The Oncology Pharmacist

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For Clinical Pharmacists, Board Certified Oncology Pharmacists, Pharmacy Directors, and P&T Committee Members CONFERENCE NEWS

SYMPTOM MANAGEMENT

Multivitamin Use During Chemotherapy May Reduce Risk for Peripheral Neuropathy

Price of Drugs and Affordability Don’t Always Jibe Phoebe Starr

Caroline Helwick

New Orleans, LA—Multivitamin supplement use was associated with a reduction in symptoms of chemotherapy-induced peripheral neuropathy

(CIPN) in a subanalysis of the SWOG S0221 trial. Patients who were using multivitamins before chemotherapy had 40% less neuropathy, and those Continued on page 8

ONCOLOGY UPDATE

The New World of Biosimilars Meg Barbor, MPH

Orlando, FL—The first oncology biosimilar—filgrastim-sndz (Zarxio)—was approved in the United States in March 2015, but this category of drugs is still fairly misunderstood, according to Jim M. Koeller, MS, Professor, College of Pharmacy, University of Texas at Austin.

“They’re new to everyone, and we’re all still trying to figure out what these

are, how we’ll deal with them, and how institutions will bring them on board,” Mr Koeller said at the 2016 Community Oncology Alliance annual meeting.

The next 2 oncology biosimilars expected to receive FDA approval in 2016 are for 2 different biosimilars to the same reference drug, pegfilgrastim (Neulasta), and many more will likely enter the market in the next few years.

Chicago, IL—A collaborative international pilot study found large differences in retail prices for 23 cancer drugs, showing highest retail prices in the United States and lowest prices in India and South Africa. Lower prices, however, did not necessarily mean the drugs were more affordable. Daniel Goldstein, MD, of Rabin Medical Center, Petach Tikvah, Israel, presented the results of the study at the American Society of Clinical Oncology 2016 Annual Meeting.

When monthly drug price was ex­ pressed as a percentage of gross domestic product per capita based on purchasing

power parity, cancer drugs appeared to be less affordable in low-income countries despite the lower retail prices.

The study is informative, even though the researchers could not obtain information about discounted prices from the drug manufacturers to factor into their computations.

“The study provides a glimpse into prices and affordability of cancer drugs around the world and sets the stage for further research. However, the implications of our findings are limited because we were not able to take discounts and rebates into account, which would better Continued on page 12

IMMUNOTHERAPY

Immunotherapy: Separating Facts from Fiction Meg Barbor, MPH

Scottsdale, AZ—Response is a poor outcome measure of immunotherapy, according to Tanguy Seiwert, MD, who addressed this and other concerning issues in immunotherapy at the 2016 Multidisciplinary Head and Neck Cancer Symposium.

“The impact of immunotherapy, at least for PD-1 [programmed death-1] checkpoint blockade, is primarily on survival,” he said. “Response rate likely

Continued on page 18

significantly underestimates its benefit, and based on what we’ve seen in other cancer types, the impact will probably be more pronounced in overall survival than in progression-free survival, given that response is not that reliable.”

According to Dr Seiwert, Associate Director of the Head and Neck Cancer Program at the University of Chicago, IL, much overall survival benefit is likely derived from patients with minor shrinkContinued on page 20

I N S I D E GUIDELINE UPDATE. . . . . . . . . . . . . . 7 DISABILITY INSURANCE. . . . . . . 17 Minor Changes in Systemic Therapy Recommendations in NCCN Breast Cancer Guideline

13

EMERGING THERAPIES. . . . . . . .

Combination Immunotherapy the New Standard for Patients with Metastatic Melanoma © 2016 Green Hill Healthcare Communications, LLC

Any-Occupation versus OwnOccupation Disability Insurance for Pharmacists

19

PROSTATE CANCER . . . . . . . . . . .

Promising Antitumor Activity of ODM201 in Metastatic Prostate Cancer

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FROM THE EDITORS

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Editor-in-Chief Patrick Medina, PharmD, BCOP

In this issue of The Oncology Pharmacist, we feature an article on the new—and often misunderstood—world of biosimilars (see cover). “They’re new to everyone, and we’re all still trying to figure out what these are, how we’ll deal with them, and how institutions will bring them on board,” explained Jim M. Koeller, MS, Professor, College of Pharmacy, University of Texas at Austin.

We also highlight a recent presentation from the 2016 Multidisciplinary Head and Neck Cancer Symposium, wherein Tanguy Seiwert, MD, Associate Director, Head and Neck Cancer Program, University of Chicago, IL, offered some immunotherapy “pearls” based on his experience from treating a substantial number of patients with immunotherapy (see cover).

Director, Creative & Design Robyn Jacobs Design Managers Chris Alpino Lora LaRocca Director, Digital Marketing Samantha Weissman Digital Content Manager Anthony Trevean Digital Editor John Parkinson Digital Media Specialist Charles Easton IV Junior Digital Content Manager Walford Guillaume Junior Digital Developer Christina Bethencourt

In addition, this issue provides insight into whether multivitamin use during chemotherapy may reduce the risk for peripheral neuropathy (see cover); about an updated survivorship guideline from the National Comprehensive Cancer Network that includes an extensive revision on addressing sexual function in cancer survivors (see page 14); and regarding the differences between any- and own-occupation disability insurance for pharmacists (see page 17).

Please visit our website, www.TheOncologyPharmacist. com, to share with us your feedback about this issue. You can also send comments to info@TheOncologyPharmacist. com. We hope you will enjoy this issue, and we look forward to your feedback. l

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 Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2016 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.

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EDITORIAL BOARD EDITOR-IN-CHIEF

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

ASSOCIATE EDITOR-IN-CHIEF

Steve Stricker, PharmD, MS, BCOP Takeda Oncology Florence, KY

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

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

Beth Faiman, PhD, MSN, APRN-BC, AOCN

Dwight Kloth, PharmD, FCCP, BCOP

Timothy G. Tyler, PharmD, FCSHP

Jim Koeller, MS

John M. Valgus, PharmD, BCOP

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

John F. Aforismo, BSc Pharm, RPh, FASCP

Christopher Fausel, PharmD

David Baribeault, BS, FCCP, BCOP

Rebecca S. Finley, PharmD, MS

Betty M. Chan, PharmD, BCOP

Heidi D. Finnes, PharmD, BCOP

Drug Knowledge LLC Wethersfield, CT

DB Pharmacy Consulting Salem, MA

USC/Norris Cancer Hospital Los Angeles, CA

Indiana University Simon Cancer Center Indianapolis, IN

Jefferson School of Pharmacy Philadelphia, PA

Mayo Clinic College of Medicine Rochester, MN

Fox Chase Cancer Center Philadelphia, PA

University of Texas at Austin San Antonio, TX

Christopher J. Lowe, PharmD Indiana University Hospital Indianapolis, IN

Emily Mackler, PharmD, BCOP University of Michigan Health System & College of Pharmacy Ann Arbor, MI

Desert Regional Medical Center Palm Springs, CA

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 BelHealth Investment Partners New York, NY

Marlo Blazer, PharmD, BCOP Steven L. D’Amato, RPh, BCOP New England Cancer Specialists Scarborough, ME

David C. Gammon, BSPh

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP The University of Texas MD Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

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

GASTROINTESTINAL HEALTH

“Overreaction” to Oxaliplatin Hypersensitivity Reactions Caroline Helwick

San Francisco, CA—A review of the incidence and management of hypersensitivity reactions to oxaliplatin revealed that many patients are unnecessarily taken off this important drug. Most reactions are mild, and most patients can be successfully rechallenged with the drug, according to a study presented at the 2016 Gastrointestinal Cancers Symposium

by Kelly Markey, PharmD, of Moffitt Cancer Center, Tampa, FL. The incidence of hypersensitivity reactions to oxaliplatin is approximately 10%, and only about 3% are serious (grade 3 or 4). Information about the treatment course of patients having these reactions has been limited to small case series, with little data on the success of rechallenging them, according to Dr Markey.

Empirically, premedications such as steroids and antihistamines are used to prevent or minimize hypersensitivity to oxaliplatin, and desensitization protocols can also be beneficial.

To better understand the frequency of hypersensitivity reactions and determine whether such patients can successfully receive oxaliplatin, Dr Markey and her colleagues retrospectively reviewed

“The majority of patients’ reactions to oxaliplatin were mild to moderate in severity and patients could be rechallenged with subsequent courses of therapy.”

Kelly Markey, PharmD

the management of 44 patients with gastrointestinal malignancies who experienced a hypersensitivity reaction to oxaliplatin. The 44 patients primarily had cancer of the colon (80%), but also of the esophagus, pancreas, and rectum. The most common regimen was FOLFOX (84%).

“We did this study after observing that we had patients referred to us who had experienced a reaction to oxaliplatin and had the drug dropped from their treatment regimen. Their clinicians tended to consider it an allergy and not give the drug anymore.

This was unfortunate, considering how important oxaliplatin is in colorectal cancer regimens,” Dr Markey said in an

interview with The Oncology Pharmacist.

The researchers recorded these reactions and whether patients were rechallenged with oxaliplatin in a subsequent infusion; whether the infusion rate was extended (and if so, by how long); whether additional premedications were given; and whether a desensitization protocol was used.

“We hypothesized that hypersensitivity reactions to oxaliplatin are mild to moderate, and that these patients can be successfully rechallenged more than 50% of the time with the use of supportive care medications and alterations of the infusion rate of oxaliplatin,” she said.

“Our retrospective evaluation showed

the majority of patients’ reactions to oxaliplatin were mild to moderate in severity and patients could be rechallenged with subsequent courses of therapy,” Dr Markey reported.

The researchers characterized 82% of the reactions as grade 1 or 2, and nurses were able to rechallenge 66% of the patients. Of those rechallenged, 61% received 3 or more additional infusions, 46% received 5 or more, and 14% received at least 10.

The nursing team added additional premedications, such as histamine antagonists, slowed the rate of infusion, and densensitized some patients by lengthening the duration of the infusion and giving small amounts of the drug until therapeutic doses were reached, Dr Markey said.

Dr Markey added that not all patients can or should be rechallenged, noting that for high-grade reactions “the risk of rechallenging could outweigh the potential benefits.” l Reference Markey K, Gatewood T, Valone T, et al. Evaluation of hypersensitivity reactions to oxaliplatin in gastrointestinal malignancies. Poster presented at: 2016 Gastrointestinal Cancers Symposium; January 21-23, 2016; San Francisco, CA. Abstract 709.

GUIDELINE UPDATE

Minor Changes in Systemic Therapy Recommendations in NCCN Breast Cancer Guideline Wayne Kuznar

T

he most recent update of the National Comprehensive Cancer Network (NCCN) guideline on breast cancer has undergone a number of “tweaks” with few major changes. The revisions include new recommendations for preoperative endocrine therapy, optimization of adjuvant endocrine therapy in premenopausal and postmenopausal women, an update on HER2-directed therapy for patients with operable breast cancer, and guidance on new agents for endocrine therapy in metastatic disease.

“There have been some tweaks, but I would not say major, major changes, within the guidelines,” said William J. Gradishar, MD, Director, Maggie Daley Center for Women’s Cancer Care, Northwestern University, Chicago, who presented the updated NCCN guideline at the 2016 NCCN annual conference.

Preoperative Systemic Therapy

“We made a modification that sug-

“We made a modification that suggests that endocrine therapy can be used selectively in the preoperative setting for patients with estrogen receptor–positive disease.”

William J. Gradishar, MD

gests that endocrine therapy can be used selectively in the preoperative setting for patients with estrogen receptor [ER]-positive disease, and there are different approaches that can be employed to accomplish the goal of treating the patient and downsizing the tumor,” said Dr Gradishar. Neoadjuvant endocrine therapy is typically considered in older postmenopausal women, but it can be

considered in other groups, including premenopausal women with comorbidities that make them poor candidates for chemotherapy.

Dr Gradishar noted that neoadjuvant chemotherapy with or without anti-­ HER2 therapy is increasingly successful in producing a pathologic complete response (CR), but only in patients with ER-negative/HER2-positive cancers. A

pathologic CR in such patients correlates with improved disease-free survival; this correlation is absent in patients with ER-positive disease.

A pathologic CR in patients with ER-positive disease is not critical, Dr Gradishar said, because pathologic CR is not as important in predicting the outcome in this group as it is in patients with ER-negative disease, in whom pathologic CR predicts an improvement in disease-free survival.

“We also have data with more recent agents, such as aromatase inhibitors, in this setting” (of ER-rich tumors), with clinical response rates of 60% to 72% and few patients with disease progression, he said.

Adjuvant Endocrine Therapy

New clinical trial data from the SOFT and TEXT clinical trials inform subtle changes in the updated guideline regarding the optimal approach for adjuContinued on page 8

SYMPTOM MANAGEMENT

Multivitamin Use During Chemotherapy May... using them during or after treatment had a 23% reduced risk.

The results were reported at the American Association for Cancer Research 2016 Annual Meeting by Gary R. Zirpoli, PhD, a postdoctoral fellow at Roswell Park Cancer Institute, Buffalo, NY. “We didn’t see any association with individual vitamin supplements, but we found that multivitamin users reported less [CIPN], compared to patients not using them,” Dr Zirpoli said in an interview with The Oncology Pharmacist.

“To our knowledge, this has not been reported before.”

Although vitamin supplements have been explored for their potentially protective effects, “promising candidates have not panned out,” he noted. “There really seems to be no good data showing their benefit.”

Dr Zirpoli’s study included 1225 participants who completed questionnaires before and at diagnosis, of whom 1068 also completed a 6-month follow-up questionnaire to capture supplement use during treatment.

Study Details SWOG S0221 evaluated the benefit of weekly versus biweekly paclitaxel (plus doxorubicin/cyclophosphamide) in patients with breast cancer at high risk for recurrence. Embedded within the trial design was a questionnaire about diet and other lifestyle factors.

Gary R. Zirpoli, PhD

“We didn’t see any association with individual vitamin supplements, but we found that multivitamin users reported less [CIPN], compared to patients not using them.”

Symptoms of CIPN were measured using the physician-assessed National Cancer Institute Common Terminology Criteria for Adverse

Events (CTCAE) and the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology GroupNeurotoxicity (FACT/GOG-Ntx) subscale. The subscale measures hand and foot numbness, hand and foot discomfort, joint and muscle pain, weakness, ringing in the ears, and trouble hearing, buttoning, feeling small objects, and walking. Answers of “quite a bit” and “very much” were grouped together to represent severe neuropathy, “somewhat” was considered moderate, and “a little bit” was considered mild.

Women were classified as supplement users if they used a supplement at least once a week. The analyses were adjusted for age, body mass index, race, smoking status, physical activity level, alcohol intake, and treatment.

CIPN and Multivitamin Use Before and During Treatment The use of multivitamins before diagnosis was associated with reduced symptoms of CIPN. This translated into a reduction in CIPN symptoms of 40% (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.42-0.87), primarily among the severe neuropathy group.

There were numerical differences favor-

Continued from cover

ing vitamin C and vitamin E, but the effect was not statistically significant.

As measured by the FACT/GOGNtx subscale, there was a 22% reduction in CIPN symptoms in women using a multivitamin before diagnosis (OR, 0.78; 95% CI, 0.61-1.00).

For supplement use during treatment, risk was reduced by 23% for multivitamin users, according to the FACT/GOG-Ntx subscale. No significant reductions were observed on the CTCAE instrument.

“Our results indicate that the use of multivitamins, but not individual dietary supplements, during treatment may reduce CIPN symptoms, although these findings require replication in larger studies,” Dr Zirpoli said.

“It’s important for other studies to verify these results, because it’s possible there is some other characteristic that helps explain why patients taking multivitamin supplements have less neuropathy,” he added. l Reference

Zirpoli GR, McCann SE, Sucheston-Campbell LE, et al.

Supplement use and chemotherapy-induced peripheral neuropathy in breast cancer patients treated on SWOG study S0221. Presented at: American Association for Cancer Research 2016 Annual Meeting; April 16-20, 2016; New Orleans, LA. Abstract 3413.

GUIDELINE UPDATE

Minor Changes in Systemic Therapy... vant endocrine therapy in premenopausal and postmenopausal women.

For premenopausal women at diagnosis, the guideline states that the optimal adjuvant endocrine therapy is tamoxifen for 5 years, with or without ovarian function suppression, or an aromatase inhibitor for 5 years with ovarian suppression or ablation. If a patient becomes postmenopausal after 5 years of endocrine therapy, tamoxifen should be considered for an additional 5 years, or the patient should switch to an aromatase inhibitor for 5 years. If the patient remains premenopausal, tamoxifen should be considered for an additional 5 years or no further endocrine therapy.

For postmenopausal women at diagnosis, “the data for an AI [aromatase inhibitor] beyond 5 years is really limited at this point…as it stands at this moment, we would say that 5 years of an AI is the optimal duration,” he said. In women with early-stage ER-positive disease, 5 years of tamoxifen has a carryover effect lasting for at least another 5 years in terms of a reduction in the odds

of breast cancer recurrence and breast cancer mortality.

It is important to discuss with patients the expected side-effect profile of ovarian suppression, specifically musculoskeletal complaints, dyspareunia, vaginal dryness, and difficulty with arousal, Dr Gradishar said.

Continued from page 7

lesions and/or positive lymph nodes.

Preliminary data from the NeoSphere clinical trial indicate that a dual anti-­ HER2 regimen with pertuzumab and trastuzumab, added to docetaxel (Taxotere), translates into superior improvement in progression-free survival compared with the other treatment

“This collation of all the data led to a provisional approval of pertuzumab in this setting, and that prompted us to put it in the guidelines,” said Dr Gradishar.

“If the adjuvant APHINITY trial proves not to be positive, and representative of what we have seen in the preoperative setting, the guidelines may change.”

Recurrent or Stage IV Disease

It is important to discuss the expected sideeffect profile of ovarian suppression, specifically musculoskeletal complaints, dyspareunia, vaginal dryness, and difficulty with arousal.

HER2-Positive Disease

Neoadjuvant HER2-directed therapy, particularly with a trastuzumab (Herceptin)-containing regimen, is recommended for at least 9 weeks before surgery. A pertuzumab (Perjeta)-containing regimen can be considered for patients with HER2-positive disease and with T2

arms in the clinical trial. In addition, data from the CLEOPATRA clinical trial showed that overall survival was significantly improved with pertuzumab plus trastuzumab and docetaxel compared with placebo plus trastuzumab and docetaxel in patients with HER2-positive metastatic disease.

The updated guideline states that premenopausal women with recurrent or stage IV hormone receptor–positive disease should have ovarian ablation or suppression, followed by a regimen recommended for the treatment of postmenopausal women.

Palbociclib (Ibrance) is a new option for this patient population, to be used in combination with letrozole or fulvestrant, based on data from the PALOMA-1 clinical trial. The results “were quite striking,” and in favor of palbociclib as first-line therapy for ER-positive metastatic disease, with a doubling of time to progression, and led to the approval of palbociclib in this setting, said Dr Gradishar. l

TECHNOLOGY UPDATE CANCER CENTER PROFILE

An Update on CancerLinQ—ASCO’s Big Data Cancer Database Meg Barbor, MPH

Why CancerLinQ? Approximately 1.7 million people are diagnosed with cancer every year in the United States, but only a small percentage of adults with cancer can participate in clinical trials where their data are captured systematically and can be retrieved. The vast majority (97%) of patient data is locked away in unconnected files and servers—formerly paper records but now electronic health rec­ ords (EHRs).

“Therefore these learnings are lost and can’t contribute to the greater knowledge,” said Dr Miller. “And quite

frankly, many of our patients think we do a much better job than we currently do in having access to this information.”

There has also been an explosion of knowledge and an increase in the data required for medical decision-mak-

Photo by © ASCO/Todd Buchanan

Phoenix, AZ—CancerLinQ (Learning Intelligence Network for Quality) is a powerful database containing a vast amount of usable, searchable, realworld cancer information, created by oncologists, for oncologists, to improve the quality of patient care, according to updates presented at the 2016 American Society of Clinical Oncology (ASCO) Quality Care Symposium.

A national initiative inspired and informed by ASCO, CancerLinQ was designed to contribute to high-quality, personalized cancer care for every patient, by bringing all of the electronic data collected from the everyday care of every patient into one rapid learning network.

“This is ASCO’s big-data health information technology platform to improve cancer care,” said Robert S. Miller, MD, a medical oncologist and Vice President, ASCO Quality and Guidelines, and Medical Director of CancerLinQ.

in these servers,” Dr Miller added.

With this database, ASCO aims to improve provider performance and patient outcomes by providing guidance about the best evidence at the point of care; it does so by incorporating ASCO’s

“We have to create a platform that will accept data from different systems to enable interoperability across many sources.”

Robert S. Miller, MD

ing. “The number of facts per decision required to manage patients in the modern era of genomics and proteomics has gone up, but what of course doesn’t change is human cognitive capacity,” said Dr Miller.

Another phenomenon is the existence of more cancers. Many molecular drivers and many diseases require a data management system that is simply outstripped by our current capacity.

A Learning Health System CancerLinQ is defined as a learning health system, where research and practice can inform each other.

“Discovery is not just limited to the 3% of patients that are in clinical trials, but in the everyday care experiences that are rendered in clinics everywhere, that are basically locked

clinical guidelines as well as more than 200 clinical quality measures from ASCO’s Quality Oncology Practice Initiative Program. “The real-world outcomes captured as part of the learning health system will be linked back to the same measures and guidelines and will inform their development,” he stated.

Secondarily, the big data aggregation that is enabled by CancerLinQ will allow for a generation of insights and data exploration on a scale not seen by the limitations of EHRs. “Another guiding principle was the fact that we recognize that hospitals and physicians will continue to use different commercial systems,” said Dr Miller “We have to create a platform that will accept data from different systems to enable interoperability across many sources.”

The web-based clinical user portal is accessed through a browser, allowing the user access to various applications like quality performance indicators, data exploration tools, and a series of customizable and standardized analytic reports.

CancerLinQ also adheres to industry standards through a series of regulatory, administrative, technical, and physical safeguards fully compliant with HIPAA (Health Insurance Portability and Accountability Act) and all appropriate state and federal guidelines.

Practice Integration “The pace of practice engagement has increased sharply in the US over the past few months,” Dr Miller reported. CancerLinQ now holds more than 250,000 patient records in its system and has participation from more than 2 dozen vanguard practices and more than 600 oncologists across the country, with a strong and growing pipeline of interest. “In the next month or so, we’ll be bringing on 2 large multisite health systems with many tens of thousands of records that will be added to the CancerLinQ database,” he added.

“Basically, the vision has always been that CancerLinQ is positioned squarely as part of the quality portfolio of ASCO,” said Dr Miller. “And most importantly, it is guided by ASCO’s mission to support all physicians, in every community and every setting.” l Reference

Miller R. CancerLinQ update. Presented at: ASCO Quality Care Symposium; February 26-27, 2016; Phoenix, AZ.

CONFERENCE NEWS

Opioid Prescriptions for Pain Management: Safe Patient, Prescriber, Community Wayne Kuznar

Hollywood, FL—Achieving balance in the appropriate use of opioids to treat cancer pain requires skill and compassion. Strategies for safely and effectively prescribing opioids while reducing the risk of drug misuse and abuse were offered by Judith Paice, PhD, RN, FAAN, at the National Comprehensive Cancer Network 21st Annual Conference.

Best practices for the management of chronic pain is a timely issue, given the

recent federal proposal to address prescription opioid abuse and the heroin use epidemic.

“We’ve learned to use opioids a little more judiciously, but the pendulum maybe swung a little bit too far in the direction of using them in people who maybe aren’t the best candidates, or using doses higher than we should,” said Dr Paice, Director, Cancer Pain Program, Division of Hematology/ Oncology, Robert H. Lurie Compre-

hensive Cancer Center, Northwestern University, Chicago, IL. “We’re starting to reevaluate…; our goal is truly a balance between analgesia, function, and safety. We need to think of those 3 components when we’re providing good pain control.”

Another way to think of the challenge is the safety of the patient, prescriber, and community, she said. The concept of no pain for 24 hours a day, 7 days a week is now considered unrealistic.

In addition to understanding the characteristics of the pain, the providers should also assess the effect the pain is having on the patient’s life. Response to interventions for past pain episodes, including the types of adverse effects, is part of this assessment. Comorbid conditions should be considered as well, since these may place the patient at risk for misuse of pain medicines. The patient’s functional goals should also be determined.

Continued on page 12

CONFERENCE NEWS

Price of Drugs and Affordability...

“Until now it hasn’t been clear what the magnitude of difference in prices is or how prices in each country relate to affordability.”

Photo by © ASCO/Scott Morgan 2016

predict affordability,” said Dr Goldstein.

“Until now it hasn’t been clear what the magnitude of difference in prices is or how prices in each country relate to affordability. The differences in prices are not proportional to ability to pay,” he noted.

Of the 23 cancer drugs, 15 were generic and 8 were patented. These drugs are used to treat a range of cancer types and stages. The 7 countries in the study were Australia, China, India, Israel, South Africa, the United Kingdom, and the United States.

Drugs of both types were most affordable in Australia. The United States had the highest median monthly prices for drugs—both generic and patented—but ranked 5th in affordability per capita for patented drugs, behind

Continued from cover

Daniel Goldstein, MD

Australia, the United Kingdom, Israel, and South Africa, and tied with the United Kingdom for 4th for generic drugs, behind Australia, Israel, and

South Africa. Drugs were least affordable in India and China, with China the highest for patented drugs and India the highest for generic drugs (Table).

Table Median Monthly Generic Drug Retail Pricesa Australia

China

India

South Africa

United Kingdom

United States

Median monthly generic drug retail price in US$

226

532

159

120

458

654

Median monthly patented drug retail price in US$

2741

3173

1515

1708

2587

8694

46,550

13,324

5808

13,094

39,826

54,370

Median monthly generic drug retail price as % of monthly GDPcap

3

48

33

11

14

14

Median monthly patented drug retail price as % of monthly GDPcap

71

288

313

157

78

192

GDPcap in US$

Data for Israel not shown.

GDPcap indicates gross domestic product per capita.

a

Opioid Prescriptions for Pain Management...

Medication choice should match the type of pain. For somatic pain, rely on nonopioids, advised Dr Paice, whereas neuropathic pain may require opioids at higher doses, along with adjuvant analgesics. Visceral pain is less well understood, but opioids and corticosteroids are reasonable choices.

Less well-known adverse effects of opioids include hormonal changes (suppression of testosterone), which may impact libido, fertility, bone health, and fatigue.

“I don’t want to lose track of the fact that we still have people who are undermanaged with pain control,” she said. Those at risk for undertreatment include infants and children, patients >65 years of age, long-term survivors, cognitively impaired persons, economically disadvantaged patients, and non–

English-speaking patients.

The oncology patient can likewise suffer from overtreatment of pain. As with undertreatment, long-term survivors are at risk of overtreatment.

Others at similar risk are patients with comorbid mental health conditions (ie, anxiety, depression, sleep disorders). “We need to be very clear with patients that you can’t take these medicines to treat your anxiety…or to help you sleep,” said Dr Paice. Patients with limited financial resources may be at risk of overtreatment with opioids because they have limited access to physical therapy and mental health counseling.

While the long-term benefits of opioid therapy have not been documented, since the duration of most studies has been 12 weeks, adverse effects of

long-term opioid use include cognitive difficulties and depression; respiratory depression is also related to opioid use.

An increasing rate of opioid prescriptions correlates with increasing rates of opioid abuse and opioid-related deaths, she pointed out. The differential diagnosis of aberrant drug-taking behavior includes pseudo-addiction, in which the amount of drug ordered is insufficient, possibly because of insurance limits.

Some patients, however, do have an opioid addiction while others attempt to obtain the drug with criminal intent (diversion). Smoking is a risk factor for addiction as are a personal history of sexual abuse and a family history of substance abuse.

Urine drug-toxicology testing can help discern whether patients are taking the drug as prescribed or are diverting it.

The study did not take into account the health insurance systems in the different countries. Depending on the insurance system, the patient may or may not bear some or all of the cost of the drugs.

“We need open access to discount prices and transparency—which we did not have. This study raises significant questions and shows us that knowing the price of drugs is not all we need to know to determine value. Some drugs save lives, while others benefit patients for weeks,” Dr Goldstein said.

“This is an interesting international comparative study. The concept of affordability is novel and adds another dimension to the discussion of the price of drugs, the value of drugs, and whether they are affordable,” said Patricia Ganz, MD, Jonsson Comprehensive Cancer Center at the University of California Los Angeles. Dr Ganz was not involved in the study.

“The prices of drugs are putting a significant burden on the healthcare system and on patients. More needs to be done to make treatments more affordable and accessible for all patients,” Dr Ganz said. l Reference

Goldstein DA, Clark J, Tu Y, et al. Global differences in cancer drug prices: a comparative analysis. Presented at: 2016 American Society of Clinical Oncology Annual Meeting; June 3-7, 2016; Chicago, IL. Abstract LBA6500.

Continued from page 9

Prescription drug–monitoring programs are available to screen for aberrant behaviors and to verify medication dose and refill dates.

When opioids are no longer beneficial, physicians should provide a strategy to wean the patient off the drug.

A slow downward titration, about a 10% reduction in dose per week, is recommended.

To ensure a safe community, educate patients and their families about safe medication practices, including keeping pain medicines locked away, Dr Paice advised. l Reference

Paice J. Cancer pain management: strategies for safe and effective opioid prescribing. Presented at: National Comprehensive Cancer Network 21st Annual Conference; March 31-April 2, 2016; Hollywood, FL.

NOTEWORTHY NUMBERS

Noteworthy Numbers Lymphoma

Lymphomas, cancers that begin in lymphatic cells of the immune system, can be divided into 2 main categories: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). HL is a fairly homogeneous disease characterized by the presence of Reed-Sternberg cells. HL is far less common than NHL—approximately 8000 new HL cases are diagnosed in the United States annually compared with over 70,000 new cases of NHL; more than 60 types of lymphoma are included in the NHL category.1 Presented below are a few facts about various forms of lymphoma. .

In 2013, an estimated 569,536 people were living with NHL. Estimates also indicate that in 2016 NHL will represent 3.4% of all new cancer cases in the United States and that 20,150 people will die of NHL.2 The 5-year relative survival rate for people with HL has increased from 40% for whites (19601963) to 88.3% for all races (2005-2011). If diagnosed with HL at age younger than 45 years, the 5-year relative survival rate is 94.1%.

For NHL, the 5-year relative survival rate rose from 31% in whites (1960-1963) to 71.9% for all races (2005-2011).3

Approximately 85% of all NHLs are B-cell lymphomas, and 15% are T-cell lymphomas.

Diffuse large B-cell lymphoma is the most common form of NHL, accounting for up to 33% of newly diagnosed cases. Anaplastic large-cell lymphoma is a T-cell lymphoma that accounts for about 3% of all lymphomas in adults and between 10% and 30% of all lymphomas in children.4 NHL can develop at any age, but more than 95% of cases occur in adults, and about 50% of patients are older than 66 years.5 HL can also occur in children and adults but is most common from ages 15 to 40 years (especially

in the 20s) and after age 55 years. While about 10% to 15% of cases are diagnosed in children and teenagers, HL is rare in children younger than 5 years.6 The Lymphoma Coalition (LC) is a worldwide nonprofit network of lymphoma patient groups. Established in 2002 by 4 lymphoma organizations, its purpose is to aid organizations that support and inform patients with lymphoma.

Currently there are 66 member organizations from 44 countries. LC helps organize World Lymphoma Awareness Day on September 15 each year.7

Sources 1.

2.

3.

4.

5.

6.

7.

http://blog.dana-farber.org/insight/2015/07/what-is-the-difference-between-hodgkin-lymphoma-and-non-hodgkin-lymphoma/. Published July 6, 2015. Accessed June 14, 2016. http://seer.cancer.gov/statfacts/html/nhl.html. Accessed June 14, 2016. www.lls.org/facts-and-statistics/facts-and-statistics-overview. Accessed June 14, 2016. www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300139#CNS. Accessed June 14, 2016. www.cancer.org/cancer/non-hodgkinlymphoma/. Updated January 22, 2016. Accessed June 14, 2016. www.cancer.org/cancer/hodgkindisease/detailedguide/hodgkin-disease-key-statistics. Updated February 9, 2016. Accessed June 14, 2016. www.lymphomacoalition.org/about-lc/lymphoma-coalition-overview. Accessed June 14, 2016.

EMERGING THERAPIES

Combination Immunotherapy the New Standard for Patients with Metastatic Melanoma Walter Alexander

T

he key arguments supporting the use of combination therapy with checkpoint blockade immunotherapies as the standard of care for treating metastatic melanoma arise from the combination’s high disease control rates; rapid deep responses; improved response rates; longer progression-free survival (PFS); and good estimated overall survival (OS), approaching 70% at 3 years, said Steven J. O’Day, MD, Professor of Medical Oncology, John Wayne Cancer Institute at Providence Saint John’s Health Center, Santa Monica, CA, at the recent HemOnc Today Melanoma and Cutaneous Malignancies meeting.

The new systemic immunotherapies produce durable tumor responses, early disease control, and symptom management. In addition, they offer patients time without symptoms or treatment and often long-term survival. Converse-

ly, traditional cell-directed therapies are characterized by short responses with little impact on survival, Dr O’Day noted.

The newer PD-1–blocking antibodies, such as nivolumab (Opdivo) and pembrolizumab (Keytruda), have demonstrated higher response rates than ipilimumab (Yervoy), the cytotoxic T-lymphocyte antigen-4 blockade agent that was the first in decades to show an OS benefit in patients with advanced melanoma.

CheckMate-067

The objective response rates in the phase 3 clinical trial CheckMate-067 were 19% with ipilimumab, 44% with nivolumab, and 58% with nivolumab plus ipilimumab. Complete responses were 2.2% with ipilimumab, 8.9% with nivolumab, and 11.5% with nivolumab plus ipilimumab. Similarly,

the median PFS was 2.9 months with ipilimumab, 6.9 months with nivolu­ mab, and 11.5 months with nivolumab plus ipilimumab.

However, the favorable response rates and survival data associated with nivolumab plus ipilimumab come with increased grade 3 or 4 adverse events, with 27.3% and 16.3% rates for ipilimumab and nivolumab, respectively, compared with 55% for nivolumab plus ipilimumab. No treatment-related deaths were reported with nivolumab plus ipilimumab.

“If patients are educated and prepared for side effects and communicate about them rapidly, early intervention reverses almost all of them,” Dr O’Day said. Although adverse events led to treatment discontinuation in 29.4% of patients who received nivolumab plus ipilimumab, the objective response rate was nearly 70% in patients who discon-

tinued the combination therapy. “Those responses are still durable, so with coming off therapy, while it shortens treatment, the opportunity for long-term survival is still there,” Dr O’Day said.

High Toxicity Remains a Concern

Jeffrey S. Weber, MD, PhD, Deputy Director, Perlmutter Cancer Center, NYU Langone Medical Center, focused on the high toxicities associated with the combination of nivolumab plus ipilimumab. “You can talk about a zero death rate in a very tightly controlled, well put together randomized phase 3 trial, but when it comes to treatment in the community, where physicians have less experience, it’s going to be a different scenario.”

Dr Weber also said that roughly 40% of patients with melanoma with PD-1 ligand 1 tumors with an “inflammatory signature” are likely to benefit from Continued on page 14

SEXUAL HEALTH

NCCN Survivorship Guidelines Update Management of Sexual Dysfunction in Cancer Survivors Wayne Kuznar

Hollywood, FL—An updated survivorship guideline from the National Comprehensive Cancer Network (NCCN) includes an extensive revision on addressing sexual function in cancer survivors. Version 1.2016 of the survivorship guidelines recommends screening for sexual dysfunction in cancer survivors at regular intervals and offering appropriate assessments, referrals, and interventions based on whether the survivor is ready to have a conversation about sexual function.1 The updated guidance was presented at the NCCN 21st Annual Conference, with presentations focusing on the guidelines for women and for men.2 Female Sexual Health Michelle Melisko, MD, presented the guideline for women, noting that sexual dysfunction is likely to become more prevalent in young breast cancer survivors with increasing use of ovarian suppression.

A recent study of 83 breast cancer survivors revealed that 77% of all study participants and 60% of sexually active ones qualified for a diagnosis of sexual dysfunction based on the Female Sexual Function Index (FSFI).3 “There is an increasing understanding of the safety and risks associated with hormonal interventions,” said Dr Melisko, Associate Professor of Hematology/Oncology, University of California San Francisco, Helen Diller Family Comprehensive Cancer Center.

With longer courses of aromatase inhibitors being recommended in

women with breast cancer, “we will be seeing more vaginal dryness and sexual complaints,” she said.

“There is an increasing understanding of the safety and risks associated with hormonal interventions.”

Michelle Melisko, MD

For women with symptoms of pain with sexual activity, the guideline adds ospemifene, a nonestrogen selective estrogen receptor modulator, to the list of treatment options, which also includes topical vaginal therapies (moisturizers, gels, and lubricants), vaginal dilators, pelvic floor physical therapy, and topical anesthetics. Ospemifene is currently contraindicated in survivors with a history of estrogen-dependent cancers, said Dr Melisko, but can be useful for other cancer survivors.

Menopausal hormone replacement therapy may be an option to manage sexual and menopausal symptoms in some patients.

For women with low libido, for the first time the updated guideline mentions the option of using flibanserin, although a footnote declares the lack of data to support its use in cancer survivors.

Recently, a study found that 4%

aqueous lidocaine applied to the vulva reduced pain during intercourse, decreased sexual distress, and improved sexual function,4 said Dr Melisko.

Seventeen of 20 patients who completed the study and who had abstained from intercourse resumed comfortable penetration. Microablative CO2 laser improved scores on the FSFI at 12 weeks in 77 postmenopausal women with vaginal dryness, and was later approved by the US Food and Drug Administration, but no data with this method are available in breast cancer patients.

Male Sexual Health An update on sexual function in male cancer survivors was presented

by Joseph B. Narus, DNP, GNP-BC, ANP, Nurse Practitioner, Sexual and Reproduction Program, Memorial Sloan Kettering Cancer Center, New York City.

Early evaluation of erectile dysfunction following recovery from cancer treatment is optimal.

Eliminated in the workup in the new guideline is hemoglobin A1C testing, lipid screening, and evaluation of creatinine. Testosterone therapy may be

indicated in men with erectile dysfunction, ejaculatory problems, or orgasmic problems if total testosterone measured in the morning is <300 ng/dL. A low-dose oral phosphodiesterase-5 inhibitor is a treatment option for erectile dysfunction. Referral to a specialist is now recommended for more complex erectile dysfunction, he said. Secondline treatment options mentioned in the guideline include intracavernosal injection therapy, penile vacuum devices, and intraurethral suppositories.

Early evaluation of erectile dysfunction following recovery from cancer treatment is optimal because untreated dysfunction may lead to long-lasting problems with erections due to fibrosis of the corporal cavernosa resulting in venous leak, said Dr Narus.

The patient’s comfort level with a discussion of sexual health should first be assessed, however, because men may initially be concerned primarily with their cancer. l References

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Survivorship. Version 1.2016. Fort Washington, PA: NCCN; 2016. www.nccn.org/professionals/ physician_gls/pdf/survivorship.pdf. Accessed April 25, 2016.

2. Melisko M, Narus J. Sexual function in cancer survivors: updates to the NCCN Guidelines® for survivorship. Presented at: National Comprehensive Cancer Network 21st Annual Conference; March 31-April 2, 2016; Hollywood, FL. 3. Raggio GA, Butryn ML, Arigo D, et al. Prevalence and correlates of sexual morbidity in long-term breast cancer survivors. Psychol Health. 2014;29:632-650.

4. Goetsch MF, Lim JY, Caughey AB. A practical solution for dyspareunia in breast cancer survivors: a randomized controlled trial. J Clin Oncol. 2015;33:3394-3400.

EMERGING THERAPIES

Combination Immunotherapy the New Standard...

PD-1 abrogation alone, with little need for adding ipilimumab.

“The toxicity of combination therapy suggests that those over 75-80 years of age or with significant comorbidities should be treated with single-agent PD-1 or a PD-1 combination other than ipilimumab,” he added.

Dr Weber noted that among patients who cannot tolerate combination therapy, but who can receive single-agent nivolumab or pembrolizumab, are patients with previous grade 3 or 4 ipilimumab-related adverse events, and patients with previous allografts or with a history of hepatitis or controlled

HIV infection.

Dr Weber suggested that patients with BRAF mutation melanoma with low-to-normal lactate dehydrogenase (LDH) levels will likely respond as well to targeted BRAF plus MEK inhibitors, such as dabrafenib and trametinib, as they will to ipilimumab plus nivolumab, with a 30% plateau in OS. Combination therapy with BRAF plus MEK inhibitors is considerably less toxic than ipilimumab plus nivolumab combined.

For patients with BRAF mutation melanoma and with high LDH levels, a brief induction with BRAF plus MEK inhibitors followed by ipilimumab plus nivolu­

mab may be preferred, because the BRAF plus MEK combination induces a T-cell influx into tumors, and converts a “cold” tumor to a responsive “warm” tumor.

Dr Weber said that an early-phase study with pembrolizumab and an indoleamine 2,3-dioxygenase inhibitor demonstrated a 53% objective response rate, similar to nivolumab plus ipilimumab, but with significantly less tox­ icity. “Therefore, ipilimumab plus nivolumab combination therapy is not indicated for all metastatic melanoma patients,” he concluded.

“I completely agree with Dr Weber that the combinations with ipilimumab

Continued from page 13

should be given through experienced hands. There needs to be a big commitment from the patient and the family to communicate information about side effects,” Dr O’Day said in an interview.

Although the pituitary cases (hypophysitis) typically require lifelong replacement therapy, which is a hassle for patients, the more important colitis and liver toxicities are generally reversible.

Combinations of a PD-1 agent with ipilimumab at lower doses, or with a third intralesional therapy, such as tal­ imogene laherparepvec (Imlygic), may also prove successful for patients with metastatic melanoma, Dr O’Day said. l

ONCOLOGY UPDATE

Molecular Profiling Is Vital in Patients with Metastatic Cancer Meg Barbor, MPH

Orlando, FL—Physicians need to advocate for molecular profiling, according to Howard “Skip” Burris III, MD. “I do think, in treating our metastatic patients, it’s going to be as good as the next PET/CT [positron emission tomography/computed tomography] scan, and it’s certainly going to be more important than the follow-up PET/CT scan that you get when the patient develops resistance or progression,” he said at the 2016 Community Oncology Conference.

But the problem is cost, he added. “I think among the list of things we have to advocate for in community oncology is how molecular profiling is going to be paid for, but the cost of this needs to be determined,” said Dr Burris. “I think the simple problem is, they’ll pay for a test when you get an answer, but in this setting the test provides a lot of potential answers, but no definitive answer, which makes it very hard.”

What Test Do I Order?

In addition to the cost, other challenges involved in molecular profiling include determining what type of test to order and knowing which technology is needed for comprehensive tissue testing, interpreting the tests and what the results might mean, determining when to rebiopsy, and getting enough tissue and prioritizing the use of that tissue.

Alterations can occur within a chromosome or across 2 chromosomes,

“so there’s a variety of opportunities for drug development, but it becomes all the more important to know what you’re actually treating in a patient,” said Dr Burris, President of Clinical Operations and Chief Medical Officer at Sarah Cannon Research Institute.

Somatic and germline mutations are important to consider as well, as more and more germline mutational abnormalities are being discovered in patients with metastatic cancer.

“But there’s a lot of competition in this space, and we’re going to see the best emerge,” said Dr Burris.

Routine single-marker molecular tests, such as immunohistochemistry (IHC), polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH), have been used for decades and will continue to play an important role in cancer diagnosis. A multigene “hot spot” test can identify prespecified mutations occurring in very limited areas of genes of interest, but could fail to detect all classes of genomic alterations.

According to Dr Burris, a comprehensive genomic profiling approach, which tests all of the known clinically relevant cancer genes for all classes of alterations, will provide the most inclusive answer.

“I think the temptation is to get the single-marker molecular test,” he said.

“But what we really want to know, if cost isn’t an issue, is the complete

genetic profile, or what the patient had at the beginning and what they have acquired. I think that’s going to be the key for us in taking care of these patients.”

He warned that a new biopsy might be needed before profiling, as a patient’s tumor may change over time depending on treatments and can acquire therapy-specific resistance mutations, so the molecular status of an historical sample may not reflect the patient’s current disease status.

“We’ve got to find the right therapy for the right patient at the right time, and I think biopsy, identification, profiling… all of these are going to be very key.”

Howard Burris III, MD

More Liquid Biopsy on the Horizon Although tissue-based assays are still the “gold standard,” according to Dr Burris, liquid biopsy—a new noninvasive technique that can detect disease biomarkers in blood, urine, and other body fluids—is going to be key in the

near future. “Many of your patients don’t have disease accessible to biopsy, so liquid biopsy is where it’s heading,” he said.

It seems that highly specific tests are more sensitive than broad-based tests and could be adopted much quicker (eg, Droplet Digital PCR–based tests are more sensitive than tests based on next-generation sequencing), he said, but currently there are biologic challenges to be addressed (eg, heterogeneity, localization, not all clonal events are cancer). In addition, 42% of patients shed no detectable circulating tumor DNA into the bloodstream, which Dr Burris called “a little discouraging.”

JP Morgan predicts liquid biopsy will be a $20-billion field in the next 5 years, “but figuring out how to pay for it will be an interesting challenge,” Dr Burris said.

“We’re taking care of the other 99% that can’t get the Dana-Farber or the MD Anderson treatment. They’re being treated in the community, and how we do this is so important,” he said. “We’ve got to find the right therapy for the right patient at the right time, and I think biopsy, identification, profiling…all of these are going to be very key.” l Reference

Burris HA. The influx of new cancer drugs: clinical, patients care, and operating ramifications. Presented at: 2016 Community Oncology Conference; April 14-15, 2016; Orlando, FL.

FDA NEWS Fluciclovine F18 Diagnostic Imaging Agent Approved to Detect Recurrent Prostate Cancer On May 27, 2016, the FDA approved fluciclovine F18 (Axumin; Blue Earth Diagnostics) injection, a radioactive diagnostic imaging agent used to detect recurrent prostate cancer.

Fluciclovine F18 injection is indicated for use with positron emission tomography (PET) imaging in patients with suspected prostate cancer recurrence based on elevated prostate-specific antigen (PSA) levels.

“Imaging tests are not able to determine the location of the recurrent prostate cancer when the PSA is at very low levels,” said Libero Marzella, MD, PhD, Director of the FDA’s Center for Drug Evaluation and Research Division of Medical Imaging Products. “Axumin is shown to provide another accurate imaging approach for these patients.”

The FDA approval was based on 2 blinded studies evaluating the safety and efficacy of fluciclovine F18 injection. The first study compared 105 scans using fluciclovine F18 injection with histopathology obtained by prostate biopsy and by biopsies of suspicious imaged lesions in patients with suspected recurrence of prostate cancer. The second study compared the results from 96 scans using fluciclovine F18 injection with C11 choline scans, an approved PET scan imaging test, in men with a median PSA value of 1.44 ng/mL. In both studies, onsite radiologists and 3 independent radiologists read the scans, and their conclusions were generally consistent with one another.

The most frequently reported adverse events were injection site pain, redness, and a metallic taste in the mouth.

Because fluciclovine F18 is a radioactive drug, the FDA recommends appropriate safety measures to limit expo-

sure to patients and providers during administration.

Tecentriq for Metastatic Urothelial Bladder Cancer

On May 18, 2016, the FDA granted accelerated approval to atezolizu­mab (Tecentriq; Genentech) for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy, or for those who have had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy.

Atezolizumab received a breakthrough therapy designation in May 2014 for the treatment of metastatic bladder cancer that expresses PD ligand 1 (PD-L1) and was granted a priority review designation by the FDA in March 2016 for the treatment of locally advanced or metastatic urothelial carcinoma.

The accelerated approval of atezo­ lizumab was based on the results of the IMvigor 210 study, an open-label, multicenter, single-arm, phase 2 study of 310 patients with locally advanced or metastatic urothelial carcinoma who received 1200 mg of atezolizumab intravenously. The study’s primary end point was objective response rate (ORR), and the secondary end point was the duration of response.

Atezolizumab conferred at least partial shrinkage of tumor in 9.4% of patients. The ORR in the study was 14.8%, and the median duration of response ranged from 2.1 months to 13.8 months. The ORRs were 9.5% in patients with PD-L1 expression of <5% and 26% in patients with PD-L1 expression ≥5%, suggesting that the level of PD-L1 expression may help identify the patients who are more likely to respond to therapy with atezolizumab; the Ventana PD-L1 assay was approved by the Continued on page 16

LUNG CANCER

Approval of First Liquid Biopsy to Detect EGFR Mutations in Lung Cancer Can Improve Patient Outcomes Jessica Miller

T

he first liquid biopsy used to detect gene mutations that are associated with non–small-cell lung cancer (NSCLC) was approved by the US Food and Drug Administration (FDA). The cobas EGFR Mutation Test v2 (Roche Molecular Systems), a blood– based companion diagnostic for erlotinib (Tarceva), is indicated as an initial test to detect EGFR gene mutations in patients with NSCLC. Lung cancer is the second most common cancer in the United States and is the leading cause of cancer-related death.

According to the National Cancer Institute, an estimated 158,080 Americans will die from the disease this year.

According to guidelines by the National Comprehensive Cancer Network, NSCLC accounts for 85% of all lung cancer cases in the United States, of which 10% to 50% are associated with EGFR gene mutations.

In patients with NSCLC, tumor DNA is released into the bloodstream.

A liquid biopsy uses the patient’s blood plasma to isolate these tumor cells and to detect specific mutations.

By detecting specific NSCLC EGFR mutations (exon 19 deletion or exon 21 [L858R] substitution mutations), clinicians can use the liquid biopsy to

determine which patients will benefit from treatment with erlotinib, which was approved by the FDA in 2013 as a

make it possible to deliver highly individualized healthcare for patients,” said Alberto Gutierrez, PhD, Director of the

“The advent of liquid diagnostic platforms in non–small cell lung cancer is truly a game changer in the diagnostic workup of advanced stage patients.

The ability to both isolate and genetically interrogate tumor DNA from a simple, minimally invasive test that can subsequently inform treatment decisions is a win for both physician and patient.”

Benjamin Levy, MD

first-line treatment for metastatic NSCLC in patients whose tumors have EGFR mutations.

A blood-based liquid biopsy is less invasive than a traditional tissue biopsy and can be repeated, whereas, in certain cases, a tissue biopsy cannot.

“Approvals of liquid biopsy tests

FDA’s Office of In Vitro Diagnostics and Radiological Health. “Liquid biopsies also have the potential to allow physicians to identify patients whose tumors have specific mutations in the least invasive way possible.”

According to research presented at the 2015 European Lung Cancer Con-

proved afatinib (Gilotrif; Boehringer Ingelheim) tablets for the oral treatment of patients with advanced squamous-cell carcinoma of the lung that has progressed after platinum-containing chemotherapy treatment.

Afatinib was already approved for the first-line treatment of patients with certain EGFR mutation–positive non– small-cell lung cancer.

Advanced squamous-cell carcinoma of the lung has a median overall survival of approximately 1 year after diagnosis and is characterized by a poor prognosis.

The approval was based on the LUX-Lung 8 head-to-head clinical trial comparing afatinib with erlotinib (Tarceva) in patients with squamous-cell carcinoma of the lung whose tumors progressed after first-line chemotherapy. Compared with erlotinib, afatinib demonstrated an 18% reduction in the risk for cancer progression and a 19% reduction in the risk for

death. There was also a significant improvement in the disease control rate with afatinib versus with erlotinib (51% vs 40%, respectively; P = .002).

The most common (in ≥20% of patients) adverse events observed with afatinib were diarrhea (75%), rash or acne (70%), stomatitis (30%), decreased appetite (25%), and nausea (21%).

The LUX-Lung 8 trial is part of the LUX-Lung program, which is a collection of 8 clinical studies involving more than 3760 patients.

“We are pleased to bring a proven therapy to patients suffering from advanced squamous cell carcinoma of the lung who have progressed despite chemotherapy,” said Sabine Luik, MD, Senior Vice President, Medicine and Regulatory Affairs, Boehringer Ingelheim Pharmaceuticals, Inc. “This approval is further evidence of Boehringer Ingelheim’s strong commitment to bringing new treatment options to the lung cancer community.”

ference, EGFR genetic testing is not done in 25% of patients with NSCLC, despite guidelines from the International Association for the Study of Lung Cancer that recommend all patients diagnosed with advanced NSCLC (except those with squamous-cell carcinoma) have EGFR genetic testing.

“The advent of liquid diagnostic platforms in non–small cell lung cancer is truly a game changer in the diagnostic workup of advanced stage patients. The ability to both isolate and genetically interrogate tumor DNA from a simple, minimally invasive test that can subsequently inform treatment decisions is a win for both physician and patient,” said Benjamin Levy, MD, Medical Director of Thoracic Medical Oncology, Mount Sinai Health Systems, New York, in a statement. “These platforms have the potential to expedite care and potentially circumvent an otherwise cumbersome process of procuring tissue (biopsy) often fraught with complications and complexity.”

The approval of the cobas EGFR Mutation Test v2 was based on the accuracy of blood samples from patients who were enrolled in a clinical study and had EGFR mutations confirmed with tumor biopsies. l

FDA NEWS Tecentriq for Metastatic Urothelial... Continued from page 15

FDA on May 18, 2016, to detect PD-L1 levels and to help clinicians identify the patients who would most benefit from treatment with atezolizumab.

The most common (≥20%) adverse events (all grades) associated with atezolizumab included fatigue (52%), decreased appetite (26%), nausea (25%), urinary tract infection (22%), pyrexia (21%), and constipation (21%). The most common (≥2%) grade 3 or 4 adverse events included urinary tract infection (9%), fatigue (6%), abdominal pain (4%), and dyspnea (4%).

Atezolizumab is being evaluated in the confirmatory phase 3 IMvigor 211 study, and is expected to become available for use in early June.

Afatinib Receives New Indication for Advanced Squamous-Cell NSCLC

On April 15, 2016, the FDA ap-

FDA Approves Netspot Diagnostic Test to Detect Neuroendocrine Tumors

On June 1, 2016, the FDA approved Netspot (Advanced Accelerator Applications USA), a diagnostic test to detect somatostatin receptor–positive neuroendocrine tumors (NETs). The radioactive diagnostic agent gallium (Ga)-68 dotatate injection is available as a single-dose injection and is used in conjunction with positron emission tomography imaging to aid in locating these tumors in adults and in pediatric patients.

The FDA previously granted an orphan drug designation and priority review status to Netspot.

NETs develop in neuroendocrine cells throughout the body, including in the stomach, intestines, pancreas, and lungs.

Ga-68 dotatate works by binding to somatostatin receptors; somatostatin is the hormone that regulates the endocrine system.

“Use of advanced imaging techniques to detect rare neuroendocrine

DISABILITY INSURANCE

Any-Occupation versus Own-Occupation Disability Insurance for Pharmacists Richard Reich

O

wn-occupation disability insurance is often a pharmacist’s best line of defense when protecting his or her income from a disabling event. As some of the top earners in the country,1 those in the pharmaceutical community need to prepare themselves for the possibility that, because of a disability, they may not be able to earn a living at some point during their career.

Like so many other healthcare professionals, pharmacists often overlook their own financial security because of time restraints, lack of information, and overwhelming workloads. But it’s important for pharmacists to take a moment to plan for the future by considering the risks of going without disability insurance, and benefits of obtaining coverage.

The Price of Becoming a Pharmacist Pharmacists work incredibly hard to get where they are today, by working around the clock to get a degree from a top university, and long hours to become a licensed professional. Pharmacy students often face some of the highest tuition costs in the country. According to a recent article from The Huffington Post, the average student loan debt in 2012 for those graduating from pharmacy school was a staggering $123,063.2 Despite being among the nation’s top earners, it can take years for working pharmacists to pay off that debt. Add those student loan payments to the rising cost of living, retirement savings, mortgage payments, and a myriad of other expenses, and it becomes clear that pharmacists need every penny they can get.

Risks of Going without OwnOccupation Disability Insurance If an accident or illness prevents a pharmacist from earning a living, his or her bills could become unmanageable much quicker than many would like to admit. Many working professionals underestimate their chances of becom-

ing disabled, despite glaring statistics that support contrary claims. According to a report, anyone aged <35 years has a 33% chance of becoming disabled for ≥6 months during their career.3 Men have a 43% chance of becoming disabled, whereas women have a 54% chance.

Six months of no income could seriously

it’s important to understand the distinction between any- and own-occupation coverage. Any-occupation disability insurance requires that the policyholder be completely disabled and unable to work in any occupation before any benefits will be paid. Own-occupation disability insurance is tailor-made for

Like so many other healthcare professionals, pharmacists often overlook their own financial security because of time restraints, lack of information, and overwhelming workloads. impact a pharmacist’s ability to make ends meet, forcing them to go further into debt. An injury or illness could also prevent a pharmacist from reaching his or her goals, such as opening their own private practice, buying a home, or saving for retirement.

Benefits of Choosing OwnOccupation Disability Insurance When it comes to protecting a pharmacist’s ability to earn a living, there is no better choice than with own-occupation disability insurance. A comprehensive insurance policy from a highly rated provider will help a pharmacist earn a living when an accident or injury prevents him or her from working at their normal capacity.4 The insurance company will pay the policyholder a monthly benefit—typically 50% to 60% of their predisability income—to help with bills, retirement savings, and rehabilitation programs.4 Any-Occupation versus OwnOccupation Disability Insurance When purchasing disability insurance,

those who work in a specific profession.

Benefits will be paid if the policyholder is unable to work in his or her occupation, and payments are based on the policyholder’s current income.4 Because pharmacists are paid well for their time, it is imperative that they choose an own-occupation disability insurance policy, and make sure that the policy’s benefits are min line with their occupation.

Important Disability Insurance Policy Features • Noncancelable, guaranteed renewable: This feature guarantees that the policy will not be canceled, and that the policyholder’s premiums will not increase. Without this feature, the insurance company could change the terms of the policy at a later date.

• Residual disability rider: This feature allows the policyholder to work in a limited capacity, including part-time, and still collect a percentage of benefits based on their percentage of lost income. If a pharmacist has partially recovered from his or her disability, they could still receive partial benefits.

• Cost-of-living adjustment: When the policyholder is disabled and receiving benefits, this feature increases benefits annually to keep up with inflation.

• Elimination period: This refers to the amount of time after the policyholder first becomes disabled, and when they receive their first benefits payment.

Elimination periods can range from 30 to 365 days; longer elimination periods are less expensive than shorter ones.

• Waiver of premium: The insurance company will waive premium payments during the period of disability.

• Rehabilitation benefit: This feature will pay a certain amount of benefits to the policyholder if they enroll in a preapproved physical rehabilitation program. It should also stipulate that the policyholder will not lose their original benefits during their time in the program.

It is important that pharmacists understand the benefits of having own-occupation disability insurance, and find the right policy for their career.

In today’s uncertain economic climate, everyone needs the financial security of disability insurance. l References

1. Smith J. The 30 highest-paying jobs in America.

Business Insider. www.businessinsider.com/top-payingjobs-in-america-2015-9. Published September 23, 2015.

Accessed June 16, 2016.

2. Dash S. How pharmacy graduates can get rid of $100k of student loans. The Huffington Post. www. huffingtonpost.com/stephen-dash/how-pharmacy-grad uates-ca_b_7035232.html. Published April 18, 2015.

Accessed May 5, 2016.

3. Intramark Insurance Services. Disability facts and statistics. www.protectyourincome.com/education-center/ disability-facts-and-statistics. Accessed July 13, 2016.

4. Richard DM. Why true “own occupation” disability insurance matters. 2014. http://trarp.com/ why-true-own-occupation-disability-insurance-matters.

Accessed July 13, 2016.

Mr Reich is President of Intramark

Insurance Services in Glendale, CA. He has more than 25 years of experience as a nationally licensed broker of life and disability insurance.

FDA NEWS tumors at an early stage in patients is critical,” said Libero Marzella, MD, PhD, Director of the FDA’s Division of Medical Imaging Products. “Netspot provides another diagnostic tool whose results will help clinicians determine the location and extent of the tumor.

This information is important for plan-

ning the appropriate course of therapy.”

The safety and effectiveness of Netspot were established in 3 clinical studies. In the first study, images using Ga-68 dotatate and an approved drug were compared and then confirmed with computed tomography scans or with magnetic resonance imaging. In

the second study, images using Ga-68 dotatate were evaluated by histopathology. The third study evaluated patients with recurrent NET using Ga-68 dotatate images. The findings from all 3 studies confirmed the efficacy of Ga-68 dotatate imaging in locating NETs. No serious adverse events were iden-

tified during the trials; however, the FDA notes that Netspot does add to patients’ overall long-term cumulative radiation exposure. The FDA encourages patients to drink and urinate as much as possible in the first hours after the administration of the diagnostic agent, to reduce the risk. l

ONCOLOGY UPDATE

The New World of Biosimilars

Continued from cover

Biosimilars Are Not Generics

Biosimilars are biologics, not generics. Made from living cells, biosimilars are designed to mimic their reference drugs. However, unlike generics, which are exact copies of an original drug, biologics will never be exact replicas of their reference drug.

“Biosimilars are complex molecules to develop, and there’s a huge development process to reverse engineer an original biologic,” said Sue Naeyaert, Senior Director of Biosimilars Policy, EMD Serono.

Batch-to-batch variabilities occur during the manufacturing of biologics, and “a biologic such as rituximab or trastuzumab is not exactly the same as that molecule was 10 to 15 years ago, because manufacturers have developed more sophisticated ways to produce the product to get better yield. By their inherent nature, biologics progressively change over time, so a biosimilar is just trying to match that process and final product,” said Ms Naeyaert.

Approval Process

Earl Dye, PhD, Director of Technical Regulatory Policy, Genentech, Washington, DC, discussed the FDA’s abbreviated approval process for biosimilars under the Biologics Price Competition and Innovation Act to provide a lower-cost alternative to biologics while encouraging continued innovation of new therapies.

“This abbreviated pathway enables a biosimilar developer to rely on certain clinical safety and efficacy data of the reference or innovator biological product, so they’re able to submit a data package that is much more abbreviated and has less preclinical and clinical data in it,” Dr Dye said.

The submission requirements for bio-

key points

➤ Unlike generics, biosimilars are biologics and are not exact copies of their reference drugs ➤ The FDA approval of biosimilars is based on clinical data from the reference drug ➤ Labeling for biosimilars and their reference drugs is very similar, with minor differences

“Pharmacovigilance is drug safety monitoring and surveillance, which is a very important issue for biosimilars and biologics overall.”

Thomas Felix, MD

“Biosimilars are complex molecules to develop….By their inherent nature, biologics progressively change over time, so a biosimilar is just trying to match that process and final product.”

Sue Naeyaert

similars include data from analytical studies, preclinical toxicity studies, and clinical studies in ≥1 indications of the innovator biologic drug.

An innovator drug undergoes 3 distinct phases of clinical development for each indication on its label. Conversely, biosimilar developers conduct extensive analytical and functional comparisons of their drug with the innovator drug to demonstrate that the 2 drugs are similar, followed by preclinical, pharmacokinetic, pharmacodynamic, immunogenic, and clinical studies to show that any differences detected during the initial assessment have no clinical significance.

“One of the important features of the FDA pathway for biosimilars is this concept of extrapolation,” said Dr Dye. Extrapolation refers to a process whereby the developer of the biosimilar can use data from one studied clinical indication to get approval for other indications on the reference biologic drug’s label, without having to do the clinical safety and efficacy studies for those indications, as long as they have a strong scientific rationale.

“Interchangeability requires extra clinical data submission to the FDA on the part of the biosimilar developer, with data showing that switching back and forth between the biosimilar and the reference drug will not reduce efficacy or increase risk to the patient.”

Jim McKay, PhD

“By providing that totality of evidence that the FDA uses to make a determination of biosimilarity, they’re able to perform this extrapolation, which goes significantly to reducing the cost of these types of products,” Dr Dye said.

Labeling Biosimilars

Jim McKay, PhD, Director of Clinical Development and Medical Affairs, Sandoz Biopharmaceuticals, discussed the FDA’s recently issued draft guidance on labeling for biosimilars.

“These biosimilar clinical studies are not necessarily designed to look at safety and efficacy independently,” Dr McKay said. For that reason, the FDA has deemed that biosimilar drugs can rely on the safety and efficacy data of their reference drugs, and use these findings in their labeling. The labels for biosimilars and their reference drugs can appear very similar, but slight differences may exist between them, such as

specific indications (if extrapolation was not granted for all indications).

Interchangeability, Dr McKay said, requires extra clinical data submission to the FDA on the part of the biosimilar developer. The data must show that switching back and forth between the biosimilar and the reference drug will not reduce the drug’s efficacy or increase the risk to the patient.

If the biosimilar is granted that designation and considered an interchangeable biologic, then pharmacists can substitute the biosimilar for the reference drug without obtaining permission from the prescribing physician; however, this is not yet permitted in the United States.

Pharmacovigilance

“Pharmacovigilance is drug safety monitoring and surveillance, which is a very important issue for biosimilars and biologics overall,” said Thomas Felix, MD, Medical Director of R&D Policy, Global Regulatory Affairs and Safety, Amgen, Washington, DC. Biosimilar manufacturers and developers are accountable for measuring the risks and benefits related to their drugs.

In the generic experience, accountability for adverse events has been directed toward the originator company, “but that’s not acceptable for the biosimilar concept,” Dr Felix said.

“So there are a number of things happening around the nation and the world to try to improve the traceability of these biosimilar and biologic products,” he added.

Naming Biosimilars

In 2015, the FDA released a guidance and a proposed rule on naming biologics, which includes adding a hyphenated, meaningless suffix made up of ­ 4 arbitrarily selected letters to all nonproprietary biologic names, such as “sndz” that was added to filgrastim (filgrastim-sndz) for the biosimilar Zarxio, to distinguish it from the originator drug filgrastim (Neupogen).

There is also a global discussion involving the World Health Organization to standardize a naming approach across countries, which is still being finalized.

Overall, physician acceptance of biosimilar drugs “is growing, but there is still a lot of education that needs to happen,” observed Ms Naeyaert. l

PROSTATE CANCER

Promising Antitumor Activity of ODM-201 in Metastatic Prostate Cancer Wayne Kuznar

T

he investigational oral androgen receptor drug ODM-201 has significant antitumor activity with a favorable safety profile in men with metastatic castration-resistant prostate cancer, according to a pooled analysis of 2 early-phase clinical trials.

In these studies, the median time to progression of serum prostate-specific antigen (PSA) was slightly longer than 1 year in men who were naïve to chemotherapy or to CYP17 inhibitors, said Neal D. Shore, MD, Medical Director, CPI, Carolina Urologic Research Center, Myrtle Beach, SC, at the 2016 American Urological Association annual meeting.

ODM-201 is an oral androgen receptor antagonist that binds with high affinity and selectivity to the androgen receptor; it inhibits testosterone-induced nuclear translocation of the androgen receptor, and blocks the activity of mutant androgen receptors to overcome resistance to androgen receptor– targeted therapies, such as enzalutamide (Xtandi).

Blood–brain barrier penetration was negligible in preclinical studies of ODM-201. This property may enhance neurocognitive tolerability, “which we have typically not seen in earlier generation lutamides, some that haven’t come to market,” said Dr Shore.

He reported on the long-term safety and antitumor activity of ODM-201 in the ARADES and ARAFOR clinical trials in chemotherapy- and CYP17-­ inhibitor–naïve patients with metastatic castration-resistant prostate cancer.

110 patients. There were no dose-limiting toxicities, “and we saw a very significant PSA decline at dosages of 1000 mg daily dose,” reported Dr Shore.

ARAFOR was an open-label pharmacokinetic study (N = 30) and an

“We demonstrated very good tolerability in a chemotherapy-, abiraterone-naïve group [and] significant PSA declines….

We saw a very significant PSA decline at dosages of 1000 mg daily dose.”

Neal D. Shore, MD

“Overall, we demonstrated very good tolerability in a chemotherapy-, abira­ terone [Zytiga]-naïve group [and] significant PSA declines,” Dr Shore said.

ODM-201 in Clinical Trials

ARADES was a nonrandomized dose-escalation study in which 24 ­patients with metastatic prostate cancer received ODM-201 at 100 mg to 900 mg twice daily, with an additional randomized extension study that included

open-label extension study (N = 30) of ODM-201 dosed at 600 mg twice daily in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer. A PSA response, defined as a ≥50% decrease in the PSA level at week 12, was observed in 25 of 30 (83%) patients.

The median PSA level in the entire cohort was 28 ng/mL, and the median Gleason score at diagnosis was 2 to 6 in 7 patients, 7 in 16 patients, and 8 to 10

in 17 patients. Overall, 36 patients had bone lesions, and 3 patients had visceral metastases.

The median duration of treatment with ODM-201 was 13.5 months (range, 2.5-25.2 months). ODM-201 was well-­ tolerated, with the majority of adverse events being grade 1 or 2 in severity.

The most frequent adverse events were fatigue (7%) and hot flashes (5%).

In the pooled analysis of 41 patients from the 2 clinical trials, 30 patients discontinued treatment—27 for disease progression, 2 for adverse events, and 1 for other reasons; 8 patients continue to receive treatment.

The median time to PSA progression was 12.4 months, and the median time to radiologic progression was 15.3 months.

“We ultimately settled on the 1200 mg daily dose, 600 mg twice a day. It’s at that dose that we saw very effective PSA declines,” said Dr Shore. The patients who received ODM-201 experienced “rather marked PSA declinations in this group of patients, chemotherapyand abiraterone-naïve…with the majority of patients having rather extended suppressive PSAs,” he added.

The data support the ongoing, global, phase 3 clinical trial of ODM-201, called ARAMIS, in men with non­ metastatic castration-resistant prostate cancer. l

Patient Tip: 5 Steps to Quit Smoking Cigarette smoking is associated with a wide variety of adverse health effects.1 In fact, >480,000 people die each year in the United States because of cigarette smoking. It is linked to cancer, cardiovascular and respiratory diseases, and other increased health risks.

The following tips are ways that you and your patients can quit smoking2:

1.

3.

2.

4.

Recognize an Oncoming Flare As a first step to quitting smoking, write down why you want to do it (eg, is it to improve your health, or so that you can be with your loved ones long-term?). Identifying why you really want to quit will motivate you to stop smoking.

Talk to Your Healthcare Professional Once you have decided that you want to quit smoking, talk to your physician or a trusted healthcare professional and identify a method for quitting that will work best for you.

Don’t Smoke Any Cigarettes When you start your smoking cessation program, quit smoking cigarettes altogether. Each cigarette you smoke damages your lungs, blood vessels, and cells throughout your body.

Don’t Give In Quitting smoking takes time and commitment. Be prepared to experience feelings of nicotine withdrawal, and find coping mechanisms to handle symptoms, such as bad moods and the desire to smoke.

5.

Focus on the Benefits Remember, taking steps to quit smoking is great news. It is the single most important step you can take to protect your health and the health of your family.

References

1. Centers for Disease Control and Prevention. Health effects of cigarette smoking. www.cdc.gov/tobacco/data_statistics/fact_sheets/ health_effects/effects_cig_smoking/#cancer. Updated March 17, 2016. Accessed June 22, 2016.

2. Centers for Disease Control and Prevention. Quit smoking. www. cdc.gov/tobacco/quit_smoking/how_to_quit/quit_tips/index.htm.

Updated March 17, 2016. Accessed June 22, 2016.

IMMUNOTHERAPY

Immunotherapy: Separating Facts... age and prolonged disease stabilization, and response is only moderately correlated with benefit of immunotherapy.

“We see patients who have rapidly growing disease, and then suddenly the disease is stable,” he said. “So it can clearly modify the disease dynamic.”

In a keynote address at the symposium, Dr Seiwert offered some immunotherapy “pearls” based on his experience from treating a substantial number of patients with immunotherapy.

A Sustainable Response Pseudoprogression is rare. “I estimate that 95% of imagery-based progression of disease is real disease,” he said. “Keeping patients on an ineffective agent for a prolonged period of time, if their disease is progressing, is potentially harmful.”

The biologic half-life of a PD-1 or its ligand (PD-L1) inhibitor is months, he added. “So if you stop the agent, you will probably still see the benefit, if such a benefit should actually occur. But in my experience, stopping the treatment and going to something like a cytotoxic agent instead is better.”

According to Dr Seiwert, unlike anticytotoxic T-lymphocyte antigen 4, the use of immune-related response criteria is of unclear benefit for PD-1/PD-L1.

“Dynamic of response is also impor­ tant,” he said. Most responses to immunotherapy occur relatively early, but delayed responses do occur. “The majority of patients who have a response seem

to have a sustainable response—not forever—but it seems to be more stable than what we see with other agents,” he said. For a faster response, he recommends the use of chemotherapy.

Continued from cover

we make patients sick as hell with chemoradiation, and yet we’re so afraid of immune-related side effects? That seems very strange.”

“These side effects may actually even

“The impact of immunotherapy, at least for PD-1 checkpoint blockade, is primarily on survival.”

Tanguy Seiwert, MD

Immune-Related Side Effects According to Dr Seiwert, PD-1/PD-L1 agents are exceptionally well-tolerated, even in older patients and patients with poor performance, and particularly when compared with chemoradiation, chemotherapy, and radiation and surgery. The most common adverse events are mild fatigue, hypothyroidism, and itchy skin. There are severe adverse events, such as pneumonitis and colitis, but they are rare, and, if recognized early, they are treatable. So intensive screenings for symptoms of pneumonitis and colitis are imperative.

“Why are we so afraid?” Dr Seiwert asked. “We treat patients with some of the most toxic treatments [available],

be a biomarker for benefit,” he continued. “What we want to do is break tolerance. We should treat more, and we shouldn’t be as afraid as we were, and I think as we learn more about these agents we might get more comfortable.”

In terms of cure and treatment duration, these questions are clearly unanswered. “I think the depth of responses really may matter. If you have a very deep response, these may be patients who have long-term survival and benefit, and maybe the disease never comes back,” he said. “And when to discontinue treatment may need to be individualized.”

A Long Way to Go “There are a lot of challenges ahead,”

Dr Seiwert stated. “We’ve taken a big step in the right direction, but we have a long way to go.”

“Cancer is inherently robust,” he said. “We’ve learned this over decades and decades of failure; we’ve seen it become resistant, and patients die. And this has not changed, ultimately, even though some patients do well.”

Fifty percent to 75% of patients with head and neck cancer do not derive benefit from anti–PD-1 agents. “So there we have patients who are constitutively resistant to immuno-oncology,” he stated. And a large fraction of patients who do respond may ultimately develop acquired resistance.

According to Dr Seiwert, immunotherapy is broadly active across human papillomavirus–positive and –negative cancers, including nasopharyngeal cancers, so it is an agent that can potentially be used very broadly. Additionally, responses to immunotherapy seem to be more durable, and “maybe for some patients, even for very advanced disease, we may be able to eradicate their disease completely,” he said.

“I think this is the point in time for a call to action,” Dr Seiwert added. “We should move forward, because we actually have something that works; we just need to do better.” l Reference

Seiwert T. Immunotherapy for head and neck cancer.

Presented at: Multidisciplinary Head and Neck Cancer Symposium; February 18-20, 2016; Scottsdale, AZ.

DRUG UPDATE

Onivyde (Irinotecan Liposome Injection) a New Treatment Option for Patients with Metastatic Pancreatic Cancer Lisa A. Raedler, PhD, RPh, Medical Writer

T

here is an urgent unmet need for more effective therapies in pancreatic cancer. The American Cancer Society estimated that approximately 49,000 new cases of pancreatic cancer will be diagnosed in the United States in 2015, and more than 40,500 people will die from this cancer.1 Pancreatic cancer is the fourth most common cause of cancer deaths in the United States.2 Survival statistics for patients with pancreatic cancer are dismal, in part because the majority of patients with pancreatic cancer are diagnosed with nonresectable advanced disease; only 4% of patients will be alive 5 years after diagnosis.2,3 Surgery and adjuvant chemotherapy with gemcitabine or 5-fluorouracil (5-FU) confers a small survival advantage, but only for patients with early-stage pancreatic cancer.3 A recent meta-analysis of patients with metastatic pancreatic cancer showed a median overall survival (OS) of 4.6 months (range, 2.8-5.7 months) from diagnosis.4 The costs associated with pancreatic cancer include significant morbidity and mortality, as well as considerable financial burden.5 A recent study analyzed the direct medical costs for pancreatic cancer using Surveillance, Epidemiology, and End Results–Medicare data from 2001 to 2007. The study included >15,000 Medicare beneficiaries aged ≥66 years with pancreatic cancer.

The mean direct medical costs were $65,500; patients with resectable locoregional disease had greater costs ($134,700) compared with unresectable or distant disease ($65,300 and $49,000, respectively).5 The popularity of targeted therapies and demographic trends are expected to affect treatment patterns and drive costs higher for patients with pancreatic cancer.5 The only potentially curative treatment for pancreatic cancer is surgical resection. However, more than 80% of patients have pancreatic cancer that is unresectable.6 Cytotoxic chemotherapy and radiation therapy are considered in the neoadjuvant and adjuvant settings, as well as for patients with unresectable disease.6 The current National Comprehensive Cancer Network guidelines for metastatic or locally advanced unre-

Copyright © 2016 American Health and Drug Benefits. Used with permission.

All rights reserved.

sectable pancreatic cancer include several category 1 recommendations—the 4-drug combination FOLFIRINOX (leucovorin, 5-FU, irinotecan, oxaliplatin); gemcitabine plus erlotinib; gemcitabine plus albumin-bound paclitaxel; other gemcitabine-based combinations; and gemcitabine monotherapy.6 Gemcitabine monotherapy and best supportive care are appropriate options for patients with advanced pancreatic cancer and poor performance status.6 Onivyde Approved for Relapsed Pancreatic Cancer

On October 22, 2015, the US Food and Drug Administration (FDA) approved the cytotoxic agent, irinotecan liposome injection (Onivyde; Merrimack Pharmaceuticals), for use in combination with leucovorin and 5-FU, for the treatment of patients with advanced or metastatic pancreatic cancer that progressed after gemcitabine-based chemotherapy, making it the first and only FDA-approved treatment option for patients in this setting.7 The drug labeling for irinotecan liposome injection includes a boxed warning regarding the risks for severe neutropenia and severe diarrhea. The drug is not approved as a single agent for metastatic pancreatic cancer.7 The approval of irinotecan liposome injection was based on the demonstration of improved OS in the NAPOLI-1 study, a phase 3, multicenter clinical trial of 417 patients with metastatic pancreatic cancer whose disease relapsed after gemcitabine-based chemotherapy.7,8 Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products, said, “Many FDA staff who review drug applications are clinicians as well, so it’s especially rewarding when we are able to expedite access to new treatments for patients with unmet needs. By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.”7 Mechanism of Action

Irinotecan liposome injection is a topoisomerase-1 inhibitor encapsulated in a lipid bilayer liposome. Topoisomerase-1 is an enzyme that relieves torsional strain in DNA by inducing single-strand breaks. By binding reversibly to the topoisomerase-1–DNA complex, irinotecan and its metabolite (SN-38) cause DNA damage and cell death.8

Dosage and Administration

The recommended dose of irinote­ can liposome injection is 70 mg/m2 administered by intravenous (IV) infusion for 90 minutes every 2 weeks. In patients known to be homozygous for the UGT1A1*28 allele, the recommended dose is 50 mg/m2 administered by IV infusion for 90 minutes. In subsequent cycles, the dose can be increased to 70 mg/m2 as tolerated.8 Irinotecan liposome injection has no recommended dose for patients with serum bilirubin above the upper limit of normal.8

“By using the Priority Review designation for the application for Onivyde, patients will have earlier access to a drug that helps extend survival.”

Richard Pazdur, MD

NAPOLI-1: Pivotal Phase 3 Clinical Trial

The efficacy and safety of irinotecan liposome injection were demonstrated in the NAPOLI-1 study, a multicenter, randomized, open-label, active-controlled, 3-arm clinical trial.8,9 This study enrolled 417 patients from >100 sites worldwide with metastatic pancreatic cancer and documented disease progression after gemcitabine-based therapy.7-9 Study inclusion criteria included serum bilirubin levels within the institutional normal range, albumin levels ≥3 g/dL, and Karnofsky Performance Status (KPS) ≥70.8 Patients in the NAPOLI-1 clinical trial were randomized to 1 of 3 of the following regimens until disease progression or until unacceptable toxicity8: 1. Irinotecan liposome injection, leucovorin, and 5-FU (ILF): irinotecan liposome injection 70 mg/m2 for 90 minutes, leucovorin 400 mg/m2 for 30 minutes, and 5-FU 2400 mg/m2 for 46 hours every 2 weeks 2. Irinotecan liposome injection 100 mg/m2 for 90 minutes every 3 weeks 3. Leucovorin and 5-FU (control arm): leucovorin 200 mg/m2 and 5-FU 2000 mg/m2 for 24 hours weekly for 4 weeks with a 2-week rest.

Patients in the first 2 arms who were homozygous for the UGT1A1*28 allele started treatment with irinotecan liposome injection at a reduced dose.7,8 The primary end point of this study was OS. Each irinotecan liposome injection–containing arm was compared with the control arm—5-FU plus leucovorin. The secondary end points were progression-free survival (PFS) and overall response rate (ORR). The tumor status assessments were performed at baseline, then every 6 weeks.8 NAPOLI-1 was initiated as a 2-arm study and amended after initiation to include the third arm—irinotecan liposome injection plus leucovorin and 5-FU. Comparisons between the ILF regimen and the control arm are limited to patients who were enrolled in the trial after this amendment.8 Patient Population

Overall, 236 patients were randomized to the ILF regimen (N = 117) or to the control arm (N = 119) after the addition of the third arm of the study.

The patients’ median age was 63 years (range, 34-81 years); the mean baseline albumin levels were 3.97 g/dL; and 53% of patients had a KPS of 90 to 100. The patients’ disease characteristics included liver metastasis (67%) and lung metastasis (31%).8 All patients previously received gemcitabine, either alone or in combination. Overall, 13% of patients received gemcitabine combined with albumin-bound paclitaxel.8

Efficacy

The OS analysis demonstrated a significant benefit for patients receiving the ILF regimen. In the intention-­totreat population, the median OS was 6.1 months (95% confidence interval [CI], 4.8-8.5) for the irinotecan liposome injection–based combination compared with 4.2 months (95% CI, 3.35.3) for the control arm (hazard ratio [HR] for death, 0.68; 95% CI, 0.50-0.93; P = .014).

The OS was not improved when irinotecan liposome injection monotherapy was compared with the control arm (HR, 1.00; P = .97).8 In addition, the PFS and ORR were significantly improved in the ILF group compared with the control group. The median PFS was 3.1 months in patients with pancreatic cancer receiving the ILF combination (95% CI, 2.7-4.2) versus 1.5 months for the control arm (95% CI, 1.4-1.8; HR, 0.55). According Continued on page 22

DRUG UPDATE

Onivyde (Irinotecan Liposome Injection)... to an independent review, the ORR was also improved with ILF compared with the control arm (Table).8 Adverse Reactions

The safety of irinotecan liposome injection was established based on results of the NAPOLI-1 clinical trial.9 The median duration of exposure was 9 weeks in both irinotecan liposome injection–containing arms compared with 6 weeks in the control arm.7,8 The most frequently reported nonhematologic adverse reactions associated with irinotecan liposome injection included diarrhea, fatigue, vomiting, nausea, anorexia, stomatitis, and fever.7 The most common (≥2%) serious adverse reactions were diarrhea, vomiting, neutropenic fever or neutropenic sepsis, nausea, pyrexia, sepsis, dehydration, septic shock, pneumonia, acute renal failure, and thrombocytopenia.8 Among patients who received ILF in the NAPOLI-1 study, grade 3 or 4 hematologic adverse reactions included lymphopenia (27%), neutropenia (20%), anemia (6%), and thrombocytopenia (2%). Grade 3 or 4 elevations in alanine aminotransferase levels were reported in 6% of patients receiving ILF.8 Adverse reactions requiring permanent discontinuation of irinotecan li­ posome injection occurred in 11% of patients receiving the ILF regimen and included diarrhea, vomiting, and sepsis.

Overall, 33% of patients receiving the ILF regimen required dose reductions of irinotecan liposome injection because of adverse reactions, which included neutropenia, diarrhea, nausea, and anemia.

Irinote­can liposome injection was held or delayed because of adverse reactions (ie, neutropenia, diarrhea, fatigue, vomiting, and thrombocytopenia) in 62% of patients receiving the ILF.8 Drug Interactions

The concomitant use of irinotecan liposome injection with strong inducers of the cytochrome (CY) P3A4 enzyme, such as phenytoin and rifampin, should be avoided.8 The use of irinotecan liposome injection with other inhibitors of CYP3A4 or UGT1A1 can increase systemic exposure to irinotecan or SN-38. The use of strong CYP3A4 or UGT1A1 inhibitors should be avoided, if possible.

These agents should be discontinued at least 1 week before starting therapy with irinotecan liposome injection.8

Contraindications

Irinotecan liposome injection is contraindicated in patients who had a severe

Continued from page 21

Table Efficacy Results from the NAPOLI-1 Clinical Trial

Efficacy end point Median overall survival, months

Irinotecan liposome injection + leucovorin + 5-FU (N = 117)

5-FU + leucovorin (N = 119)

6.1 (95% CI, 4.8-8.5)

4.2 (95% CI, 3.3-5.3)

Hazard ratio Median PFS, months

0.68 (95% CI, 0.50-0.93) 3.1 (95% CI, 2.7-4.2)

Hazard ratio ORR (complete or partial responses) Death

1.5 (95% CI, 1.4-1.8)

0.55 (95% CI, 0.41-0.75) 7.7%

0.8%

77 (66%)

86 (72%)

5-FU indicates 5-fluorouracil; CI, confidence interval; ORR, objective response rate; PFS, progression-free survival.

Adapted from Onivyde (irinotecan liposome injection) prescribing information; October 2015.

hypersensitivity reaction to this medication or to irinotecan hydrochloride.8 Warnings and Precautions

Boxed warning. The prescribing information for irinotecan liposome injection contains a boxed warning stating that treatment with irinotecan liposome injection is associated with severe neutropenia and severe diarrhea.8 Severe neutropenia. Irinotecan liposome injection can cause life-threatening neutropenia and fatal neutropenic sepsis. These complications were more common in Asian patients in the NAPOLI-1 study.8 Complete blood cell counts should be performed on days 1 and 8 of every cycle or more frequently, if clinically indicated. Irinotecan liposome injection should be withheld if the absolute neutrophil count (ANC) falls below 1500/mm3 or if neutropenic fever occurs. It can be resumed when the ANC is at least 1500/mm3. After recovery from grade 3 or 4 neutropenia or neutropenic fever, subsequent doses should be reduced.8 Severe diarrhea. Life-threatening diarrhea can occur with irinotecan liposome injection therapy. This agent should not be administered to patients with bowel obstruction.

Early-onset diarrhea sometimes ­occurred with other symptoms of a cho­ linergic reaction. An individual patient can experience early- and late-­ onset diarrhea.8 Irinotecan liposome injection should be withheld for grade 2, 3, or 4 diarrhea, and loperamide should be administered for late-onset diarrhea of any severity.

For early-onset diarrhea of any severity, IV or subcutaneous atropine should be administered (unless it is contraindicated). After recovery to grade 1 diarrhea, irinotecan liposome injection can be resumed at a lower dose.8 Interstitial lung disease. Irinotecan can cause severe and fatal interstitial

lung disease. The drug should be withheld in patients with new or progressive dyspnea, cough, and fever. It should be discontinued in patients whose diagnosis of interstitial lung disease is confirmed.8 Severe hypersensitivity reaction. Patients with severe hypersensitivity reaction to irinotecan liposome injection should permanently discontinue its use.8 Embryofetal toxicity. Irinotecan liposome injection can cause fetal harm.

Pregnant women should be advised of this risk.8

This combination is the first FDA-approved treatment option for patients with metastatic pancreatic cancer that has relapsed after a gemcitabine-­containing regimen.

Use in Specific Populations

Pediatric patients. The safety and efficacy of irinotecan liposome injection have not been established in children.8 Geriatric use. No overall differences in efficacy or safety of irinotecan liposome injection were observed between older (aged ≥65 years) and younger ­patients.8 Pregnancy. Pregnant women should be advised that irinotecan liposome injection can cause fetal harm.8 Nursing mothers. It is not known whether irinotecan liposome injection is excreted in human milk. Nursing should be discontinued during irinote­ can liposome injection therapy and for 1 month after the last dose.8 Men and women of reproductive

potential. Women of childbearing potential should use effective contraception during treatment with irinotecan liposome injection and for 1 month after the final dose.8 Males should use condoms during treatment with irinotecan liposome injection and for 4 months after the final dose.8 Renal impairment. Mild and moderate renal impairment had no effect on irinotecan liposome injection or on SN-38 levels. Irinotecan liposome injection has not been studied in patients with severe renal impairment.8 Hepatic impairment. Irinotecan liposome injection has not been studied in patients with hepatic impairment.8 Conclusion

The FDA approval of irinotecan liposome injection has added a new treatment option for patients with pancreatic cancer. The drug is only approved for use in combination with leucovorin and 5-FU. This combination is the first FDA-approved treatment option for patients with metastatic pancreatic cancer that has relapsed after a gemcitabine-­ containing regimen.

This combination offers a significant survival benefit, with an acceptable tolerability profile. Additional studies of irinotecan liposome injection in pancreatic cancer are currently under way, as well as in adults with recurrent, highgrade glioma, and in children with solid tumors.10 l

References

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3. American Cancer Society. Pancreatic cancer survival by stage. Revised January 9, 2015. www.cancer.org/can cer/pancreaticcancer/detailedguide/pancreatic-cancersurvival-rates. Accessed October 29, 2015.

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6. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): pancreatic adenocarcinoma. Version 2.2015. March 6, 2015. www.nccn.org/professionals/ physician_gls/pdf/pancreatic.pdf. Accessed October 29, 2015.

7. US Food and Drug Administration. FDA approves new treatment for advanced pancreatic cancer. Press release. October 22, 2015. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm468654.htm.

Accessed October 29, 2015.

8. Onivyde (irinotecan liposome injection) [prescribing information]. Cambridge, MA: Merrimack Pharmaceuticals, Inc; October 2015.

9. Wang-Gillam A, Li CP, Bodoky G, et al; for the NAPOLI-1 Study Group. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545-557.

10. ClinicalTrials.gov. MM-398. Search results. https:// clinicaltrials.gov/ct2/results?term=MM-398&Search= Search. Accessed November 9, 2015.