VBCC June 2015 | Vol 6 | No 5

JUNE 2015 VOL 6 NO 5

INTEGRATING COST, QUALITY, ACCESS INTO CLINICAL DECISION-MAKING IN ONCOLOGY www.ValueBasedCancer.com

Expert Panel Discusses Quality Measures, Data Collection, and Outcomes in Oncology

By Wayne Kuznar

Risk Management a Key Challenge in the New Oncology Payment Models Continuing evolution toward integrated networks

By Wayne Kuznar Washington, DC—Change is coming to oncology coverage by the Centers for Medicare & Medicaid Services (CMS), which plans to incorporate risk management strategies over a traditional micro-

management style of provision, according to Bruce Pyenson, FSA, MAAA, Principal at Milliman, New York.

At the Fifth Annual Conference of the Association for Value-Based CanContinued on page 7

ASCO 2015 HIGHLIGHTS Panel members, from left: Michael Kolodziej; Gary M. Owens; Heidi Schumacher; Bruce Pyenson; John Fox

Washington, DC—How to overcome practical challenges in quality assessment metrics and data collection was

the focus of a panel discussion at the Fifth Annual Conference of the Association for Value-Based Cancer Care.

Continued on page 14

ASCO 2015 HIGHLIGHTS

Combination Immunotherapy Superior to Monotherapy in Patients with Melanoma

By Chase Doyle

Chicago, IL—Combination treatment with the 2 immunotherapies nivolumab (Opdivo) and ipilimumab (Yervoy) led to a doubling in progression-free sur­ vival (PFS) compared with ipilimumab

Elotuzumab, First-in-Class Monoclonal Antibody Immuno­­ therapy, Improves Outcomes in Patients with Multiple Myeloma

By Phoebe Starr

Chicago, IL—The addition of the novel monoclonal antibody elotuzumab to dexamethasone (Decadron) plus lenalidomide (Revlimid) resulted in a 30%

Continued on page 24

alone in patients with advanced melanoma, investigators from the CheckMate 067 trial reported at the 2015 American Society of Clinical Oncology (ASCO) meeting.

Continued on page 17

INSIDE IN THE LITERATURE . . . . . . . . . . . . .

Palbociclib prolongs PFS in advanced breast cancer

3

VALUE PROPOSITIONS . . . . . . . . . . 5 Large PBM seeking value-based drug pricing from pharmaceutical companies 5th CONFERENCE . . . . .

Pathways reduce care variation and cost, improve outcomes

6

ASCO 2015 HIGHLIGHTS . . . . . . . . 17 Elotuzumab improves outcomes in multiple myeloma Adding ibrutinib to standard therapy reduces CLL progression by 80%

© 2015 Engage Healthcare Communications, LLC

Julie M. Vose, reduction in the MD, MBA risk for disease pro­ ­gression and death in patients with relapsed or refractory multiple myeloma.

PALLIATIVE CARE . . . . . . . . . . . . . . 26 Early use of palliative care improves survival ECONOMICS OF CANCER CARE . . 27 Increasing use of value analysis committees in US hospitals

PERSONALIZED MEDICINE . . . . . . 29 Biomarker testing in Europe linked to cancer drugs availability SURVIVORSHIP . . . . . . . . . . . . . . . . .

Less is more in survivorship care

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DRUG UPDATE . . . . . . . . . . . . . . . . 32 Jakafi first FDA-approved medication for polycythemia vera

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

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

Indication » GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

In the Literature Palbociclib Prolongs Progression-Free Survival in Patients with Advanced Breast Cancer

dex) has moderate activity in these patients, and a phase 2 clinical trial has shown that single-agent palbociclib (Ibrance), an inhibitor of cyclin-­ Endocrine therapies are the basis of dependent 4 (CDK4) and CDK6, intreatment for patients with hormone-­ duces responses in patients with HR-­ receptor (HR)-positive breast cancers, positive breast cancer. but many women experience disease A new double-blind, phase 3, randomrelapse during or after completing adju- ized clinical trial investigated the efficacy vant therapy. The selective estrogen of fulvestrant plus palbociclib in patients receptor degrader fulvestrant (Faslo- with HR-positive, HER2-­negative ad-

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

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

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian.

In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

vanced breast cancer that had relapsed or progressed during endocrine therapy (Turner NC, et al. N Engl J Med. 2015 Jun 1. Epub ahead of print).

The study included 521 patients from 144 centers in 17 countries who were randomly assigned to receive palbociclib (125 mg daily orally for 3 weeks, followed by 1 week off) and fulvestrant (500 mg intramuscularly per standard of care every 14 days for

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day.

Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day.

This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported.

the first 3 injections and then every 28 days) or placebo and fulvestrant.

The primary end point was investigator-assigned progression-free survival (PFS), and the secondary end points were overall survival, objective response rate, patient-reported outcomes, and safety.

The median PFS was 9.2 months (95% confidence interval [CI], 7.5 to not estimable) with the combination of palbociclib plus fulvestrant compared with 3.8 months (95% CI, 3.55.5) with fulvestrant plus placebo, a significant difference (hazard ratio for disease progression or death, 0.42; 95% CI, 0.32-0.56; P <.001).

The most common grade 3 or 4 adverse events in the combination therapy were neutropenia, leukopenia, anemia, thrombocytopenia, and fatigue. The rate of discontinuation because of adverse events was 2.6% with palbociclib and 1.7% in the fulvestrant-alone group.

“

Targeting CDK4 and CDK6 may represent a therapeutic strategy across diverse mechanisms of acquired resistance to endocrine therapy, including activation of receptor tyrosine kinase signaling.

”

Among patients with HR-positive metastatic breast cancer who had progression of disease during endocrine therapy, the addition of palbociclib to fulvestrant resulted in significantly longer PFS than fulvestrant alone, regardless of menopausal status. Quality of life was generally maintained with the addition of palbociclib but declined significantly in the fulvestrant-alone group.

Patients receiving palbociclib also had a significant improvement in emotional functioning compared with patients receiving fulvestrant alone.

These results suggest that “targeting CDK4 and CDK6 may represent a therapeutic strategy across diverse mechanisms of acquired resistance to endocrine therapy, including activation of receptor tyrosine kinase signaling,” upregulation of mTOR signaling, and mutation of ESR1, the investigators concluded.

©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Surveillance Imaging Not Cost-Effective in Patients with Diffuse Large B-Cell Lymphoma After First Remission

Routine surveillance imaging is a common practice after first remission in patients with diffuse large B-cell lymContinued on page 18

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www.ValueBasedCancer.com

3

IN THIS ISSUE IN THE LITERATURE

INTEGRATING COST, QUALITY, ACCESS INTO CLINICAL DECISION-MAKING IN ONCOLOGY

Palbociclib prolongs PFS in advanced breast cancer Surveillance imaging not cost-effective in diffuse large B-cell lymphoma after first remission More…

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com

Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini THE LYNX GROUP President/CEO Brian Tyburski

Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

Expert panel discusses quality measures and outcomes in oncology Comprehensive genomic profiling enables efficient “N of 1” trials More…

Biomarker testing in Europe linked to cancer drugs availability Genomic sequencing for pancreatic cancer still facing hurdles

ASCO 2015 HIGHLIGHTS

Less is more in cancer survivor care

Content Marketing Director Samantha Weissman

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Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 11 times a year by Engage Healthcare Communica­ tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2015

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Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY Philip E. Johnson, MS, RPh, FASHP Pharmacy, Oncology, Healthcare, and School Health Consulting, Tampa, FL Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Jakafi (ruxolitinib): first FDA-approved medication for the treatment of patients with polycythemia vera

Co-Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Michael Kolodziej, MD Ted Okon, BS, MBA National Medical Director, Oncology Solutions Executive Director Aetna, Hartford, CT Community Oncology Alliance, Washington, DC Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, Anthem, Inc John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd Albuquerque, NM Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

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4

DRUG UPDATE

Co-Editor-in-Chief Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

Creative & Design Assistants Lora LaRocca Wayne Williams

Project Managers Deanna Martinez Jeremy Shannon

SURVIVORSHIP

VBCC Editorial Board

Director, Creative & Design Robyn Jacobs

Meeting & Events Planner Linda Mezzacappa

PERSONALIZED MEDICINE

Encouraging results for pembrolizumab in head and neck cancer Nicotinamide prevents skin cancers Elotuzumab improves outcomes in myeloma Adding ibrutinib to standard therapy reduces CLL progression More…

Chief Operating Officer Pam Rattananont Ferris

Jr Digital Media Specialist Charles Easton IV

Increasing use of value analysis committees in US hospitals The new PC-SAF instrument: a patientreported outcome diagnostic tool for pancreatic cancer

5TH CONFERENCE

Senior Associate Editor Lilly Ostrovsky

Digital Programmer Michael Amundsen

ECONOMICS OF CANCER CARE

Large PBM seeking value-based drug pricing More…

Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com

Content Digital Manager Allison Musante

Early initiation of palliative care improves survival

VALUE PROPOSITIONS

Publisher Cristopher Pires cpires@the-lynx-group.com

Web Content Manager Anthony Trevean

PALLIATIVE CARE

VALUE-BASED CANCER CARE

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JUNE 2015

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy, Aetna, Hartford, CT Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD President, W-Squared Group Longboat Key, FL

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VALUE PROPOSITIONS

Advance Care Planning

Value-Based Drug Pricing a New Target for a Large PBM Company in Its Negotiations with Pharmaceutical Companies Express Scripts, a large prescription benefit manager (PBM) company that is handling the pharmacy benefits for many health plans and employers, is negotiating with various pharmaceutical companies to link the pricing of high-cost drugs to their true value, or how well they perform in the real world, according to a recent report in the Wall Street Journal.

With the rising cost of drugs, especially for many cancer drugs with an annual cost of >$100,000, value-based pricing or reimbursement continues to be a strong concern for many in healthcare, and the pressure to curb costs continues to be a top issue for insurers and PBMs. In May 2015, Express Scripts said it was working with drug makers to come up with a payment plan that will tie the cost of their drugs to their performance based on the specific indication in each tumor type, reported Steve Miller, MD, Chief Medical Officer at Express Scripts.

“One of the big frustrations has always been people paying top dollar for drugs that aren’t always giving them the best response,” Dr Miller said in an interview with the Wall Street Journal. “If pharma is truly sincere about wanting value-based reimbursement, we now have the sophistication to do that.”

Dr Miller did not specify which drugs Express Scripts is looking for this type of indication-specific pricing. The company hopes this new arrangement will go into effect in 2016.

Drug pricing has been “very hard for the payers to do anything about,” said Steven Pearson, president of the Institute for Clinical and Economic Review, a nonprofit company in Boston that evaluates cost-effectiveness in medicine. “Now they’re starting to think very hard about it, to look for practical ways to have more of an influence on pricing.” The Wall Street Journal; May 26, 2015

Prenatal Blood Test Can Also Detect Cancer in Pregnant Women, Potentially in Other Populations Previous studies have suggested that using noninvasive prenatal testing (NIPT) by scanning for cell-free DNA (cfDNA) circulating in the blood may have value as a prognostic tool for diagnosing malignancies. Now a new study from Belgium shows that using this new method and cfDNA can indeed reveal the presence of cancer in pregnant women before any symptoms become apparent. The study was presented at the European Society of Human Genetics Conference in Glasgow in June and was simultaneously published in JAMA Oncology (Jun 5 2015; Epub ahead of print).

Frederic Amant, MD, PhD, of the University of Leuven, Belgium, and colleagues used the prenatal blood testing from 4000 pregnant women to perform a cfDNA analysis for any signs of cancer. Their analysis revealed that among the 4000 pregnant women, 3 showed signs of cancer, including 1 woman with stage IV-A ovarian cancer, 1 woman with stage III follicular lymphoma, and 1 woman with stage II Hodgkin lymphoma.

The 3 women then underwent whole-body magnetic resonance imaging, which further revealed the presence of a tumor in all 3 instances. A biopsy performed in each of the 3 women confirmed the number of copy variations initially found in the original prenatal screening.

“We show that plasma DNA profiling allows for presymptomatic detection of tumors in pregnant women undergoing routine NIPT,” the investigators wrote.

“We aim to further investigate the potential of NIPT for cancer detection, not only in pregnant women, but also in the general population,” they added, suggesting that this method could be applied to a population-wide cancer screening using “genomic analysis of plasma DNA.” This study was funded by grants from the University of Leuven Center of Excellence in Computational Biology, the Belgian Ministry of Health, and the Belgian Science Policy Office Interuniversity Attraction Poles program. European Society of Human Genetics Conference/JAMA Oncology; June 5, 2015

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Myxoma, a Virus Found in Rabbits, Prevents GVHD in Bone Marrow Transplant While Destroying Cancer Cells According to researchers from the University of Florida, the myxoma virus, which is found in rabbits, can simultaneously help to kill cancer cells while also eliminating a common complication of bone marrow transplants, a treatment used in patients with hematologic cancers (especially in multiple myeloma and acute myeloid leukemia).

Although bone marrow transplant is used to treat hematologic cancers, it also increases the risk for graft-versus-host disease (GVHD), in which the newly transplanted T-cells attack the host tissue, causing skin rash, shortness of breath, abdominal pain, jaundice, and muscle weakness. These common complications can be fatal in severe cases. The risk for GVHD increases when there is no full match between the donor and the patient’s blood marrow.

Christopher R. Cogle, MD, lead investigator and Associate Professor, University of Florida College of Medicine, Division of Hematology and Oncology, said that the myxoma virus can prevent these transplant-related side effects, as well as help to destroy the patient’s cancer cells. The rabbit virus could be especially helpful to patients with recurring disease who are unable to find a bone marrow donor with a perfect match, Dr Cogle said.

The risk for GVHD from bone marrow transplants of partially matched donors is approximately 80%, which can be eliminated by the use of the rabbit virus.

“Myxoma is one of the best strategies, because it is effective but doesn’t affect normal stem cells,” Dr Cogle said. This is especially important in African-Americans patients and in elderly patients, who are less likely to find perfectly matched donors.

The myxoma virus originates in rabbits in Australia and parts of Europe and is benign to humans.

This is the first time that a virus has been shown to simultaneously prevent GVHD and help to kill cancer cells, according to the researchers, who suggest that this process could one day have broader applications for other kinds of cancers.

The investigators hope to be able to raise the money to start a clinical trial within 1 year. University of Florida press release; June 5, 2015

First-in-Class Inducer of the KLF4 Gene Receives FDA Designation as Orphan Drug The FDA granted an orphan drug designation to APTO-253, a first-in-class inducer of the Krüppel-like factor 4 (KLF4) tumor suppressor gene for the treatment of patients with acute myeloid leukemia (AML).

“AML is a particularly challenging cancer of the blood and bone marrow for which there are currently few treatment options,” said William G. Rice, PhD, Chairman, President, and CEO of Aptose Biosciences Inc, a company developing new targeted oncology drugs.” APTO-253, with its unique mechanism of action, has the potential to emerge as an entirely new therapeutic approach for this patient population, and receiving orphan drug designation is a key regulatory milestone along the path.”

APTO-253 is currently in a phase 1b clinical trial in patients with relapsed or refractory AML, high-risk myelodysplastic syndrome, and other hematologic malignancies involved in suppressing the KLF4 gene.

Suppression of the KLF4 gene has been reported as a key feature in the development of AML. APTO-253 is a targeted inducer of the KLF4 gene and has shown a good safety profile, with no evidence of suppression of normal blood cells. Preclinical studies with APTO-253 have demonstrated its strong activity in killing AML cells as a single agent, as well as a potent synergy when used in combination with other drugs. Aptose Biosciences press release; June 2, 2015 n

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5th Conference

Comprehensive Genomic Profiling Enables Efficient “N of 1” Trials

By Wayne Kuznar

Washington, DC—Genomically driven medicine has created an opportunity for value in oncology by substantially improving outcomes and quality of life for patients with advanced cancer, said Vincent A. Miller, MD, Chief Medical Officer, Foundation Medicine, Cambridge, MA, at the Fifth Annual Conference of the Association for Value-­ Based Cancer Care.

Two premises behind the genomic characterization of cancer are: ➤C ancer is a disease of the genome, with each profile unique to the patient ➤G enomically driven treatment with targeted agents is generally safer, more efficacious, and more cost-­ effective than traditional systemic treatment applied universally across a population with advanced cancer, said Dr Miller.

As our understanding of cancer complexity and the pathways through which cancers are activated is increasing, a comprehensive approach is required to best inform pathway-driven cancer care.

“Comprehensive genomic profiling is an optimized solution to improve outcomes and manage utilization costs,” Dr Miller said.

“Our approach at Foundation Medicine is to get the data,” he said. “To get the data, one needs a rigorous, well-­ validated genomic characterization of the patient’s tumor, and a way to extract the data in a believable, accurate, and understandable format from which multiple stakeholders can ask their questions and assess the value for them.”

Types of Genomic Testing

Three types of genomic testing are done in clinical practice today: ➤C ategory 1 tests are single gene markers

at a glance ➤ N of 1 trials could save millions of dollars that are spent on inappropriate interventions and conventional phase 3 trials ➤ The combined results of many N of 1 trials will offer data about how to better treat subsets of a population or even a population overall

6

“

Comprehensive genomic profiling is an optimized solution to improve outcomes and manage utilization costs.

”

—VINCENT A. MILLER, MD

➤C ategory 2 tests are hot spot next-­

generation sequencing panels that focus on a narrow subset of genes ➤C ategory 3 tests comprise comprehensive genomic profiling.

Category 3 tests sequence the entire coding region of cancer genes, not only the high-probability common regions.

Genomic profiling based on comprehensive next-generation sequencing focuses on all exons of the 315 known clinically and biologically relevant cancer genes, and the introns of 28 genes that are frequently rearranged in human cancer.

This type of profiling has validated high accuracy achieved by high, uniform coverage of >99.5% of exons covered more than 100 times. It sequences from all clinically relevant specimen types, including those from fine-needle aspiration.

The Value of Comprehensive Genomic Profiling

Non–small-cell lung cancer (NSCLC) has proved to be fertile ground for establishing the value of comprehensive genomic profiling in patients with cancer, said Dr Miller. He illustrated the impact of comprehensive genetic profiling by showcasing a female patient with NSCLC with a rare mutation who received targeted therapy that significantly extended her survival.

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The woman presented in mid-2010 with NSCLC and visual changes, and was found to have bilateral retinal metastases. She received systemic chemotherapy and did well for 18 months before her disease progressed with bony metastases. A tumor specimen sent to Foundation Medicine was profiled and was found to harbor a never-before-seen TRIM33-RET fusion, for which there were no approved therapies. Foundation Medicine documented that a clinical trial of cabozantinib (Cometriq) for patients with RET fusions was available.

The woman had symptomatic and radiographic improvement for 7 months, her vision improved, and her bone pain resolved with the anti-RET therapy.

One year after identifying RET gene fusions, Cancer Discovery published in-

These “N of 1” trials could save millions of dollars that are spent on inappropriate interventions and conventional phase 3 trials. For example, in the classical pathway approach, for every patient that the 10 most frequently prescribed drugs help, they fail to improve the condition of 3 to 24 patients.

—VINCENT A. MILLER, MD

terim results of the clinical trial (Drilon A, et al. 2013;3:630-635), when 3 of the first 6 patients with RET fusion–positive lung adenocarcinoma had responded to cabozantinib. “We went from a discovery to an N of 1,” said Dr Miller.

Initial profiling of lung adenocarcinomas using next-generation sequencing is an efficient and sensitive strategy.

Among a series of 47 patients with no or light smoking history and “pan-negative” lung adenocarcinomas, next-generation sequencing was successfully performed in 31 patients and uncovered ≥1 genomic alterations in 94% of patients. A total of 96 genomic alterations were identified.

An actionable genomic alteration with a targeted agent based on National Comprehensive Cancer Network guidelines was found in 26% of patients, and a targeted agent in a clinical trial in

39%. A genomic alteration that was not previously detected in lung cancers (SHC2-ERBB2) was found in 1 patient.

Some of the challenges of comprehensive genomic profiling were also laid out.

“Much of the testing is done in patients with advanced disease who are unlikely to have multiple opportunities for additional systemic therapy,” Dr Miller said.

Many times, tissue available for testing has been depleted. In addition, unpredictable genomic alterations are often detected, and the likelihood of a molecular match is proportional to the number of trials available. Finally, because the patients have advanced disease, they are mostly eligible for phase 1 trials that often have “starts and stops” because of the toxicities that are discovered.

Umbrella Trials versus Basket Trials

The 2 recently introduced clinical trial designs—umbrella trials and basket trials—can quickly evaluate novel targeted agents in patients with cancer and specific mutations.

Umbrella trials test the impact of different drugs on various genetic mutations in a single type of cancer. Basket trials test the effect of drugs on a single genetic mutation in a variety of cancer types.

An example of an umbrella trial is MASTER LUNG-1, which is being conducted in squamous-cell lung cancer.

Patients undergo biomarker profiling, are grouped according to the type of genomic alteration found, and are randomized to a targeted therapy or standard of care (usually chemotherapy). The trial has multiple phase 2 and phase 3 arms, with “rolling” opening and closure.

The basket approach is exemplified by the neratinib HER2 mutation basket study, in which a HER2 mutation is identified in patients with bladder, colon, endometrial, gastric, ovarian, or other solid tumor cancer and is then treated with neratinib until disease progression or the development of intolerable side effects.

These “N of 1” trials could save millions of dollars that are spent on inappropriate interventions and conventional phase 3 trials, said Dr Miller. For example, in the classical pathway approach, for every patient that the 10 most frequently prescribed drugs help, they fail to improve the condition of 3 to 24 patients. The aggregated results of many “N of 1” trials will offer information about how to better treat subsets of the population, or even the population at large, Dr Miller argued. n

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5th Conference

Risk Management a Key Challenge in the New Oncology Payment...

Continued from the cover

cer Care, Mr Pyenson contrasted the pros and cons of 2 payment models in oncology, the risk management strategies ­initiated by CMS in its innovative ­Oncology Care Model (OCM), and a micro­management strategy, the capitated payment model pilot from United­ Healthcare and M.D. Anderson used for specific types of head and neck cancer.

The Decade of Provider Risk

Calling this the “decade of provider risk,” Mr Pyenson predicted continued evolution toward integrated networks and bundled payments in healthcare, especially in oncology.

The CMS OCM shift to risk management is “very profound” and addresses population health. “Medicare, which is the world’s largest insurance company, has said it is going to have its payment system and its providers under some form of risk within a few years,” said Mr Pyenson.

Commercial insurance companies, the large provider systems, are currently under contracts for attributed lives, but are moving toward capitation. This mind-set differs from an “actuarial control cycle,” which is how insurance companies manage risks, Mr Pyenson said.

The new value in healthcare depends on financial models rather than on clinical outcomes. Financial data are easier to obtain, process, and audit, and directly address the financial con-

To protect against catastrophe, financial results need to be monitored as they emerge, This even in healthcare. is part of the business of operating an accountable care organization or any other kind of enterprise.

“

”

—BRUCE PYENSON, FSA, MAAA

cerns of payers (ie, potential savings from generics and biosimilars, spending associated with new products and new indications).

Clinical outcomes models, by contrast, require much more data and ­­are more difficult to administer, Mr P ­ yenson said, and the data require audit and inter-

Table 1 New Payment Models: Micromanagement versus Risk Management Micromanagement Example: UnitedHealthcare/ M.D. Anderson

Risk management Example: Medicare’s Oncology Care Model

8 bundles for head and neck cancers

All cancers

Specifies most details in treatment

Assumes the practitioner will work out details; there are many ways to successfully treat patients

Avoids surprises, provides a high degree of Assumes oncologists will manage out predictability for oncologists enough waste to earn bonuses Assumes oncologists will track care and match protocols

Assumes oncologists will document the link to the accepted pathway

Minimize risk

Live with risk

Table 2 Medicare’s New Oncology Care Model What to watch for • Risk adjustment will not take care of fluctuations Risk adjustment is not micromanagement Any risk adjustment will be based on claims data only • Stop-loss (outlier protection) will be essential (eg, cap spending at $75,000 per patient), but too much outlier protection will reduce the potential for savings • Expect targets to involve averages, trends, and other adjustments • In the future, expect Medicare to adopt the Oncology Care Model for all providers They are talking about using the acute care bundled payments method, which is now voluntary, for all providers

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pretation. Experience with real-­ world clinical outcomes may be different from clinical trial out­­ comes, which could prove controversial. Changes in provider reimbursement will either focus on risk management or on micromanagement.

“To the extent that we go with population health, in my view that means it’s not micromanagement—it’s risk,” Mr Pyenson said.

Using the analogy of Hurricane Katrina to explain predictive modeling of risk, he related that risk management manifests itself by preparing for the risk and managing the situation, and not managing risk by prediction.

To protect against catastrophe, financial results need to be monitored as they emerge, even in healthcare. “This is part of the business of operating an accountable care organization or any other kind of enterprise,” Mr Pyenson said.

He also acknowledged that this type of risk management may not be possible on a small practice basis. “As the healthcare system shifts toward risk, consolidation is inevitable,” Mr Pyenson said.

The New CMS Oncology Care Payment Model

Two different payment models have emerged in oncology—the UnitedHealthcare/M.D. Anderson system has proposed 8 bundles for new patients with head and neck cancers, and the new CMS OCM is a global approach to risk management (Table 1).

Mr Pyenson noted the generosity of the new CMS OCM to oncology care as a “teaser” for it to enter into risk management, with an upside payment of $160 per patient monthly for 6 months.

“That comes up to about $60,000 per oncologist in the fees and the upside in shared savings. If a practice goes into this, and it doesn’t even do anything, there’s a pretty good chance, just by random fluctuation, that it will get a windfall payment.”

In addition, the OCM requirements for service and support are minimal.

“They’re going to get some experience, and then CMS is going to roll it out in general in a few years,” Mr Pyenson said.

“That is going to be their new model.”

He asked how Medicare can pull off the OCM. At-risk providers need a lot of patients under the same risk arrangement. Medicare has the volume; the hope is that commercial payers “shadow” Medicare.

Medicare must assume that oncologists have large opportunities (ie, “margin”) to reduce costs, Mr Pyenson said, JUNE 2015

I

much more than the potential savings of 2% or 5% that have been proposed. He pointed out that risk adjustment would not remove the fluctuations (Table 2).

“Risk adjustment is not the same thing as micromanagement,” Mr P ­yenson noted. “It doesn’t take away the risk. It makes things fairer,” he said.

Stop-loss (outlier protection) will be essential (eg, cap spending at $75,000 per patient, because the average of 6 months of Medicare is $50,000), but then too much protection will reduce the potential savings. In the future, expect Medicare to adopt the OCM for all providers; there is discussion of using the acute care bundled payment method for all providers.

Medicare is analyzing feedback, Mr ­Pyenson said. Some of the questions include whether the program is stable, if trends will be used immediately, and whether benchmarks are being set correctly.

“

That comes up to about $60,000 per oncologist in the fees and the upside in shared savings. If a practice goes into this, and it doesn’t even do anything, there’s a pretty good chance, just by random fluctuation, that it will get a windfall payment.

”

—BRUCE PYENSON, FSA, MAAA

“That’s critically important for the oncology world, because whatever comes out is going to be the platform, or it is a good chance it is going to be the platform, for the Medicare standard for it starting the next 3 to 5 years from now,” Mr Pyenson said. “Getting that program right and set in an effective way is going to just be critical.”

ASCO’s Payment Proposal

The American Society of Clinical Oncology (ASCO)’s proposal, which is still in progress, relies on consolidated payments for oncology care. It is based on 3 elements, including (1) higher pay for oncologists, (2) accountability for costs oncologists can control, and (3) accountability for outcomes.

This approach attempts to minimize risk by applying different models for different kinds of oncology practices. n

www.ValueBasedCancer.com

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5th Conference

Pathways Reduce Care Variation and Cost of Care, Improve Overall Outcomes

By Wayne Kuznar

Washington, DC—The establishment of pathways in oncology can reduce care variation and enhance value in pa­ ­tient care, said Michael Kolodziej, MD, National Medical Director, Oncology ­ Solutions, Aetna, at the Fifth Annual Conference of the Association for Value-­ Based Cancer Care.

“

Pathways are the first step to continuous quality improvement, being able to measure performance, look for opportunities for improvement, and improve processes of care.

”

—MICHAEL KOLODZIEJ, MD

Dr Kolodziej contrasted the viability of N of 1 drug evaluations with evidence-based cancer treatment pathways, also known as population management.

Value in oncology can be defined as achieving the best possible outcome at a fair price, he said (Figure 1). The price of new cancer drugs, however, does not reflect the amount of benefit they bring to society or to the patient. A recent

8

examination by Mailankody and colleagues in JAMA Oncology (2015 Apr 2.

Epub ahead of print) of the correlation between the cost of new cancer drugs at the time of their commercialization and clinically meaningful end points—such as response rate, progression-free survival, and overall survival—yielded a correlation coefficient of 0.1 (no correlation), “meaning that the price is determined by what the market will bear,” Dr Kolodziej said.

Pathways are a construct to identify the right treatment for a patient, a task made increasingly difficult in cancer with an expanding array of choices, such as in non–small-cell lung cancer (NSCLC). In the setting of NSCLC, pathways that adhere to evidence have been shown to lower cost without negatively impacting treatment efficacy.

“We started preaching the gospel of pathways,” said Dr Kolodziej. “Pathways are population management. They do not individualize therapy. They say that for the average patient, this is the best way to treat.”

Payers are catching on to the value of pathways, he said. National payers favor pathways, because they reduce care variability as well as costs, and they facilitate quality measurement and quality improvement. Physicians are starting to support pathways and are recognizing the value of an evidence-­ based treatment plan.

A pilot study by Aetna to measure adherence to evidence-based medicine showed that before the institution of a clinical decision support system, for every 100 patients treated in 6 oncology practices over 6 months, only 62 patients received an evidence-based treatment plan. After the use of the clinical decision support system, adherence to evidence-based treatment increased to 87 of 100 patients over 6 months, which is a 43% relative improvement. “This occurred in every single disease, not just in rare cancers,” Dr Kolodziej noted.

Oncology practices do not have a process for weighing evidence, which is

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Figure 1 Can Oncologists Make the Case for Value?

Guideline-based therapies Targeted impact Low toxicities Improved survival

Quality

Improved quality of life

Value

Best supportive care

Cost

Avoidance of hospital days Avoidance of emergency department visits Lower site-of-care costs Reduced medically unnecessary care at end of life

Figure 2 How Are Pathways Developed?

1. Major compendia

Regimen A

Regimen B

Regimen C

Regimen D

Regimen E

Regimen F

Regimen B

Regimen C

Regimen D

Regimen E

Regimen F

Regimen C

Regimen D

Regimen E

Regimen F

Regimen D

Regimen E

Regimen F

Regimen E

Regimen F

2. Equal efficacy (National Comprehensive Cancer Network categories 1 and 2A)

3. Side-effect profile

4. Cost

Preferred pathways one of the elements required to develop a pathway (Figure 2). They also do not have any way to put evidence in front of the physician at the point of care. Second, practices do not have a method to document the decisions that physicians have made and to measure the consequences of those decisions.

Payers also like pathways because they allow a better understanding of a

disease, by structuring the data.

“When you’re a payer and you’re looking at claims, you don’t have that clinical granularity that allows you to understand what’s going on,” Dr Kolodziej said. “Pathways are the first step to continuous quality improvement, being able to measure performance, look for opportunities for improvement, and improve processes of care.” n

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In men with mCRPC who progressed on ADT

The story for ZYTIGA® has significantly evolved.

Presenting…

mCRPC = metastatic castration-resistant prostate cancer; ADT = androgen-deprivation therapy.

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Please see additional Important Safety Information on the next pages.

Please see brief summary of full Prescribing Information on subsequent pages.

In men with mCRPC who progressed on ADT, consider ZYTIGA® (abiraterone acetate) first.

Final analysis of the pivotal phase 3 trial.*

Every day tells a story.

IMPORTANT SAFETY INFORMATION Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were OS and radiographic progression-free survival (rPFS).

Select exclusion criteria included AST and/or ALT ≥ 2.5X ULN, liver metastases, moderate or severe pain, opiate use for cancer pain, and visceral organ metastases. †At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo + prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer. § rPFS was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 [PCWG2] criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

IIAt the prespecified rPFS analysis, 150 (28%) of patients treated with ZYTIGA® + prednisone and 251 (46%) of patients treated with placebo + prednisone had radiographic progression.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 028724-150129

Please see brief summary of full Prescribing Information on subsequent pages.

In the final analysis. . .

ZYTIGA® (abiraterone acetate) + prednisone achieved a median overall survival (OS) of almost 3 years (34.7 months).1† • 4.4 months improvement in median OS—34.7 months with ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound)‡ Co-primary end point—median OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033.

Co-primary end point—rPFS: median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.§II

With a median 49 months of follow-up, there were no notable changes in the safety profile of ZYTIGA® + prednisone since the previously reported interim analyses.1 In your patients with mCRPC…

CONSIDER ZYTIGA® FIRST.

Reference: 1. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study.

Lancet Oncol. 2015;16(2):152-160.

Learn more today at

www.zytigahcp.com.

Every day tells a story.

003307-150130

B:14.125 in

S:13.375 in

T:13.875 in

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Prednisone Placebo with Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse

events graded according to CTCAE version 3.0 terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 2 Includes 3 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) All Grades Grade 3-4 Laboratory Abnormality (%) (%) Hypertriglyceridemia 62.5 0.4 High AST 30.6 2.1 Hypokalemia 28.3 5.3 Hypophosphatemia 23.8 7.2 High ALT 11.1 1.4 High Total Bilirubin 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone Placebo with Prednisone (N=542) (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Prednisone Placebo with Prednisone (N=542) (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in Phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (ChildPugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves.

Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo.

There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms.

There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment.

If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drugmetabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily.

Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: March 2015 030924-150310

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Expert Panel Discusses Quality Measures, Data Collection, and Outcomes...

Continued from the cover

“

Two key messages gleaned from the discussion are that in the short-term, data silos make it necessary to prioritize process measures rather than true outcomes measures; however, in the longer-term, retrospective analyses of big data should more effectively differentiate between different approaches to cancer care based on care quality and evidence-based, clinically meaningful outcomes.

You could probably get 90% of the value of the health information exchange…by using claims. You have history, you have details of visits. You may not know if it’s stage I or stage II lung cancer, but you can certainly get a huge amount of information about the care.

Claims Data and Cost Measures

Costs and mortality are the easiest outcomes for a payer to measure from claims data, said Bruce Pyenson, FSA, MAAA, Principal and Consulting Actuary at Milliman. “If you’re going to measure something, you start with what you can measure,” Mr Pyenson said.

“You can measure money, and you can measure that as certainly as an outcome….Another metric that’s really basic is mortality,” he said. We can argue about what is progression-free survival, “but usually you know if someone’s dead or alive. Start with the basics like that, and work up from there,” he advises. It is not perfect, but it is a good start.

Other measures promulgated are the amount of time in hospice, the number of admissions in the last 2 weeks of life, and the administration of chemotherapy in the last 2 weeks of life, said panel moderator John Fox, MD, MHA, Senior Medical Director and Associate Vice President of Medical Affairs at Priority Health. “Simply knowing that the employer stopped paying the claims does not often provide sufficiently sensitive data to measure those types of things,” Dr Fox said.

None of these metrics is perfect, said Mr Pyenson, who said he prefers to use existing data reporting systems, many of which are not being tapped for useful information.

“I’ve annoyed some information technology vendors by saying you could probably get 90% of the value of the health information exchange at about 5% of the cost by using claims,” Mr ­Pyenson said. “You have history, you have details of visits, procedures, and so forth. You may not know if it’s stage I or stage II lung cancer, but you can certainly get a huge amount of information about the care that someone got.”

The discussion over measuring quality in cancer care must be separated into measuring clinical outcomes and measuring the cost of care, said Michael Kolodziej, MD, National Medical Director of Oncology Solutions at Aetna.

”

—BRUCE PYENSON, FSA, MAAA

“

Simply knowing that the employer stopped paying the claims does not often provide sufficiently sensitive data.

”

—JOHN FOX, MD, MHA

“

I don’t see a shortcut to getting the measured true outcomes for a long time perhaps.

We have insufficient measurement systems to measure the things that really count.

”

—GARY M. OWENS, MD

“

I can link quality metrics to a very precise outcome. I want to know that you have recorded performance status. I want to know that you looked at that patient, and you decided that patient was well enough to tolerate chemotherapy.

”

—MICHAEL KOLODZIEJ, MD

Survival is not a good outcome measure, because too many factors have an impact on survival that have nothing to

do with the skill of the physician.

The challenge in coming to grips with variability in cost of care lies in address-

ing high-cost outliers, Dr Kolodziej said, noting that a small proportion of patients is responsible for approximately 75% of the total cost of care.

Process Measures as Surrogates

Process measures, such as prescribing hormone therapy to women with estrogen receptor–positive breast cancer, have been accepted as surrogates for desired outcomes, said Dr Kolodziej.

“I’ve defended the quality metrics in our programs by saying that they’re process measures, but I can link them to a very precise outcome,” he said. “I want to know that you have recorded performance status. I want to know that you looked at that patient, and you decided that patient was well enough to tolerate chemotherapy. I want to know if you assessed pain,…because I’m going to give you the benefit of the doubt that you know how to manage pain.”

Getting to the point at which real outcomes are measured may take a while, because the data are in multiple silos and must be aggregated and normalized.

Gary M. Owens, MD, co-chair of the conference, agreed that process measures are imperfect, but they remove the bad luck variables that can affect outcomes. “I don’t see a shortcut to getting the measured true outcomes for a long time perhaps,” Dr Owens said.

He added, “There is a phrase, ‘Not everything that can be measured matters, and not everything that matters can be measured.’ But I think it highlights the dilemma that we have insufficient measurement systems to measure the things that really count.”

Meaningful Outcomes

Linking process measures to meaningful outcomes would be useful, said Dr Kolodziej. For instance, a prescription for an antiemetic for a patient receiving chemotherapy is a process measure that would be more meaningful if linked to the patient’s experience with nausea and vomiting, perhaps by counting the number of phone calls the patient made to the practice in the immediate 72 hours after they received chemotherapy, and whether the patient returned for his or her next visit.

“The truth of the matter is that the world we live in now is very unidimensional, or at most bidimensional, and we need to think of a 3-dimensional solution to this problem,” Dr Kolodziej said.

In responding to the challenges in data collection, Dr Kolodziej predicted, “Ideally, this problem [of measuring Continued on page 16

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“Data in Motion” Will Promote Patient-Centric Care Models

By Wayne Kuznar

Washington, DC—Personalized medicine will become even more critical ­­as care transitions to patient-centric, outcomes-based care models. The use of real-time data, along with an increasingly advanced understanding of cancer biology, will exponentially increase the number of treatment options for patients, making personalized treatment more effective and ultimately leading to better clinical and financial outcomes.

These were the themes sounded by Sanjeev Wadhwa, Chief Executive ­Officer at Digital Health Venture, and Alex Jung, Principal in the Global Strategic Advisory Services practice of Ernst & Young, at the Fifth Annual Conference of the Association for Value-Based Cancer Care.

Real-World Data May Shift Focus to Prevention

Mr Wadhwa began by questioning what really matters to health. “Are we approaching this whole equation of health the right way?” he asked.

“What is the context in which we are treating diseases?” Mr Wadhwa argued that before the focus turns to personalized medicine, perhaps we should be

concerned with personalized health ­(Figure 1).

We need to go beyond the data at rest that are collected during visits to physicians, clinics, and hospitals, and

almost $3 trillion annually on healthcare. Only 3% of this amount goes toward preventive health measures, whereas 90% is spent on healthcare after events have occurred. Yet, Mr

“

We always intervene at a late stage or after the event has been discovered, hence the entire discussion about how to fix quality in care and outcomes. Big data is about to change how we measure health.

”

—SANJEEV WADHWA

we need to measure the context of an individual’s health. This means measuring components such as physical and mental health; lifestyle factors; community conditions; and general socioeconomic, cultural, and environmental conditions.

The United States currently spends

Wadhwa pointed out, health is determined largely (90%) by an individual’s health context and behaviors and only 10% by healthcare measures.

He believes that the emphasis on healthcare intervention after an event is a result of the idea that this approach is measurable. Because measuring health

Figure 1 P ersonalized Medicine Is Important for the Transition to Patient-Centric, Outcomes-Based Care Models

Outcomes-based model: bringing the patient to the center of care

Traditional development model (product-centric)

Marketing and sales

Regulatory approval

In a one-size-fits-all approach, 40%-70% of patients do not respond to available treatments

Personalized medicine

Prevention

R&D Early diagnosis

Target identification

Community engagement

Care

• ACO • PCMH • EHR • Payer • Provider • Pharma • Physician communities

From laboratories • Biobanks • E-health • Clinical decision support • Bionetworks • Genome-wide studies • System biology • Stem-cell therapy

Patient data

Coordinated care

From patients • iHealth • Patient communities • Social media

Patient

Selfmanagement

Self-care Home care

From patients and providers • Remote patient monitoring • Home care hubs • Sensor technologies

Opportunity space for innovation and investment ACO indicates accountable care organization; EHR, electronic health record; PCMH, patient-centered medical home; R&D, research and development.

context and behaviors is difficult at this point, the overall holistic health of an individual is not addressed, nor is the focus on preventive healthcare.

“We always intervene at a late stage or after the event has been discovered, hence the entire discussion about how to fix quality in care and outcomes.

Could we have captured some of these [data] earlier in the patient’s journey?”

Mr Wadhwa asked.

He proposed that with the use of real-world data and “data in motion,” ­ prevention could be the focus in healthcare, which would lead to better outcomes.

“Big data is about to change how we measure health,” Mr Wadhwa claimed.

He acknowledged that an already overwhelming amount of data will become even larger with the use of biosensors and wearables on patients to capture real-world data.

An Expanding Number of Patient Profiles

Ms Jung predicted that this huge increase in data will be difficult for physicians to manage using traditional statistical methodology and actuarial models that were created 30 to 40 years ago to establish standards and ranges for treatment. The traditional approach has led to treatments that are not effective for 40% to 70% of patients.

She believes that, in the future, proxies will become important to the development of standards of care for various patient profiles. By applying logic, archetypes can then be determined and used to match the appropriate therapy to the appropriate patient archetype. The result will be more effective treatment.

In oncology, an increasingly sophisticated knowledge of cancers is giving rise to more targeted diagnostics and treatments. This knowledge leads to growing numbers of patient profiles for each type of cancer. For example, the number of patient profiles for breast cancer will increase from 4 that are based on the progression or stage of the tumor to dozens with the existence of an array of biomarkers.

Ms Jung speculated that factoring in 1 or more other chronic diseases in a patient with cancer will probably produce hundreds of patient profiles, all with very unique characteristics in terms of their response to treatment.

It will be untenable for an oncologist to determine treatment for hundreds of Continued on page 16

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“Data in Motion” Will Promote Patient-Centric... different profiles of patients, she pointed out. “There has to be a way to correlate the profile of the patient and the profile of the therapy,” Ms Jung said. “We have to rely on some of these larger data sets

Continued from page 15

Figure 2 Data in Motion Will Provide Wider Context of Health: True Real-World Evidence Required for Comparative Effectiveness

Devices Wearables, implants, sensors

Providers Electronic medical record data, unstructured notes

Authenticate data Data aggregate Wearable authenticated user interface app

Payers Claims, health status

Personalized feedback

Retailers

Apps

Pharma, optical

“

There has to be a way to correlate the profile of the patient and the profile of the therapy.

We have to rely on some of these larger data sets to make that link…to simplify the decision-making process for the doctor.

”

—ALEX JUNG

to make that link for us to simplify the decision-making process for the doctor.”

She explained that deciding which treatment will be most effective is much like an algebraic equation, but when

Coaching, health maintenance

Smart cities Environment

there are so many options (variables) available and so much dynamic input, a multivariate analysis must be used.

“It completely changes the way decisions are going to be made and it exponentially increases the number of treatment choices,” Ms Jung noted.

She insisted that this high-speed, high-intensity data analysis will make it possible for physicians to personalize treatment paths.

According to Mr Wadhwa, healthcare ecosystems will be necessary to make the transition to patient-centric, outcomes-based care. They are essential to bring all of the stakeholders to the table to collaborate and to create standard protocols, he said. By bringing together all of the entities involved in healthcare, the opportunity for creativity increases, as do new ideas to improve healthcare.

Mr Wadhwa foresees that real-­ world evidence will mean a dynamic measurement of health. Technology; the use of biosensors, such as Garmin, Fitbit, and iHealth; and smart cities will provide these real-world data (Figure 2).

If data at rest and data in motion are brought together, the information can be used to define what our health may be, he suggested. n

Expert Panel Discusses Quality Measures, Data... practice performance efficiently] will be technology-enabled to allow practices to focus not on collecting data but on improving performance.”

He added, “Rather than having to hire a bunch of people to do the work, is there a technological solution that allows the practice to measure its performance and then concentrate on how to improve performance, as opposed to concentrate on how to do the measurement?”

Patient Satisfaction and Care Quality

Dr Fox questioned whether patients’ satisfaction with their physician is a

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good metric for quality of care, citing a study showing that patients with stage IV metastatic colorectal cancer who thought they were receiving curative chemotherapy had the highest level of satisfaction with their physician.

Adopting the American Society of Clinical Oncology’s Choosing Wisely recommendations is an example of a performance measure that can be integrated into an oncology care model, commented Rita Shane, PharmD, Chief Pharmacy Officer at Cedars-Sinai Medical Center, Los Angeles, CA. A comprehensive medication review that includes measures of adherence

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and adverse events would make for another logical performance indicator, Dr Shane said.

Barbara L. McAneny, MD, CEO, New Mexico Oncology Hematology Consultants, Albuquerque, commented on the discussion, saying, “As we look at measuring quality, I think that we need to do two things. One is to recognize that the quality measures themselves need to be evidence based. By that I mean that they need to actually measure something that is useful.” The second thing, she added, is “that it is very expensive for practices, which are struggling and strapped for cash these days, to be able to

Continued from page 14

provide a lot of quality measures.”

Other measures of quality, panel members noted, may include discussions of treatment plans with patients, including the goals of therapy, the ability to work while receiving treatment, and advance directives, said various panel members. Reimbursement for these services would aid in the collection of such data toward improved outcomes.

Data collection and assessment of quality metrics may also guard against underutilization of quality care as payment models shift to episode-based care and an incentive to withhold care, the panel members observed. n

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ASCO 2015 Highlights

Combination Immunotherapy Superior to Monotherapy in Patients with...

Continued from the cover

The CheckMate 067 Phase 3 Trial

CheckMate 067 was the first phase 3 clinical trial to evaluate the combination of an anti–PD-1 and an anti– CTLA-4 agent. The trial randomized 945 treatment-naïve patients with advanced or metastatic melanoma in a 1:1:1 fashion to 1 of 3 arms—(1) nivolumab 1 mg/kg every 2 weeks plus ipilimumab 3 mg/kg every 3 weeks for ­4 doses, followed by nivolumab 3 mg/kg every 2 weeks; (2) nivolumab 3 mg/kg every 2 weeks plus placebo; or (3) ipi­ limumab 3 mg/kg every 3 weeks for 4 doses plus placebo, until disease progression or unacceptable toxicity.

The study’s coprimary end points were (1) PFS with nivolumab alone and (2) PFS with nivolumab plus ipilimu­ mab versus ipilimumab alone.

“Nivolumab alone and nivolumab plus ipilimumab significantly improved progression-free survival and objective response rates versus ipilimumab alone in patients with previously untreated

“

Photo by © ASCO/Scott Morgan 2015

Nivolumab alone and nivolumab plus ipilimumab significantly improved progression-free survival and objective response rates versus ipilimumab alone in patients with previously untreated melanoma.

”

—JEDD D. WOLCHOK, MD, PHD

Photo by © ASCO/Scott Morgan 2015

The study also suggested promise for PD-ligand 1 (PD-L1) as a biomarker of response that could help determine whether patients would benefit most from 1 or from 2 forms of immunotherapy, said Jedd D. Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center, New York.

“Based upon the available evidence, the combination represents a means to improve outcomes, versus nivolumab alone, particularly for patients whose tumors have <5% PD-L1 expression,” Dr Wolchok said.

Patients who expressed PD-L1 derived essentially as much benefit from single-agent nivolumab as from the combination of nivolumab and ipilimumab, he said.

The important findings were presented at a plenary session at ASCO 2015.

Results of the phase 2 clinical trial were presented earlier this year.

“

Nivolumab and nivolumab plus ipilimumab are superior to ipilimumab. These treatments (along with pembrolizumab) are a new standard for advanced melanoma therapy.

”

—MICHAEL B. ATKINS, MD

melanoma,” Dr Wolchok said.

In the overall population, the median PFS was 11.5 months with the combination (hazard ratio [HR], 0.42

vs ipilimu­mab; P <.001), 6.9 months with nivolumab alone (HR, 0.57 vs ipilimu­mab; ­P <.001), and 2.9 months with ipilimumab alone.

The combination also produced a higher response rate of 57.6% versus 43.7% with nivolumab alone and 19.0% for ipilimumab alone; both nivolumab-­ containing arms were statistically significant versus the ipilimumab monotherapy arm (P <.001).

The duration of response in all 3 arms was not yet reached at a minimum follow-up of 9 months. The median change in tumor burden was –51.9% with the combination, –34.5% with nivolumab alone, and +5.9% with ipilimumab alone.

reassured that their progression-free survival will be very similar,” whether they receive a single-agent anti–PD-1 agent or 2 immunotherapies together.

The dual immunotherapy regimen proved to be relatively well-tolerated, although 55% of patients had grade 3 or 4 adverse events compared with 16.3% of patients receiving nivolumab and 27.3% receiving ipilimumab, Dr Wolchok reported. These side effects were consistent with previous reports.

“We had no drug-related deaths in the combination arm. This is a very important point, because the trial was conducted in 137 sites globally. Safety guidelines were put into place so that physicians in a variety of venues were able to handle the side effects,” Dr Wolchok said.

Superior Combination

Michael B. Atkins, MD, Deputy Director, Lombardi Comprehensive Cancer Center of Georgetown University, Washington, DC, discussed CheckMate 067 at the plenary session, commenting, “Nivolumab and nivolumab plus ipilimu­ mab are superior to ipilimumab. These treatments (along with pembrolizumab [Keytruda]) are a new standard for advanced melanoma therapy.”

However, Dr Atkins objected to the concept of PD-L1 as a biomarker, at least at this point. “PD-L1 must be viewed as The Importance of a weak biomarker,” he maintained.

PD-L1 Expression For a number of reasons, he said, PD-L1 expression defined a group of PD-L1 and its assays need to be validatpatients with melanoma whose out- ed before PD-L1 can be used for clinical comes were different from the overall decision-making. study population. In patients whose tuDr Atkins added that based on availmors had at least 5% PD-L1 expression, able data on the 2 PD-1 inhibitors, nivolumab alone and nivolumab plus nivolumab and pembrolizumab have no ipilimumab resulted in a similar prolon- “clear-cut distinction of therapeutic gation in PFS, 14 months in each arm, index.” versus 3.9 months with ipilimumab In the absence of a clinical trial, he alone, Dr Wolchok reported. believes physicians will choose them Steven O’Day, MD, a melanoma ex- based on factors such as dosing schedpert, commented, “Right now, in PD-­ ule, clinical experience, marketing, preL1–positive patients, we can be fairly dictability of biomarkers, and cost. n

Highlights from the 2015 ASCO Conference!

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In the Literature Surveillance Imaging Not Cost-Effective in Patients with Diffuse Large B-Cell Lymphoma After First...Continued from page 3

phoma (DLBCL); however, its utility in asymptomatic patients is debatable.

A recent study by Scott F. Huntington, PhD, and colleagues, found that routine surveillance imaging every 6 months during the first 2 years of remission offered little clinical benefit and was associated with considerable economic costs in asymptomatic patients with DLBCL (Huntington SF, et al. J Clin Oncol. 2015;33:1467-1474).

Bronchial Gene-Expression Classifier Improves Lung Cancer Diagnosis with Bronchoscopy

When patients with pulmonary lesions that are suspicious for lung cancer undergo biopsy, screening can include bronchoscopy. Bronchoscopy is often nondiagnostic in these patients, which can result in additional invasive testing.

However, approximately 20% to 25%

of surgical biopsies are performed in patients who ultimately have benign lesions. Given the risks associated with invasive testing, alternative testing is needed for patients who have a reduced likelihood of lung cancer.

A new study investigated whether a bronchial airway gene-­expression classifier could improve lung cancer diagnosis with bronchoscopy (Silvestri GA, et al. N Engl J Med. 2015 May 17.

Epub ahead of print).

Current or former smokers undergoing bronchoscopy for suspected lung cancer were registered in the 2 independent, prospective, multicenter AEGIS-1 and AEGIS-2 trials. The investigators developed a new gene-expression classifier of the bronchial epithelial cells that were collected from the patients’ mainstem bronchus via bronchoscopy, to differentiate between

NOW APPROVED

In addition to providing minimal clinical benefit, surveillance imaging is associated with patient anxiety during remission follow-up––further raising questions about its routine utility.

Even LEN ≥ Gra LENV until or di of re

Even treat perfo

QT/Q or gr or pa abno prolo or ba

LENVIMATM (lenvatinib) is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Using a decision-analytic Markov model, researchers compared the cost-­ effectiveness of 3 follow-up strategies i­n patients aged 55 years who were in their first complete remission. Quality-adjusted life-years (QALYs), the lifetime costs, and the incremental cost-effectiveness ratios (ICERs) were calculated for each surveillance strategy, which included routine follow-up without serial imaging, routine follow-up with biannual computed tomography (CT) scans for 2 years, or routine follow-up with biannual F-­fluorodeoxyglucose positron emission tomography (PET)/CT for 2 years.

The study results showed that improvements in QALY for CT (0.02) and for PET/CT (0.025) compared with routine follow-up alone were marginal. Conversely, the lifetime costs and the ICERs were substantial. Compared with follow-up alone, the incremental costs for routine imaging for the first 2 years were $3310 for CT and $4270 for PET/CT. Furthermore, the ICER for imaging strategies compared with standard follow-up totaled $164,960 per QALY for CT and $168,750 per QALY for PET/CT. In addition to providing minimal clinical benefit, surveillance imaging is associated with patient anxiety during remission follow-up––further raising questions about its routine utility. Although updated guidelines from the National Comprehensive Cancer Network recommend up to 2 annual CT scans for the first 2 years of remission, these study results support limiting surveillance imaging in asymp­tomatic patients with DLBCL.

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Hypo levels adjus of hy

Visit LENVIMAinfo.com

Reve in wh RPLS persi

Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2.

Discontinue LENVIMA for life-threatening hypertension.

Hem The frequ hem hem LENV dose LEN

Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

LENV base med

Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

LEN pote treat

4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Advi

Adve

The m respe (62% stom eryth

Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

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In the Literature patients with and without lung cancer.

A total of 639 patients underwent bronchoscopy for suspected lung cancer. Overall, 272 (43%; 95% confidence interval [CI], 39-46) of the bronchoscopy tests were nondiagnostic, including 120 (25%; 95% CI, 2129) of the 487 patients who were ultimately diagnosed with lung cancer.

In AEGIS-1, the gene-expression classifier accurately identified 194 of the

The combination use of the gene-expression classifier and bronchoscopy increased the testing sensitivity to 96% and 98% in AEGIS-1 and AEGIS-2, respectively, compared with 74% and 76% with bronchoscopy alone.

220 patients with lung cancer (sensitivity, 88%; 95% CI, 83-92) and 37 (spec-

ificity, 47%; 95% CI, 37-58) of the 78 patients without lung cancer. In AEGIS-

2, the classifier accurately identified 237 of the 267 patients with lung cancer (sensitivity, 89%; 95% CI, 84-92) and 35 of the 74 patients without lung cancer (specificity, 47%; 95% CI, 36-59).

The combination use of the gene-­ expression classifier and bronchoscopy increased the testing sensitivity to 96% (95% CI, 93-98) and 98% (95% CI, 96-99) in AEGIS-1 and AEGIS-2, respectively, compared with 74% and Continued on page 20

Events of renal impairment were reported in 14% of LENVIMA-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

% of after old e 2.

Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

or ent or

LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

or udied

LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

AST A. or nce

Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

or ne sume e.

Please see Brief Summary of Prescribing Information on the following pages.

LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved.

Printed in USA/February 2015 LENV0185

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In the Literature Bronchial Gene-Expression Classifier Improves Lung Cancer Diagnosis with...Continued from page 19

76% with bronchoscopy alone (P <.001 for both comparisons).

The prevalence of lung cancer was 74% and 78% in AEGIS-1 and AEGIS2, respectively. The patients with lung cancer were older and had higher cumulative tobacco exposure than the

patients without cancer (P <.001 for both comparisons).

The gene-expression classifier had high sensitivity with different lesion sizes, locations, stages, and cell types of lung cancer. Bronchoscopy had poor sensitivity for the detection of lung cancer in patients with small, peripheral, or early-stage lesions. This indicates that the gene-expression classifier may help with clinical decision-making for

patients with an intermediate probability of cancer.

The benefit of these studies is strengthened by the high prevalence of lung cancer among patients who undergo nondiagnostic bronchoscopic examination and who have an intermediate risk for cancer, as well as a negative predictive value of 91% for the gene-expression classifier. A negative classifier score in these patients may necessitate a diagnos-

LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information.

1 INDICATIONS AND USAGE LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food. Continue LENVIMA until disease progression or until unacceptable toxicity occurs.

Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.

Severe Renal or Hepatic Impairment The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C).

2.2 Dose Modifications Hypertension • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment.

• Withhold LENVIMA for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2.

• Discontinue LENVIMA for life-threatening hypertension.

Cardiac dysfunction or hemorrhage • Discontinue for a Grade 4 event.

• Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of the adverse event.

Arterial thrombotic event • Discontinue LENVIMA following an arterial thrombotic event.

Renal failure and impairment or hepatotoxicity • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline.

• Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of renal impairment or hepatotoxicity.

• Discontinue LENVIMA for hepatic failure.

Proteinuria • Withhold LENVIMA for ≥2 grams of proteinuria/24 hours.

• Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours.

• Discontinue LENVIMA for nephrotic syndrome.

Gastrointestinal perforation or fistula formation • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

QT prolongation • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation.

• Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline.

Reversible posterior leukoencephalopathy syndrome (RPLS) • Withhold for RPLS until fully resolved.

• Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve.

Table 1

Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa Adverse Reaction

Modification

Adjusted Doseb

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

20 mg (two 10 mg capsules) orally once daily

Second occurrencec

Interrupt until resolved to Grade 0-1 or baseline

14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily

Third occurrencec

Interrupt until resolved to Grade 0-1 or baseline

10 mg (one 10 mg capsule) orally once daily

Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of LENVIMA Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification 4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hypertension In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients.

The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group.

Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension.

5.2 Cardiac Dysfunction In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMAtreated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.

Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

5.3 Arterial Thromboembolic Events In Study 1, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMAtreated patients and 1% in the placebo group.

Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

5.4 Hepatotoxicity In Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.

Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until a b

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78618ha_b.indd 3

tic strategy involving imaging rather than invasive screening.

Serial Biomarker Measurements Double the Amount of ScreeningDetected Cancers

The strategies for cancer screening usually use a single biomarker to idenT:14.625” tify any potential abnormality. A new S:14.375”

resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

5.5 Proteinuria In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group.

Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

5.6 Renal Failure and Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting.

Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment.

5.7 Gastrointestinal Perforation and Fistula Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group.

Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula.

5.8 QT Interval Prolongation In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics.

Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline.

5.9 Hypocalcemia In Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction.

Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment.

Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia.

5.10 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

5.11 Hemorrhagic Events In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.

However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients.

Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline.

Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

5.12 Impairment of Thyroid Stimulating Hormone Suppression LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.

Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 5.13 Embryofetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions sections in the full prescribing information.

• Hypertension • Cardiac Dysfunction • Arterial Thromboembolic Events • Hepatotoxicity • Proteinuria • Renal Failure and Impairment • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation • Hypocalcemia • Reversible Posterior Leukoencephalopathy Syndrome • Hemorrhagic Events • Impairment of Thyroid Stimulating Hormone Suppression 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Safety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions. The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months.

The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinerefractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo.

Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.

In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).

Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%).

Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAtreated patients than patients receiving placebo in the double-blind phase of the DTC study.

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Table 2

Adv Vasc H H Gast D N S V A C O D D Gene F E Mus A Meta W D D Nerv H D D Rena P Skin P R A H Resp D C E Psyc I Infec D U Card

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In the Literature study investigated the use of a multimodal strategy using a risk algorithm with serial biomarker measurements to enhance the impact of screening (Menon U, et al. J Clin Oncol. 2015 May 11. Epub ahead of print).

In the large-scale, multicenter UK Collaborative Trial of Ovarian Cancer Screening, 50,640 randomly assigned women in the multimodal screening T:14.625” arm underwent serial serum cancer S:14.375” the

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LENVIMA 24 mg N=261 All Grades Grades 3-4 (%) (%)

Adverse Reaction Vascular Disorders Hypertensiona 73 Hypotension 9 Gastrointestinal Disorders Diarrhea 67 Nausea 47 41 Stomatitisb Vomiting 36 Abdominal painc 31 Constipation 29 d Oral pain 25 Dry mouth 17 Dyspepsia 13 General Disorders and Administration Site Conditions e Fatigue 67 Edema peripheral 21 Musculoskeletal and Connective Tissue Disorders Arthralgia/Myalgiaf 62 Metabolism and Nutrition Disorders Weight decreased 51 Decreased appetite 54 Dehydration 9 Nervous System Disorders Headache 38 Dysgeusia 18 Dizziness 15 Renal and Urinary Disorders Proteinuria 34 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 32 21 Rashg Alopecia 12 Hyperkeratosis 7 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 Cough 24 Epistaxis 12 Psychiatric Disorders Insomnia 12 Infections and Infestations h 10 Dental and oral infections Urinary tract infection 11 Cardiac Disorders Electrocardiogram QT prolonged

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Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4

9

Placebo N=131 All Grades Grades 3-4 (%) (%)

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Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes rash macular, rash maculo-papular, rash generalized, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively). a

Table 3

Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

Laboratory Abnormality

Chemistry Creatinine increased Alanine aminotransferase (ALT) increased Aspartate aminotransferase (AST) increased Hypocalcemia Hypokalemia Lipase increased Hematology Platelet count decreased

LENVIMA 24 mg N=258b Grades 3-4 (%)

Placebo N=131b Grades 3-4 (%)

3 4 5 9 6 4

0 0 0 2 1 1

2

0

With at least 1 grade increase from baseline Subject with at least 1 post baseline laboratory value In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia.

7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. a b

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.

Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).

8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.

8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman.

Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Infertility Females LENVIMA may result in reduced fertility in females of reproductive potential.

Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration.

8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established.

Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.

8.5 Geriatric Use Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied.

8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily.

10 OVERDOSAGE There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).

Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated.

Cardiac Dysfunction: Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles.

Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke.

Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure.

Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine.

Gastrointestinal perforation or fistula formation: Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain.

Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding.

Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA.

values for the detection of invasive epithelial ovarian and/or tubal cancers within 1 year of the first prevalence screening were 89.5%, 99.8%, and 35.1%, respectively.

The median number of incidence screens was 7 (range, 1-10; interquartile range, 6-8). The median follow-up from the last incidence screening to the latest cancer registration update was 3.1 years. In all, 29,584 of the 296,911 of the annual screenings involving 20,485 of the 46,237 volunteers (10%) of annual screenings resulted in a recommendation for a repeat screening.

A risk algorithm using the serial biomarker measurement doubled the number of screening-detected cancers compared with the use of a single-threshold rule. Of the 155 women with ovarian and/or tubal cancers, the risk algorithm detected 86.4% of cancers, whereas annual serum CA-125 would have identified only 41.3%, 48.4%, and 66.5% of cancers, respectively.

Overall, 55 (41.4%) of 133 women were diagnosed with stage I or II disease.

A majority (82%) of screening-detected ovarian and/or tubal cancers were aggressive type II, which is associated with the highest mortality rates.

The risk algorithm increases the sensitivity by individualizing the interpretation of serial biomarker values, which explains the higher sensitivity observed in this trial compared with other trials that used a single-threshold CA-125 rule.

The sensitivity (85.8%) and specificity (99.8%) for detecting ovarian and/or tubal cancers in low-risk postmenopausal women during the prevalence screening continued during the incidence screening. High sensitivity remained when primary peritoneal cancers were included as an outcome measure, which is encouraging because these cancers likely have common origins with primary high-grade serous ovarian and/or tubal cancers.

The impact of this screening on ovarian cancer mortality will be known when follow-up is complete later this year. These early results, however, show a need to examine serial change in biomarker levels during screening to improve the early detection of cancer.

T:10” S:9.5”

me at nue

Table 2

A risk algorithm using the serial biomarker measurement doubled the number of screening-detected cancers compared with the use of a single-threshold rule.

antigen 125 (CA-125) testing between 2001 and 2005. CA-125 velocity was interpreted by using a risk algorithm for ovarian cancer, which compares a woman’s serial profile with cases’ and controls’ serial profiles to estimate her risk for ovarian cancer.

In the multimodal screening arm, 50,078 (98.9%) women underwent a prevalence screening. The sensitivity, specificity, and positive predictive

Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine Tumors

Treatment options are scarce for patients with pancreatic neuroendocrine tumors (NETs) or carcinoid tumors, which are NETs with an extrapancreatic primary site. Pazopanib (Votrient) is an oral multitargeted kinase inhibitor

LENVIMA™ is a trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0176

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ASCO 2015 Highlights

Adding Radiation to First-Line FOLFOX Reduces Liver Metastases Progression in Patients with Metastatic Colorectal Cancer Chicago, IL—In patients with metastatic colorectal cancer (mCRC) with liver-dominant metastases who received first-line FOLFOX (leucovorin, fluorouracil [Adrucil], and oxaliplatin [Eloxatin]) with or without bevacizumab (Avastin) plus selective internal radiation therapy (SIRT) compared with FOLFOX with or without bevacizumab, progression-free survival (PFS) in the liver was extended by 7.9 months, according to the results of the SIRFLOX trial, which were presented at the 2015 American Society of Clinical Oncology (ASCO) meeting.

Commenting on the SIRFLOX trial, Ricky Sharma, PhD, MA, MBBChir, FRCP, FRCR, Associate Professor, University of Oxford, England, called the benefit “an impressive change in local control,” but cautioned that it came at the cost of increased adverse events.

In SIRFLOX, SIRT was delivered to liver tumors via a hepatic artery injection of yttrium-90 resin microspheres (Sirtex), said lead investigator Peter Gibbs, MBBS, MD, FRACP, Associate Professor, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. Sirtex was approved by the FDA in 2002 for the treatment of CRC liver metastases. Dr Gibbs noted that despite several decades of work with other liver-directed therapies, there remains uncertainty about their

Photo by © ASCO/Max Gersh 2015

By Walter Alexander

“

Adverse events had no negative impact on duration of systemic therapy and were acceptable and as predicted.

”

—PETER GIBBS, MBBS, MD, FRACP

clinical utility, because large phase 3 randomized controlled trials are lacking. Liver metastases are the dominant disease site in mCRC and are the predominant cause of death, he added.

The international, multicenter, open-label, randomized controlled ­SIRFLOX trial enrolled chemotherapy-­ naïve patients with nonresectable,

liver-­only or liver-dominant (liver plus lung and/or lymph node metastases) mCRC. The patients received either modified (m)FOLFOX6 with or without bevacizumab (N = 263) or mFOL­ FOX6 plus Sirtex administered once with cycle 1 with or without bevacizumab until disease progression (N = 267).

PFS was the primary end point.

The primary tumor was removed in approximately 45% of patients. Extrahepatic disease was present in 40% of the patients.

The PFS at any site was similar between the groups, Dr Gibbs reported, at 10.2 months for FOLFOX, with or without bevacizumab, and 10.7 months for FOLFOX, with or without beva­ cizumab, plus SIRT. The PFS in the liver, however, was 12.6 months for FOLFOX, with or without bevacizu­ mab, and 20.5 months for FOLFOX, with or without bevacizumab, plus SIRT (hazard ratio, 0.69; 95% confidence interval, 0.55-0.90; P = .002), a 7.9-month improvement.

In addition, the objective response rate, although modestly higher overall for the SIRT arm (76.4% vs 68.1%; P = .113), was significantly higher in the liver (72.7% vs 66.9%; P = .042). Furthermore, the complete response rate overall displayed a trend for improvement in the SIRT-containing arm (4.5% vs 1.5%; P = .054), but in the

liver was significantly higher (6.0% vs 1.9%; P = .02).

“Adverse events had no negative impact on duration of systemic therapy and were acceptable and as predicted,” Dr Gibbs stated. Grade ≥3 events were significantly increased in the SIRT arm, including neutropenia of 40.7% versus 28.5% in the FOLFOX arm, and thrombocytopenia (9.8% vs 2.6%, respectively). Gastric or duodenal ulcers and ascites were higher for the SIRT group as well.

Dr Sharma speculated that the failure to achieve an overall PFS advantage with Sirtex in SIRFLOX was likely attributed to the inclusion of 40% of patients with extrahepatic disease. He underscored, as well, that there is a need for additional therapies for this population. Despite the FDA approval of 71 drugs for solid cancers between 2002 and 2014, improvements in median PFS and median overall survival have been only 2.5 months and 2.1 months, respectively, Dr Sharma said.

“We eagerly anticipate the subgroup analyses and the combined analysis, which will tell us which patients benefit the most from SIRT,” he said. Dr Sharma’s current recommendation is, “For local control of liver metastases not amenable to surgery plus thermal ablation, consider SIRT in combination with chemotherapy.” n

Encouraging Results for Pembrolizumab in Head and Neck Cancer

By Phoebe Starr tive as we have seen with standard therapy with cetuximab [Erbitux], the

only approved targeted therapy for this cancer. Responses are durable, which

“

Pembrolizumab was twice as effective as we have seen with standard therapy with cetuximab, the only approved targeted therapy for this cancer.

Responses are durable, which has not been seen before in head and neck cancer.

Photo by © ASCO/Scott Morgan 2015

Chicago, IL—Pembrolizumab (Keytruda) achieved “remarkable” results in a phase 1 study of previously treated patients with recurrent, squamous-cell carcinoma of the head and neck, according to presenters at the 2015 American Society of Clinical Oncology (ASCO) annual meeting.

Tumor shrinkage was observed in 57% of these heavily pretreated patients with poor prognosis, and 24.8% had a partial or complete response on treatment with pembrolizumab in an expansion cohort of ­­ the phase 1 KEYNOTE 012 trial.

“This is the largest experience of immunotherapy in head and neck cancer. Pembrolizumab was twice as effec-

”

—TANGUY Y. SEIWERT, MD

has not been seen before in head and neck cancer,” said lead author Tanguy Y. Seiwert, MD, Assistant Professor of Medicine and Associate Head and Neck Cancer Program Leader at the University of Chicago.

“Pembrolizumab was effective in both HPV-positive and HPV-negative tumors, which is not typically seen in head and neck cancer,” he added.

Pembrolizumab is the first anti–PD-­1 therapy to be approved by the FDA for the treatment of melanoma, and this immunotherapy is under study in head and neck, lung, bladder, and other cancers.

In the current era, the median survival in previously treated recurrent or metastatic head and neck cancer is apContinued on page 23

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Oral Nicotinamide Prevents Common Skin Cancers in High-Risk Patients

By Phoebe Starr Chicago, IL—The prevention of common skin cancers and precancers is possible by taking an inexpensive, widely available, oral pill twice daily. The pill—the vitamin B3 supplement called nicotinamide—cut the rate of new squamous-cell and basal-cell skin cancers by 23% compared with placebo after 1 year among patients at high risk for skin cancer. Nicotinamide also reduced the risk for developing actinic keratosis, a common precancer of the skin.

The results of the phase 3 ONTRAC skin cancer prevention study were presented at the 2015 American Society of Clinical Oncology (ASCO) meeting.

These findings have the potential to lower healthcare costs. In the United States, skin cancer accounts for approximately $4.8 million annually.

The investigators emphasized that these results were achieved in individuals who previously had skin cancer and were thus at high risk for new skin cancers. The results do not apply to other patient populations.

In addition, the investigators emphasized that nicotinamide is the form of vitamin B3 that should be taken for prevention—not other forms of vitamin B, such as niacin—and that continuous treatment is advised.

“This form of prevention is safe and inexpensive, costing around $10 per month, and it is widely available. It is ready to go straight to the clinic for high-risk patients with a track record of skin cancer. This is a new opportunity for skin cancer prevention,” said lead investigator Diona Damian, MBBS,

“

This form of prevention is safe and inexpensive, costing around $10 per month, and it is widely available. It is ready to go straight to the clinic for high-risk patients with a track record of skin cancer. This is a new opportunity for skin cancer prevention.

”

—DIONA DAMIAN, MBBS, PHD

PhD, Professor of Dermatology, Dermatology University of Sydney, New South Wales, Australia. “The pill does not take the place of sunscreen use and regular skin checkups by dermatologists for people at high risk,” Dr Damian noted.

As the aging population continues to grow, basal- and squamous-cell carcinomas will become even more common than they currently are. The investigators are from Australia, which has extremely high rates of sun-induced skin cancers. A previous phase 2 study by this group showed that nicotinamide reduced the number of new actinic keratoses in Australian patients with ­ sun-damaged skin.

The present study included 386 patients aged 30 to 91 years who had ≥2 nonmelanoma skin cancers over the past 5 years, and were therefore deemed high-risk. The patients were randomized to oral nicotinamide 500 mg twice daily or to placebo for 12 months. Dr Damian

said that the patient mix reflected those seen in a typical skin cancer clinic. The average age was 66 years, and 66% of the patients were men, many with ongoing chronic comorbidities.

“These patients were typical of the ‘warts-and-all’ type of patients we see in the clinic,” Dr Damian said.

The patients were checked by a dermatologist every 3 months and ­ ­suspicious lesions were biopsied. Nico­ tinamide reduced the rates of new basal-cell cancer and squamous-cell cancer diagnoses by 23% compared with placebo (P = .02). Nicotinamide reduced the rates of actinic keratoses (precancers) by 11% at 3 months and by approximately 15% after 12 months of treatment compared with placebo.

“This preventive treatment has no side effects. Unlike niacin, another form of vitamin B3, nicotinamide does not cause headache or increased blood pressure,” Dr Damian said.

“

With this study, we have a remarkably simple and inexpensive way to help people avoid repeat diagnoses of some of the most common skin cancers.

”

—PETER PAUL YU, MD

This “is welcome news. With this study, we have a remarkably simple and inexpensive way to help people avoid repeat diagnoses of some of the most common skin cancers. With just a [twice-]daily vitamin pill, along with sun protection and regular skin cancer screenings, people at high risk for these types of skin cancers have a good preventive plan to follow,” said ASCO President Peter Paul Yu, MD, Director of Cancer Research, Palo Alto Medical Foundation, CA. n

Encouraging Results for Pembrolizumab in Head... proximately 6 months. The standard of care for first-line therapy is platinum-based doublet chemotherapy with or without cetuximab. The second-line options are methotrexate (Trexall), docetaxel (Taxotere), and cetuximab.

In the first phase of KEYNOTE 012, pembrolizumab achieved a response rate of 20% at a dose of 10 mg/kg every 2 weeks in patients enriched for PD ligand 1 (PD-L1) expression. The expansion cohort of KEYNOTE 012, the results of which were presented at ASCO, included 132 patients who were unselected for PD-L1 expression and received a fixed dose of pembrolizumab (infusion of 200 mg every 3 weeks) for VOL. 6

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24 months or until disease progression or intolerable toxicity. Approximately 59% of the patients had received ≥2 previous therapies.

Tumor shrinkage was reported in 57% of the patients. The overall objective response rate was 24.8%, and was 26.3% in HPV-negative patients and 20.6% in HPV-positive patients. Approximately 25% of patients had stable disease, for a disease control rate of approximately 50%, which Dr Seiwert called “remarkable” in this setting.

The duration of response in responders was encouraging, and 86% of the responding patients were still responding at the time of the ASCO meeting.

Pembrolizumab was better tolerated than aggressive chemotherapy and radiation, he said, with approximately 60% of patients having any adverse event, and 15% reporting fatigue.

Other side effects included hypothyroidism (9.1%), decreased appetite (7.6%), and rash (7.6%).

Serious side effects occurred in <10% of patients. A total of 4 patients experienced serious immune-related adverse events that included 2 patients with pneumonitis and 2 with swelling of the face.

Longer follow-up is needed to assess survival. As has been seen with other immunotherapies, “Some patients who JUNE 2015

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Continued from page 22

have any degree of response or even disease progression at the beginning of therapy may ultimately benefit and have a survival improvement,” Dr Seiwert noted.

PD-L1 may be a biomarker to predict for benefit from pembrolizumab, he continued. The analysis of PD-L1 status and response is ongoing in this trial.

The optimal cutoff for PD-L1 expression and the clinical utility of this biomarker have yet to be determined in patients with head and neck cancer.

Pembrolizumab is currently being compared with standard treatment in ­­2 ongoing phase 3 studies in patients with recurrent or metastatic head and neck cancer. n

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ASCO 2015 Highlights

Elotuzumab, First-in-Class Monoclonal Antibody Immunotherapy, Improves Outcomes in...

Continued from the cover

These interim results of a landmark ELOQUENT-2 phase 3 trial, which were presented at the 2015 American Society of Clinical Oncology (ASCO) meeting, represent the largest study of a monoclonal antibody in multiple myeloma and the first positive findings for a targeted immunotherapy approach in a phase 3 clinical trial in patients with multiple myeloma. Further studies of elotuzumab are ongoing in myeloma, and the drug has received a breakthrough therapy designation from the FDA for patients who have received ≥1 previous therapies for multiple myeloma.

“We are excited about the progression-free survival [PFS] results attributable to this novel first-in-class monoclonal antibody. Elotuzumab achieved a longer duration of remission and improved overall response rates, without a significant increase in adverse events and no reduction in quality of life,” said lead investigator Sagar Lonial, MD, Chief Medical Officer, Winship Cancer Institute, Emory University School of Medicine, Atlanta. “We hope elotuzu­ mab will be the first immune approach to be added to the management of ­relapsed/refractory multiple myeloma.”

Dr Lonial explained that elotuzu­ mab’s novel mechanism of action contains a “double whammy,” by attaching to a cell-surface protein called SLAMF7 (signaling lymphocytic activation molecule F7), which is found on multiple myeloma cells and natural killer cells.

“Thus, it acts directly on the tumor itself, and enhances the activity of natural killer cells to kill the tumor,” he said.

“

We are excited about the progression-free survival results attributable to this novel first-in-class monoclonal antibody.

Elotuzumab achieved a longer duration of remission and improved overall response rates, without a significant increase in adverse events and no reduction in quality of life.

”

—SAGAR LONIAL, MD

“

This therapy is an innovative approach, one that combines the precision of a targeted, immunebased therapy with traditional myeloma therapy. The results are very encouraging, giving renewed hope to patients who have relapsed.

”

ELOQUENT-2 Phase 3 Trial

The study randomized 646 patients with relapsed or refractory multiple myeloma to standard therapy with lenalid-

—JULIE M. VOSE, MD, MBA

omide and dexamethasone or to standard therapy plus elotuzumab. All patients had disease refractory to 1 to 3 previous therapies.

“These patients enrolled in the trial early in the treatment phase. They had failed initial therapies but not multiple therapies, so they do not represent end-stage truly refractory patients,” Dr Lonial said.

At a median follow-up of 24 months, the PFS rates were 41% in the triple-­ therapy arm and 27% in the standard-­ therapy arm (P = .004). At 1 year, the PFS rates were 68% and 57%, ­respectively.

The overall response rates were 79% and 66% (P = .002), respectively, representing an absolute difference of 13% at 24 months.

“It is striking that 2 curves for each treatment arm remain separated at 2 years, which speaks to the duration of response and the power of an immune approach as part of treatment of multiple myeloma,” Dr Lonial said.

Of note, patients at high risk as a result of the 19p deletion or t(4;14) genetic abnormalities had a similar benefit from elotuzumab as patients with aver-

at a glance ➤ I n this phase 3 clinical trial, the monoclonal antibody elotuzumab achieved a longer remission and improved overall response rates in patients with multiple myeloma ➤A dverse events were not significantly increased with elotuzumab ➤E lotuzumab brings a new mechanism of action to the treatment of multiple myeloma by acting on the tumor directly to enhance the activity of natural killer cells that kill cancerous cells

age risk. These patients typically have less benefit from conventional therapies, Dr Lonial noted.

Overall, elotuzumab was well-tolerated, with no significant increases in adverse events. Approximately 10% of the patients had a mild infusion reaction with the first few doses of the mono­ clonal antibody immunotherapy.

“This therapy is an innovative approach, one that combines the precision of a targeted, immune-based therapy with traditional myeloma therapy. The results are very encouraging, giving renewed hope to patients who have relapsed,” stated ASCO President-Elect Julie M. Vose, MD, MBA, Chief of the Division of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, who was not involved in this trial. n

Immunotherapy Makes Headwinds into Liver Cancer

By Wayne Kuznar Chicago, IL—Immunotherapy with nivolumab (Opdivo) resulted in durable responses and promising overall survival (OS) in a dose-escalation and expansion trial of patients with advanced liver cancer. The 12-month OS rate exceeded 60% in patients in whom sorafenib (Nexavar) had failed, and responses occurred in patients with the hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, reported Anthony B. El-Khoueiry, MD, Assistant

Professor of Clinical Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, at the 2015 American Society of Clinical Oncology (ASCO) meeting.

The safety of nivolumab was also established, with manageable toxicity levels, regardless of HBV and HCV infection.

“Sorafenib remains the only standard-of-care systemic therapy for patients with advanced hepatocellular carcinoma, with median survival limited

to less than 11 months,” said Dr El-­ Khoueiry. “Patients who progress on sorafenib have no standard-of-care second-­line therapy options. Based on recently completed phase 3 trials in the setting of sorafenib failure, the median survival with best supportive care is approximately 7 to 8 months.”

The rationale for evaluating anti– PD-1 therapy in hepatocellular carcinoma is extensive, he said. Hepatocellular carcinoma is typically an inflamma-

tion-associated cancer that can be immunogenic. Furthermore, HCV infection and HBV infection have been associated with the upregulation of PD-1. The upregulation of PD-1 and its ligand 1 ­ (PD-L1) have been associated with worse prognosis in hepatocellular carcinoma, especially after resection or ablation.

Study Details

In the phase 1/2 study, nivolumab was evaluated in patients enrolled in Continued on page 25

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ASCO 2015 Highlights

Docetaxel Boosts Survival in Patients with HormoneNaïve Metastatic Prostate Cancer

By Phoebe Starr

The STAMPEDE Trial

STAMPEDE is the largest randomized

clinical trial to date in prostate cancer; it has a multiarm, adaptive design. The standard-of-care (SOC) arm continues to enroll patients on an ongoing basis, as ineffective treatments are discarded and more effective treatments are added to the SOC arm according to the trial results.

The trial includes 2962 hormone-naïve men with advanced pros-

androgen-deprivation therapy with local radiation for suitable patients. At a median follow-up of 42 months, 948 deaths were reported.

The OS was a median of 77 months in the docetaxel arm versus 67 months for SOC, for a 24% relative improvement in survival. The OS was longer in the subset of men with metastatic dis-

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Photo by © ASCO/Scott Morgan 2015

dose escalation in 2 parallel cohorts— patients with HBV or HCV and uninfected patients. Dose escalation was followed by ongoing dose expansion.

Patients were permitted ≥1 lines of previous systemic therapy, including sorafenib. Patients received nivolumab 0.1 mg/kg to 10.0 mg/kg intravenously every 2 weeks for up to 2 years.

Overall, 47 patients were evaluable for safety (43 from the dose-escalation phase and 4 from the dose-expansion phase) at the time of the interim analysis presented at ASCO 2015. In all, 66% of patients had previous surgical resection, and 75% had previous systemic therapy (mostly with sorafenib).

A maximum tolerated dose was not defined, and drug-related adverse events occurred in 68% of patients, with 19% being grade 3 or 4.

Increases in aspartate aminotransferase or alanine aminotransferase, an increase in lipase, and pruritus were

Further Evidence

ease when docetaxel was added to hormone therapy, a difference of 22 months favoring docetaxel.

Comparing men with metastatic versus nonmetastatic disease, patients with metastatic disease had a clinically and statistically significant 37% improvement in survival, but the study was not fully powered to detect a significant survival benefit in the nonmetastatic group.

Immunotherapy Makes Headwinds into Liver...

“

”

—ANTHONY B. EL-KHOUEIRY, MD

events, and 2 from achieving a complete response.

Response was measured using the modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Of 42 patients who were evaluable for response, 8 (19%) had an objective response (5% had a complete response and 14% had a partial response). In all, 48% of the patients had stable disease.

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The STAMPEDE trial adds further support to the results of the CHAARTED trial, which were presented at ASCO 2014 and showed a significant survival advantage when docetaxel was added to hormone therapy in patients with hormone-sensitive advanced prostate cancer.

The current SOC for men with newly diagnosed hormone-sensitive metastatic prostate cancer should be upfront doce­ taxel plus hormone therapy. n

Continued from page 24

The durable responses and prolonged stable diseases, along with the encouraging 12-month OS, lend strong support…for continued exploration of nivolumab in hepatocellular carcinoma.

the most common adverse events.

Only 1 patient had grade 4 toxicity, which was an increase in lipase. Adverse events were consistent across all of the etiologic cohorts.

Currently, 17 patients remain in the study; a total of 30 patients discontinued treatment, with 26 discontinuations resulting from disease progression, 2 from drug-related adverse

➤ Docetaxel plus hormone therapy extends overall survival (OS) by 10 months versus hormone therapy alone in newly diagnosed, advanced, hormone therapy– naïve prostate cancer

The addition of docetaxel to hormone therapy does lead to some increased toxicity, Dr James noted.

—NICHOLAS DAVID JAMES, MD, PHD

tate cancer who were randomized to 1 of 4 treatment arms from 9 ongoing treatment arms. The men were randomized between October 2005 and March 2013 in a 2:1:1:1 ratio to SOC, SOC with docetaxel for 6 cycles, SOC with zoledronic acid for 2 years, or to SOC with docetaxel and zoledronic acid.

In this comparison of hormone-naïve men, SOC treatment was ≥3 years of

at a glance

➤ Men with metastatic, hormonenaïve prostate cancer should receive docetaxel upfront in their treatment

Docetaxel should be routinely used in patients with metastatic hormone-naïve prostate cancer as part of upfront treatment. In nonmetastatic disease, docetaxel should be offered to men about to start hormones for the first time, because it prolongs failure-free survival.

Photo by © ASCO/David Eulitt 2015

Chicago, IL—Adding docetaxel (Taxotere) to standard hormone therapy extends overall survival (OS) by a median of 10 months versus hormone therapy alone in men with newly diagnosed, advanced, hormone therapy–naïve prostate cancer, according to the results of the STAMPEDE trial. The survival benefits were more pronounced in metastatic disease and were less certain in nonmetastatic disease. Another finding of this analysis of STAMPEDE is that zoledronic acid (Zometa) had no benefit in this setting.

“Docetaxel should be routinely used in patients with metastatic hormone-naïve prostate cancer as part of upfront treatment. In nonmetastatic disease, docetaxel should be offered to men about to start hormones for the first time, because it prolongs failure-free survival. There is some uncertainty regarding its effect on overall survival in men with nonmetastatic disease, and longer follow-up is needed,” said lead investigator Nicholas David James, MD, PhD, Founding Director of the Cancer Research Unit, University of Warwick, Coventry, England.

Dr James presented the results of the STAMPEDE trial at the 2015 American Society of Clinical Oncology (ASCO) meeting.

Responses occurred across all the etiologic cohorts. “In addition to the confirmed responses,…40% of patients had some reduction in the size of their tumors,” said Dr El-Khoueiry. Among the 8 responders, 7 had responses lasting >9 months, and responses are ongoing in 6 patients. Of the 8 patients who responded, 7 did so within 3 months of beginning treatment.

The OS rate at 12 months is 62%.

“To put this in context, the 12-month OS rate after sorafenib failure, based on recently completed phase 3 trials, is about 30%,” Dr El-Khoueiry said.

“The durable responses and prolonged stable diseases, along with the encouraging 12-month OS, lend strong support to the ongoing dose-expansion phase of the study to validate the promising signal and for continued exploration of nivolumab in hepatocellular carcinoma,” Dr El-Khoueiry concluded. n

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Palliative Care

Early Initiation of Palliative Care Improves Survival in Patients with Advanced Cancer

By Laura Morgan

P

alliative care offers symptom relief, comfort, and peaceful death to patients with advanced cancer. Historically, palliative care was provided to patients who were near death. Based on recent research, however, the American Society of Clinical Oncology now recommends combining palliative care with curative treatment early in the disease course. Nevertheless, an important question remains: How early in the disease trajectory should patients with advanced cancer begin receiving palliative care?

According to Marie A. Bakitas, DNSc, NP-C, FAAN, Associate Director, Center for Palliative and Supportive Care, University of Alabama at Birmingham, palliative care is not being offered to patients in a timely manner.

“

A culture shift is needed whereby clinicians and the general public understand that palliative care is not just about end of life. It is a type of supportive care and an extra layer of support that can be received at the same time as other medical treatments aimed at cure.

”

—MARIE A. BAKITAS, DNSC, NP-C, FAAN

“Focusing the goals of cancer treatment on acquiring as much time as possible for a person by eradicating the

underlying disease should be complemented by care and treatments that mitigate symptoms, treat the psychoso-

cial and spiritual dimensions of a person, and maximize the quality of a ­person’s life. Palliative care is this complementary component of care, yet it is often introduced far too late in the illness trajectory,” Dr Bakitas told Value-­ Based Cancer Care.

Study Details

To provide scientific evidence to clinicians and the general public that the early initiation of palliative care confers additional benefits in patients with cancer, Dr Bakitas and colleagues conducted ENABLE III, a phase 3 clinical trial in patients with advanced cancer (Bakitas MA, et al. J Clin Oncol.

2015;33:1438-1445).

Between October 2010 and March Continued on page 27

ASCO 2015 Highlights

Adding Ibrutinib to Standard Therapy Reduces Disease Progression by 80% in Previously Treated Patients with CLL A new standard of care?

By Phoebe Starr

Comparing Novel Targeted Drug and Chemoimmunotherapy

HELIOS is the first placebo-controlled study of ibrutinib in CLL/SLL and the first large phase 3 trial to evaluate a novel targeted drug with chemoimmunotherapy.

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There are countless patients with CLL for whom this drug is a blessing. Ibrutinib reduced the risk of progression or death by 80%.

Photo by © ASCO/Scott Morgan 2015

Chicago, IL—The combination of ibrutinib (Imbruvica) plus standard therapy with bendamustine (Treanda) and rituximab (Rituxan) significantly reduced the risk for disease progression or death by 80% compared with bendamustine plus rituximab alone in previously treated patients with chronic l­ymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), according to lead investigator Asher A. Chanan-Khan, MD, Chair, Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL. These results come from HELIOS, one of the largest phase 3 trials in this setting, and were presented at the 2015 American Society of Clinical Oncology (ASCO) meeting.

“There are countless patients with CLL for whom this drug is a blessing.

Ibrutinib reduced the risk of progression or death by 80%. This is an impactful therapy that changes the course of disease early on,” said Dr Chanan-Khan.

—ASHER A. CHANAN-KHAN, MD

The randomized, double-blind, international HELIOS trial included 578 patients with previously treated CLL/ SLL requiring therapy to receive ibrutinib plus standard bendamustine and rituximab, followed by ibrutinib maintenance or placebo plus bendamustine and rituximab, followed by placebo maintenance.

The treatment was given for a maximum of 6 cycles, and maintenance therapy was continued until progression or unacceptable toxicity. Crossover to ibrutinib maintenance was allowed for patients with progressive disease in the placebo maintenance arm. Any patients with deletions in 17p were excluded.

At baseline, 26% of the patients were purine analog–refractory. Approx-

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imately 49% of the patients received 1 previous line of therapy, approximately 25% received 2 previous lines, and approximately 26% received ≥3 previous lines of therapy.

The primary end point was progression-free survival as assessed by an Independent Review Committee. At 17 months of follow-up, the median progression-free survival had not yet been reached in the group receiving ibrutinib, but it was 13.3 months with standard bendamustine and rituximab (P <.001). Ibrutinib significantly reduced the risk for progression or death by 80% compared with placebo plus bendamustine and rituximab.

Ibrutinib was favored in all of the subgroups that were analyzed, including

age, sex, diagnosis, Rai stage at screening, previous lines of therapy, bulky disease, baseline Eastern Cooperative Oncology Group status, and the presence or absence of deletions in 11q and immunoglobulin VH. At a median follow-up of 17.2 months, the overall survival had not been reached in either arm. Ibrutinib reduced the risk for death by 37% (P = .05598). Dr Chanan-Khan noted that the survival results are confounded by crossover to single-agent ibrutinib for maintenance by 90 patients in the placebo arm (31%).

The overall response rate was significantly higher in the ibrutinib plus bendamustine and rituximab arm (82.7%) versus the placebo plus bendamustine and rituximab arm (67.8%).

No unexpected side effects were reported. The safety profiles were consistent for each of the drugs. The most frequent side effects were low blood cell counts, nausea, and diarrhea.

“These results represent a changing point in the treatment of CLL. The standard of care should now be ibrutinib plus bendamustine and rituximab for previously treated patients,” Dr Chanan-­ Khan stated. n

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Economics of Cancer Care

Increasing Use of Value Analysis Committees in US Hospitals: Implications for Healthcare Providers and Manufacturers

By Laura Morgan Philadelphia, PA—The growing focus on identifying and preventing overpayments and reducing waste in the healthcare system has prompted hospitals to adopt value analysis committees to curb unnecessary medical supply spending.

In 2012, as many as 64% of US hospi-

tals were using a value analysis committee to evaluate new devices and new supplies used in their institutions.

Value analysis committees are currently responsible for identifying the best-in-class drugs and obtaining them at lower prices through volume dis-

at a glance ➤ Increasing emphasis on costs and waste prevention has prompted hospitals to adopt value analysis committees ➤ These value committees are responsible for identifying the best-in-class drugs and getting them at lower prices through volume discounts ➤ Value analysis committees are now standard at US hospitals ➤ These committees comprise physicians, hospital administration, nurses, technicians, and supply management

➤ The physicians have a very strong influence over drug selection by the committees ➤ Operating room physicians and supervisors are the most influential in presenting new technologies to the value analysis committee ➤ A value committee review is done for all new drugs and other medical products in all hospitals included in this study ➤ Understanding the requirements of these committees would benefit medical device and drug companies

counts; these committees help to maintain balance between providing cost-­ effective patient care and the use of novel medical technologies.

A new study by Daniela Hristova-­ Neeley, PhD, MBA, Consultant, GfK, Wayland, MA, and colleagues, showed that value analysis committees have become integral to US hospitals; therefore, medical device companies could benefit from learning what criteria these committees use when evaluating and approving new medical devices.

The results of the study were presented at the 2015 International Society for Pharmacoeconomics and Outcomes Research annual international meeting.

Study Details

Using qualitative interviews (N = 40)­and quantitative online surveys (N = 76), Dr Hristova-Neeley and colleagues collected data from hospital decision makers associated with value analysis committees to quantify the use of value analysis committees among US hospitals and to examine the functions of value analysis committees, triggers of drug reviews, and evidence needed for drug reviews.

“

The one-size-fits-all approach to value message communication is no longer sufficient, and attention must be paid to the specifics of the individual facility in order to secure product approval.

”

—DANIELA HRISTOVA-NEELEY, PHD, MBA, AND COLLEAGUES Continued on page 28

Palliative Care

Early Initiation of Palliative Care Improves Survival...

2013, a total of 207 patients with advanced cancer from a National Cancer Institute cancer center, a Veterans Affairs Medical Center, and community outreach clinics were randomly assigned to 1 of 2 groups—early or delayed palliative care; 104 patients received palliative care 30 to 60 days after being informed of their advanced cancer ­ diagnosis (early group), and 103 pa­ tients received palliative care 3 months later (delayed group).

Patients in both groups received 3 palliative care interventions, including inpatient palliative consultation, outpatient consultation by palliative care clinicians, and 6 weekly telephone coaching sessions by advanced practice nurses. The study outcomes assessed patient-reported quality of life (QOL), symptoms, and mood; 1-year survival VOL. 6

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and overall survival; and resource use and location of death.

The relative rates for resource use were similar between the 2 groups, including hospital days, intensive care unit days, emergency department visits, chemotherapy, and home death. Conversely, the 1-year survival rates were 63% in the early group versus 48% in the delayed group. The investigators expected that the improved survival rates in the early palliative care group would also coincide with improved QOL or mood.

The investigators, however, reported that there were no significant differences in QOL, symptom impact, and mood between the early palliative care group (QOL, P =.34; symptom impact, P = .09; mood, P = .33) and the delayed group (QOL, P = .73; symptom impact,

P = .30; mood, P = .82). They attributed these differences in the survival rates and QOL to several factors, including a reduced study sample size and power.

Early Introduction of Palliative Care Needed

Dr Bakitas further emphasized the importance of initiating palliative care early in the disease process. “First and foremost, a culture shift is needed whereby clinicians and the general public understand that palliative care is not just about end of life. It is a type of supportive care and an extra layer of support that can be received at the same time as other medical treatments aimed at cure,” she said.

“Currently, palliative care is often introduced very late when a person is near death and, therefore, patients and JUNE 2015

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Continued from page 26

families rarely are able to experience the full range of palliative care services,” she said.

“Furthermore, this means palliative care is often mistakenly associated only with end of life. Second, reimbursement mechanisms need to incentivize this care to be offered regardless of prognosis (Medicare currently limits palliative care via hospice only to patients with a 6 month or less prognosis). Third, increased clinician education is needed to train both specialists and general practitioners in palliative care,” Dr Bakitas added.

Overall, the investigators concluded that although early palliative care improved survival in patients with advanced cancer, more research is needed to determine the optimal timing, essential elements, and personnel to deliver the high-quality palliative care. n

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Economics of Cancer Care

The New PC-SAF Instrument: A Patient-Reported Outcome Tool for Identifying the Symptoms of Pancreatic Cancer

By Laura Morgan Philadelphia, PA—The prognosis for patients with pancreatic cancer, the leading cause of cancer-related deaths in the United States, remains poor. The diagnosis of pancreatic cancer is often delayed to a late stage, which affects impact. Improving the understanding of the early signs and symptoms of this cancer may improve outcomes.

Patient-reported outcome tools have been shown to help determine the key signs, symptoms, and impact of a disease, but there are currently no patient-reported outcomes instruments for pancreatic cancer. In an effort to fill this need, investigators developed the new Pancreatic Cancer Symptom Assessment Form (PC-SAF), a new daily electronic diary instrument containing a preliminary set of patient-reported outcome items for patients with pancreatic cancer.

Diane M. Turner-Bowker, PhD, MA, Engagement Leader, Advisory Services, Quintiles, Cambridge, MA, and colleagues, reported on encouraging results of this new PC-SAF tool ­­at the 2015 International Society for Pharmacoeconomics and Outcomes Research annual international meeting.

Dr Turner-Bowker and colleagues sought to assess a content-validated patient-reported outcomes tool, the PC-SAF, using face-to-face, open-ended qualitative and cognitive interviews with adults with advanced metastatic pancreatic cancer. They conducted qualitative interviews with 18 patients and explored the important signs,

symptoms, and impact of pancreatic cancer. They further measured the saturation of concept and inter-rater agreement to assess the quality of the collected data.

“

These findings support the content validity of the PC-SAF, a new instrument that includes PRO items to assess the key signs, symptoms, and impacts experienced by adults with pancreatic cancer.

”

—DIANE M. TURNER-BOWKER, PHD, MA, AND COLLEAGUES

The investigators conducted cognitive interviews with 14 patients, and examined the patients’ understanding of, and ability to respond to, electronically administered PC-SAF items.

Predominant Signs and Symptoms of Pancreatic Cancer

Based on the patients’ responses to the qualitative interviews, the predominant signs and symptoms reported by patients with pancreatic disease included: • Gastrointestinal symptoms, including loss of appetite, early satiety, gas/ bloating, constipation, diarrhea, nausea, and vomiting

• Pain and discomfort, particularly in the abdomen • Tiredness/low energy level • Weight loss.

Furthermore, the patients reported difficulties with: • Activities of daily living • Physical difficulties (eg, limitations in walking, standing, climbing stairs) • Social difficulties • Dietary changes • Emotional problems, especially ­depression.

New Tool Validated

Dr Turner-Bowker and colleagues noted that their study “findings support the content validity of the PC-SAF, a new instrument that includes PRO [patient-reported outcome] items to assess the key signs, symptoms, and impacts experienced by adults with pancreatic cancer.”

Overall, the inter-rater agreement and the quality of the collected data were strong, and the patient responses to the qualitative interviews helped to finetune the contents of the PC-SAF tool.

The PC-SAF items were generally well-understood, and overall, the patients considered the PC-SAF easy to use. However, the researchers did slightly modify the wording and included colloquial terms to enhance the use of the PC-SAF tool by all patients, and to improve clarity of this type of cancer.

The PC-SAF Tool in Clinical Trials

The PC-SAF instrument is current-

at a glance ➤T he PC-SAF tool is a generally well-understood and user-friendly tool to determine the key signs, symptoms, and impact of pancreatic cancer ➤T he PC-SAF uses face-toface, open-ended qualitative and cognitive interviews with patients to assess the change from baseline in the symptoms of pancreatic cancer ➤T he new instrument is currently being used in a phase 3 clinical trial that is comparing the use of ruxolitinib plus capecitabine versus capecitabine plus placebo in this patient population

ly being used in a phase 3 clinical trial of patients with advanced or metastatic pancreatic cancer to compare the benefits of ruxolitinib (Jakafi) plus capecitabine (Xeloda) versus capeci­ tabine plus placebo in this patient population; the PC-SAF tool is being used to assess the change from baseline in the symptoms reported by patients with pancreatic cancer. n

Increasing Use of Value Analysis Committees in US...

Study participants were all part of their hospital value analysis committee and had served in that position for ­≥1 year.

Based on this study, the value analysis committees comprise: • Physicians • Hospital administration • Nurses • Technicians • Supply management.

The physicians have a very strong influence over drug selection. Overall, operating room physicians and supervisors were listed as the most influential ­­in presenting new technologies to the value analysis committee.

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In addition, 100% of the hospitals included in this study use value analysis committees for selecting new drugs.

These committees meet several times annually to make decisions based on established criteria.

According to the investigators, value analysis committees “are now a standard process at US hospitals; therefore, medical device companies must have a thorough understanding of the process and evidence requirements.”

Implications to Providers and Manufacturers

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views, including a price increase of ≥5% for an existing drug, the introduction of a new drug into the market, and the review of an existing drug if a new drug emerges with improved features.

All the hospitals in this study conduct a value analysis committee review of all new drugs and other medical products.

All of the decision makers regarded clinical outcomes as the most important factor when reviewing a drug; however, the participants agreed that clinical trial outcomes may not translate well to all hospitals. Conversely, economic outcomes ranked the lowest in priority

Continued from page 27

during drug reviews and were more relevant to hospital administrators than to pharmacy directors and to physicians.

These study findings highlight the important role that value analysis committees play in selecting medical devices, and provide valuable criteria information to medical device and hospital supply companies.

“The one-size-fits-all approach to value message communication is no longer sufficient, and attention must be paid to the specifics of the individual facility in order to secure product approval,” Hristova-Neeley and colleagues concluded. n

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Personalized Medicine

Biomarker Testing Trends in Europe Linked to Availability of Specific Targeted Cancer Drugs

By Laura Morgan Philadelphia, PA—In an era of personalized care, targeted cancer therapies are on the rise and are expected to reach nearly 60% of the global oncology and hematology drug markets by 2017. By testing for genetic biomarkers, physicians can predict patient response to cancer therapy and identify patients who will benefit most from these treatments, thus serving the 2 purposes of increasing the efficiency of treatment decisions and reducing the use of unnecessary drug prescribing and the associated costs.

A recent multicountry, multicenter retrospective review by Siva Narayanan, MSc, MHS, Senior Vice President, Global Evidence, Value and Access, Ipsos Healthcare, Washington, DC, and colleagues, assessed and compared the rate of biomarker testing in breast cancer, metastatic non–small-cell lung cancer (NSCLC), and metastatic colorectal cancer (CRC) in the 4 European Union (EU4) countries (ie, France, Germany, Italy, and Spain) and the United Kingdom. The results of the study were presented at the 2015 International Society for Pharmacoeconomics and Outcomes Research annual meeting.

Using online physician panels, the researchers recruited treating physicians from the EU4 countries and the United Kingdom. The physicians identified 10 to 25 patients in each of the 3 disease

“

at a glance

The testing rates may be linked to the availability and approval of the associated targeted agents; the delay in biomarker testing, especially in the UK, may be correlated to the delay in corresponding product approvals.

➤G enetic biomarker testing can increase the efficiency of treatment decisions and can reduce unnecessary drug prescribing

”

—SIVA NARAYANAN, MSC, MHS, AND COLLEAGUES

cohorts who were receiving anticancer regimens, and reported the patients’ biomarker status, namely, HER2, EGFR, and KRAS mutations linked to breast cancer, NSCLC, and metastatic CRC, respectively.

The study results showed that testing for HER2 breast cancer in the EU4 countries had increased from 70% in 2004 to 97% by 2013. Conversely, testing for HER2 breast cancer in the United Kingdom was lagging, with only 23% of patients having undergone such genetic testing in 2004, but testing rates reached 98% in 2013.

Similar to HER2 testing, testing for EGFR mutations in patients with NSCLC was also lagging in the United Kingdom compared with the other 4

European countries, particularly between 2009 and 2012; however, UK testing for EGFR mutations caught up in 2013, with 62% of patients undergoing testing in the United Kingdom and the EU4 countries.

Although the gap in HER2 and EGFR testing eventually closed in 2013 between the 2 groups, this was not the case for KRAS testing.

The results showed that testing for KRAS mutations in patients with NSCLC in the EU4 countries increased from 61% in 2009 to 92% in 2013, but significantly lagged in the United ­Kingdom, with 6% of patients under­ going testing in 2009 and 62% being tested ­­in 2013.

The researchers concluded that fac-

➤P redicting patient responses to cancer therapy and identifying patients who will benefit most from cancer treatments can affect the availability and approval of targeted agents ➤F actors that impact biomarker testing trends need to be evaluated in depth to improve patient care via targeted oncology drugs

tors impacting biomarker testing trends need to be thoroughly evaluated to improve patient care via targeted oncology drugs. Furthermore, the researchers postulated that “the testing rates may be linked to the availability and approval of the associated targeted agents; the delay in biomarker testing, especially in the UK, may be correlated to the delay in corresponding product approvals.” n

Genomic Sequencing for Pancreatic Cancer Still Facing Hurdles

By Phoebe Starr Philadelphia, PA—Although whole genomic sequencing can be done on a patient’s tumor, it does not mean that this will translate to a patient’s getting targeted therapy to identified genetic abnormalities, especially if that patient has pancreatic cancer.

In the Individualized Molecular Pancreatic Cancer Therapy (IMPaCT) trial, no patient with an identified genetic abnormality proceeded to targeted therapy. The trial’s results were presented at the 2015 American Association for Cancer Research meeting and were simultaneously published in Clinical Cancer Research (Chantrill LA, et al. 2015;21:2029-2037).

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“

We are in the middle of a learning curve. The technology is ahead of what our healthcare systems can deliver.

It will take a long time for this to become a reality.

”

—LORRAINE A. CHANTRILL, BSC, MBBS

Pancreatic cancer is particularly difficult to treat. If not treated, the average life span is approximately 31 days, and

5-year survival is very poor. Thus, the identification of targetable mutations may improve outcomes.

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Of 93 patients screened in IMPaCT, 76 were eligible for whole genomic sequencing. Of these, actionable targets were identified in 22 patients, and none went on to receive targeted therapy in the trial.

The reasons cited for the failure to get patients to targeted therapy include difficulty in obtaining adequate tumor tissue for biopsy, lag time in getting tumor tissue to the laboratory and back, a short life span of patients with pancreatic cancer, the patients’ desire not to be randomized if they have an identifiable genetic abnormality, an urgency to get treatment as quickly as possible, and a lack of teamwork among the specialties involved.

Continued on page 30

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Survivorship

Less Is More in Cancer Survivor Care

By Rosemary Frei, MSc

T

wo oncologists from Fox Chase Cancer Center in Philadelphia have added their weight to the growing call for less intensive follow-­up ­­of cancer survivors whenever appropriate.

Megha Shah, MD, a hematologist/ oncologist, and Crystal S. Denlinger, MD, an attending physician, both from the Department of Medical Oncology, Fox Chase Cancer Center, reviewed the current surveillance of prostate, colo­ rectal, and breast cancer survivors (Oncology [Williston Park]. 2015;29:230-240).

Drs Shah and Denlinger recommend standardized, evidence-based surveillance practices that follow guidelines rather than overusing tests that do not increase quality of life or length of survival but add to the cost of care and patient anxiety.

“Providers need to understand the data and national guidelines regarding surveillance, and be willing to have open discussions with their patients regarding the current state of the data,” Dr Denlinger told Value-Based Cancer Care. “In addition, more studies focusing on optimal surveillance strategies are necessary in various cancers to better inform surveillance practices and guidelines. The assumption that more is better is not always true.”

Prostate Cancer

The investigators noted that close monitoring of prostate-specific antigen (PSA) levels and PSA doubling time in men with nonmetastatic prostate cancer who have had radiation or prostatectomy can detect aggressive disease that may be treatable by salvage therapies. However, the investigators recommended against routine imaging in ­asymptomatic individuals, citing a 1997 literature review that indicated that using these imaging studies across the board after radiation or prostatectomy can reduce surveillance costs by $330

million per 1000 people over 10 years.

Drs Shah and Denlinger believe that similar approaches could be used in patients undergoing active surveillance, as well as in patients receiving androgen-deprivation therapy alone, or those who have metastatic disease, with PSA level monitoring key to watching the disease.

Overall, the researchers recommend a physician visit, physical examination, and PSA testing every 6 months for 5 years posttreatment for prostate cancer surveillance. They further state that imaging and digital rectal examinations are only useful for patients with rapid PSA elevations or for those who become symptomatic.

Whether PSA testing should be continued annually for more than 5 years posttreatment for prostate cancer should be based on the person’s age, comorbidities, and life expectancy.

Colorectal Cancer

Drs Shah and Denlinger also recommend limiting the surveillance period to 5 years for patients who have undergone primary treatment for colorectal cancer. The investigators remarked that until a consensus is reached on a more standardized, evidence-based approach, the consensus appears to be a physician visit every 3 to 6 months in the first 5 years after therapy, with a physical examination and carcinoembryonic antigen level testing. The patient should also undergo a colonoscopy 1 year after treatment and, if the results are normal, every 3 to 5 years thereafter.

Patients who are at high risk for the recurrence of colorectal cancer based on individual factors such as tumor characteristics can benefit from radiographic imaging with annual computed tomography scans for up to 5 years, Drs Shah and Denlinger noted. They do not rec-

ommend routine radiographic surveillance for low-risk colorectal cancer, and instead suggested individualized radiographic surveillance strategies.

“

Providers need to understand the data and national guidelines regarding surveillance, and be willing to have open discussions with their patients regarding the current state of the data.

”

—CRYSTAL S. DENLINGER, MD

Breast Cancer

Large randomized studies in breast cancer have demonstrated that intensive surveillance strategies with routine tumor marker testing, bone scans, and other radiology studies did not improve survival over clinical evaluation with annual mammography. Thus, the National Comprehensive Cancer Network and the American Society of Clinical Oncology (ASCO) surveillance guidelines call for follow-up visits after curative-intent treatment with surgery, chemotherapy, and/or radiation every 6 months for 5

Genomic Sequencing for Pancreatic Cancer...

The investigators suggested that healthcare systems are not set up for expediting genomic results. “We are in the middle of a learning curve. The technology is ahead of what our healthcare systems can deliver. It will take a long time for this to become a reality,” said lead investigator Lorraine A. Chantrill, BSC, MBBS, Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

30

VALUE-BASED CANCER CARE

Continued from page 29

The study screened for 3 molecular targets—HER2 amplification, KRAS wild-type, and mutations in DNA damage repair pathways (BRCA1, BRCA2, PALB2, ATM). Of the 76 patients screened, 17 were unsuitable for tissue processing for a variety of reasons, including ineligibility, objecting to randomization, and death from pancreatic cancer.

Only 22 of the screened patients were candidate cases. Of the 22 patients with

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years, as well as annual mammography.

“Intensive follow-up with additional imaging studies and routine tumor marker tests does not improve” clinical outcomes in breast cancer, the investigators noted. However, they observed, “oncologists continue to engage in intensive surveillance approaches.” One study using the Surveillance, Epidemiology, and End Results (SEER) database showed that patients who had follow-up with an oncologist had higher rates of nonrecommended tests than other patients (Keating NL, et al. J Clin Oncol.

2007;25:1074-1081). Another SEER database study showed that almost 50% of patients with early-stage breast cancer had ≥1 tumor marker assessments within 2 years of diagnosis; this was associated with a 29% increase in overall medical costs (Ramsey SD, et al. J Clin Oncol. 2015;33:149-155).

“While outcomes with recurrent disease are best when patients are asymptomatic at the time of recurrence detection, there are no current data to suggest that intensive surveillance strategies using various imaging modalities and tumor marker tests improve those outcomes,” Drs Shah and Denlinger concluded. “Thus, adherence to the guidelines that recommend routine clinician visits with physical and clinical breast exam and annual mammography would reflect the optimal strategy in post-­ treatment breast cancer surveillance.”

The researchers highlighted the important role played by ASCO’s Choosing Wisely initiative, together with interdisciplinary survivorship plans, in making the best choices for posttreatment surveillance of cancer survivors.

They also called for more research on surveillance measures that takes into account cost-effectiveness, overall quality of life, and the physical and psychologic risks associated with overtesting. n

actionable targets identified, 6 died before results were obtained, and the other 16 could not receive treatment for a variety of reasons.

To move the field along, the infrastructure has to change to incorporate the various specialties involved as a team, Dr Chantrill said.

At present, the cost of multiple gene panels is not reimbursed by insurance companies, which is yet another hurdle. n

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Drug Update

Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of Patients with Polycythemia Vera

By Lisa A. Raedler, PhD, RPh, Medical Writer

S

imilar to myelofibrosis and essential thrombocythemia, polycythemia vera is a Philadelphia chromosome–negative myeloproliferative neoplasm.1 Polycythemia vera is characterized by the clonal stem-cell proliferation of red blood cells, white blood cells, and platelets.2,3 Increased red blood cell mass results in the hyperviscosity of the blood, an increased risk for thrombosis, poor quality of life, and a shortened life expectancy.4 Polycythemia vera is a rare condition.

The incidence rate of polycythemia vera for all races and ethnicities is higher among men than among women: approximately 2.8 per 100,000 men and approximately 1.3 per 100,000 women.3 Based on several small studies, approximately 22 in 100,000 individuals are affected by polycythemia vera.3 The condition is typically diagnosed in older adults aged 60 to 65 years, and is uncommon in younger people aged <30 years.3 Approximately 96% of patients with polycythemia vera have a mutation of the Janus-associated kinase (JAK) 2 gene.5 In the polycythemia vera progenitor cells, JAK2 is directly involved in the intracellular signaling that occurs after exposure to specific cytokines.5,6 The course of the disease varies.3 Some patients with polycythemia vera have few symptoms, and the condition is discovered only after blood work is performed during a periodic health examination. In others, the signs, symptoms, and complications result from the high red blood cell count and platelet count.3 In addition, polycythemia vera evolves to postpolycythemia vera myelofibrosis in up to 10% of patients by year 10.7 Transformation to acute myeloid leukemia has been observed in up to 15% of patients with polycythemia vera after 10 years of the disease.8 The symptoms of polycythemia vera are primarily related to thrombi that result from increased blood viscosity and high platelet counts. The thrombotic complications are divided into microvascular and macrovascular complications. The microvascular complications result from thrombi in small blood vessels and can cause a variety of Copyright © 2015 American Health & Drug Benefits. Used with permission.

All rights reserved.

32

signs and symptoms, including headaches, dizziness, and paresthesia (Table 1).9 The macrovascular complications, often referred to as major thrombotic events, are serious events that are secondary to thrombi in large arteries or veins, including myocardial infarction (Table 1).10 Cardiovascular events are the primary cause of mortality in patients with polycythemia vera, accounting for 45% of deaths.11 Other major causes of death in this patient population include solid tumors (20%) and hematologic transformations (13%).11 Although polycythemia vera is incurable, it can be managed effectively for long periods.3 The treatment of patients with polycythemia vera is designed to reduce the hematocrit and platelet concentrations, control polycythemia vera symptoms, decrease the risk for thrombotic events and other complications, and avoid leukemic transformation.3,12,13 The need for treatment is determined after assessing the patient’s risk status, based on age and thrombosis history. Patients aged >60 years or those

“

The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases.

”

—RICHARD PAZDUR, MD

with a history of thrombosis have highrisk polycythemia vera, whereas younger patients aged <60 years or those with no history of thrombosis have low-risk disease.3,13 Patients with low-risk polycythemia vera are often phlebotomized and receive low-dose aspirin. Conversely, patients with high-risk disease require medical therapy to lower their hematocrit concentration permanently (ie, <45% in men and <42% in women), eliminate the need for phlebotomy, and decrease the risk for clotting.3,13 Cytoreductive therapy is recommended to control red blood cell volume in patients for whom phlebotomy

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Table 1 T hrombotic Complications in Polycythemia Vera Microvascular complications Erythromelalgia Headache Dizziness Visual disturbances Paresthesia Transient ischemic attack Macrovascular complications Arterial thrombotic events Myocardial infarction Unstable angina Stroke Peripheral arterial occlusion Venous thrombotic events Deep vein thrombosis Pulmonary embolism Intra-abdominal vein thrombosis Cerebral vein thrombosis Sources: Michiels JJ, et al. Semin Thromb Hemost. 2006;32:174-207; Falanga A, ­Marchetti M. Hematology Am Soc Hematol Educ Program. 2012;2012:571581; Marchioli R, et al. J Clin Oncol.

2005;23:2224-2232.

is poorly tolerated, in patients with a high thrombotic risk, and in those with symptomatic splenomegaly.3 Among the available cytoreductive medication options, hydroxyurea is currently the treatment of choice for patients with polycythemia vera who are older than 40 years.12-14 Although it effectively improves myelosuppression and reduces the risk for thrombosis compared with phlebotomy alone, hydroxyurea’s utility is limited by its risk for secondary leukemia.14,15 Patients who are intolerant of or are resistant to hydroxyurea can be effectively managed with pegylated interferon (IFN)-alpha or with busulfan.16 A 2011 article recommends the use of IFN-alpha for the treatment of patients with polycythemia vera aged <65 years, and the use of busulfan in older patients, although no other evidence is available to validate this recommendation.16 Data regarding the economic burden of polycythemia vera and other myelo­ proliferative neoplasms are sparse.

However, a study presented at the 2011 annual meeting of the American Society of Hematology demonstrated that the medical costs for patients with mye­ loproliferative neoplasms are significant and are up to 6 times higher than the medical costs incurred by patients with other noncancer conditions.17 The in-

vestigators assessed the medical costs of more than 25,000 patients with mye­ loproliferative neoplasms using claims data from approximately 100 US-based payers. Patients with myelofibrosis incurred the highest total annual costs, averaging $34,690, with outpatient costs accounting for the ma­jority of the costs. The total medical costs for patients with essential thrombocythemia averaged $19,672, ­­and $11,927 for patients with polycythemia vera.17 Ruxolitinib First Therapy Approved by the FDA for Polycythemia Vera

On December 4, 2014, the US Food and Drug Administration (FDA) approved ruxolitinib (Jakafi; Incyte Corporation), an oral kinase inhibitor, for the treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.18,19 Ruxolitinib is the first drug approved by the FDA for the treatment of polycythemia vera.18 “The approval of Jakafi for polycythemia vera underscores the importance of developing drugs matched to our increasing knowledge of the mechanisms of diseases,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “The trial used to evaluate Jakafi confirmed clinically meaningful reductions in spleen size and the need for phlebotomies to control the disease.” 18 The FDA approved ruxolitinib under its priority review program, because the medication demonstrated the potential to provide significant improvement in safety or efficacy over the other available therapy for polycythemia vera at the time its application was submitted.

In addition, ruxolitinib received an orphan ­­drug designation.18 Polycythemia vera is the second indication for ruxolitinib. Ruxolitinib was first approved by the FDA in November 2011 for the treatment of patients with intermediate or high-risk myelofibrosis, including primary mye­ lofibrosis, postpolycythemia vera mye­ lofibrosis, and postessential thrombocythemia myelofibrosis.18,20 Mechanism of Action

Polycythemia vera is associated with dysregulated JAK1 and JAK2 signaling.

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Drug Update Ruxolitinib inhibits JAK1 and JAK2; these kinases mediate the signaling of cytokines and growth factors that are important for hematopoiesis and for immune function. JAK signaling involves the recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, as well as the activation and the subsequent localization of STATs to the cell nucleus. This process results in the modulation of gene expression.19 Dosing and Administration

The starting dose of ruxolitinib is 10 mg taken orally twice daily with or without food. The doses of ruxolitinib can be altered based on the drug’s safety and ­efficacy.19 The drug labeling provides detailed recommendations for dose reduction and dose reinitiation after interruption of treatment with ruxolitinib.19

Clinical Trials

The approval of ruxolitinib for the treatment of patients with polycythemia vera was based on a randomized, open-label, active-controlled phase 3 clinical trial known as the RESPONSE trial.18,19,21 In this clinical trial, ruxolitinib (10 mg twice daily) was compared with best available care in patients with polycythemia vera who had unacceptable side effects from or who had an inadequate response to hydroxyurea.19,21 The primary end point of the RESPONSE study included hematocrit control and a spleen volume reduction of ≥35% by week 32.19,21 The secondary end points included the proportion of randomized patients who reached the primary end point and maintained their response 48 weeks after randomization, and the proportion of patients who reached complete hematologic remission at week 32.19,21 A total of 222 phlebotomy-dependent patients with splenomegaly received ruxolitinib (N = 110) or best available therapy (N = 112), which was determined by the investigators on an individualized basis19,21; patients in the best available therapy group typically received hydroxyurea, IFN-alpha, or no medication.21 The doses of ruxolitinib were individualized based on tolerability and efficacy, with a maximum dose of 25 mg twice daily.19,21 The majority of patients in the RESPONSE trial had been diagnosed with polycythemia vera for 8 years or longer (range, 0.5-36 years).21 Approximately 95% of patients had the JAK2 V617F mutation.21 The patients’ median age was 61 years (range, 33-90 years), with 30% of patients aged >65 years.19,21 Overall, 66% of patients were male.19 The median spleen volume was 1272 cm3 (range, 254 cm3-5147 cm3), and the

median palpable spleen length below the costal margin was 7 cm.19,21 As shown in Table 2, 21% of patients who received ruxolitinib reached the primary end point compared with <1% of patients who received best available therapy.19,21 The majority (77%) of patients in the ruxolitinib group reached at least 1 component of the primary end point by week 32.21 The results of the secondary end point analyses also favored ruxolitinib.19,21 The likelihood that the response to therapy was maintained 48 weeks after randomization was higher in patients who received ruxolitinib compared with patients who received best available therapy. In addition, a significantly larger proportion of patients who received ruxolitinib reached complete hematologic remission at week 32 compared with patients who received best available therapy.19,21

ESPONSE: Patients with Polycythemia Vera Reaching Primary and Key Table 2 R Secondary End Points Ruxolitinib, N (%) (N = 110)

Best available therapy, N (%) (N = 112)

P value

Response at week 32

23 (21)

1 (<1)

<.001

Durable responsea at week 48

21 (19)

1 (<1)

<.001

Complete hematologic remissionb at week 32

26 (24)

10 (9)

.003

Hematocrit control at week 32

66 (60)

22 (20)

—

Spleen volume reduction ≥35% from baseline at week 32

42 (38)

1 (<1)

—

Patients achieving primary/ secondary end points a

Defined as hematocrit control and a ≥35% reduction from baseline in spleen volume at week 32. b Defined as hematocrit control, platelet count ≤400 × 109/L, and white blood cell count ≤10 × 109/L at week 32.

Sources: Jakafi (ruxolitinib) tablets prescribing information; December 2014; Vannucchi AM, et al. N Engl J Med. 2015;372:­­426-435. a

ESPONSE: Treatment-Emergent Adverse Events in ≥6% of Patients Table 3 R Receiving Ruxolitinib Up to Week 32 Patients receiving ruxolitinib (N = 110)

Safety

The safety of ruxolitinib has been assessed in 617 patients who participated in 1 of 6 clinical trials.19 The median duration of follow-up was 10.9 months.19 This cohort included 110 patients with polycythemia vera whose disease was resistant to or who were intolerant of hydroxyurea in the RESPONSE clinical trial19; in this study, the most frequent adverse drug reaction was anemia.19 Table 3 lists the most common nonhematologic treatment-emergent adverse events that occurred up to week 32 in the RESPONSE trial, which included headaches, abdominal pain, and diarrhea.19 Other clinically important treatment-emergent adverse events that were noted in <6% of patients who received ruxolitinib were weight gain, hypertension, and urinary tract infections.19 Of the patients who received ruxolitinib in the ­RESPONSE trial, 4% discontinued the use of the drug as a result of adverse events.19 Ruxolitinib has no contraindications.

Warnings and Precautions

Thrombocytopenia, anemia, and neutropenia. Thrombocytopenia, anemia, and neutropenia can occur after treatment with ruxolitinib. Thrombocytopenia should be managed by reducing the dose of ruxolitinib or by temporarily interrupting its use; platelet transfusions may be required. If anemia occurs, blood transfusions and/or dose modification of ruxolitinib may be necessary. Severe neutropenia is generally reversible after the discontinuation of ruxolitinib therapy. Patients should undergo a complete blood count before starting treatment with ruxolitinib, followed by every 2 to 4 weeks until the doses are stabilized.19

Patients receiving best available therapy (N = 111)

All grades,a % Grade 3-4,a % All grades,a % Grade 3-4,a %

Adverse events Headache

16

<1

19

<1

Abdominal pain

15

<1

15

<1

Diarrhea

15

0

7

<1

Dizziness + vertigo

15

0

13

0

Fatigue

15

0

15

3

14

<1

23

4

b

Pruritus Dyspnea

13

3

4

0

Muscle spasms

12

<1

5

0

Nasopharyngitis

9

0

8

0

Constipation

8

0

3

0

Cough

8

0

5

0

Edema + peripheral edema

8

0

7

0

Arthralgia

7

0

6

<1

Asthenia

7

0

11

2

Epistaxis

6

0

3

0

Herpes zoster + postherpetic neuralgia

6

<1

0

0

Nausea

6

0

4

0

c

National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0.

Including lower and upper abdominal pain. c Including dyspnea exertional.

Source: Jakafi (ruxolitinib) tablets prescribing information; December 2014. a

b

Risk for infection. Ruxolitinib has been associated with serious bacterial, mycobacterial, fungal, and viral infections. Ruxolitinib therapy should not be started until active serious infections have resolved. Patients who receive ruxolitinib should be observed for the signs and symptoms of infection and should be managed promptly.19 Tuberculosis has been reported in patients who received ruxolitinib. Patients should be evaluated for tuberculosis risk before starting ruxolitinib

therapy. Patients at high risk for tuberculosis should be tested for latent infection. If evidence of active or latent tuberculosis is found, a physician with expertise in the treatment of tuberculosis should be consulted before starting ruxolitinib therapy. The decision to continue ruxolitinib therapy while active tuberculosis is being treated should be based on the overall risk– benefit determination.19 Progressive multifocal leukoencephalopathy (PML) has occurred with ruxContinued on page 34

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Drug Update

Jakafi (Ruxolitinib): First FDA-Approved Medication for the Treatment of...

Continued from page 33

olitinib in the treatment of patients with myelofibrosis. The use of ruxolitinib therapy should be discontinued if PML is suspected.19 Patients who receive ruxolitinib should be advised about the early signs and symptoms of herpes zoster and should seek treatment if it is suspected.19 Symptom exacerbation after ruxolitinib discontinuation. Symptoms associated with myeloproliferative neoplasms may return to pretreatment levels approximately 1 week after ruxolitinib therapy is discontinued.19 If symptoms occur, patients should be evaluated and treated for any intercurrent illness; in addition, restarting ruxolitinib therapy or increasing its dose should be considered.19 Patients should not interrupt or discontinue ruxolitinib therapy without consulting their physician. If therapy is stopped for reasons other than thrombocytopenia, the dose of ruxolitinib should be tapered.19 Nonmelanoma skin cancer. Skin cancers, including basal-cell, squamous-cell, and Merkel-cell carcinoma, have occurred in patients receiving ruxolitinib.

Therefore, the skin should be examined periodically while taking ruxolitinib.19

Nursing mothers. It is not known whether the components of ruxolitinib are present in human breast milk. Nursing or ruxolitinib should be discontinued on the basis of the importance of ruxolitinib to the mother.19 Pediatric use. The safety and efficacy of ruxolitinib have not been established in patients aged <18 years.19 Geriatric use. Overall, 52% of patients with myelo­ fibrosis in clinical studies of ruxolitinib were aged ≥65 years. No overall differences in safety or efficacy were observed between older and younger patients.19 Renal impairment. The dose of ruxolitinib should be reduced in patients with moderate or severe renal impairment, or in patients with endstage renal disease (ESRD) who are on dialysis. Ruxolitinib should not be used by patients with ESRD who are not ­on dialysis.19 Hepatic impairment. A dose reduction is recommended in patients with hepatic impairment; ruxolitinib should be started at 5 mg twice daily in patients with mild, moderate, or severe hepatic impairment.19

Use in Specific Populations

Ruxolitinib is the first medication to receive FDA approval for the treatment of patients with polycythemia vera.

This medication demonstrated superior efficacy in controlling hematocrit levels, reducing spleen size, and improving disease-related symptoms in a randomized clinical trial that compared oral

Pregnancy. Ruxolitinib is a pregnancy category C teratogen; there are no adequate and well-controlled studies with ruxolitinib in pregnant women.

Ruxolitinib should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.19

Conclusion

ruxolitinib with best available therapies, including hydroxyurea, for the treatment of patients with polycythemia vera. By contrast, best available therapies offered little to no benefit.

This novel kinase inhibitor represents an important new, and the only FDA-approved, option for the treatment of patients with polycythemia vera. Clinical trials continue to explore the potential role of ruxolitinib in myeloproliferative neoplasms, as well as in other hematologic malignancies, such as acute myeloid leukemia and chronic myeloid leukemia, as well as in solid tumors, such as metastatic pancreatic cancer.21 n References

1. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care ­diagnostic algorithms. Leukemia. 2008;22:14-22.

2. Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100:4272-4290.

3. Leukemia & Lymphoma Society. Polycythemia vera facts. No. 13. Revised June 2012. www.lls.org/content/ nationalcontent/resourcecenter/freeeducationmaterials/ mpd/pdf/polycythemiavera.pdf. Accessed March 2, 2015.

4. Kumar C, Purandare AV, Lee FY, Lorenzi MV. Kinase drug discovery approaches in chronic myeloproliferative disorders. Oncogene. 2009;28:2305-2313.

5. Passamonti F, Rumi E, Pietra D, et al. Relation between JAK2 (V617F) mutation status, granulocyte activation, and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders.

Blood. 2006;­107:3676-3682.

6. Vannucchi AM, Antonioli E, Guglielmelli P, et al.

Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008;22:1299-1307.

7. Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: current management and the prospect of targeted therapy. Am J Hematol. 2008;­83: 491-497.

8. Finazzi G, Caruso V, Marchioli R, et al; for the ECLAP Investigators. Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105:2664-2670.

9. Michiels JJ, Berneman Z, Van Bockstaele D, et al.

Clinical and laboratory features, pathobiology of platelet-­ mediated thrombosis and bleeding complications, and the molecular etiology of essential thrombocythemia and polycythemia vera: therapeutic implications. Semin Thromb Hemost. 2006;32:174-207.

10. Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581.

11. Marchioli R, Finazzi G, Landolfi R, et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23:2224-2232.

12. Barbui T, Barosi G, Birgegard G, et al; for the European LeukemiaNet. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. ­­J Clin Oncol. 2011;­29:761-770.

13. Finazzi G, Barbui T. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia. 2008;22:1494-1502.

14. Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythaemia vera and allied disorders: prospective study of efficacy and leukaemogenicity with therapeutic implications. Eur J Haematol.

1994;52:134-139.

15. Fruchtman SM, Mack K, Kaplan ME, et al. From efficacy to safety: a Polycythemia Vera Study Group report on hydroxyurea in patients with polycythemia vera. Semin Hematol. 1997;34:17-23.

16. Tefferi A. Annual clinical updates in hematological malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. Am J Hematol. 2011;86:­292-301.

17. Price GL, Pohl GM, Xie J, Walgren RA. A retrospective observational study of annual healthcare costs for patients with forms of myeloproliferative neoplasms (MPN). Blood (ASH Annual Meeting Abstracts). 2011; 118. Abstract 2060.

18. US Food and Drug Administration. FDA approves Jakafi to treat patients with a chronic type of bone marrow disease: first FDA-approved drug for polycythemia vera. Press release. December 4, 2014. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm425677. htm. Accessed March 2, 2015.

19. Jakafi (ruxolitinib) tablets [prescribing information].

Wilmington, DE: Incyte Corporation; December 2014.

20. US Food and Drug Administration. FDA approves first drug to treat a rare bone marrow disease. Press release. November 16, 2011. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm280102.htm. Accessed March 2, 2015.

21. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;­372:426-435.

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In the Literature Pazopanib with Depot Octreotide Has Antitumor Activity in Patients with Advanced Neuroendocrine... Continued from page 21

that targets VEGF receptors 1, 2, and 3 and is approved for the treatment of advanced renal-cell carcinoma.

A new multicenter, single-group, phase 2 study examined whether pazopanib would have a therapeutic effect in patients with NETs (Phan AT, et al.

Lancet Oncol. 2015 May 5. Epub ahead of print).

The researchers tested this hypothesis in parallel cohorts of patients with pancreatic NETs and of patients with carcinoid tumors, because there is evidence that carcinoid tumors and pancreatic NETs respond differently to systemic therapies, such as pazopanib.

The results suggest that pazopanib is well-tolerated in patients with advanced carcinoid tumors and pancreatic NETs, but antitumor activity was only detected in patients with advanced pancreatic NETs.

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The grade 4 toxicities included 1 patient with hypertriglyceridemia and 1 patient with thrombosis. In all 52 patients, the most frequently observed toxicities were fatigue (75%), nausea (63%), diarrhea (63%), and hypertension (54%).

The results suggest that pazopanib is well-tolerated in patients with advanced carcinoid tumors and pancreatic NETs, but antitumor activity was

only detected in patients with advanced pancreatic NETs. The effect of pazopanib on advanced carcinoid tumors cannot be thoroughly assessed based on these results, because progression-free survival is likely a better end point for this group than radiographic response.

A randomized, controlled, phase 3 study is needed to assess pazopanib in advanced pancreatic NETs. n

S:7”

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

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

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

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

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

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The study included patients with metastatic or locally advanced grades 1 or 2 carcinoid tumors and patients with pancreatic NETs, with a single-­ group, 2-stage study design. The patients received pazopanib 800 mg orally once daily until disease progres­ sion or until the completion of 12 ­ treatment cycles of 28 days each; they also received octreotide at their preprotocol dosage.

The primary end point was the proportion of patients achieving an objective response, as assessed by investigators, with an intention-to-treat analysis. The secondary end points were overall survival and progression-­ free survival.

Between April 2007 and July 2009, 52 patients were enrolled in the study, including 32 with pancreatic NETs and 20 with carcinoid tumors. Of the 32 patients with pancreatic NETs, 7 achieved an objective response.

There were no responses in the first stage of the cohort with carcinoid tumors, and accrual was terminated at ­­20 patients.

In an intention-to-treat analysis of ­­the pancreatic NET cohort, 7 (22%) of the 32 patients achieved partial responses, yielding an overall objective response of 21.9%. In the carcinoid tumors cohort, there was no overall objective response.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-14-0258 All rights reserved. Printed in USA

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What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+MP provided an OS advantage over MP that was not regained with subsequent therapies Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration.

Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR §II

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

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE adjacent to this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE-HCP.com.

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.

Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.