it is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” said Smitha Krishnamurthi, MD, associate professor of medicine, Division of Hematology and Oncology, at Case Western Reserve University School of Medicine, Cleveland, Ohio. “This is accomplished without the side effects of chemotherapy.” l Reference

Le DT, Wang-Gillam A, Picozzi V Jr, et al. A phase 2, randomized trial of GVAX pancreas and CRS207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: updated results. J Clin Oncol. 2014;32(suppl 3):Abstract 177. Presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.

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Cancer Personalized CenterMedicine Profile

Immunotherapy Holds Promise to Extend Survival in GI Cancers Wayne Kuznar

ecent advances in molecular technologies have enabled the dissection of inhibitory pathways within tumors and identification of inflammatory signals within the tumor microenvironment that regulate host immune responses. These responses can be altered to effectively treat cancers, including gastrointestinal (GI) malignancies, said Elizabeth M. Jaffee, MD, in her keynote address at the 2014 Gastrointestinal Cancers Symposium. She provided an overview of immunotherapy for the treatment of GI cancers and described the signaling networks that regulate immune responses to different cancers.

ulatory or an activating signal is determined by the summation of signals that are ongoing in the tumor microenvironment, she said. New immune checkpoint agents act on T cells. “This is important because if you don’t have a T cell in a cancer, the agent won’t work,” said Jaffee. Only 20% to 30% of renal cell carcinomas and 10% to 20% of colorectal tumors have T cells. For most cancers, therefore, immune modulation alone is insufficient for treatment; a T-cell–generating agent is also needed. “Combinations are needed to achieve the full potential of the immune system to recognize and kill all cancers,” she said. “Understanding all of the signaling

“The main goal of immunotherapy is to raise an army of T cells to attack the tumor. These T cells need to get into the tumor, but they also have to be activated.” Elizabeth M. Jaffee, MD

“The main goal of immunotherapy is to raise an army of T cells to attack the tumor. These T cells need to get into the tumor, but they also have to be activated,” said Jaffee, professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland. “To do this...we have to understand the many signals within the tumor microenvironment that inhibit effective T-cell trafficking and function into tumors.” A T cell has inhibitory and activating signals. Whether it receives a down-reg-

networks that regulate responses to the different cancers is necessary to figure out the right combinations.” Many signals can inhibit an immune response in the tumor, and there are also many ways to activate T cells. The goal is to achieve an anticancer response when the tumor microenvironment naturally wants a procarcinogenic response, she explained. It may require not only targeting a specific antigen but also costimulation to present antigens in the right form so that an activated T cell can be generated. Activated T cells in combination with

1 or more immune checkpoint blockers will be necessary. Vaccines are especially needed for cancers that do not naturally induce intratumoral immune responses. Radiation and chemotherapies can act like adjuvants and potentiate the T-cell response obtained with vaccines. Effector T-cell infiltration is not a natural response to pancreatic cancer, but there is evidence that the immune system can be provoked in pancreatic cancer, she said. The combination of gemcitabine and an agonist signal (CD40 agonist) was able to induce tumor regression, which means that “T cells are likely getting in and are associated with the clinical response,” she said. A pancreatic tumor vaccine study at Johns Hopkins provides new evidence for antitumor immunity. The vaccine is administered 2 weeks before surgical resection of the tumor. A single dose of IV cyclophosphamide is given with the vaccine in an effort to enhance immune response. Cyclophosphamide allows trafficking of antigen-specific T cells to the tumor. “In 85% of the patients studied, we found lymphoid aggregates coming into the tumors,” said Jaffee. “They’re located throughout the tumor, and they’re located around the tumor. When examined closely, they look like germinal center–like structures; they stain for T cells on the outside, B cells on the inside.” What is known so far is that vaccines can induce tumor-infiltrating lymphocytes in traditionally “nonimmunogenic” tumors. “But vaccine-induced infiltrating T cells likely get downregulated by suppressive mechanisms within the tumor,” Jaffee said. “Vaccines must be given with agents that modulate these suppressive mechanisms to activate the T-cell response.” In the mouse model, anti–PD-1 ther-

Elizabeth M. Jaffee, MD

apy enhances infiltration of vaccine-induced tumor-specific infiltrating lymphocytes. In pancreatic cancer, regulatory pathways can be modulated to enhance vaccine efficacy. Ipilimumab plus a vaccine extended median overall survival compared with ipilimumab alone in a small pilot study of patients with metastatic pancreatic cancer in whom 2 or more chemotherapies had failed. Two vaccines may be better than 1, she said. A vaccine platform based on live attenuated, double-deleted Listeria monocytogenes targeting mesothelin (GVAX/ CRS-207 combination) improved median overall survival in patients with metastatic pancreatic cancer in whom chemotherapy was refused or had failed. Listeria is an intracellular bacterium that induces a T-cell response against antigen targeting the tumor, but it also induces T-cell responses against helper T cells that propagate that T-cell response. l Reference

Jaffee E. Immunologic treatments for gastrointestinal cancers: current status and future strategies. Keynote lecture presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.

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May 2014 I VOL 7, NO 2

Best Practices

Maximizing Safety of Chemotherapeutic Drugs During Pregnancy Caroline Helwick

ith little information in the literature, pharmacists and oncologists may feel insecure about the use of chemotherapy in a pregnant patient. Attendees at the Hematology/Oncology Pharmacy Association 10th Annual Conference received some guidance from Erica Hochard, PharmD, hematology/oncology clinical pharmacist at the University of Kansas Hospital, Kansas City. Hochard sought to “clarify the conundrum” regarding the safety of chemotherapy during pregnancy, she said, by outlining what is known about risks— which drugs to avoid and which can be safely given. The information should help pharmacists “make good clinical recommendations for these patients,” she explained. Cancer During Pregnancy Approximately 6000 pregnant women are diagnosed with cancer each year—an estimated 1 in 1000 pregnancies. As more women delay childbearing, this number is expected to increase. These cancers are most likely to be cervical, followed by breast, melanoma, Hodgkin lymphoma, and non-Hodgkin lymphoma. Since suboptimal doses of chemotherapy may predispose patients to recurrence, weight-based dosing is recommended, with doses adjusted for continued weight gain as pregnancy progresses, Hochard advised.

Table

Most chemotherapy agents are rated as Category D in terms of fetal risk, indicating there is positive evidence of human fetal risk based on adverse reaction data; nevertheless, the potential benefits may warrant the use of the drug during pregnancy. Almost all agents have been found to be teratogenic in animals, but in humans it has been difficult to interpret retrospective data since most drugs are used in combination, she pointed out. “In general, the teratogenicity of a drug depends on the timing of exposure, dose, and drug characteristics,” Hochard said. During the first 4 weeks, when the embryo is undifferentiated, there is an “all or none phenomenon,” wherein either the fetus aborts or the pregnancy continues. The first trimester, when organogenesis occurs, carries a risk of spontaneous abortion, fetal death, and congenital malformation as high as 20%. The main concern during the second and third trimesters is the risk that chemotherapy imposes on intrauterine growth restriction; however, the risk of fetal malformation diminishes to only 1.3%. “Malformations and toxicity to the fetus are really a reflection of gestational age,” Hochard noted. Treatment considerations should include maternal prognosis, trimester of pregnancy, feasibility of delaying chemotherapy until after the first trimester, timing of chemotherapy to avoid delivery during the maternal nadir, and chemo-

Erica Hochard, PharmD

therapy after 35 weeks, as well as the potential effect of treatment on future fertility. It is best to have a multidisciplinary team on board for these decisions, she added. What Agents to Avoid? In a nutshell, there are about half a dozen agents that should strictly be avoided during all trimesters: bevacizumab, trastuzumab, high-dose chemotherapy (ie, preparative regimens for transplant), idarubicin (and possibly epirubicin), methotrexate, and tamoxifen. Many other agents are considered relatively safe in the second and third trimesters, but most

Preferred Chemotherapy Agents During Pregnancy

Type of Cancer

Preferred Regimen

Breast

Doxorubicin + cyclophosphamide ± 5-FU (in 2nd and 3rd TMs)

Acute leukemia

1st TM: consider termination of pregnancy AML 2nd or 3rd TM: 7 + 3 regimen ALL >20 weeks: modified protocol until 3rd TM

Hodgkin lymphoma

ABVD or single-agent vinblastine

Non-Hodgkin lymphoma

Regimens containing cyclophosphamide, doxorubicin, vincristine (CHOP, CVP); rituximab is probably acceptable

Ovarian

Observation or single-agent platinum; if advanced disease, sequential taxane

Chronic myelogenous leukemia

Continue imatinib if patient becomes pregnant during therapy; if initiating treatment, consider hydroxyurea or interferon during 2nd or 3rd TM

Cervical

Consider delaying treatment until baby is mature enough for delivery

Abbreviations: ABVD, doxorubicin hydrochloride, bleomycin, vinblastine sulfate, dacarbazine; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; 5-FU, 5-fluorouracil; TM, trimester.

May 2014 I VOL 7, NO 2

should be avoided in the first trimester whenever possible, she said. Hochard also shared her list of preferred agents for the common cancers that occur in the pregnant population (Table). With bevacizumab, there is a theoretical concern regarding angiogenesis inhibition. With trastuzumab, oligohydramnios has been observed in more than 50% of cases; however, there have been no reports of congenital anomalies or cardiac events. With tamoxifen, reported birth defects have included ambiguous genitalia, Goldenhar syndrome (associated with incomplete development of the ear, nose, soft palate, lip, and mandible), and Pierre Robin sequence (smaller-than-normal lower jaw, tongue that falls back in the throat, and difficulty breathing). Idarubicin has been associated with transient and permanent cardiomyopathy and congenital abnormalities. With methotrexate, there have been cases of aminopterin-like syndrome, skeletal abnormalities, ambiguous genitalia, spontaneous abortion, low birth weight, and pancytopenia. Discussing the taxanes, she noted 12 exposures of which 92% resulted in a healthy newborn. It is theorized that placental P-glycoprotein could prevent transplacental transfer of the drug. Use in the treatment of breast cancer in the second and third trimesters, however, is controversial. Regarding the platinums, cisplatin is preferred over carboplatin. Targeted Agents In addition to trastuzumab and bevacizumab on the “do not give” list, Hochard discussed other targeted agents. She noted that rituximab is believed to be relatively safe but may suppress B cells; no cases of fetal morbidity or mortality have been reported. Alemtuzumab has shown no adverse reproductive effects in animal studies. Patients receiving cetuximab and panitumumab have shown some increased risk of weight loss and spontaneous abortion. Imatinib should not be the drug of choice for initiating therapy for chronic myelogenous leukemia, but if patients become pregnant while on this therapy, it should be continued due to the risk of disease progression, Hochard indicated. l Reference

Hochard E. The use of chemotherapy during pregnancy: clarifying the conundrum. Presented at: 10th Annual Conference of the Hematology/Oncology Pharmacy Association; March 26-29, 2014; New Orleans, LA.

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CancerGastric Center Cancer Profile

Investigational Angiogenesis Inhibitor Ramucirumab Improves Survival as Second-Line Treatment Wayne Kuznar

hase 3 data from a global clinical trial indicated an improvement in overall survival (OS) when the investigational angiogenesis inhibitor ramucirumab was added to chemotherapy as second-line therapy in patients with

advanced gastric cancer. The improvement in survival was more than 2 months with ramucirumab when used after progression with first-line therapy in the study known as RAINBOW (Study of Paclitaxel With or Without

Ramucirumab in Metastatic Gastric Adenocarcinoma), said lead investigator Hansjochen Wilke, MD, at the 2014 Gastrointestinal Cancers Symposium. “This trial and the recently published REGARD trial demonstrate that ramu-

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Ramucirumab, a human IgG1 monoclonal antibody that blocks the vascular endothelial growth factor receptor 2, represents the only second-line agent to extend life by as much as 2 months.

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cirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer and gastroesophageal junction [GEJ] cancer,” said Wilke, director of the Department of Oncology/Hematology and Center of Palliative Care, Kliniken Essen-Mitte, Germany. Ramucirumab, a human IgG1 monoclonal antibody that blocks the vascular endothelial growth factor receptor 2, represents the only second-line agent to extend life by as much as 2 months for patients with advanced gastric cancer, noted Smitha Krishnamurthi, MD, who was not involved in the study. “We’re excited to have what appears to be an active drug in the second-line setting that can be used instead of best supportive care or in addition to second-line chemotherapy for patients who can tolerate chemotherapy,” said Krishnamurthi, associate professor of medicine, Division of Hematology and Oncology, at Case Western Reserve University School of Medicine, Cleveland, Ohio. RAINBOW involved 665 patients with metastatic GEJ or gastric adenocarcinoma who exhibited disease progression within 4 months after standard first-line chemotherapy with platinum- and fluoropyrimidine-based combinations. Patients were randomized to either a combination of ramucirumab and paclitaxel or paclitaxel alone. Treatment was administered until disease progression, unacceptable toxicity, or death. Adding ramucirumab to second-line paclitaxel significantly improved response rates, OS, and progression-free survival (PFS). The objective response rates were 28% in patients randomized to ramucirumab plus paclitaxel compared with Continued on page 21

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CONFERENCE NEWS: ESMO

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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CancerGastric Center Cancer Profile

Investigational Angiogenesis Inhibitor… 16% in patients randomized to paclitaxel alone (P = .0001). The median OS was 9.6 months in the ramucirumab plus paclitaxel arm and 7.4 months in the paclitaxel-only arm, corresponding to a 20% reduction in the hazard ratio with ramucirumab (P = .0169). Six-month survival was 72% versus 57%, and 12-month survival was 40% versus 30% in the ramucirumab plus paclitaxel and paclitaxel-only arms, respectively. Median PFS was 4.4 months for the combination of ramucirumab and paclitaxel compared with 2.9 months for paclitaxel alone, corresponding to a 36% reduction in risk (P <.0001). Patients who received ramucirumab plus paclitaxel also reported a reduction in pain and other improvements in their

The most common side effects of treatment with ramucirumab and paclitaxel include neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia.

Continued from page 19

quality of life. The most common side effects of treatment with ramucirumab and paclitaxel include neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Although neutropenia was more frequently reported in the ramucirumab plus paclitaxel group, the incidence of febrile neutropenia was comparable to treatment with paclitaxel alone. All of these side effects were manageable, and very few patients discontinued treatment due to toxicities. The most common grade 3 adverse events with ramucirumab were neutropenia (40.7% vs 18.8% in the paclitaxelonly group), leukopenia (17.4% vs 6.7%), and fatigue (11.9% vs 5.5%); febrile neutropenia occurred with similar frequency

in both groups (3.1% vs 2.4%). Other grade 3 adverse events that occurred more often with ramucirumab compared with paclitaxel alone were hypertension (14.7% vs 2.7%), bleeding/ hemorrhage (4.3% vs 2.4%), gastrointestinal bleeding (3.7% vs 1.5%), proteinuria (1.2% vs 0%), and gastrointestinal perforation (1.2% vs 0%). l Reference

Wilke H, Van Cutsem E, Oh SC, et al. RAINBOW: a global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE). J Clin Oncol. 2014;32(suppl 3):Abstract LBA7. Presented at: 2014 Gastrointestinal Cancers Symposium; January 16-18, 2014; San Francisco, CA.

Prostate Cancer

Enzalutamide Extends Survival in Previously Untreated Metastatic Prostate Cancer Phoebe Starr

nzalutamide prolonged survival and delayed radiographic progression of disease in men who had not received chemotherapy for metastatic castration-resistant prostate cancer (mCRPC), according to complete results from the phase 3 PREVAIL trial. An interim analysis in 2013 was so favorable that the trial was halted prematurely, and all patients receiving placebo were offered enzalutamide. The drug was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of patients with mCRPC who had received previous therapy. “Enzalutamide provides clinically meaningful benefit for men with mCRPC. It is approved by the FDA in men previously treated with docetaxel, but not yet approved for use prior to docetaxel. If it does get expanded approval for this indication, it is likely to become an important standard option for use in patients with asymptomatic or minimally symptomatic advanced prostate cancer,” said lead author Tomasz Beer, MD, deputy director of the Knight Cancer Institute at Oregon Health & Science University, Portland, at the 2014 Genitourinary Cancers Symposium. Between September 2010 and September 2012, PREVAIL included 1717 patients with asymptomatic or mildly symptomatic mCRPC who had not received previous chemotherapy. They were randomized to enzalutamide

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or to placebo plus standard hormone therapy. For the coprimary end points of the trial—overall survival and radiographic progression-free survival— enzalutamide reduced the risk of death by 29% (hazard ratio [HR] 0.70; P <.0001), and reduced the risk of radiographic progression by 81% (HR 0.19; P <.0001).

Tomasz Beer, MD

Overall response rate according to imaging of soft tissue disease was 59% with enzalutamide (20% complete responses and 39% partial responses) versus 5% with placebo (P <.0001).

Importantly, enzalutamide delayed the need for chemotherapy by a median of 28 months versus 10.8 months for placebo. “This is important from a pragmatic perspective. Many men don’t want to take chemotherapy, especially if they are asymptomatic or mildly symptomatic,” Beer stated. Safety observation was 3 times longer with enzalutamide, reflecting the longer duration of treatment in this arm, he continued. Enzalutamide was well tolerated after 17 months of treatment; the most common side effects (in 20% of patients) were fatigue (36% of enzalutamide patients, 26% of placebo patients), constipation (22% and 27%, respectively), back pain (27% and 22%, respectively), and joint pain (20% and 16%, respectively). Grade 3 or higher adverse events were reported in 43% of the enzalutamide group versus 37% of the placebo group. Six percent of patients in both arms discontinued treatment due to adverse events. Charles Ryan, MD, moderator of the press cast where these data were discussed, emphasized that this study breaks new ground for enzalutamide in chemotherapy-naive patients with mCRPC. “The interim analysis showed benefit in this patient group, and this is an important study in our field, to be sure,” Ryan noted. Beer said that both abiraterone and

enzalutamide have shown benefit in docetaxel-naive patients with metastatic disease, but at present there are no headto-head comparisons to guide treatment selection. Decisions should be made on an individual patient basis, he stated. Further studies comparing these treatments and sequencing them are needed, as well as studies earlier in the disease process, Beer noted. l

Importantly, enzalutamide delayed the need for chemotherapy by a median of 28 months versus 10.8 months for placebo.

Reference

Beer TM, Logothetis C, Gerritsen WR, et al. Characterization of immune-related adverse events (irAEs) in a phase 3 trial of ipilumumab (Ipi) versus placebo (Pbo) in post-docetaxel mCRPC. J Clin Oncol. 2014;32(suppl 4):Abstract 52. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; Orlando, FL.

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Side Effects Management

Skin Toxicity With Targeted Agents… Continued from cover are sterile, and the Propionibacterium that causes acne is not recovered from skin biopsies. “We also see quite a lot of xerosis,” she said. “This again is associated with a mixed perivascular infiltrate; there are alterations in the stratum corneum, you can see parakeratosis, the keratinocytes can be apoptotic, and the eccrine glands can be miniaturized.” Pustular Rash and Other Skin Toxicities Skin lesions are most common on the face, chest, and back. Rash develops early, whereas paronychia and fissures are later events. Red papulopustules affecting the face and upper body develop in 45% to 100% of patients treated with EGFR inhibitors, usually occurring within 8 to 10 days and peaking at 2 weeks. Before these lesions appear, patients may be aware of sensory disturbance, erythema, and edema, Burtness noted. The telangiectatic phase occurs late (at approximately 6 weeks) and may be hastened by the use of topical steroids and retinoids. In patients treated with EGFR inhibitors, there is evidence that the intensity of their rash correlates with outcomes. For example, patients with colorectal cancer who were treated with cetuximab and who developed prominent rash had better overall survival than those who developed minimal rash, underscoring the importance of managing rash to enable patients to stay on treatment, said Burtness. Severe rash, however, does adversely affect quality of life. Skin toxicities related to EGFR inhibitor therapy can lead to bacterial, viral, or fungal infectious complications in about one-third of patients. Bacterial super-

infection (ie, impetigo, dissecting cellulitis) can be severe, she said. Fissures are a late, postinflammatory symptom. They respond to topical steroids. Larger fissures may benefit from cyanoacrylate adhesive dressing, but liquid bandage treatments should be avoided because they may ooze into the fissure, preventing complete closure.

30 to 40 mg/day have been used for EGFR inhibitor skin reactions with success. “Even though lesions don’t resolve, they become more telangiectatic and less pustular,” she said. “There has been some interest in the possibility of using prophylactic treatment to protect patients from these complications with agents known to

Emergence of new skin cancers—melanomas in non–sun-exposed areas and squamous cell cancers in sun-exposed areas—is a skin manifestation of vemurafenib and regorafenib.

Periungual and nail alterations, which develop in 12% to 16% of patients treated with EGFR inhibitors, usually occur 4 to 8 weeks after therapy and can progress to paronychia. Burtness recommends starting treatment with topical steroids; culture with evidence of superinfection and begin antibiotics as indicated. Early alopecia presents as mixed inflammatory infiltrate. Late alopecia is usually nonscarring and is associated with hair changes, such as hair curling and brittle hair. Clobetasol shampoo is “worth trying” and is more helpful in the early stage when rash and crusting are more prevalent, she said. Acitretin 10 mg/day and isotretinoin

have a very high rate of rash,” she said. Prophylaxis with systemic minocycline reduced the number of facial lesions compared with placebo in patients treated with cetuximab. In patients with metastatic colorectal cancer treated with panitumumab, prophylactic use of oral antibiotics with topical steroids was associated with significantly fewer grade 2 or higher skin toxicities compared with reactive treatment (62% vs 29%, respectively). However, the incidence of any-grade nausea and vomiting was higher with prophylactic treatment, although diarrhea was worse with reactive treatment (any-grade diarrhea, 85% for reactive vs

56% for prophylactic; grade 3 diarrhea, 32% vs 15%). Ocular Complications Ocular side effects also occur with EGFR inhibitors. Blepharitis usually responds to warm compresses, lid hygiene with antibacterial eye cleansers, and a short course of a topical eye ointment. Other complications include conjunctivitis, trichomegaly, corneal erosion, dry eye, and ectropion. Dysfunctional tear syndrome is the most common tear film change, and while the use of artificial tears and topical anti-inflammatory agents can be helpful, topical steroids should not be used without involvement of an ophthalmologist, advised Burtness. Skin Toxicity With RAF Inhibitors Emergence of new skin cancers—melanomas in non–sun-exposed areas and squamous cell cancers in sun-exposed areas—is a skin manifestation of vemurafenib and regorafenib. Granulomatous eruptions are also possible and respond to topical steroids; unlike the skin lesions associated with EGFR inhibitors, these eruptions are not pustular. Profound hand-foot syndrome has been associated with regorafenib. In addition, atypical melanocytic nevi and Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported in some patients treated with RAF inhibitors. l Reference Burtness B. Targeted agents: management of dermatologic toxicities. Presented at: 2014 Annual Conference of the National Comprehensive Cancer Network; March 13-15, 2014; Hollywood, FL.

Cancer Center Profile

Jefferson School of Pharmacy… Continued from cover The classroom, laboratory, pharmacypractice experiences, and extracurricular activities at the Jefferson School of Pharmacy are designed to produce competent and confident practitioners who apply their knowledge and skills to caring for individual patients as well as improving the overall health of the community. The Jefferson School of Pharmacy benefits from an integral partnership with the Thomas Jefferson University Hospitals, Department of Pharmacy Services. The Jefferson School of Pharmacy is part of a legacy of collaborative teaching, research, and service uniquely positioned to impact the health and well-being of the local community and the broader world. The Oncology Pharmacist spoke with Ginah Nightingale, PharmD, BCOP,

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assistant professor, Department of Pharmacy Practice, Jefferson School of Pharmacy at Thomas Jefferson University in Philadelphia, Pennsylvania, about her job. What are your job responsibilities at Jefferson? Ginah Nightingale (GN): I have a fulltime faculty appointment as assistant professor at the Jefferson School of Pharmacy. I serve as the course coordinator and the principal lecturer in our Clinical Diagnosis/Pharmacotherapy VI Oncology Module. I also precept professional year 3 (P3) and P4 students during their introductory and advanced pharmacy-practice experiences. My clinical practice sites are the Medical Oncology Inpatient Unit

at Thomas Jefferson University Hospital (TJUH) and the ambulatory Senior Adult Oncology Center at TJUH. What is your focus and research interest? GN: I took the initiative to become more involved with oncology research with a focus on senior adult oncology and medication use, specifically, polypharmacy and potentially inappropriate medication use in this vulnerable population. My abstract, “The Prevalence of Polypharmacy (PP) and Potentially Inappropriate Medication (PIM) Use in Senior Adult Oncology (SAO) Patients at an Academic Medical Center,” was accepted as a platform presentation at the 2014 Hematology/Oncology

Pharmacy Association (HOPA) Annual Conference. My study found that 41% of senior oncology patients seen at our center used at least 5 concurrent medications at the time of their initial visit and 43% of patients used 10 or more concurrent medications. Additionally, 51% of patients used a PIM, a medication that has the potential to increase the risk of adverse events in the elderly. The majority of patients in this cohort were 80 years of age or older with a mean comorbidity count of 7.69 (excluding the primary cancer). These findings demonstrated that a pharmacist-led medication assessment identified a high prevalence of PP and PIM use compared to previously published literature, probably attributed to

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Cancer Center Profile the fact that previous studies incorporated antiquated criteria for defining PP and PIM use and relied heavily on patient self-report/chart extraction versus a pharmacist-led assessment. What is the biggest challenge in your current job? GN: Balancing my work-related responsibilities/roles as faculty and lecturer in the didactic curriculum, experiential educator for students on pharmacy-practice experiences, and providing direct patient care clinical services, while at the same time trying to carve out adequate time for research/scholarly activities and active participation in professional organizations and institutional committee work. What is your biggest reward professionally? GN: I am most gratified when I see student pharmacists who are enthusiastic about a career in pharmacy and the contributions they can make to patients who will benefit from the pharmaceutical care provided by pharmacy school graduates. I love to see students involved in research and scholarly pursuits that offer students an opportunity to travel and present their

Ginah Nightingale, PharmD, BCOP

research findings at professional meetings. Three Jefferson School of Pharmacy students were actively involved in collecting research data that they presented in 2013 at the student poster session of the American Society of Health-System Pharmacists (ASHP) 48th Midyear Clinical Meeting and Exhibition in Orlando, Florida.

What led you to become an oncology pharmacist? GN: As a pharmacy student, I did not have an interest in cancer or cancer research. The experiential education process at my pharmacy school required me to select a rotation in medical oncology, so I was placed at the Cancer Institute of New Jersey (and my preceptor was Susan Goodin, PharmD, BCOP, FCCP). This rotation was truly an unexpected life-changing experience. I had an opportunity to work closely with the inpatient medical oncology rounding team, and they involved me in the care of each patient right from the start. The attending physician and medical residents had a lot of questions about supportive care therapies, chemotherapy toxicity/side effect management, pain management, and infection control. My oncology rotation was truly a rewarding experience that fostered my interest in pursuing oncology pharmacy. What advice would you give to new pharmacy students considering specializing in oncology? GN: I would encourage students to join an oncology-based professional organization

such as HOPA and to participate on institutional committees (during experiential rotations) that focus on cancer care, like the Pharmacy and Therapeutics Oncology Committee, or the Medication Safety (Oncology) Committee. Participating on such committees is a great way to stay informed about emerging cancer research and new treatment regimens, clinical updates on cancer treatments, and new supportive care therapies, not to mention a great way to network and collaborate. In this way, students will be well positioned to participate in healthcare initiatives and clinical decision making that will have a direct and positive impact on cancer patient management. If you won the lottery and didn’t have to work anymore, what would you do? GN: I am passionate about cancer care and research and I love to travel. I would want to travel the world and bring healthcare/cancer care aid and relief to countries across the globe. I would focus on improving healthcare/cancer care and advancing cancer care educational opportunities to underdeveloped countries across the world. l

Prostate Cancer

Immunotherapy in Metastatic Castration-Resistant Prostate Cancer Alice Goodman

mmunotherapy with ipilimumab improved progression-free survival (PFS) and prostate-specific antigen response compared with placebo, but improvement in overall survival (OS) failed to reach statistical significance in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). These results of a randomized phase 3 trial (CA184-043) were presented at the 2014 Genitourinary Cancers Symposium. Although the failure to significantly improve survival is disappointing, the study provided hints of subsets of patients who might derive greater benefit from ipilimumab: patients with more favorable prognostic factors (ie, no visceral metastasis, lower levels of alkaline phosphatase, and elevated hemoglobin). “Results of this trial support further investigation of ipilimumab in patients with fewer adverse prognostic features than those enrolled in this trial,” said lead author Charles G. Drake, MD, PhD, of the Johns Hopkins Sidney Kimmel Cancer Center, Baltimore, Maryland. CA184-043 enrolled 799 patients with mCRPC who had received docetaxel therapy. After being treated

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with at least 1 dose of bone-directed radiotherapy, patients were randomized in a 1:1 ratio to ipilimumab versus placebo. During the maintenance phase, those in the ipilimumab arm received ipilimumab every 12 weeks, and those in the placebo arm received placebo every 12 weeks. Median OS was 11.2 months for ipilimumab versus 10 months for placebo (hazard ratio [HR] 0.85; 95% confidence interval [CI], 0.72-1.00; P = .0530). The secondary end point of PFS was met, Drake reported. Median PFS was 4 months in the ipilimumab group and 3 months in the placebo group. In a prespecified subset analysis, the presence of visceral metastases appeared to interfere with the treatment effect of ipilimumab. Drake explained that most clinical trials exclude patients with visceral metastases, but this trial did not. Multivariate analysis identified the following favorable prognostic factors for OS: age <70 years, alkaline phosphatase <1.5 times the upper limit of normal, hemoglobin >11 g/dL, and absence of visceral metastases. Median OS was 14.4 months with ipilimumab in patients with no visceral metastases

versus 5.7 months in the presence of visceral metastases. Drake acknowledged that the trial was underpowered to show an interaction between ipilimumab and visceral metastases, “but the hazard ratio is clearly in the wrong direction.” HR was 1.644 (95% CI, 1.157-2.336) and P = .0056. The safety of ipilimumab in this study was similar to the experience with ipilimumab in metastatic melanoma, an indication for which it has received approval from the US Food

and Drug Administration. Based on the findings of CA184-043, a separate phase 3 trial of ipilimumab has been launched (CA184-095) in chemotherapy-naive mCRPC patients without visceral metastases. l Reference

Drake CG, Kwon ED, Fizazi K, et al. Results of subset analyses on overall survival (OS) from study CA184-043: ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2014;32(suppl 4): Abstract 2. Presented at: 2014 Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, CA.

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