VBCC Feb 2015 | Vol 6 | No 1

FEBRUARY 2015 VOL 6 NO 1

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

Immunotherapy’s Future May Be in Combinations

By Wayne Kuznar

BREAST CANCER SYMPOSIUM

Ovarian Function Suppression Reduces Recurrence in Premenopausal HR-Positive Breast Cancer

By Phoebe Starr

© American Society of Hematology. All rights reserved.

San Antonio, TX—The role of ovarian function suppression (OFS) in premenopausal breast cancer is controversial, with studies to date showing equiv-

San Francisco, CA—Immunotherapy for cancer has entered a new phase as researchers focus on monoclonal antibodies that target proteins in T-cells that normally prevent the immune system from responding, or “taking the brakes off the immune system.” In the future, immune therapies may be matched up with targeted therapies for even better efficacy, said Ronald Levy, MD, Professor of Medicine, Division

Continued on page 14

GI CANCERS SYMPOSIUM

of Oncology, Stanford University, CA, during a keynote lecture at the 2015 ASCO Gastrointestinal Cancers Symposium.

Dual Antibody Therapies

A pioneer in monoclonal antibodies, Dr Levy discussed recent breakthroughs in immunotherapy. His team was the first to successfully treat patients with lymphoma with monocloContinued on page 7

Promising Therapies in Development for Hematologic Cancers

By Dana Taylor

logic cancers, including new immunotherapies, and drugs that are expanding from one tumor type to another. Some of the most promising compounds in development are described below.

Continued on page 12

© 2015 Engage Healthcare Communications, LLC

More Evidence that Low Vitamin D Levels Reduce Survival in Metastatic Colorectal Cancer

Clinical trials are under way to facilitate a new intervention

By Wayne Kuznar San Francisco, CA—Higher vitamin D levels are associated with better outcomes after treatment of newly diagnosed metastatic colorectal cancer (CRC). The median overall survival

(OS) was 8.1 months longer for patients with highest 25-hydroxyvitamin D (25[OH]D) levels versus lowest levels, said Kimmie Ng, MD, MPH, Assistant Professor of Medicine, Dana-Farber Continued on page 8

EMERGING THERAPIES

San Francisco, CA—Many of the presentations at the 2014 annual meeting of the American Society of Hematology centered on the abundance of new molecules being developed for hemato-

ocal results. Results of the large International Breast Cancer Study Group SOFT trial shed light on this issue, providing important findings that

INSIDE FDA NEWS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Olaparib approved with companion diagnostic for advanced ovarian cancer

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VALUE PROPOSITIONS . . . . . . . . . . . . . . . . 6 Medicare covers lung cancer screening GI CANCERS SYMPOSIUM . . . . . . . . . . . .

Pembrolizumab produces good responses in gastric cancer

7

CANCER REHABILITATION . . . . . . . . . 23 Interview with a thoracic surgeon ECONOMICS OF CANCER CARE . . . .24 Specialty drugs offer value for complex diseases ASH 2014 HIGHLIGHTS . . . . . . . . . . . . . . .27 New Choosing Wisely recommendations released

VBCC PERSPECTIVE . . . . . . . . . . . . . . . . . 13 Discuss cost of care with patients

PERSONALIZED MEDICINE . . . . . . . . . 30 Novel gene panel predicts prostate cancer progression

BREAST CANCER SYMPOSIUM . . . 14 Longer anti-HER2 therapy boosts response

DRUG UPDATE . . . . . . . . . . . . . . . . . . . . . . . . . 33 Opdivo: second PD-1 inhibitor for unresectable/metastatic melanoma

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.

FDA News Imbruvica Gets New FDA Indication for Waldenström’s Macroglobulinemia

The FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with Waldenström’s macroglobulinemia (WM), a rare type of non-Hodgkin lymphoma. Ibrutinib had earlier received a breakthrough therapy designation by the FDA for this

use. The approval was done under the FDA’s priority review process, and the drug was designated as an orphan drug.

WM progresses gradually over time, resulting in the overproduction of B lymphocytes (B-cells) within the bone marrow, lymph nodes, liver, and spleen.

These B-cells also overproduce immunoglobulin M that may lead to bleeding, as well as vision and nervous system prob-

lems. Ibrutinib works by inhibiting the abnormal activity of the B-cells.

“Today’s approval highlights the importance of development of drugs for supplemental indications,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products.

“Continued research has discovered new uses of Imbruvica.”

The new FDA approval for WM was

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Brief Summary 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.

Opdivo Second Immunotherapy to Receive FDA Approval for Melanoma

S:10”

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.

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

based on a clinical study of 63 previously treated patients with WM. The patients received 420 mg daily, administered orally, until disease progression or until side effects became intolerable. The overall response rate was 62% with ibrutinib, and the duration of response ranged from 2.8 months to approximately 18.8 months.

The most common adverse events reported with ibrutinib are thrombocyto­ penia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, ­ nausea, upper respiratory tract infection, and rash.

Ibrutinib was initially approved by the FDA in November 2013 for patients with mantle-cell lymphoma who had received 1 previous therapy. In February 2014, the FDA granted a second accelerated approval to ibrutinib for the treatment of patients with previously treated chronic lymphocytic leukemia (CLL), and again in July 2014, for patients with CLL and a deletion in chromosome 17. (January 29, 2015)

8/14

The FDA granted accelerated approval to nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma that is no longer responding to other drugs. Nivolumab is the second PD-1 antibody immunotherapy to receive FDA approval for this patient population; the drug inhibits the PD-1 protein, which blocks the body’s immune system from attacking melanoma cells. It is approved as second-line therapy in patients who had received therapy with ipilimumab, and in patients with the BRAF V600 mutation, for use after treatment with ipilimumab and a BRAF inhibitor.

“Opdivo is the seventh new melanoma drug approved by the FDA since 2011,” said Dr Pazdur. “The continued development and approval of novel therapies based on our increasing understanding of tumor immunology and molecular pathways are changing the ­ treatment paradigm for serious and life-threatening diseases.”

The FDA granted nivolumab a breakthrough therapy designation, priority review, and orphan drug designation, requiring the manufacturer to conduct further clinical trials to confirm the preliminary positive evidence regarding the drug’s efficacy.

Nivolumab’s efficacy was established in 120 patients with unresectable or metastatic melanoma. The objective response rate was 32%, lasting for more than 6 months. The safety of nivolumab was demonstrated in the overall trial population of 268 patients who received nivolumab versus 102 patients who received chemotherapy.

Continued on page 10

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

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 Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris 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

FDA NEWS

CANCER REHABILITATION

Olaparib for advanced ovarian cancer More…

A conversation with thoracic surgeon Timothy Sherwood

VALUE PROPOSITIONS

ECONOMICS OF CANCER CARE

Medicare begins coverage of lung cancer screening More…

GI CANCERS SYMPOSIUM Pembrolizumab produces good responses in advanced gastric cancer More…

EMERGING THERAPIES

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VALUE-BASED CANCER CARE

PD-1 blockers show “amazing” potential in Hodgkin lymphoma More…

Top 10 reasons against routine genomic profiling of tumors More…

VBCC PERSPECTIVE The imperative to discuss cost of care with patients

BREAST CANCER SYMPOSIUM Oncotype DX validated for risk assessment in DCIS More…

DRUG UPDATE Opdivo: second PD-1 inhibitor for unresectable or metastatic melanoma

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL 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, CPh H. Lee Moffitt Cancer Center Tampa, FL Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

Ted Okon, BS, MBA Executive Director Community Oncology Alliance, Washington, DC

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy, Aetna, Hartford, CT

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, 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 Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX 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.

Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com

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ASH 2014 HIGHLIGHTS

PERSONALIZED MEDICINE

Promising therapies in development More…

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

Brentuximab vedotin cost-effective after transplant in Hodgkin lymphoma More…

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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 Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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VALUE PROPOSITIONS

Advance Care Planning

Medicare Begins Coverage of Lung Cancer Screening with Low-Dose Computed Tomography for High-Risk Beneficiaries

The Centers for Medicare & Medicaid Services (CMS) announced that effective immediately, as of February 5, 2015, Medicare will begin to cover the cost of screening for lung cancer with low-dose computed tomography for beneficiaries who are at high risk for lung cancer based on their smoking history and other risk criteria.

“This is the first time that Medicare has covered lung cancer screening.

This is an important new Medicare preventive benefit, since lung cancer is the third most common cancer and the leading cause of cancer deaths in the United States,” said Patrick Conway, MD, MSc, CMS’ Chief Medical Officer and Deputy Administrator for Innovation and Quality.

The coverage is for an annual screening for beneficiaries who are (1) aged 55 to 77 years and are either current smokers or have quit smoking within the past 15 years; (2) have a history of tobacco smoking of ≥30 “pack-years” (an average of 1 pack daily for 30 years); and (3) have received a written order from a physician or a qualified nonphysician provider who meets certain ­requirements.

This new Medicare coverage also includes a counseling visit on the benefits and risks of lung cancer screening. The decision also includes required data collection and specific coverage eligibility criteria for radiologists and for radiology imaging centers, consistent with current national recommendation and evidence-based guidelines.

“We believe this final decision strikes an appropriate balance between providing access to this important preventive service and ensuring, to the best extent possible, that Medicare beneficiaries receive maximum benefit from a lung cancer screening program,” Dr Conway said. The Centers for Medicare & Medicaid Services; February 5, 2015

NIH Awards $1.08 Million for Breast Cancer Research Using Genomic Sequencing and Computer Modeling to Investigate the Underlying Mechanism of Human Diseases

The National Institutes of Health (NIH) has awarded the University of Texas at San Antonio (UTSA) a $1.08-million grant for breast cancer research that involves genomic sequencing and computer-modeling strategies to investigate what causes breast tissue cells to become cancerous. The research is being conducted by a team of electrical and computer engineering professors. The team will look into the correlation between cancer cells and mRNA methylation, an epigenetic process that oversees the normal functions of human cells. The goal is to discover abnormalities in the methylation process that may explain the development of cancerous cells and other disease processes.

“By bringing together computer engineers who are experts in computational modeling with experts in biology and genome sequencing, we have added a new dimension to the emerging study of mRNA methylation,” said Yufei Huang, PhD, Computer Engineering Professor, at UTSA. “We are going to conduct some truly groundbreaking research over the next few years.” Dr Huang explained that uncovering the role of mRNA methylation in the regulation of the transformation from normal cells to breast cancer cells will provide new insights for the development of more effective therapeutic i­nterventions.

“The research to be performed at UTSA through this prestigious NIH grant has the potential to fundamentally change how we see human diseases,” said Daniel Pack, PhD, Chair, Department of Electrical and Computer Engineering, UTSA. University of Texas at San Antonio; December 18, 2014

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Northwestern Onco-SET Introduces Genomics-­Based, Personalized Medicine to All Patients with Cancer

The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Chicago, IL, is collaborating with Northwestern Medicine Developmental Therapeutics Institute (NMDTI) and Northwestern Memorial Hospital to launch a new program known as Northwestern Onco-SET (Sequence, Evaluate, Treat) to focus on personalized medicine in oncology by directly connecting patient care and genomics. The focus will initially be on all patients with cancer that is not responsive to available therapy for that cancer.

“Northwestern Onco-SET will help establish Chicago as a national and international leader in precision medicine for cancer,” said Leonidas Platanias, MD, PhD, Director of the Lurie Cancer Center. “This is the first time cancer treatment in Chicago will be offered in a comprehensive, multidisciplinary program using molecularly defined genomic targets as a basis for determining treatment options, including novel early-phase clinical trials.”

Onco-SET will personalize treatment for every patient by sequencing the genetic profile of the patient’s tumors to select appropriate treatment or enter the patient into a clinical trial if no appropriate treatment is available.

“As part of our work with Onco-SET, we are also planning to initiate a pilot program of site-agnostic, pathway-driven tumor clinics,” Dr Platanias said. The goal is to focus on targeted therapies to address that patient’s genetic abnormalities with new targeted therapies on the market or those still in early-stage clinical trials.

“Onco-SET will provide the environment and infrastructure in which we can deliver personalized cancer treatment for patients who currently have very limited options, while accelerating our other research focused on developing novel individually tailored agents,” said Francis Giles, MD, Deputy Director of the Lurie Cancer Center, Co-Chair of the Molecular Tumor Board, and Director of NMDTI. We will be able to learn more about which genomic targets are most important to effectively treat cancer and identify potential targets for which no drugs may currently exist.” Northwestern Memorial Hospital; February 5, 2015

Hematologic Drugs Offer Value Despite High Costs

A new cost-effective analysis of studies related to oncology and hematologic cancer drugs sheds a new light onto the debate about the high price of novel cancer therapies in the United States, showing that, in many cases, breakthrough therapies for hematologic cancers provide good value for patients, despite their high cost.

“Given the increased discussion about the high cost of these treatments, we were somewhat surprised to discover that their cost-effectiveness ratios were lower than expected,” said lead investigator Peter S. Neumann, ScD, Director of the Center for Evaluation of Value and Risk in Health, Tufts Medical Center, Boston. “Our analysis had a small sample size and included both industry- and nonindustry-funded studies. In addition, cost-effectiveness ratios may have changed over time as associated costs or benefits have changed. However, the study underscores that debates in health care should consider the value of breakthrough drugs and not just costs,” Dr Neumann said.

Using the patient quality-adjusted life-year (QALY) measure to determine acceptable ratios, the research team observed that most ratios were lower or more favorable than thresholds often used in the United States as benchmarks for cost-effectiveness ($50,000-$100,000 per QALY). The median reported cost-effectiveness ratio was highest for chronic myeloid leukemia at $55,000 per QALY, and lowest for non-Hodgkin lymphoma at $21,500 per QALY. American Society of Hematology Press Release; February 5, 2015 n

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GI Cancers Symposium

Immunotherapy’s Future May Be in Combinations nal antibodies, and he made important contributions to the development of the CD20 monoclonal antibody rituximab (Rituxan). Rituximab “opened the door for monoclonal antibody treatment for other cancers, including those of the breast and colon,” he said.

Dr Levy has piloted an approach to boost the immune system in patients with cancer using a dual antibody strategy in which one antibody targets the cancer and the other targets the immune system.

egy are in progress in patients with lymphoma and colon cancer.

A New Phase of Immunotherapy

New research is concentrating on monoclonal antibodies that target T-cells that prevent the immune system from responding. Monoclonal antibodies that block the interaction between programmed cell death (PD) and its ligand 1 (L1) or L2, such as pembrolizumab (Keytruda), are being used

“ Photo by © ASCO/Todd Buchanan 2015

We’ll be seeing immune therapies matched with targeted therapies. We’ll be seeing a lot of mixing and matching based on the genetics of the tumor. The future of cancer therapy will be clever combinations of immunotherapy and targeted therapies.

”

—RONALD LEVY, MD

In one example, CD137 is being tested to determine whether it can activate the immune system’s natural killer cells.

“A second antibody against CD137 identifies this target on the immune cell, providing a ‘1-2 punch’ to the immune system,” Dr Levy said. Phase 2 clinical trials of the dual antibody strat-

to release the brake on T-cells to enable them to attack the cancer.

“These new antibodies can interrupt the cross-talk between the tumor and the immune system, allowing the immune system to find the tumor wherever it is,” said Dr Levy.

Exciting results were presented at the

meeting with pembrolizumab in gastric cancer (see article below). In the ­KEYNOTE-012 study, pembrolizumab recipients had an objective response rate of 22.2% by central review (and 33.3% by investigator review), despite two-thirds of the patients having received ≥2 previous therapies for advanced disease.

“Not many of the tumor cells need to express this ligand for this drug [pembrolizumab] to work,” said Dr Levy in commenting on KEYNOTE-012. Patients eligible for KEYNOTE-012 had to have positive PD-L1 staining in the stroma or in ≥1% of tumor cells, but only 40% of patients had the 1% necessary for eligibility, and most did not respond, Dr Levy noted.

Combination Therapy and Intratumor Injection on the Horizon

Removing the brake on the immune system by targeting the PD-1 inhibitory pathway is only part of the story to stimulate an immune response. To obtain the most effective and durable immune response, the immune system most likely needs to be stimulated as well, which will require combination therapies.

“We’ll be seeing immune therapies matched with targeted therapies,” Dr Levy said. “We’ll be seeing a lot of mixing and matching based on the genetics of the tumor. The future of cancer therapy will be clever combinations of immunotherapy and targeted therapies.”

Already, combination therapy with the anti–4-1BB/anti–PD-1 monoclonal

Continued from the cover

antibodies therapy has elicited an antitumor effector/memory T-cell response in an aggressive tumor model, and represents a candidate for combination therapy, according to Dr Levy.

“

A lot of checkpoint inhibitors are going to work by local injection to trigger an immune response, essentially a vaccine maneuver.

”

—RONALD LEVY, MD

“There’s a lot of preclinical rationale to combine these 2 agents, and we’ll see clinical trials coming soon combining those 2 agents systemically,” said Dr Levy.

Another way forward is intratumor injection “to change the tumor milieu of the infiltrating T-cells, and to bias the system away from the bad T-cells toward the good T-cells,” Dr Levy said.

“I think that a lot of checkpoint inhibitors are going to work by local injection to trigger an immune response, essentially a vaccine maneuver.”

Targeting immunosuppressant molecules elaborated by the tumor, other than PD-L1, may also improve response. “Isn’t it remarkable that just by blocking one of them, we already have our foot in the door in the clinic with amazing responses happening,” Dr Levy said. “I think we’ll have amazing opportunities.” n

PD-L1 Inhibitor Pembrolizumab Produces Good Responses in Advanced Gastric Cancer San Francisco, CA—Add gastric cancer to the list of cancers that respond to immunotherapy. In patients with advanced gastric cancer who express programmed cell death (PD)-1 ligand 1 (PD-L1), the humanized monoclonal antibody pembrolizumab (Keytruda), which binds to its ligands L1 and L2, demonstrated robust antitumor activity and an acceptable safety profile, according to updated results presented at the 2015 ASCO Gastrointestinal Cancers Symposium.

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Photo by © ASCO/Todd Buchanan 2015

By Wayne Kuznar

“

These findings support the importance of the PD-L1 pathway in gastric cancer and the further development of pembrolizumab as a treatment option for patients with advanced gastric cancer.

”

—KEI MURO, MD

umab, said Kei Muro, MD, of the Aichi Cancer Center Hospital, Nagoya, Japan,­ and lead investigator of the KEYNOTE-012 trial.

“Overall, these findings support the importance of the PD-L1 pathway in gastric cancer and the further development of pembrolizumab as a treatment option for patients with advanced gastric cancer,” said Dr Muro.

“PD-1 is a negative costimulatory receptor expressed on the surface of the activated T-cell and plays an important role in suppressing immune surveillance,” he said. “Binding of PD-1 to its ligands, PD-L1 and PD-L2, inhibits efContinued on page 8

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www.ValueBasedCancerCare.com

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GI Cancers Symposium

More Evidence that Low Vitamin D Levels...

key points ➤ Using data from patients with newly diagnosed metastatic CRC who were enrolled in clinical trials, the link between high vitamin D levels and survival was undeniable ➤ Overall survival was 32.6 months with high vitamin D levels versus 24.5 months with low levels ➤ Controlling lifestyle factors, including obesity and physical activities, did not change the results ➤ Previous studies have shown similar results ➤ Clinical trials are ongoing and should help to translate this information into a new clinical intervention ➤ Should physicians recommend vitamin D supplementation to patients with CRC?

“

Even adjustment for obesity or lower physical activity did not change our results….The persistence of the significant relationship between higher [vitamin D] levels and survival was still seen.

Photo by © ASCO/Todd Buchanan 2015

Cancer Institute, Harvard Medical School, Boston, at the 2015 ASCO Gastrointestinal Cancers Symposium.

The study adds to the growing body of evidence that shows significantly better survival for patients with CRC with higher vitamin D levels.

“The ultimate goal is to translate this research into an effective intervention for patients, by conducting randomized trials of vitamin D supplementation for treat-

”

—KIMMIE NG, MD, MPH

ment of colorectal cancer,” said Dr Ng. “Vitamin D is known to inhibit cell proliferation and angiogenesis, induces cell differentiation and apoptosis, and also has anti-inflammatory effects,” she said. “Obviously, many of these processes are quite dysregulated in cancer, which led to the hypothesis that perhaps vitamin D had anticancer activity. Laboratory data support this hypothesis, with experiments demonstrating that the administration of vitamin D to mouse models of intestinal cancer results in decreased tumor burden.”

Epidemiologic studies also support this hypothesis, said Dr Ng, with multiple prospective observational studies reporting that higher serum levels of vitamin D are significantly associated with a decreased risk for CRC, as well as improved survival of patients already diagnosed with CRC. “Our previous work has also demonstrated that metastatic colorectal cancer

patients are commonly deficient in vitamin D, and this is concerning if we believe that higher levels may be beneficial,” said Dr Ng.

“

Metastatic colorectal cancer patients are commonly deficient in vitamin D, and this is concerning if we believe that higher levels may be beneficial.

”

—KIMMIE NG, MD, MPH

She and colleagues measured 25[OH]D­ levels in 1043 patients with newly diagnosed disease enrolled in the CALGB 80405 clinical trial, which compared 3 frontline treatments—chemotherapy

Continued from the cover

plus bevacizumab, cetuximab, or beva­ ciz­umab and cetuximab.

The median plasma vitamin D level for the entire group was 17.2 ng/mL, which constitutes deficiency, said Dr Ng. Vitamin D levels <20 ng/mL constitutes a deficiency. Patients with lowest vitamin D levels had a median level of 8.0 ng/mL compared with a median of 27.5 ng/mL for those with the highest levels. Very few patients reported taking supplemental vitamin D. Patients with the highest level of vitamin D lived significantly longer than those with the lowest level (median, 32.6 vs 24.5 months). The hazard ratio (HR) for the median OS in the highest versus lowest levels of vitamin D was 0.65 (P = .001).

Higher vitamin D levels were also associated with better progression-free survival: 12.2 months with the highest levels versus 10.1 months with the lowest levels (HR, 0.79; P = .01).

Lifestyle factors were controlled for in the analysis. “Even adjustment for obesity or lower physical activity did not change our results,” said Dr Ng. “We also tried to address this issue by excluding patients who died very quickly after their vitamin D blood levels were measured. Those tend to be patients with the most aggressive disease and who tend to do more poorly. Even after excluding that group of patients, the persistence ­of the significant relationship between higher [vitamin D] levels and survival was still seen,” she said.

Randomized clinical trials are needed to establish causality, and are currently ongoing, she said. n

PD-L1 Inhibitor Pembrolizumab Produces... fector T-cell function, which dampens the immune response and leads to neoplastic growth.” The expression of PD-L1 in tumors correlates with poor prognosis.

Pembrolizumab is a selective, humanized monoclonal antibody designed to block the interaction between PD-1 and its ligands (L1 and L2), thereby reactivating the immune system to eradicate the host tumor.

The use of pembrolizumab 10 mg/kg monotherapy every 2 weeks was evaluated in KEYNOTE-012 in patients with recurrent or metastatic stomach or gastroesophageal cancer with PD-L1 expression. Of the 162 evaluable patients, 65 (40%) had PD-L1 expression. Of these 65 patients, 39 were enrolled in the trial and received pembrolizumab intravenously.

Overall, 51.3% of the patients had

8

previous gastrectomy; 66.7% received ≥2 previous therapies for advanced disease.

After a median follow-up of 8.8 months, “pembrolizumab demonstrated strong evidence of anticancer activity,” said Dr Muro. The response rate was 22.2% by central review, or 33.3% by investigator review; all were partial responses. Stable disease was recorded in 13.9% of patients by central review (12.8% by investigator).

“Overall, 53.1% experienced a decrease from baseline in the size of their target lesions,” Dr Muro said.

The median time to response was 8 weeks, and the median duration of response was 24 weeks. “Response to pembrolizumab was durable, with 6 of the 8 responders maintaining response,” said Dr Muro.

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The 6-month rate of progression-free survival (PFS) was 24%, and the median PFS was 1.9 months. The overall survival (OS) rate at 6 months was 69%, and

“

Pembrolizumab demonstrated strong evidence of anticancer activity….53.1% experienced a decrease from baseline in the size of their target lesions… with 6 of the 8 responders maintaining response.

”

—KEI MURO, MD

Continued from page 7

the median OS had not been reached at the time of the analysis.

“There was a trend toward an association between higher levels of PD-L1 expression and response, PFS, and OS,” Dr Muro said. “Further analysis of these preliminary data is ongoing to help determine the relationship between PD-L1 expression and antitumor activity in gastric cancer.”

The safety profile of pembrolizumab was acceptable. Most adverse events were grade 1 or 2. The most common adverse events were fatigue (17.9%), decreased appetite (12.8%), hypothyroidism (12.8%), and arthralgia (10.3%). Four patients had severe adverse events (peripheral sensory neuropathy, fatigue, decreased appetite, and pneumonitis); 1 patient died from treatment-associated hypoxia. n

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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.

FDA News Opdivo Second Immuno­ therapy... Continued from page 3

The most common side effects of the drug were rash, itching, cough, upper respiratory tract infections, and edema.

The most serious side effects were severe immune-mediated effects involving the lung, colon, liver, kidneys, and hormone-­producing glands. (December 22, 2014)

Lynparza, First PARP Inhibitor Approved with a Companion Diagnostic for Ovarian Cancer

The FDA granted accelerated approval to olaparib (Lynparza; AstraZeneca), a poly ADP-ribose polymerase (PARP) inhibitor, for the treatment of women with advanced ovarian cancer associated with BRCA gene mutations. Olaparib is in-

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.

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tended for use in women with heavily pretreated ovarian cancer that is associated with BRCA gene mutations.

“Today’s approval constitutes the first of a new class of drugs for treating ovarian cancer,” Dr Pazdur said. “Lynparza is approved for patients with specific abnormalities in the BRCA gene and is an example of how a greater understanding of the underlying mechanisms of disease can lead to

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. ©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.

FEBRUARY 2015

targeted, more personalized treatment.”

The efficacy of olaparib was demonstrated in a clinical study of 137 patients with ovarian cancer and a BRCA mutation. The objective response rate was 34%, lasting for an average of 7.9 months.

Common side effects of olaparib included nausea, fatigue, vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis, cough, arthralgia, musculoskeletal pain, myalgia, back pain, dermatitis, and abdominal pain. Serious side effects included the development of myelo­ dysplastic syndrome, acute myeloid leukemia, and lung inflammation. The most common laboratory abnormalities were increased creatinine, increased mean corpuscular volume elevation, decreased hemoglobin, decreased lymphocytes and neutrophils, and decreased platelet levels.

In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11 to 2 against the accelerated approval of olaparib as maintenance therapy, recommending that the manufacturer provides further data regarding efficacy.

The company then submitted additional information supporting the use of olaparib for patients with ovarian cancer and BRCA mutations who have received ≥3 chemotherapy treatments.

The FDA has approved this new indication for ovarian cancer under its accelerated approval program, and this new application was reviewed under the FDA’s priority review program.

Furthermore, olaparib was approved together with a genetic laboratory developed test (LDT) called BRACAnalysis CDx (Myriad Genetic Laboratories), a companion diagnostic test that is designed to detect the presence of BRCA1 and BRCA2 mutations in blood samples of patients with ovarian cancer. If the test is positive for BRCA1 or BRCA2 mutations, the patient is then a candidate for treatment with olaparib. Women with mutations in the BRCA genes are at an increased risk for ovarian cancer.

The FDA evaluated BRACAnalysis CDx’s safety and efficacy under the agency’s premarket approval pathway used for high-risk medical devices. The new test is approved specifically to identify patients with advanced ovarian cancer who may be candidates for treatment with olaparib.

“The approval of safe and effective companion diagnostic tests and drugs continues to be important developments in oncology,” said Alberto Gutierrez, PhD, Director of the FDA’s Office of ­­­­In Vitro Diagnostics and Radiological Health. “We are very excited that the BRACAnalysis CDx is the FDA’s first approval of an LDT under a premarket approval application and is the first approval of an LDT companion diagnostic.

(December 19, 2014) n

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GI Cancers Symposium

FOLFOXIRI Regimen a New Upfront Option for Some Patients with Metastatic Colorectal Cancer

By Wayne Kuznar

By the Numbers 136,830

—Estimated new cases of colorectal cancer (CRC) in 2014

50,310—Estimated deaths from CRC in 2014

89.8%—5-year survival rate for localized disease

4.7%—Of US population diagnosed with CRC

3.1%—Annual reduction in new CRC cases over the past 10 years Source: National Cancer Institute.

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Study Details

In the TRIBE trial, 508 patients with metastatic CRC were random-

more than double in the FOLFOXIRI arm versus the FOLFIRI arm (24.9% vs 12.4%, respectively).

ment, even for patients with a rather unfavorable prognosis. This is a remarkable step forward in the treatment of this disease.”

In addition, the FOLFOXIRI regimen conferred progression-free survival (PFS) advantage compared with FOLFIRI—12.3 versus 9.7 months, respectively (P = .006). All subgroups analyzed showed improvements in OS and PFS with FOLFOXIRI. The FOLFOXIRI regimen also increased the risk for grade 3/4 diarrhea, mucositis, neuropathy, and neutropenia compared with FOLFIRI. There was no increased incidence of serious adverse events, however.

Significantly Improved Survival

Photo by © ASCO/Todd Buchanan 2015

San Francisco, CA—Upfront treatment with the FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) regimen plus bevacizumab significantly improves survival compared with the FOLFIRI (fluorouracil, leucovorin, and irinotecan) regimen plus bevacizumab in patients with metastatic colorectal cancer (CRC), said Chiara Cremolini, MD, Medical Oncologist, Tuscan Tumor Institute, Pisa, Italy, at the 2015 ASCO Gastrointestinal Cancers Sym­ ­­posium. However, this regimen is not appropriate for older patients aged >75 years.

Updated results from the phase 3 TRIBE trial demonstrated that bevaciz­ umab plus the FOLFOXIRI regimen extended overall survival (OS) by approximately 4 months in patients with metastatic CRC, said Dr Cremolini. The results were also published late last year (Loupakis F, et al. N Engl J Med. 2014;371:16091618).

The FOLFOXIRI regimen adds oxaliplatin (Eloxatin) to the FOLFIRI regimen, which can also result in more adverse effects. A smaller phase 3 trial, the GONO trial, had already shown that FOLFOXIRI alone improved OS compared with FOLFIRI in the frontline setting for patients with metastatic CRC. The data presented at the meeting confirmed the superior efficacy of FOLFOXIRI compared with FOLFIRI.

“

FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment of metastatic colorectal cancer. This new approach offers a substantial survival improvement, even for patients with a rather unfavorable prognosis. This is a remarkable step forward in the treatment of this disease.

ized to up to 6 months (12 cycles) ­­of induction therapy with FOLFIRI plus bevacizumab or to FOLFOXIRI plus bevacizumab. Induction treatment was followed by maintenance with bevacizumab in combination with 5-fluorouracil until disease ­progression.

The proportion of patients in each group who were able to undergo radical resection after induction was similar—15% in the FOLFOXIRI group and 12% in the FOLFIRI group.

After a median follow-up of 48.1 months, the median OS was 29.8 months in the FOLFOXIRI plus bevaciz­umab arm compared with 25.8 months in the FOLFIRI plus bevacizumab arm (P = .03).

The benefit of FOLFOXIRI increased over time, said Dr Cremolini.

The estimated 5-year OS rate was

”

—CHIARA CREMOLINI, MD

Based on these data, “FOLFOXIRI plus bevacizumab represents a valuable option for the upfront treatment

Although the intensive FOLFOXIRI regimen was well-tolerated in this study, it is not a regimen for every patient, emphasized Dr Cremolini. It should not be administered to patients aged >75 years or those aged 70 to 75 years with poor health status.

“We have to consider that 90% of the patients in this study were asymptomatic at the time of enrollment, and patients over the age of 75 were not eligible. The regimen is not for everyone, but for the right patients, this is one of the most active regimens, with an impressive almost 25% difference in survival rate at 5 years,” commented Smitha S. Krishnamurthi, MD, of University Hospitals Case Medical Center, Cleveland, OH. A follow-up phase 3 trial is testing first-line FOLFOXIRI plus bevacizumab followed by either reintroduction of FOLFOXIRI plus bevacizumab at

“

The regimen is not for everyone, but for the right patients, this is one of the most active regimens, with an impressive almost 25% difference in survival rate at 5 years.

”

—SMITHA S. KRISHNAMURTHI, MD

of metastatic colorectal cancer,” Dr Cremolini said. “This new approach offers a substantial survival improveFEBRUARY 2015

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disease progression or followed by FOLFIRI plus bevacizumab in patients with progressing metastatic CRC. n

www.ValueBasedCancerCare.com

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Emerging Therapies

Promising Therapies in Development for...

Hodgkin Lymphoma

Nivolumab and pembrolizumab, the 2 most recently approved programmed-­ cell death receptor (PD)-1 inhibitors for patients with melanoma, show promise in patients with Hodgkin lymphoma. Although the results for these 2 PD-1 inhibitors came from small, phase 1 studies, they received much press coverage and drew many attendees at the meeting. The overall response rate (ORR) was 87% for nivolumab and 66% for pembrolizumab in patients with Hodg­kin lymphoma that has progressed despite the use of standard therapies.

MK2206, an oral AKT inhibitor, induced response in patients with classic Hodgkin lymphoma and indolent lymphoma; however, its single-agent activity was low in patients with diffuse large B-cell lymphoma (DLBCL), T-cell lymphoma, or mantle-cell lymphoma in a phase 2 study of 50 patients with refrac­tory disease. MK2206 is the first oral n ­on-ATP competitive allosteric inhibitor of the AKT pathway 1, 2, and 3 that is currently in clinical development. Objective responses were observed in 14% of patients (20% among patients with Hodgkin lymphoma), and 40% of patients showed some tumor reduction. The median response duration was approximately 6 months.

MK2206 was well-­tolerated, with rash being the main toxicity.

Non-Hodgkin Lymphoma

Polatuzumab vedotin and pinatuz­ umab vedotin, 2 antibody-drug conjugates, showed activity and tolerability in a phase 2 randomized ROMULUS trial of patients with relapsed or refractory non-Hodgkin lymphoma (NHL).

Patients received polatuzumab or pina­ tuzumab, plus rituximab. Both regimens were generally well-tolerated, with similar toxicities, including neutropenia, peripheral neuropathy, and diarrhea. In patients with DLBCL, the ORR was 56% with polatuzumab and 57% with pinatuzumab (plus rituximab), and the complete response (CR) was 15% and 24%, respectively.

MOR00208, an Fc-engineered humanized anti-CD19 antibody, was evaluated as a single agent in a phase 2a study of patients with relapsed or refractory B-cell NHL. Among the first 51 patients in the trial, the response rate was 24%. The drug was well-tolerated, without significant toxicity from the infusion. Accrual to the study is continuing.

Alisertib (MLN8237), an oral Aurora A kinase inhibitor, was investigated alone and in combination with ritux-

12

imab in a phase 2 study of 11 patients with high-risk relapsed or refractory B-cell NHL. Alisertib was well-tolerated, with 1 patient responding and able to proceed to transplant. Enrollment is continuing.

Copanlisib, a novel PI3K inhibitor, was explored in 33 patients with indolent NHL or with chronic lymphocytic leukemia (CLL). The ORR in both patient populations was 44%; when divided by disease state, the ORR was 48% in patients with NHL and 38% in patients with CLL. The combined median duration of response was 390 days, and the median progression-free survival was 288 days. Grade ≥3 events included hypertension (48%), neutropenia (33%), hyperglycemia (30%), anemia (15%), and thrombocytopenia (15%). A phase 2b study in patients with relapsed or refractory indolent NHL has been initiated.

Mogamulizumab, a humanized monoclonal antibody targeting the CC chemokine receptor 4 (CCR4), achieved stable disease or better in 46% of patients (11% responses) with peripheral T-cell lymphoma, with an acceptable safety profile, in a multicenter phase 2 study of heavily pretreated relapsed or refractory patients.

The CCR4 is expressed on 30% to 65% of tumor cells in patients with peripheral T-cell lymphoma, whose prognosis is generally poor. Mogamulizumab binds to CCR4. The drug is already approved outside of the United States for this patient population.

Multiple Myeloma

Monoclonal antibodies may be poised to be the “rituximab of myeloma,” experts predict. Elotuzumab (which received breakthrough therapy designation for myeloma in May 2014), in combination with lenalidomide and dexamethasone, induced an 84% ORR in a phase 1b/2 study of patients with relapsed or refractory myeloma.

The data were less mature but were at least as impressive for the 2 anti-CD38 antibodies, SAR650984 and daratumumab. SAR650984 yielded a 63% response rate in optimally treated patients with myeloma. Daratumumab (which received a breakthrough therapy designation for myeloma in 2013) showed impressive results in combination with standard regimens, yielding a 100% response rate in some cohorts.

Ricolinostat (ACY-1215), a selective oral histone deacetylase (HDAC) 6 inhibitor, is in early-phase studies but has shown promising results. In a phase 1b study of 42 patients with relapsed or refractory myeloma, ricolinostat, in

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Continued from the cover

combination with bortezomib and dexamethasone, was well-tolerated, with diarrhea as the only dose-related side effect. The response rate was 44%, and only 3 patients showed progressive disease. Responses were also seen in bor­tezomib-refractory patients.

Panobinostat, another HDAC inhibitor, is in phase 3 development. In a study of panobinostat in combination with bortezomib, lenalidomide, and dexamethasone, 31 newly diagnosed patients with myeloma showed an ORR of 95%, including 50% CRs or nearCRs. The regimen was well-tolerated, with limited grade 3 or 4 toxicity.

Ixazomib and oprozomib, 2 novel oral proteasome inhibitors, have shown promising results in myeloma. Long-term data were presented for ixazomib; oprozo­ mib is in earlier-stage development.

Dr Stein called the 56% response rate “a very big deal” in this hard-to-treat population. The targeting of a specific genotype will increase efficacy, he said, and potentially “extend life spans and minimize toxicity.”

Leukemia Chronic Lymphocytic Leukemia

Olaptesed pegol, a novel L-stereoisomer RNA aptamer that binds and neutralizes CXCL12/SDF-1, produced an 82% ORR when combined with bendamustine and rituximab in an open-label study of 28 patients with relapsed or refractory CLL. The ORR of bendamustine plus rituximab without olaptesed has historically been 59%. Olaptesed in combination with bendamustine and rituximab was safe and well-tolerated.

XmAb5574, a novel humanized immunoglobulin G1 CD19 monoclonal antibody with an engineered Fc region to enhance Fc gamma receptor binding affinity, showed promising preliminary efficacy in high-risk patients with heavily pretreated CLL. Responses were reported in 67% of 16 patients who received XmAb5574. The results with this drug compare favorably with single-agent CD20 antibodies in relapsed CLL. Current studies are investigating XmAb5574 in combination with other agents.

Another anti-CD19 antibody, MEDI-551, was evaluated in combination with bendamustine versus ri­

tuximab and bendamustine in 147 patients with relapsed or refractory CLL in a phase 2 trial that was presented by Douglas E. Gladstone, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. The preliminary results showed clinical activity, with comparable safety observed between the MEDI-551 and rituximab arms. The investigators may also have identified a biomarker of response— low baseline levels of a microRNA signature.

Acute Myeloid Leukemia

ABT-199, an oral selective BCL-2 inhibitor, showed considerable clinical activity in patients with poor-prognosis acute myeloid leukemia (AML).

ABT-199 selectively binds to and is inhibiting the BCL-2, a key regulator of apoptosis.

AG-221, an oral selective inhibitor of the IDH2 gene, showed preliminary efficacy in patients with IDH2-positive AML or with myelodysplastic syndrome (MDS). AG-221 was used in 45 patients with IDH2-mutated AML or MDS at escalating doses. Responses were seen in 56% of patients, including 15 CRs and 10 partial responses. Responses were durable, with CRs lasting up to 8 cycles. Many patients continue to receive AG-221, reported Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center, New York. Dr Stein called the 56% response rate “a very big deal” in this hard-to-treat population. The targeting of a specific genotype will increase efficacy, he said, and potentially “extend life spans and minimize toxicity.”

Pracinostat, an investigational oral HDAC inhibitor, resulted in a rate of 45% for the composite end point of CR and CR with incomplete blood count recovery and morphologic leukemia-free status when combined with azacitadine in a phase 2 trial of 33 patients with AML and intermediate- or unfavorable-risk cytogenetics.

Vosaroxin, a first-in-class anticancer quinolone derivative, in combination with cytarabine improved the median overall survival compared with placebo plus cytarabine (7.5 months vs 6.1 months, respectively) in a phase 3 study of patients with relapsed or refractory AML.

Acute Lymphocytic Leukemia

CTL019, a chimeric antigen receptor targeting CD19, achieved durable remission in children with relapsed or refractory acute lymphocytic leukemia who were given T-cells engineered with CTL019. n

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VBCC Perspective

The Imperative to Discuss Cost of Care with Patients with Cancer

By Michael Kolodziej, MD, FACP National Medical Director for Oncology Solutions, Aetna

I

grew up in a lower middle class household. My dad was an insurance salesman, and we needed to live within a budget. The thought that we might buy something without considering the cost was unfathomable.

As a doctor now, I wonder how we expect our patients to make health-

and/or coinsurance in return for healthcare services and treatments.

Medicare beneficiaries have been responsible for a 20% coinsurance for Medicare Part B benefits. Unless the cost of care became so great that it approached the maximum benefit, few people paid attention.

Healthcare insurance is changing. The financial stability of families, employers, and the government is impacted by escalating, unsustainable healthcare costs. The patient has much more financial responsibility and risk in the new healthcare system. care purchases without this information. Why do we need to even justify discussing cost with patients?

For a long time, patients have been insulated from the total cost of healthcare. Employer-subsidized health insurance, which came into its own after World War II, has been the predominant mechanism by which working-age Americans obtain healthcare.

Employers historically paid the majority of the premium costs. Patients historically paid a portion of the premium, a modest deductible, and a copay

By the Numbers $124.6 billion— Estimated US cancer care expenditures in 2010

$134.8 billion—

Mortality cost from the approximate 600,000 cancer deaths in 2005

$158 billion

— Projected cost of cancer care by 2020 Source: National Cancer Institute.

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To make things more confusing, healthcare continues to be billed separately by each provider in a byzantine array of charges and discounts. An explanation-of-benefits form may outline the majority of the costs, although most people cannot really understand these documents.

But healthcare insurance is changing. The financial stability of families, employers, and the government is impacted by escalating, unsustainable healthcare costs. The patient has much more financial responsibility and risk in the new healthcare system.

Many employers who remain committed to providing healthcare benefits have shifted financial responsibility to their employees. More of the premium cost is now borne by the employee. In addition, employees are responsible for more out-of-pocket expenses through higher deductibles, coinsurance, and copays.

Health plans have aggressively implemented solutions to help control these rising costs, such as creating networks of high-value providers and tiering pharmacy benefits. Medicare is also exploring novel delivery methods to increase value. The emergence of health exchanges has also aided a new influx of patients with insurance benefit designs that build on highly man-

aged care to optimize value and benefit. Many of the plans include high deductibles and high copays. What does all of this mean? Patients are feeling it in the pocketbook.

Patients with cancer are a special high-cost group. Active treatment is expensive. The deductible is almost always met in the first month of therapy. Coinsurance of many high-cost services requires that patients pay more out of pocket. Specialty pharmacy is especially expensive. Most patients are totally unprepared for these expenses, and many cannot afford them. Medical costs are now the most common cause of personal bankruptcy.

Growing evidence (and common sense) suggests that concerns regarding cost of care have a significant impact on patient quality of life. This is such a widely recognized problem that it has even earned a name: “financial toxicity.”

In general, oncologists have been ill-equipped to manage this type of toxicity. Most physicians have a fundamental understanding of health insurance, but they do not always understand the difference between Medicare Part A, B, C, and D, or the relationship among patients’ deductibles, coinsurance, and copays. And in oncology, they almost never really know the cost of the treatment plan they recommend. They may know in a qualitative way what is expensive, and what is really expensive, but when the incredible variety of insurance benefit designs is added, they are incapable of providing even a ballpark quantitative estimate.

Many practices offer financial counseling services, which do allow patients the opportunity to review outof-pocket costs after a plan has been formulated. But only in cases where patients really cannot afford the expense is this plan changed. After all, patients trust that the doctor recommended the best personalized plan.

This view of the oncology world is wrong. There are many factors that contribute to a particular treatment plan, including efficacy and toxicity.

Cost should be one of them. This is especially true when there are a number of equivalent options. Honesty and a fair presentation of efficacy, toxicity, as well as cost is the moral responsibility of the physician.

FEBRUARY 2015

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Several immediate actions will help to achieve evaluation and transparency of costs. First, physicians need to have access to the cost of care at the point of care. Several electronic medical record systems and clinical pathway tools are offering this information now. Second, physicians need to be educated about the “value” of the many options available to patients. In other words, they need to understand the quality of care provided for the costs. The National Comprehensive Cancer Network and the American Society of Clinical Oncology have projects to objectively present this information to oncologists.

Finally, medical students, residents, and fellows need education in the economics of healthcare. Less than 15% of oncologists will pursue academic careers, and the rest will be directly impacted by how healthcare is paid for in this country. Doctors are responsi-

Attention to cost is a patient-centric approach.

Patients must plan for out-of-pocket costs. Cost and quality should be discussed transparently with patients as a component of shared decision-making.

Ignorance on the part of the physician is not an excuse. ble for discussing how healthcare decisions affect the whole patient, and our next generation of physicians should learn this at the same time they learn to read electrocardiograms.

Attention to cost is a patient-centric approach. Patients must plan for out-of-pocket costs. Cost and quality should be discussed transparently with patients as a component of shared decision-making. Ignorance on the part of the physician is not an excuse.

When patients can make decisions that are informed by all aspects of their care—from risks to benefits to costs—they will have more confidence in their path and with the physician guiding their care. n

www.ValueBasedCancerCare.com

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Breast Cancer Symposium

Ovarian Function Suppression Reduces Recurrence...

“

In my opinion, this trial is practicechanging. I now know how to advise a woman under age 35 with HR-positive breast cancer that is higher risk. I also will feel more comfortable with tamoxifen alone in a woman age 46 or older with small, low-risk breast cancer.

Photo by © SABCS/Scott Morgan 2014

”

—PRUDENCE FRANCIS, MD, MBBS, BMEDSC

tamoxifen alone or exemestane plus OFS. Women randomized to OFS could choose monthly injections of triptorelin (a gonadotropin-releasing hormone agonist), surgical removal of the ovaries, or radiation; 81% received triptorelin.

The 3 arms were stratified according to receipt of previous chemotherapy.

Approximately half of the women (53%) received chemotherapy, and on average, were younger (average age, 40 years) with larger tumors and node-positive. The remaining women (47%) did not need chemotherapy, because they had low-risk tumors.

In the primary analysis at a median follow-up of 5.6 years, no overall benefit was observed for adding OFS to tamoxifen versus tamoxifen alone: the 5-year event-free survival for tamoxifen was 84.5% versus 86.6% for the combination of tamoxifen plus OFS.

Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

should be used in treatment discussions with patients.

The SOFT study showed that tamoxifen plus OFS reduced the risk of recurrence in younger premenopausal women with hormone receptor (HR)-positive early breast cancer at high enough risk to receive previous chemotherapy, and exemestane plus OFS was even more effective in reducing risk in this cohort of women.

Tamoxifen alone was sufficient for risk reduction in premenopausal women with lower-risk breast cancer who did not receive previous chemotherapy.

A unique factor in the study design makes the results more compelling than previous studies. The SOFT trial included only women who were premenopausal or who regained menses after chemotherapy, whereas other trials included younger women based on age alone, not menopausal status.

“In my opinion, this trial is practice-changing. I now know how to advise a woman under age 35 with HR-positive breast cancer that is higher risk. I also will feel more comfortable with tamoxifen alone in a woman age 46 or older with small, low-risk breast cancer,” stated lead investigator Prudence Francis, MD, MBBS, BMedSc, Head of Breast Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

The investigators randomized 3047 premenopausal women with HR-positive breast cancer to 5 years of treatment with tamoxifen plus OFS versus

“

This is a solid study.

The fact that only premenopausal women were included makes these findings convincing.

”

—CARLOS L. ARTEAGA, MD

Continued from the cover

However, in the cohort that remained premenopausal after chemotherapy, OFS added to tamoxifen achieved a 22% reduction of recurrence risk versus tamoxifen alone. In a secondary analysis, the combination of exemestane plus OFS achieved a 35% risk reduction for recurrence versus tamoxifen alone.

The 5-year event-free survival was 78% for tamoxifen alone, 82.5% for tamoxifen plus OFS, and 85.7% for exemestane plus OFS. “In women under age 35, 1 in 3 women on tamoxifen alone—the standard of care—had a further recurrence within 5 years compared with 1 in 6 for exemestane plus OFS,” Dr Francis stated.

The cohort of women who did not receive chemotherapy (average age, ­ 46 years) had excellent outcomes with all 3 treatments—the 5-year eventfree survival was 95.8% with tamoxifen alone, 95.1% with tamoxifen plus OFS, and 97.1% with exemestane plus OFS. “In this older group of women who did not have chemotherapy, there is no reason to add OFS. The average age is 46 years, and some of these women will go into menopause soon,” Dr Francis said.

“This is a solid study. The fact that only premenopausal women were included makes these findings convincing,” stated the American Association for Cancer Research President Carlos L. Arteaga, MD, Leader, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville. n

Oncotype DX Clinically Validated for Risk Assessment in Patients with Ductal Carcinoma in Situ

By Phoebe Starr

San Antonio, TX—Ductal carcinoma in situ (DCIS) in itself is not dangerous, but some patients will eventually develop invasive breast cancer. Until recently, there was no way to predict which patients with DCIS were at high risk and required more aggressive treatment. Thus, many patients have been overtreated or undertreated.

Oncotype DX DCIS is a predictive tool that can be used to inform appro­ priate treatment selection according to risk level. This assay was validated

14

“

­ ith DCIS in a large population-­ w based, real-world study presented at Our results confirm the 2014 San Antonio Breast Cancer the ECOG E5914 Symposium.

A previous study with more narrow results in a more diverse selection criteria validated Oncotype population.

DX DCIS. “Our results confirm the —EILEEN RAKOVITCH, MD, MSC ECOG E5914 results in a more diverse population,” explained lead investigator Eileen Rakovitch, MD, MSc, of the Sunnybrook Health Sciences Cen“This is the first biomarker assay to tre, University of Toronto, Ontario, provide individualized estimates of the Canada. risk of local recurrence in women treat-

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”

ed by breast conservation alone. The DCIS score can be used for discussions between patients and physicians to decide upon a course of further treatment.

Hopefully, this will improve individualized management of DCIS and reduce overtreatment of women at low risk of recurrence and reduce undertreatment of women at higher risk of recurrence,” Dr Rakovitch stated.

The Assay

Oncotype DX DCIS is a 12-panel Continued on page 15

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Breast Cancer Symposium

Longer Neoadjuvant Therapy Boosts Response in HER2-Positive Breast Cancer

By Charles Bankhead

with stage II/III HER2-positive breast cancer, 12 weeks of neoadjuvant therapy with lapatinib and trastuzumab resulted

Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

San Antonio, TX—Doubling the duration of neoadjuvant treatment with dual anti-HER2 therapy more than doubled the pathologic complete response (pCR) rate in patients with early HER2-positive breast cancer, which nonetheless fell short of the improvement goal, results of a randomized trial showed.

The pCR rate increased from 12% with 12 weeks of lapatinib and trastuzu­ mab to 28% by 24 weeks before surgery, said Mothaffar F. Rimawi, MD, a medical oncologist at Baylor College of Medicine, Houston, at the 2014 San Antonio Breast Cancer Symposium.

Patients with hormone receptor (HR)-­ positive tumors benefited the most from prolonged neoadjuvant therapy: the pCR rate was almost 4 times greater in patients who received dual anti-HER2 therapy for 24 weeks plus endocrine therapy.

“This is the first trial to show that longer treatment with dual anti-HER2 therapy, in combination with endocrine therapy and without chemotherapy, leads to a meaningful increase in pathologic complete response rate in estrogen receptor [ER]-positive, HER2-­ positive breast cancer,” said Dr Rimawi.

“Targeted therapy without chemotherapy may offer a promising treatment strategy to patients with ER-positive/ HER2-positive breast cancer and warrants further study.”

In a previous trial involving women

in a pCR rate of 27%. “On the basis of the earlier results, we hypothesized that in HER2-positive breast cancer, longer treatment with anti-HER2 therapy and endocrine therapy, if tumors are also ER-positive, will result in a higher pCR rate,” said Dr Rimawi.

Study Results

The investigators randomized patients (1:2) with early-stage HER2-positive

breast cancer to receive 12 or 24 weeks of neoadjuvant therapy with lapatinib and trastuzumab. Women with HR-pos-

“

This is the first trial to show that longer treatment with dual anti-HER2 therapy, in combination with endocrine therapy and without chemotherapy, leads to a meaningful increase in pathologic complete response rate in estrogen receptor–positive, HER2positive breast cancer.

”

—MOTHAFFAR F. RIMAWI, MD

itive breast cancer also received endocrine therapy.

All patients had tumor biopsies at baseline and after 12 weeks of neoadjuvant therapy, and the group randomized to 24 weeks of neoadjuvant treatment had a third biopsy at the completion of therapy. The primary end point was pCR in the breast.

Data analysis included 94 randomized patients (median age, 51 years), with an

gene test with a scoring system that categorizes cancers as low-, intermediate-, or high-risk for local recurrence over 10 years after treatment with breast-conservation surgery alone.

Oncotype DX DCIS categorizes results in a score ranging from 0 to 100; a DCIS score of <39 indicates low risk for recurrence, 39 to 54 indicates intermediate risk, and ≥55 indicates high risk.

The study screened 1658 women diagnosed with pure DCIS and treated with breast-conservation surgery alone in Ontario, Canada; tissue samples for Oncotype DX DCIS analysis were available for 858 women, and 257 ­were excluded.

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Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

Oncotype DX Clinically Validated for Risk...

Continued from page 14

“

This is the first biomarker assay to provide individualized estimates of the risk of local recurrence in women treated by breast conservation alone. The DCIS score can be used for discussions between patients and physicians to decide upon a course of further treatment.

”

—EILEEN RAKOVITCH, MD, MSC

FEBRUARY 2015

equal number of women aged >50 and ≤50 years. Overall, 55% of the patients were postmenopausal. Approximately 40% of the patients had tumor size >5 cm, 70% had clinical stage II disease, 71% had histologic grade 3 tumors, and 66% had HR-positive tumors.

The neoadjuvant regimen was well-­ tolerated, regardless of duration. In the 12-week arm, grade 3 toxicity consisted of 1 case each of anemia and kidney stone. Among patients who received treatment for 24 weeks, grade 3 toxicity consisted of elevated liver function tests in 5 patients and diarrhea and mucositis in 1 patient each. No grade 4 toxicity occurred.

In the group that received 12 weeks of neoadjuvant therapy, the 4 pCRs consisted of 2 each in patients with HR-­ positive and HR-negative tumors.

Longer-­duration therapy led to pCR in 13 (33%) patients with HR-positive tumors and 4 (18%) pCRs in the HR-­ negative subgroup.

Closer inspection of the response data showed that 35% of patients with HR-­ positive tumors in the 12-week group had residual tumor burden of ≤1 cm compared with 13% of patients who received 24 weeks of neoadjuvant therapy.

This supports the position that the higher pCR rate with longer therapy results from the conversion of more tumors from minimal residual burden to pCR, said Dr Rimawi. n

I

of 9.4 years, 100 cases of local recurrence were identified (57, invasive; ­­44, DCIS).

Applying the DCIS DX score retrospectively, the 10-year local recurrence risk was estimated at 12.7% for low-risk patients, 27.8% for intermediate-risk patients, and 33% for high-risk patients. The score also predicted invasive recurrence and DCIS recurrence.

“The Oncotype DX DCIS improves risk stratification and provides individualized estimates of risk that will help clinicians and patients better understand risk of recurrence, and individuals weigh their own risk in ­ making treatment decisions,” Dr ­Rakovitch said.

Oncotype DX DCIS is reimbursed by Medicare and by some private insurers. n

www.ValueBasedCancerCare.com

15

Breast Cancer Symposium

Estrogen Receptor Antagonist Fulvestrant Tops Aromatase Inhibitor Anastrozole for ER-Positive Breast Cancer

By Charles Bankhead

124.6

—New cases of breast cancer per 100,000 women annually

61 years—Median age at diagnosis

12.3%—US women diagnosed

2.89 million—Women living with breast cancer in the United States

89.2%—Patients with

breast cancer surviving ≥5 years

22.2—Annual deaths per 100,000 women

68 years—Median age at death

Source: National Cancer Institute.

16

The median survival with fulvestrant is the highest yet reported from phase 3 randomized studies of first-line endocrine therapy in advanced This is breast cancer. the second randomized controlled trial where fulvestrant has shown a survival advantage over the control arm.

“

”

—JOHN F. R. ROBERTSON, MD

son. “In this trial, the overall survival benefit of fulvestrant 500 mg over anastrozole was consistent across predefined groups. We observed no new safety findings for either fulvestrant 500 mg or anastrozole.”

The primary end point analysis showed a benefit of 72.5% with fulvestrant compared with 67.0% for the anastrozole arm, a 30% improvement in the odds ratio; however, this difference was not significant (P = .386).

The results add another chapter to a growing volume of evidence suggesting that fulvestrant has an edge over other endocrine therapies for breast cancer.

Previous randomized trials demonstrated numerically higher progression-free survival with 250 mg of fulvestrant versus anastrozole as second-line therapy and versus tamoxifen in first-line. Subsequently, a comparison of 500 mg and 250 mg of fulvestrant as first-line endocrine treatment showed a significant advantage for the higher dose.

Study Details

At the meeting, Dr Robertson reported findings of a phase 2 trial comparing ful-

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vestrant 500 mg and anastrozole 1 mg.

Patients were randomized to the therapies and continued treatment until disease progression. Follow-up included prespecified analysis of time to progression (TTP) and OS.

FEBRUARY 2015

Data analysis included 205 randomized patients. In addition to the improvement in OS with fulvestrant, analysis of TTP

Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

By the Numbers

“This is the second randomized controlled trial where fulvestrant has shown a survival advantage over the control arm, the first being a phase 3 trial that compared 250 mg of fulvestrant with anastrozole,” said Dr Robert-

Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

San Antonio, TX—First-line treatment with the synthetic estrogen receptor antagonist fulvestrant led to significant improvement in overall survival (OS) versus anastrozole in patients with advanced, hormone receptor–positive breast cancer, despite failing to meet the primary end point, analysis of a randomized trial showed.

Patients who received fulvestrant 500 mg had a median OS of 54.1 months compared with 48.4 months with anastrozole 1 mg. The median survival with fulvestrant is the highest yet reported from phase 3 randomized studies of first-line endocrine therapy in advanced breast cancer, said John F. R. Robertson, MD, Chairman of Academic Breast Surgery at City Hospital Nottingham and the University of Nottingham, Derby, United Kingdom, at the 2014 San Antonio Breast Cancer Symposium.

However, the data showed only a numerical (nonsignificant) improvement in clinical benefit rate, the primary end point.

“

I routinely use fulvestrant in my own practice, and I haven’t seen any problems with adherence or patient satisfaction.

”

—C. KENT OSBORNE, MD

at a glance ➤ Fulvestrant has the longest median survival in advanced breast cancer seen to date ➤ Median OS was 54.1 months with fulvestrant versus 48.4 months with anastrozole ➤ Adverse events frequency and severity did not differ much between the treatments ➤ For first-line treatment, 500-mg fulvestrant was significantly better than the 250-mg dose

showed a significant advantage in favor of the fulvestrant group—23.4 versus 13.1 months (P = .01).

Analysis of OS occurred after a median follow-up of 49.6 months in the fulvestrant arm and 42.5 months in the anastrozole arm. Dr Robertson noted that OS was not a prespecified end point in the initial trial design but was added as a protocol amendment after the trial had begun. Subgroup analysis showed a consistent improvement in survival with fulvestrant.

The results compared favorably with those of previous studies involving tamoxifen and aromatase inhibitors, which demonstrated a median OS of 30.0 to 43.3 months.

The frequency and severity of adverse events did not differ substantially between the groups.

The trial results support many oncologists’ belief that fulvestrant is superior to other available endocrine therapies, said C. Kent Osborne, MD, Professor of Medicine, Baylor College of Medicine, Houston, TX. Some clinicians have considered the subcutaneous route of administration a hindrance to uptake of and patient satisfaction with fulvestrant, but Dr Osborne said he has not seen evidence of an adverse impact.

“I routinely use fulvestrant in my own practice, and I haven’t seen any problems with adherence or patient satisfaction,” he said at a press briefing he moderated. n

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Breast Cancer Symposium

Mammographically Negative Dense Breasts Should Have Second Look with Ultrasound

By Phoebe Starr

“

The middle-of-theroad patient with dense breasts who is mammographically negative should be offered screening with ultrasound.

”

—JEAN M. WEIGERT, MD

In fact, 19 states have notification laws mandating that breast density be included in the mammography report, and 3 other states have laws similar to the one in Connecticut.

This new retrospective was based on more than 30,000 women undergoing yearly mammography over a 4-year period at 5 different sites in Connecticut.

Approximately 3000 women with dense breasts were mammographically negative and underwent subsequent screening with ultrasound.

Breast cancers were detected in 3.2 per 1000 ultrasound screens in each of the 4 years (approximately 11 cancers annualVOL. 6

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ly). These cancers, which were masked by dense breast tissue on mammograms, in-

B:7.625 in

cluded lobular invasive T:7.375 in breast cancers, ductal carcinoma in situ (DCIS), lobular

cancer plus DCIS, and atypical hyperplasia (a risk factor for breast cancer).

Continued on page 18

In mCRPC therapy…

Is there more to the story?

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.

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.

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.

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.

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. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page.

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

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Photo by © SABCS/MedMeetingImages/Todd Buchanan 2014

San Antonio, TX—Approximately 50% of all women who undergo mammography have dense breasts, and density by itself is a well-recognized risk factor for cancer. Women with dense breasts whose mammograms are negative should be offered ultrasound to improve detection of mammographically occult cancers, according to a study presented at the 2014 San Antonio Breast Cancer Symposium.

“The middle-of-the-road patient with dense breasts who is mammographically negative should be offered screening with ultrasound,” stated lead investigator Jean M. Weigert, MD, a radiologist at the Hospital of Central Connecticut, New Britain. “This is the law in the state of Connecticut,” Dr Weigert added.

Breast Cancer Symposium Mammographically Negative... Continued from page 17 “Most of them were estrogen receptor– positive small invasive tumors. These are exactly the types of cancers we look for on mammograms,” Dr Weigert noted.

The number of cancers detected over time remained stable each year, but the positive predictive value of ultrasound improved from 7.1% at year 1 to 18% at

year 4. Dr Weigert attributed this to a learning curve, where the radiologists and ultrasound technicians improved their ability and confidence level about lesions that did not require biopsies.

Unnecessary biopsies from false-­ positive results are the main drawbacks of ultrasound, so it is good news that the investigators were able to ­cut way down on that number with more experience.

Most of the same patients returned 4 years in a row, Dr Weigert said.

Critics may argue that ultrasound increases the cost of screening, and it is not always reimbursable. “There is no free lunch,” Dr Weigert said. “Finding a cancer that is easier to treat would certainlyB:7.625 havein the potential to reduce costs ofT:7.375 treating a more adin vanced cancer.”

In a discussion of this abstract, Jafi Lipson, MD, Assistant Professor of (General) Radiology, Stanford University Medical Center, CA, agreed that mammographically negative women with dense breasts should have a second screening, but she believes that digital tomosynthesis is far superior to ultrasound.

“Many more biopsies are generated by screening ultrasound than mammogra-

For men with mCRPC who progressed on ADT

In a clinical trial, patients had a median overall survival on ZYTIGA® (abiraterone acetate) of…*

More than 1,000 days.

And every day tells a story.

MEDIAN OVERALL SURVIVAL FOR ZYTIGA plus prednisone† 35.3 vsMONTHS 30.1 MONTHS with placebo plus prednisone (active compound).‡ IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone. ®

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

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IMPORTANT SAFETY INFORMATION (cont) 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.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). 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.

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. *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 overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2014 6/14 016819-140612

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

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Date: 7/28/14

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Breast Cancer Symposium phy, and most are false positives,” Dr Lipson stated.

Cost-Benefit Considerations

A recent study (Sprague BL, et al.

Ann Intern Med. 2014;162:157-166) showed that 4 breast cancer deaths were averted for every 10,000 women screened by ultrasound and that 1.7 quality-adjusted life-years (QALYs)

“

Many more biopsies are generated by screening ultrasound than mammography, and most are false positives.

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”

—JAFI LIPSON, MD T:7.375 in

were gained. The annual cost of QALY gained was $325,000, which exceeds the threshold considered acceptable by healthcare experts. The cost per QALY gained was $246,000 when only women with extremely dense breasts had ultrasound screening, which is still excessively high.

Dr Lipson stated that digital tomosynthesis increases the rate of cancer detec-

tion by up to 50% and reduces the false-positive rate by up to 30% compared with ultrasound.

Dr Weigert pointed out that digital tomosynthesis equipment costs approximately $500,000, and this technology is only available in a few specialized centers.

“I’m from the real world, where we only have ultrasound. Everyone has ultrasound.

It’s widely available,” Dr Weigert said. n

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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 enzyme CYP2D6. 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 vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

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Quality Care

Main Barriers to Quality Lung Cancer Care Relate to Navigating the Healthcare System

By Kate O’Rourke

Boston, MA—A study involving a series of focus groups at a community cancer center has identified several barriers to quality lung cancer care.

Troubles with navigating the healthcare system and understanding the illness and treatment were the most common barriers. The study was pre-

sented at the 2014 ASCO Quality Care Symposium.

The diagnosis and treatment of lung cancer involve multiple steps and pro-

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

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FEBRUARY 2015

viders, which may lead to distress or conflict among patients and caregivers.

To identify barriers to quality care in lung cancer, a team of researchers from

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 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 ≥2.5X ULN 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.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (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 11.5 infection 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

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Quality Care the University of Tennessee Health Science Center, Memphis, conducted 10 focus groups between March 2013 and January 2014, with 22 patients with lung cancer and 24 caregivers.

Participants were recruited by nurses and doctors working in the Memphis area. Navigating the system was complicated for patients.

“The basic things that we intuitively

know about barriers to care could be a major issue for them,” said lead investigator Satish Kedia, PhD, Professor of Social and Behavioral Sciences, University of Memphis, TN. “Seemingly simple things could pose big problems for patients, such as cancellation of appointments. A lot of these patients cannot drive themselves to their appointments. They may have

caregivers who work, and when an appointment is cancelled, transportation becomes an issue.”

Barriers to Quality Care

The biggest barriers identified were related to navigating the healthcare system and accessing information. The following things presented significant challenges to patients with lung cancer:

➤ Lack of insurance ➤ Lag time in insurance approvals and

processing

➤ Understanding their disease and inad-

equate explanations by providers

➤ Uncertainty about coverage ➤ Insurance coverage caps for tests and

office visits.

Patients also expressed frustration about: Continued on page 22

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % 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 7 discomfort 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 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes 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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % 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 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 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.

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) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 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 Placebo with Prednisone (N=542) Prednisone (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

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Quality Care

Main Barriers... ➤ Appointment delays ➤ Appointment rescheduling ➤ Long wait times in the office ➤ Cancellations by providers ➤ Inflexibility to accommodate schedules.

“It took my husband a month to get an appointment,” said one caregiver. Pa-

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tients complained that their “scheduling should have been spread out more,” and that they have “waited a long time” for a response from their insurance company.

Communication was a significant challenge. Patients complained that their initial diagnosis, prognosis, and

Left to right: Nick Faris, Stephanie Boyd, Kristi Roark, Orion Osborne, Dr Raymond Osarogiagbon, Professor Satish Kedia, Courtney Foust, and Michael Sheean.

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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 drug-metabolizing enzyme CYP2D6. 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 vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

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.

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 (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh 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. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

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treatment preparations were not adequately explained in language they could understand, and that clinicians did not spend enough time with them.

“There was a lot of confusion. The patients didn’t understand what the disease was all about, whether their treatment was curative, or what they were dealing with,…especially patients who were from a low socioeconomic status background,” said Dr Kedia.

“

Seemingly simple things could pose big problems for patients, such as cancellation of appointments. A lot of these patients cannot drive themselves to their appointments. They may have caregivers who work, and when an appointment is cancelled, transportation becomes an issue.

”

—SATISH KEDIA, PHD

Patient Navigators, Support Services

The stress and confusion caused by navigating the healthcare system and accessing information were reduced when support was available from within the healthcare system itself. Support was beneficial for coping with lung cancer, expediting appointments, seeking information, connecting with physicians, and receiving timely diagnoses and treatments.

Using patient navigators is another way to help these patients. Healthcare providers can help reduce the burden associated with a lung cancer diagnosis and improve quality of care by offering patients and caregivers more resources, including support groups, help with referrals, appointment scheduling, and direction to sources of credible information. A new study supports the use of patient navigators as one possible solution (Coughlin SS, et al. Cancer Med. 2014;3:1467-1476).

“Having a support group, some networking within the system, seemed to help,” said Dr Kedia. n

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Cancer Rehabilitation

A Conversation with Dr Timothy Sherwood, a Thoracic Surgeon Who Refers Patients for Cancer Prehabilitation

By Julie K. Silver, MD

for patients going to surgery. That is not their model. The cardiopulmonary rehab is not designed to improve surgical outcomes in patients with lung cancer but rather to treat patients who have serious cardiac and/or pulmonary disease.

M

ary Washington Healthcare is a regional medical system in Virginia that provides inpatient and outpatient care through more than 40 facilities and services, including Mary Washington Hospital, a 437bed regional medical center, and Stafford Hospital, a 100-bed community hospital. Mary Washington Healthcare recently adopted the STAR Program, a best practices cancer rehabilitation ­­ model of care.

Rehabilitation Director and STAR Program Coordinator Kathy Duval, MS, reported that she and her team were getting many referrals for newly diagnosed patients with lung cancer from Timothy Sherwood, MD, a thoracic surgeon at Mary Washington Healthcare, and having impressive outcomes, including decreasing the hospital length of stay from an average of 5 to 3 days, and improving patient functioning from their baseline status at diagnosis.1 In a recent interview, Dr Sherwood explained why he is referring patients to the STAR Program Prehab.

Q: What do you like about the STAR Program Prehab better than the car­ diopulmonary rehabilitation you used for your patients in the past?

Timothy Sherwood, MD: The STAR Program team gets my patients in much faster, within 2 to 3 days, or sometimes on the same day. This increases the patient’s confidence in me and my care.

It used to take 3 to 4 weeks to get my patients into the conventional cardiopulmonary rehab.

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Q: Are there other reasons why the STAR Program is better and/or easier?

Dr Sherwood: Yes. With the STAR Program, the care is generally covered by insurers. With the other model, my patients would have to qualify by having a reduced cardiac ejection fraction or a cardiac valvular disease. Even if I could get my patients seen by the program, they would not always be covered for it, because they weren’t sick enough based on cardiac and pulmonary criteria.

Q: Are you concerned with delays in surgery with the STAR Prehab?

Dr Sherwood: No. My patients go through the STAR Program lung ­cancer prehab for 4 to 8 weeks. These

­­ my mid- and high-risk patients. I are would rather have them get through surgery safely than have a horrific postoperative outcome.

Timothy Sherwood, MD

Q: What else happens during this 4- to 8-week period?

Dr Sherwood: Usually I do the cancer staging, and I see the patients for several visits and monitor their progress.

I have them climb 2 flights of stairs

Figure Multimodal STAR Program Prehab Model of Care

Stress reduction

Nutrition

General exercise

Smoking cessation

Targeted exercise

Survivor

Acute cancer treatment The STAR Program Prehab incorporates a 5-prong multimodal approach, with general and targeted exercise, stress reduction, nutrition, and smoking cessation. Protocols are diagnosisspecific and incorporate the latest research. As with all medical care, treatment should be recommended on an individual basis, depending on cancer diagnosis, premorbid health conditions, and other factors such as age and frailty.

Reprinted from the STAR Program and used with permission from McKesson Corporation and/or one of its subsidiaries. Copyright © 2015. All rights reserved.

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every time I see them. As a thoracic surgeon, I have been trained to be very concerned with “performance status,” and not just the ECOG status or the pulmonary function tests. I make notes about how well they climb stairs during every visit to see their progress.

Q: What postoperative issues are you concerned about?

Dr Sherwood: Pneumonia is one of the major complications. The targeted exercise of the STAR Program helps to improve the patients’ respiratory muscles, so that after surgery they can breathe better (Figure). They will have pain from their incision, and if they cough they have more pain. This means that they may take very shallow breaths and get atelectasis, which puts them at risk for pneumonia. The targeted exercises are very important in addition to the general fitness exercise component.

Q: We have just added a nutrition component to the STAR Program Prehab protocol. What do you think about the protein supplementation?

Dr Sherwood: I like it a lot, and I want to add that.

Q: You currently send some of your patients for mental health counseling.

What do you think about the coping skills component of STAR Program Prehab that recommends a specific stress reduction strategy approach for all patients (eg, progressive muscle relaxation, guided imagery)?

Dr Sherwood: I like that a lot, and I think it removes the stigma of a mental health referral, which is a barrier for some patients who don’t want to be labeled with a mental health problem but clearly need help with their stress and distress.

Q: What do you think about the STAR Program Prehab approach overall?

Dr Sherwood: I like it, because it provides objective goals, with checklists and protocols. n Reference

1. Hunt E, VanderWijst K, Stokes B, et al. Prehabilitation improves the physical functioning of a newly diagnosed lung cancer patient before and after surgery to allow for a safe surgical resection and decreased hospital length of stay: a case report. J Oncol Navig Surviv.

2014;5:34-35.

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Economics of Cancer Care

Generic Imatinib Will Be the Most Cost-Effective Therapy for Chronic Myeloid Leukemia

By Rosemary Frei, MSc

Miami, FL—In 2016, when its patent protection period expires, imatinib (Gleevec) will take the pole position as the most cost-effective first-line treatment for patients with chronic-phase chronic myeloid leukemia (CML) in the United States, according to a new analysis presented late last year at the Society for Medical Decision Making annual meeting.

Lifelong treatment with a tyrosine ­kinase inhibitor (TKI) is recommended for patients with chronic-phase CML, and although out-of-pocket costs vary among health plans, the costs can be considerable and can influence patient adherence and outcomes.

Currently, the 3 TKIs imatinib, dasatinib (Sprycel), and nilotinib (Tasigna) are approved by the FDA as frontline therapies for chronic-phase CML. Of these 3 agents, imatinib will lose its patent first.

The study was based on a Markov cost-effectiveness analysis comparing step therapy versus physician choice for the treatment of incident, chronic-phase CML in 2016, when imatinib will be losing its patent. The step therapy in the model consisted of the use of imatinib followed (in the event of treatment failure or intolerance) by the second-generation TKIs dasatinib or nilotinib. With physician choice, the physician would choose the firstline drug used, and if treatment fails with that drug, the physician would switch the patient to one of the other TKIs.

“

Imatinib provides very similar mortality and morbidity benefits to patients compared with the other drugs, at a much lower cost.

”

—RENA M. CONTI, PHD

The efficacy data came from a meta-­ analysis of published studies and data on the annual incidence rate of CML and the associated costs, using observational studies. The per-person medical treatment costs were estimated based on claims data.

Based on previous studies of cancer drugs price decline after the generic entry to the market, the investigators assumed that the price of imatinib would be 100% of the branded price for the first 6 months, then fall to 60% to

80% of the branded price for the second 6 months, and then to 60% to 90% after that.

The model showed that stepwise therapy is as effective as but less expensive than physician choice, resulting in an incremental cost-effectiveness ratio of $227,136 per quality-adjusted life-year (QALY).

This translated to an additional $227,000 cost per person over starting with step therapy at baseline to gain 1 additional QALY. “Our results are driven by the fact that imatinib provides very similar mortality and morbidity benefits to patients compared with the other drugs, at a much lower cost,” said lead investigator Rena M. Conti, PhD, Assistant Professor,

ters, including a lower price for imatinib, and higher and lower probabilities of imatinib-associated cytogenetic re­­ sponse or major molecular response.

A multivariate probabilistic sensitiv­ ity analysis showed that the stepwise therapy was more cost-effective than the physician choice in 73.3% of 10,000 simulations.

“This simulation step creates a more realistic view of how the population will respond to each arm of the study.

Thus, in the real world, given random effects that are difficult to control for in medicine, because of human behavior, we can still be confident that most people (73%) will respond positively to step therapy compared to physician choice. Furthermore, this approach is

“

In the real world…we can still be confident that most people (73%) will respond positively to step therapy compared to physician choice.

Furthermore, this approach is cost-saving, except only in rare cases.

”

—WILLIAM PADULA, PHD, MS

­ ediatrics and Public Health Sciences, P University of Chicago.

These results remained consistent when the model used different parame-

cost-saving, except only in rare cases,” said coinvestigator William Padula, PhD, MS, Postdoctoral Fellow, University of Chicago. n

Should DNA Ploidy Analysis Replace Pap Smears for Cervical Cancer Screening?

New study suggests DNA analysis more cost-effective

By Rosemary Frei, MSc Miami, FL—Researchers are suggesting that DNA ploidy analysis may be a more cost-effective screening tool for cervical cancer than routine Pap smears.

In a presentation at the 2014 Society for Medical Decision Making annual meeting, Van T. Nghiem, MSPH, of the Department of Health Services Research, M.D. Anderson Cancer Center, Houston, showed results from a Markov model analysis of the natural history of human papillomavirus infection in a hy-

24

pothetical group of females aged 12 years. The investigators compared 5 ploidy strategies—having 1, 2, 3, 4, or 5 cells per specimen without the normal number of chromosomes—with liquid-based Pap smear analysis.

The team found that a cutoff of ≥4 aneuploid cells per specimen was cost-­ effective compared with no screening and appeared to be more cost-effective than using Pap smears. The ploidy 4-cell screening strategy increased the

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quality-adjusted life expectancy by 0.083 quality-adjusted life-years (QALYs) and was associated with a cost of $8744 per QALY gained.

The investigators determined that the cost-effectiveness of ploidy 4-cell screening for cervical cancer was most sensitive to the ploidy strategies’ operating characteristics, the cost of ploidy analysis, the cost of the Pap smear procedure, and the cost of treatment of high-grade squamous intraepithelial lesions.

The ploidy 4-cell screening was cost-effective in most scenarios in the sensitivity analysis. Moreover, the team constructed cost-effectiveness acceptability curves that indicated that this strategy is more cost-effective than Pap smear screening.

The group concluded that ploidy analysis is “less costly and comparably effective” versus liquid-based Pap smear screening “using the standard willingness-to-pay threshold.” n

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Economics of Cancer Care

Brentuximab Vedotin Cost-Effective After Transplant in Relapsed/Refractory Hodgkin Lymphoma

By Chase Doyle

San Francisco, CA—The use of brentuximab vedotin to prevent progression after autologous stem-cell transplantation (ASCT) in patients with Hodgkin lymphoma is expected to increase survival and quality-adjusted survival and be cost-effective, according to a cost-effectiveness analysis presented at ASH 2014.

Relapsed or refractory Hodgkin lymphoma after ASCT carries an unfavorable prognosis, with a median overall survival of less than 2 years. It is also very costly to treat. Novel agents that reduce the risk for disease progression and the need for further treatment, including ASCT, offer the potential to be not only clinically effective but also cost-effective, noted Joshua A. Roth, PhD, MHA, of the Hutchinson Institute for Cancer Outcomes Research, Seattle, WA. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, significantly improved progression-free survival when given after ASCT in the AETHERA trial.

Cost-Effectiveness Analysis

The objective of the current analysis was to evaluate the cost-effective-

ness of brentuximab treatment strategy after ASCT to prevent or delay disease progression in patients with Hodgkin lymphoma compared with best supportive care.

then receive brentuximab vedotin plus best supportive care or best supportive care alone.

After treatment, patients are tracked in monthly cycles through the 5 health

When used after ASCT to prevent progression, brentuximab vedotin has the potential to be costeffective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma.

—JOSHUA A. ROTH, PHD, MHA

The investigators constructed a decision model evaluating the potential cost-effectiveness of brentuximab vedotin versus best supportive care.

Adults with relapsed or refractory Hodg­ kin lymphoma “enter” the model immediately after receiving ASCT, and

states of remission, relapse/salvage therapy, relapse/palliative care, second remission, and death, with transition probabilities derived from peer-reviewed literature, bone marrow transplant registry data, and US life tables.

In the base case, a brentuximab ve-

dotin strategy yields 2.01 quality-adjusted life-years (QALYs) at a total cost of $147,790. With an incremental cost-effectiveness ratio of $74,000 per QALY, treatment with brentuximab vedotin is cost-effective by contemporary standards of willingness to pay in the United States ($100,000-$150,000 per QALY). Probabilistic sensitivity analysis results demonstrated that brentuximab vedotin is expected to be cost-effective in 24%, 81%, and 95% of simulations at willingness-to-pay levels of $50,000, $100,000, and $150,000 per QALY, respectively.

The investigators concluded that when used after ASCT to prevent progression, brentuximab has the potential to be cost-effective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma.

Dr Roth also noted that the results ­­of the forthcoming phase 3 AETHERA trial would provide definitive evidence of the efficacy of brentuximab in this setting and, consequently, more precise evidence of the cost-effectiveness of this strategy. n

Cost-Effectiveness Analysis Shows Specialty Drugs Offer Value Despite High Cost

By Charles Bankhead

D

espite substantially higher costs, specialty drugs can offer value comparable with that of traditional medications under certain circumstances, according to a recent cost-effectiveness analysis covering 12 years of FDA drug approvals (Chambers JD, et al. Health Aff [Millwood]. 2014; 33:1751-1760).

Specialty drugs, many of which are cancer drugs, offered larger health gains and improved survival but at an average cost per quality-adjusted life-year (QALY) of more than 15 times greater than the traditional drugs in the same class.

Three times as many specialty drugs had a cost per QALY in excess of $150,000. Even so, the overall cost-­ effectiveness was comparable for spe­ cialty and traditional drugs.

“Payers have not yet found the formula for managing specialty drugs,” concluded the investigators, led by

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“

Insurers should continue to experiment with a combination of existing formulary management tools and novel strategies to maximize patient access to specialty drugs while minimizing their cost.

”

—JAMES D. CHAMBERS, PHD, AND COLLEAGUES

James D. Chambers, PhD, MPharm, MSc, Assistant Professor at Tufts Medical Center Institute for Clinical Research and Health Policy Studies, Boston. “Insurers should continue to ­

experiment with a combination of existing formulary management tools and novel strategies to maximize patient access to specialty drugs while minimizing their cost.”

In recent years, many of the drugs approved by the FDA are classified as specialty or “large-molecule” agents.

Specialty drugs have represented therapeutic advances for a variety of conditions, especially in cancer. However, the high cost of these medications has attracted considerable attention.

Dr Chambers and colleagues evaluated FDA drug approvals of new molecular entities (NMEs) from 1999 to 2011.

They focused on incremental health improvements and incremental costs associated with specialty drugs after their introduction to the marketplace.

The team calculated QALYs for each agent to determine incremental health benefit. Incremental cost was derived FEBRUARY 2015

I

from the difference in cost between the specialty drugs and the existing treatment options. Incremental costs included direct drug costs and related costs (hospitalization and other health resource utilization).

Drugs were classified as specialty or traditional on the basis of inclusion (or exclusion) on the specialty drug lists of CVS Caremark and Express Scripts.

Dr Chambers and colleagues identified 279 NMEs approved by the FDA during the study period. Overall, 154 (55.2%) of the approvals involved specialty drugs.

The illness categories represented by the drugs included 25 for cancer (22 specialty drugs), 16 for infectious disease (12 specialty drugs), 14 for circulatory disease (4 specialty drugs), 11 for endocrine disease (2 specialty drugs), 11 for musculoskeletal and rheumatoContinued on page 26

www.ValueBasedCancerCare.com

25

Economics of Cancer Care

Use of Advanced Practice Providers May Accrue Cost-Savings in Stem-Cell Transplant

By Wayne Kuznar

San Francisco, CA—A specialized service model that uses nurse practitioners and physician assistants for patients undergoing allogeneic stem-cell transplant (ASCT) may have cost benefits over house staff–based ASCT as a result of the decreased utilization of medical resources, according to researchers at Abramson Cancer Center of the University of Pennsylvania, Philadelphia, at the 2014 American Society of Hematology annual meeting.

A retrospective analysis showed no detriment in clinical outcomes, and perhaps some benefit, to an advanced practice provider model for administering ASCT. “A specialized inpatient advanced provider practice allogeneic transplant service may decrease the length of stay and result in fewer ICU [intensive care unit] transfers and fewer in-hospital deaths,” said lead investigator Nirav N. Shah, MD, Fellow, Division of Hematology/ Oncology, Abramson Cancer Center.

“There were potential cost-saving benefits due to the decreased utilization of laboratory and radiologic testing.”

Traditionally, most ASCTs occur at tertiary academic centers where the

house staff (ie, medical residents) provides daily care. “With new limitations on resident work hours, alternative models of team-based care replacing residents with advanced practice providers [nurse practitioners and physician assistants] have been used,” he said.

“

A specialized inpatient advanced provider practice allogeneic transplant service may decrease the length of stay and result in fewer ICU transfers and fewer in-hospital deaths.

There were potential costsaving benefits.

”

—NIRAV N. SHAH, MD

Dr Shah and colleagues compared outcomes from a house staff–based ASCT service in use at the University of Penn-

sylvania before July 2012 with outcomes from an advanced practice provider–based service that was instituted July 2012.

In the house staff service model, a 24hour house staff provided care, and residents and a hematologic malignancy attending physician rotated on service every 2 weeks. The advanced practice provider service was staffed by nurse practitioners and physician assistants (Monday–Friday coverage), overnight moonlighters provided weekend and night coverage, and a hematologic malignancy attending physician rotated every 2 weeks.

The evaluation included 86 patients admitted to the house staff service from May 2011 to May 2012, and 81 patients admitted to the advanced practice provider service from October 2012 to October 2013.

The primary analysis compared patient, provider, and cost outcomes before and after the advanced practice provider service was instituted. Patient outcomes included 100-day relapse-free survival and overall survival, length of stay, 14day and 30-day readmission rates, in-­ hospital death rate, ICU transfers, and infectious complications (ie, pneumonia,

urinary tract infections, bacteremia, and Clostridium difficile colitis).

The rate of pneumonia was significantly less in the advanced practice provider service group than in the house staff group (15% vs 28%, respectively); other infectious complications were similar in both groups.

Although not statistically significant, there were fewer in-hospital deaths in the advanced practice provider service model versus the house staff model (4% vs 10%, respectively), a decrease in ICU transfers (8.6% vs 18.6%, respectively), and a 3-day shorter mean length of stay. There were no differences in 14-day or 30-day readmission rates. The 100-day survival rates and relapse-free survival rates were similar in the 2 groups, with less relapse in the advanced practice provider group, which did not achieve significance.

Hospital charges and total costs of the hospitalization were not significantly different between the 2 models, although the number of radiologic films ordered ­­(5 vs 8, respectively) and the number of blood cultures ordered (4 vs 7, respectively) were significantly less in the advanced practice provider model. n

Cost-Effectiveness Analysis Shows Specialty... logic conditions (8 specialty drugs), and 10 for neuropsychiatric and neurologic conditions (1 specialty drug).

Quality and Cost

The median incremental QALY gain across all 102 drugs was 0.031, equivalent to 1.5 weeks of quality-adjusted survival gain. The mean QALY gain was 0.17.

at a glance ➤ Specialty drugs offer value, increased survival, but at a high cost versus traditional agents ➤ In a recent cost analysis, 26% of specialty drugs versus 9% of traditional drugs exceeded the $150,000 threshold per QALY gained ➤ Insurers need to develop new strategies to maximize patient access to specialty drugs and minimize patients’ burden

26

Specialty drugs had a median QALY gain of 0.183 versus 0.002 for traditional drugs (P <.01) and mean gains of 0.25 and 0.08, respectively.

Approximately 33% of the drugs (15 specialty and 17 traditional drugs) were less effective or no more effective than the existing care. In addition, 14 specialty drugs and 2 traditional drugs were associated with ≥0.5 QALYs gained, or 6 months of quality-adjusted life expectancy.

For all 102 drugs included in the analysis, the median additional cost over existing care was $2950, with a mean of $42,561.

Specialty drugs were associated with a median additional cost of $12,238 compared with $784 for traditional drugs. The mean values were $72,917 and $3237, respectively.

Specialty drugs accounted for 13 of the leading 15 drugs in QALY gains and all 15 of the drugs associated with the largest additional costs. Furthermore, 26% of specialty drugs versus 9% of traditional drugs exceeded a cost per QALY gained of $150,000.

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Continued from page 25

“

Many of the drugs that have offered the largest clinical advancements have been specialty drugs.

However, the incremental costs for specialty drugs have exceeded the incremental costs of more conventional novel treatments.

Nevertheless, specialty drugs can offer good value for various complex and burdensome diseases.

”

—JAMES D. CHAMBERS, PHD, MPHARM, MSC, AND COLLEAGUES

“Our study suggests that many new specialty and traditional drugs offer relatively modest benefits over preexisting care,” the researchers wrote.

“Many of the drugs that have offered the largest clinical advancements have been specialty drugs,”

they added. “However, the incremental costs for specialty drugs have exceeded the incremental costs of more conventional novel treatments. Nevertheless, specialty drugs can offer good value for various complex and burdensome diseases.” n

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ASH Highlights

Multiple Myeloma No Longer Considered a Single Disease Entity, as Reflected by New Treatment Regimens

By Wayne Kuznar

patients have evidence of mutations in ≥1 of the 11 recurrently mutated genes, and mutations are often present in subclonal populations; mutations within the same pathway can be observed in the same patient. The role of micro­

© American Society of Hematology. All rights reserved.

San Francisco, CA—Multiple myeloma is not a single disease entity but has genomic complexity and frequent intraclonal heterogeneity of myeloma cells. This realization, together with the availability of a number of new treatment possibilities, has underscored a need for better disease prognostication and monitoring tools, said Jesús San Miguel, MD, PhD, Professor of Hematology, and Director of Clinical and Translational Medicine, Clínica Universidad de Navarra, Pamplona, Spain, in delivering the Ham-Wasserman Lecture at the 2014 American Society of Hematology meeting.

The scientific landscape of multiple myeloma has evolved rapidly, Dr San Miguel said, with new insights into its genetics, pathogenesis, mechanisms of resistance, and newer tools to assess response to therapy.

Almost all patients with myeloma have abnormal cytogenetics, including chromosomal translocations, mostly involving the immunoglobulin heavy ­ (IGH) locus on chromosome 14q32.

A unifying event in the pathogenesis is likely. “It is possible that all IGH translocations involved in multiple myeloma converge on a common pathway that is essential in the pathogenesis of the disease and cause the inhibition of differentiation and an increase in cell survival and proliferation,” Dr San Miguel said.

Furthermore, gene-expression pro­ filing analysis has demonstrated that the expression of the cyclin proteins ­ CCND1, CCND2, and CCND3 is increased in almost all patients. Such profiling also confirms the genetic diversity of the disease. Approximately 65% of

RNAs in the pathogenesis of cancer has also generated interest.

Most genetic lesions in patients with myeloma are already present in an early benign phase of the disease known as monoclonal gammopathy of undetermined significance (MGUS).

Progression from MGUS to an intermediate/indolent phase, known as smoldering myeloma, and eventually to multiple myeloma, would involve a clonal expansion of abnormal cells, “implying a complex evolutionary process with intraclonal heterogeneity,” said Dr San Miguel.

Evaluating Response

Survival in myeloma hinges on the quality of response to frontline therapy, he said. Better techniques to assess com-

plete response and minimal residual disease are needed. A failure to suppress tumor metabolic activity after transplantation is associated with shorter survival.

Persistent minimal residual disease has been associated with poorer out-

Almost all patients with multiple myeloma have abnormal cytogenetics….

It is possible that all IGH translocations involved in multiple myeloma converge on a common pathway.

“

”

—JESÚS SAN MIGUEL, MD, PHD

comes among patients who have had a transplant and in older patients. “Further standardization of MFC [multiparametric flow cytometry] is still required,” said Dr San Miguel. Preliminary data indicate high applicability and 90% sensitivity for minimal residual disease, making it a potential alternative to MFC. Early Treatment

The possibility of early treatment at the smoldering myeloma stage is intriguing. The combination of lenalidomide and dexamethasone delayed progression to symptomatic myeloma compared with observation in a phase 3 randomized trial. Improved criteria for defining the high-risk population with smoldering multiple myeloma are needed before

treatment at this stage can be accepted as standard of care, he said.

Novel Agents Emerging

The use of novel proteasome inhibitors and immunomodulatory agents and the introduction of high-dose therapy followed by autologous stem-cell transplantation have significantly improved outcomes for patients with multiple myeloma over the past decade, Dr San Miguel said.

New agents are emerging, including monoclonal antibodies, second- and third-generation proteasome inhibitors, and histone deacetylase inhibitors. The most clinically developed monoclonal antibody is elotuzumab, a humanized immunoglobulin G1 monoclonal antibody targeting signaling lymphocytic activation molecule F7. In combination with lenalidomide and dexamethasone, elotuzumab resulted in an 84% overall response rate in patients with relapsed or refractory multiple myeloma in a phase 2 study.

Daratumumab is also in phase 2 study, and has demonstrated activity as monotherapy, with response rates of 30% to 40%. Daratumumab is now being investigated in combination with lenalidomide or bortezomib with dexamethasone.

A combination of the deacetylase inhibitor panobinostat with bortezomib and dexamethasone produced a partial response in 35% of bortezomib-refractory patients with multiple myeloma and was associated with better progression-free survival than bortezomib plus dexamethasone in a phase 3 trial. n

Venetoclax Moves Forward in Chronic Lymphocytic Leukemia, Acute Myeloid Leukemia

By Phoebe Starr

San Francisco, CA—The results of a phase 1b study of the combination of venetoclax plus rituximab (Rituxan) showed encouraging safety and excellent activity in patients with chronic lymphocytic leukemia (CLL). Venetoclax will move on to a phase 3 trial comparing venetoclax plus rituximab versus bendamustine (Treanda) plus ri­ tuximab in patients with previously treated CLL. The drug is also being studVOL. 6

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ied in acute myeloid leukemia (AML).

The study included 49 patients with relapsed/refractory CLL who had a maximum of 3 previous myelosuppressive regimens and no previous transplant. The complete response (CR) rate was encouraging.

“Venetoclax plus rituximab is high­ ly active in relapsed/refractory CLL, achieving an overall response rate of 88% and a complete response rate of

31%. The results suggest that rituximab adds to the efficacy of venetoclax,” said lead investigator Andrew W. Roberts, MBBS, PhD, Bone Marrow Transplant Physician and Clinical Hematologist, Royal Melbourne Hospital, Parkville, Victoria, Australia.

“Seventeen patients became minimal residual disease-negative on treatment, which is impressive bone marrow clearance,” Dr Roberts noted.

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Venetoclax (formerly ABT-199/GDC0199) is an oral selective BCL-2 inhibitor that rapidly induces responses in approximately 80% of patients with relapsed/ refractory CLL as a single agent. Venetoclax has synergy with rituximab in preclinical models of CD20-positive lymphoid malignancies. This study was undertaken to determine if the addition of rituximab would improve the efficacy of venetoclax.

Continued on page 28

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ASH Highlights

PD-1 Blockers Show “Amazing” Potential in Hodgkin Lymphoma, Limited Role in Other Hematologic Cancers

By Dana Taylor

San Francisco, CA—The checkpoint inhibitors—the anti–CTLA-4 agent ipi­ limumab (Yervoy) and the PD-1 blockers nivolumab (Opdivo) and pembrolizumab (Keytruda)—have shown promise in multiple solid tumors and are showing hints of activity in hematologic malignancies as well. But based on early research, their use in hematology may be more limited.

At the 2014 American Society of Hematology meeting, Stephen M. Ansell, MD, PhD, Mayo Clinic, Rochester, MN, declared immune therapies “the new frontier” in cancer. “It holds real promise, and it’s only the beginning of a new wave,” Dr Ansell said.

Checkpoint inhibitors are “taking the brakes off the immune system,” blocking signals that keep T-cells from attacking tumors and correcting the unfavorable environment that keeps T-cells sup-

pressed, he added.

Ronald Levy, MD, Stanford University, Palo Alto, CA, noted that pharmaceutical companies are rapidly taking advantage of “the plethora of

drugs that will unleash the T-cell immune response that’s always been lurking there.”

“Ipilimumab and PD-1 blockers are the subject of enormous excitement, and

“

Ipilimumab and PD-1 blockers are the subject of enormous excitement, and they are not redundant, so we may be able to combine them for enhanced effect.

We are already seeing responses, dramatically so, in ways we could not have predicted.

targets” described by immunologists.

“Each target and antibody is the subject of a clinical development path for a number of companies,” he said. “The future holds an amazing array of new

”

—RONALD LEVY, MD

they are not redundant, so we may be able to combine them for enhanced effect. We are already seeing responses, dramatically so, in ways we could not have predicted,” Dr Levy noted.

But he doubted that checkpoint inhibitors will have a prominent place in the treatment of most hematologic malignancies, based on the lackluster responses observed in most tumor types.

Instead, Dr Levy predicted their benefit may be reserved for Hodgkin lymphoma, a malignancy that is tailor-made for the mechanism of action of these drugs, noting that the results were “amazing” in this cancer.

Nivolumab and pembrolizumab made impressive showings in patients with Hodgkin lymphoma, which involves an increased PD-1 ligand expression.

“Here, we have a perfect situation for PD-1 blockade to work,” Dr Levy said.

“We have a target that is overexpressed by the tumor cells. When we take the brakes off the interaction between the PD-L1 ligand and the T-cells, amazing things happen.” n

Venetoclax Moves Forward in Chronic Lymphocytic Leukemia, Acute Myeloid...

Continued from page 27

The study was designed to identify a maximal tolerated dose of venetoclax and the optimal schedule for using the drug with rituximab and the safety of the combination, but remarkable bone marrow clearance was observed with this

at a glance ➤ When rituximab was added to venetoclax, patients with relapsed/refractory CLL achieved an overall response rate of 88% and a CR rate of 31% ➤ Of 49 patients with CLL in this study, 17 showed no minimal residual disease after treatment with venetoclax ➤ Venetoclax is generally well-tolerated, with mild gastrointestinal toxicity and grade 3 or 4 myelosuppression ➤ In patients with AML, venetoclax achieved an overall response rate of 15.5%

28

combination, said Dr Roberts.

Discontinuations were reported in 10 patients, 1 after the occurrence of tumor lysis syndrome, which led to adjustments in the schedule by modifying the dose of venetoclax and giving 1 dose of rituximab every 4 weeks. “The new schedule overcomes tumor lysis syndrome,” Dr Roberts said.

Venetoclax was generally well-tolerated, with mild gastrointestinal toxicity and grade 3 or 4 myelosuppression (47% neutropenia, 16% thrombocytopenia, and 14% anemia).

The overall response rate was 88%; 31% of patients achieved CR or CR with incomplete platelet recovery, 45% showed partial response, and 12% showed unconfirmed partial response.

“Good responses to the combination were observed in patients with del 17p, known to have poor prognosis,” Dr Roberts said.

Overall, 9 of the 15 patients who achieved CR showed no minimal residual disease, and 1 patient with CR showed no minimal residual disease at 14 months. Of the patients with partial response, 8 had no minimal resid-

VALUE-BASED CANCER CARE

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FEBRUARY 2015

ual disease. Of the 5 patients who achieved CR and discontinued therapy, none has progressed to date (up to 26 weeks).

“

Venetoclax plus rituximab is highly active in relapsed/ refractory CLL, achieving an overall response rate of 88% and a complete response rate of 31%.

”

—ANDREW W. ROBERTS, MBBS, PHD

Based on toxicity and efficacy data, 400 mg is the recommended dose.

Slightly more neutropenia, gastrointestinal toxicity, and dose reductions were observed at higher doses.

During the question and answer session, Dr Roberts was asked about biomarkers for venetoclax. He said that most patients with CLL express BCL2

and are sensitive to this drug, and, in his opinion, biomarkers for response are not needed in this setting.

Acute Myeloid Leukemia

A separate presentation showed encouraging first results from a phase 2 clinical trial evaluating venetoclax in patients with AML, justifying further investigation of this drug in AML. Venetoclax achieved an overall ­r esponse rate of 15.5%; there were 5 patients who achieved CR, 4 of whom had incomplete platelet recovery. These responses were in patients with relapsed/refractory AML or patients who received venetoclax as frontline therapy but who were unfit for intensive treatment.

“AML is an aggressive cancer with low survival rates, and there is a high need for new, effective treatment options. The results of this trial of venetoclax are encouraging and warrant additional study in patients with AML,” said Marina Y. Konopleva, MD, PhD, Associate Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston. n

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ASH Highlights

First-Line Therapy Failure in Patients with MDS Incurs High Financial Burden

By Wayne Kuznar

San Francisco, CA—Most first-line therapies for myelodysplastic syndromes (MDS) fail, and this failure represents a greater financial burden to patients than was previously estimated by Medicare, according to Christopher R. Cogle, MD, Associate Professor of Medicine, University of Florida, Gainesville, and colleagues at the Cleveland Clinic in a poster presented at the 2014 American Society of Hematology meeting.

The 6-month treatment cost for patients with newly diagnosed MDS has been estimated at more than $24,000 in the Medicare population.

“High-risk patients with MDS are usually treated first with hypomethylating agents—azacitidine or decitabine—but most will not achieve clinical improvements, and nearly all MDS patients eventually progress and die of relapsed/refractory disease,” Dr Cogle noted.

Using a commercial claims database, the investigators identified 1366 patients with MDS who used a hypomethylating agent. Of these, 402 patients (average age, 73 years) were eligible for second-line

therapy, 96% of whom had cytopenia and 51.7% were receiving blood transfusions

of patients had ≥1 MDS-specific visits ­­to the emergency department compared

“

High-risk patients with MDS are usually treated first with hypomethylating agents— azacitidine or decitabine— but most will not achieve clinical improvements.

”

—CHRISTOPHER R. COGLE, MD

and/or growth factors. The patients had an average of 6.1 treatment cycles of a hypomethylating agent before being considered for second-line therapy.

During the year before first-line treatment failure, the patients had a mean of 42.7 MDS-specific office visits compared with 18.9 visits during the first 6 months after first-line treatment failure. In the year before treatment failure, almost 8%

with nearly 7% during the initial 6 months after first-line treatment failure.

In addition, during the first year before treatment failure, almost 30% of patients had an MDS-specific hospitalization versus nearly 17% of patients in the first 6 months after treatment failure. During the first year before treatment failure, the mean length of stay for MDS-specific hospital admissions was almost 9 days

compared with almost 13 days during the initial 6 months after treatment failure.

Furthermore, in the first year before treatment failure, the mean MDS-specific cost was $80,673 (63.4% of the total cost), including chemotherapy and hematologic supportive care agents, such ­­as erythropoietin-stimulating agents, growth factors, and blood transfusions.

After treatment failure, the mean 6-month MDS-specific healthcare cost was $45,564 (59.2% of the total cost).

The cost of commercially insured care for patients with MDS was 3 times higher than the previously published costs of patients with Medicare coverage.

The health resource burden of patients with MDS who fail first-line therapies was estimated to exceed $24,000.

The researchers provided a more accurate estimate of costs by examining the healthcare resource utilization and costs in patients with MDS before and after the failure of first-line therapy with the hypomethylating agents azacitidine and decitabine using US commercial health insurance claims data. n

ASH Releases Second “Choosing Wisely” List of Treatments to Avoid

By Alice Goodman

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• Don’t test or treat for suspected heparin-induced thrombocytopenia (HIT) in patients with a low pretest probability of HIT

© American Society of Hematology. All rights reserved.

San Francisco, CA—At its 2014 meeting, the American Society of Hematology (ASH) released its second list of 5 common tests, treatments, and procedures to avoid in routine care.

This list adds to the first list of 5 practices to question, with the goal of initiating discussions between patients and physicians about the risks and benefits of certain procedures (www.hematology.org/choosingwisely).

The new Choosing Wisely recommendations are: • Don’t treat with an anticoagulant for more than 3 months in a patient with a first venous thromboembolism occurring in the setting of a major transient risk factor • Don’t routinely transfuse patients with sickle-cell disease for chronic anemia or uncomplicated pain crisis without an appropriate clinical indication • Don’t perform baseline or routine surveillance computed tomography scans in patients with asymptomatic, early-­ stage chronic lymphocytic leukemia

• Don’t treat patients with immune thrombocytopenic purpura in the ab-

sence of bleeding or a very low platelet count.

“Unnecessary treatments or tests not only add waste to the healthcare sys-

“

Unnecessary treatments or tests not only add waste to the healthcare system, but in some cases they also expose our patients to a risk of harm.

”

—LISA HICKS, MD, MSC

tem, but in some cases they also expose our patients to a risk of harm,” said FEBRUARY 2015

I

ASH Choosing Wisely Task Force Chair Lisa Hicks, MD, MSc, of St Michael’s Hospital and the University of Toronto, Ontario, Canada.

“ASH developed its second Choosing Wisely list to help hematologists manage the utilization and delivery of patient care resources, and the society encourages hematologists to consider these recommendations in all facets of their work, including patient care, teaching, innovation, and research,” she said.

The guiding principle for the practices included in Choosing Wisely is to do no harm. Since the launch of the campaign in 2012, more than 100 national and state medical specialty societies, regional organizations, and consumer partners have joined this initiative.

Consumer Reports has joined the effort, spreading the word to patients all over the country to stimulate important discussions between physicians and patients about these and other practices. n

www.ValueBasedCancerCare.com

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Personalized Medicine

Genomic Landscape of Pancreatic Cancer Being Uncovered, Showing 4 Common Mutations, with KRAS Almost Ubiquitous

By Wayne Kuznar

San Francisco, CA—Genetic analysis reveals multiple drivers of pancreatic cancer. During a keynote address at the 2015 ASCO Gastrointestinal Cancers Symposium, Sean Grimmond, PhD, BSc, Chair of Medical Genomics, Institute of Cancer Sciences, University of Glasgow, Scotland, discussed the genetic characterization of pancreatic cancer, and how the current landscape may be used to target driver genes for drug development.

Pancreatic cancer is a “morass” of damage that includes somatic-point mutations, somatic-coding mutations, germline mutations, chromosomal re­arrangements, and

at a glance ➤ The challenge is to find the driver genes that lead to tumor formation ➤ The 4 common mutations are KRAS, TP53, SMAD4, and CDKN2A, with KRAS almost ubiquitous in pancreatic cancer ➤ A variety of genes are driving genomic instability in about 12% of patients

focal amplifications, said Dr Grimmond.

The challenge is to identify the driver genes that cause the transformation of the tumor “and where the Achilles’ heels may lie in targeting it therapeutically,” he said.

Tumor cellularity can confound the identification of somatic events from next-generation sequencing. “Whenever possible, if the tumor has high enough cellularity, or we can enrich it enough, we will do deep whole-genome sequencing, because we believe that will give you the maximum amount of information about a patient’s tumor,” said Dr Grimmond. When whole-genome sequencing is not possible, deep exome sequencing is performed.

The mutation rate among various cancers varies considerably. For pancreatic cancer, the number of somatic mutations in a donor’s exomes is approximately 1 mutation per megabase, which is relatively moderate compared with melanoma or lung cancer.

“There are 5 signatures we can see across the genomes of pancreatic cancer patients,” Dr Grimmond said.

“We can find some patients in whom the vast majority of mutations have been driven by BRCA deficiency, whereas in others the majority is coming from a completely different mecha-

nism,” said Dr Grimmond.

“Those with a higher BRCA signature have biallelic damage to a series of genes within the BRCA pathway. That damage can occur through a variety of genomic events, not just point mutations.”

“

We can find some patients in whom the vast majority of mutations have been driven by BRCA deficiency, whereas in others the majority is coming from a completely different mechanism.

”

—SEAN GRIMMOND, PHD, BSC

Drivers of Pancreatic Cancer

In pancreatic cancer, 4 genetic mu­ tations are common—KRAS, TP53, SMAD4, and CDKN2A—with “KRAS being almost ubiquitous,” Dr Grimmond said.

Among the many genes that contribute to pancreatic cancer, 3% to 10% are mutated; the other genes are mutated less frequently.

Prostate Cancer Progression May Be Predicted by a Novel Gene Panel

By Rosemary Frei, MSc

A

novel gene panel is showing promise for determining which treatment-naïve patients with prostate cancer could benefit from intensified treatment. A new study indicates that a 100-gene-loci panel can identify which patients with prostate cancer are most likely to fail treatment within 18 months, with a multivariable analysis yielding a hazard ratio of 2.9 for relapse (Lalonde E, et al. Lancet Oncol. 2014;15:1521-1532).

The study was not powered to analyze cancer-specific mortality and overall survival. However, its results will be the basis for further analyses of the ­impact of adjuvant treatment on the DNA panel’s performance.

“We will be culling out patients with the gene signature into novel clinical

“

If the intensified treat­ment is more successful than the standard treatment for signaturepositive patients, then our prognostic signature turns into a predictive signature.

”

—ROBERT G. BRISTOW, MD, PHD

trials that will compare adjuvant treatment versus no adjuvant treatment, with the end point being biochemical failure at 18 months and local control, using postradiotherapy biopsies,” lead

investigator Robert G. Bristow, MD, PhD, clinician scientist at Princess Margaret Cancer Centre, Toronto, Ontario, Canada, told Value-Based Cancer Care. “If the intensified treatment is more successful than the standard treatment for signature-positive patients, then our prognostic signature turns into a predictive signature.”

Dr Bristow; colead investigator Paul C. Boutros, PhD, of the Ontario Institute for Cancer Research, Toronto; and their coinvestigators, first extracted DNA from 126 preradiotherapy biopsies from patients with low or intermediate risk for prostate cancer progression.

They identified 4 distinct genetic profiles or subtypes based on the resulting gene-alteration panel. Patients with subtype 4 had an 89% 5-year biochemi-

Many of the genes that are mutated less frequently fall into the same pathways, pointing to a common set of pathways that must be damaged to instigate a tumor. TGF-beta is a pathway that is frequently mutated. Few of these mutations are silent. “These are all coding events,” Dr Grimmond said. “We also get geographical rearrangements to chromosomes that can knock these genes out.”

Two other pathways are genes involved in DNA damage repair and genes in chromatin remodeling. Approximately 10% to 15% of patients with pancreatic cancer have chromatin remodeling genes that are inactivated through genomic rearrangements that would be invisible on an exome or a small panel-based study.

“Whole-genome sequencing is needed to give you the appropriate sensitivity to pick up these inactivating events,” said Dr Grimmond.

Histone-modifier genes are involved in changing the proteins that interact with the DNA and organize the chromatin. “We see many of those genes being mutated,” Dr Grimmond said.

“They are very damaging mutations, and in some structural variations can be driving events within those tumors.”

An increasing number of RNA processing mutations are being observed within pancreatic cancer, such as SF3B1 and RMB10. Mutation in regulators of Wnt signaling, such as RNF43, and mutation in 2 regulators, ROBO and SLIT, have been shown to be drivers of pancreatic cancer mutagenesis.

Actionable Mutations and Drug Development

In pancreatic cancer, “we see a variety of genes that we believe are driving genomic instability, in about 12% of patients,” said Dr Grimmond. “We have a variety of other mutations for which there are compounds in preclinical testing, or there may be other drugs that can be repurposed that we can potentially test in a clinical setting.”

A retrospective study of patients in whom sequencing has been performed demonstrated a strong signal that unstable pancreatic cancer may be particularly sensitive to platinums.

Of 8 patients with unstable disease who were exposed to platinum, 7 showed a response compared with none of 7 patients who had a stable genome. n

Continued on page 32

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VALUE-BASED CANCER CARE

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FEBRUARY 2015

VOL. 6

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

“Better informed teams provide better care.”

Matthew P. Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

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

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2015 All rights reserved.

VBMKsize_Mitchell_020215

Personalized Medicine

Top 10 Reasons Against Routine Genomic Profiling of Tumors in Patient Care

By Chase Doyle

San Francisco, CA—Neal J. Meropol, MD, of the University Hospitals Seidman Cancer Center, and Case Western Reserve University, Cleveland, OH, has long advocated against unnecessary treatment and testing of patients with cancer.

At the 2015 Gastrointestinal Cancers Symposium, Dr Meropol outlined his reasons why clinicians should not bend to pressure to routinely test all tumors.

“Here are my top 10 reasons why I believe we are not ready for routine molecular profiling of tumors,” he told the audience, listing the following reasons.

1. Assay Platform Limitations

“

The reasons not to try it are that these are costly interventions, they may not work, they have side effects, and they provide false hope. This should not be our routine approach with patients.

”

—NEAL J. MEROPOL, MD

Variability in the sensitivity and specificity of the many platforms being promoted raises questions regarding analytic validation, said Dr Meropol, asking questions that raise concern. How are the genes selected for these panels? Does the platform look at the transcriptome or just the genome? Are we looking at epigenomic changes that may be relevant in selecting treatments? What is the turnaround time for the results? And what is the cost of these assays?

Meropol said.

Nor will finding a single driver mutation guarantee that a single drug intervention will be effective, because of “cross talk” between pathways occurring downstream of a key mutation. “If we’re going to use a tumor biopsy for selecting treatment for an individual patient,” he said. “This biopsy should be done proximate to the time that we’re going to intervene with a new therapy.”

2. Tumors Are Heterogenous and Complex

According to Dr Meropol, definitions used in the MATCH trial for identifying drivers to explore in a clinical trial are not yet good enough for routine care. “The reasons not to try it are that these are costly interventions, they may not work, they have side effects, and they provide false hope. This should not be our routine

Mutations in a tumor may be different between sites. “Although they may look the same under a microscope, colon cancers and gastric cancers are extremely complex, and extremely heterogenous in terms of their molecular profiles,” Dr

3. We Don’t Know the Drivers

Prostate Cancer... cal relapse-free survival rate compared with 53% to 58% rates for the other 3 subtypes. The team also determined that the test’s prognostic power comes from the presence of specific gene alterations and general genomic instability.

Furthermore, tissue hypoxia, which had already been well-established as linked to worse prognosis, is associated with accuracy of the genomic panel.

Patients with a high proportion of gene alteration and high hypoxia had the worse prognosis, whereas those with only high hypoxia did well after radical prostatectomy.

The researchers then created the 100-loci DNA signature and validated its ability to identify patients at risk for cancer progression using radical prostatectomy samples from patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and in Cambridge,

32

Continued from page 30

United Kingdom.

The hazard ratio for biochemical relapse was 2.8 among patients with a Gleason score of 7. The gene panel was also highly prognostic for low-risk patients and those who went on to develop metastases; for example, 89% of low- to intermediate-risk patients at MSKCC who were classified by the gene panel as having a good prognosis were relapse free at 5 years compared with 58% of those who were classified as having a poor prognosis.

Further validation yielded a 2.9 hazard ratio for progression in patients deemed by the gene panel to have a poor prognosis versus those with a good prognosis.

The team also found that the genomic signature provided better prognostication than 23 RNA panels that had been previously investigated by other researchers. n

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approach with patients,” he advised.

4. We Don’t Have the Evidence that Links Drugs to These Drivers

The best level evidence is an FDA-approved dyad, but Dr Meropol stressed that this level of evidence is missing in nearly all drug cases. “Even if an agent meets a clinical end point, and there’s evidence of target inhibition, and there’s plausible evidence of a predictive or selection assay or analyte,” he said, “until it’s been proved in a prospective clinical trial, the evidence may be viewed as weak in terms of routine clinical practice.”

Preclinical evidence is an even poorer prognosticator for patient outcomes. Dr Meropol iterated the need for incentivizing the development of biomarkers worldwide.

5. Investigational Drugs Are Not Widely Available

There are limited clinical trial sites; patients have to seek studies and travel for them. “Not everybody lives in close proximity to a research center that has access to multiple clinical trials and new agents,” Dr Meropol said, “and getting compassionate access to a new drug in development is a logistically complicated process.

It’s time-consuming and rather opaque.”

6. It Isn’t Practical to Screen Many to (Maybe) Help a Few

The evidence is simply not there at this time, he said, highlighting a phase 1 study conducted at M.D. Anderson Cancer Center that intended to show the benefit of identifying clinical trials that might be appropriate for patients’ tumors. Of the 1283 patients assessed, 31% had at least 1 mutation, and among those who could be matched for treatment, approximately 10% had an antitumor response. But the overall response rate based on matching was only 2.4%.

7. There Is No Mechanism to Pay for Drugs for Off-Label Use

Off-label use of expensive targeted agents is increasingly scrutinized by payers, and costs are falling on patients.

“Recommending cancer drugs with high copays may not be ethical without strong evidence that it’s going to help that individual patient,” he said.

8. Drug Approval Based on Tumor Type, Not on Genotype

The current (and old) paradigm is histology-based and requires large prospective phase 3 trials to provide the level of evidence that leads to a FDA and worldwide drug approval. But an emerging paradigm for drug approval is

“

Recommending cancer drugs with high copays may not be ethical without strong evidence that it’s going to help that individual patient.

”

—NEAL J. MEROPOL, MD

genome-based, using small studies looking for big effect to make decisions, “but we’re simply not there yet,” he said.

9. No Statistical Approach to Interpreting a Series of Anecdotes

Dr Meropol asked: How much evidence is needed to conclude that a particular mutation should receive a particular therapy? How many patients are needed with outcome data across how many tissues of origin? And when looking at a major response, how can we distinguish between a fluke and an outcome that is real? The answers to these questions remain unknown.

10. Unintended Consequences for Patients

Given the potential for confusion over interpretation, it is important to know who is interpreting the data and making the recommendations. “We don’t want to give our patients false hope,” said Dr Meropol. “We don’t want to subject them to the risks of needless biopsies, and we don’t want to subject them to the financial burden of therapies and procedures that are not destined to help them.” n

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Drug Update

Nivolumab (Opdivo): Second PD-1 Inhibitor Receives FDA Approval for Unresectable or Metastatic Melanoma

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

A

lthough less common than other skin cancers, melanoma is the most dangerous form of skin cancer.1 According to data collected between 2004 and 2010, the 5-year relative survival rate for Americans with distant melanoma is only 16% for all ages, races, and sexes.2 The National Cancer Institute estimated that there were 76,100 new cases of skin melanoma in 2014, and more than 9700 patients died from this disease during the same period.2 The incidence of melanoma continues to rise, particularly among children and adolescents.3 Analysis of first-time melanoma diagnoses between 1970 and 2009 in patients aged 18 to 39 years showed that the number of new cases of skin melanoma increased 8-fold among young women and 4-fold among young men.3 Using data from 1973 to 2009, another study documented an average increase in melanoma of 2% annually in individuals aged between 0 and 19 years.4 The potential effect on healthcare resource use is just one reason for concern regarding these trends. Based on an assessment of Medicare administrative claims data between 1991 and 2005, patients with melanoma, particularly those with metastatic disease, accrued an average of more than $11,000 monthly in total healthcare costs5; the majority of these costs were related to inpatient hospital services.5 This cost analysis was conducted in 2009, before the approval of novel targeted therapies for metastatic melanoma.

As evidenced by its low 5-year survival rates, metastatic melanoma is difficult to cure.6 Surgery and radiation therapy are feasible options for tumors that are localized to the skin or to the lymph nodes.

Depending on their number and location, the surgical removal of melanoma metastases in internal organs is also an option.6 In the past, the management of patients with advanced stages of melanoma was very challenging. Today, however, the development and the introduction of targeted agents have significantly changed the treatment landscape. The current armamentarium of systemic treatments for metastatic melanoma features immunotherapy agents (ie, ipilimumab, pembrolizumab) and BRAF inhibitors (ie, vemurafenib, Copyright © 2015 American Health & Drug Benefits. All rights reserved.

Used with permission.

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dabrafenib, trametinib), in addition to traditional chemotherapy.6 Several of these novel agents offer superior efficacy compared with older cytotoxic drugs.6 Immune checkpoint blockade with monoclonal antibodies that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4, such as ipilimumab, as well as programmed-cell death (PD)-1 and PD ligand 1 (PD-L1), have emerged as successful treatment options in the treatment of patients with melanoma.7 Ipilim­ umab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and highly durable objective tumor responses in patients with advanced melanoma.7 Specifically in the management of patients with metastatic melanoma and the BRAF V600 mutation, a contrast has been observed between the use of BRAF inhibitors, which offer high re-

A Novel PD-1 Inhibitor for Unresectable or Metastatic Melanoma

On December 22, 2014, the FDA approved nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy and, if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.10,11 Nivolumab is a monoclonal antibody that blocks PD-1 and is administered via intravenous infusion. This agent was approved under the accelerated approval program based on the surrogate end points, overall response rate, and duration of response.10,11 When discussing data supporting the efficacy of nivolumab in relapsed metastatic melanoma, Jeffrey S. Weber, MD, PhD,

“

These data are important as they mark the first presentation of results from a phase 3 randomized study for the PD-1 immune checkpoint inhibitor class. The response rate and duration of response in patients treated with Opdivo are consistent with findings from the early phase 1 trial in previously treated advanced melanoma.

”

—JEFFREY S. WEBER, MD, PHD

sponse rates with limited response durability, and the use of ipilimumab, which offers a relatively low response rate but very durable responses.7 On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab, the first PD-1 inhibitor for the treatment of patients with unresectable or metastatic melanoma.8 This agent demonstrated objective and durable responses in a large phase 1b study that involved patients with un­ resectable or metastatic melanoma and disease progression after treatment with ipilimumab and, if the patient had the BRAF V600 mutation, after treatment with a BRAF inhibitor.8,9 To increase the proportion of patients with metastatic melanoma who achieve durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4, PD-1, and PD-L1 inhibitors.7

Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at Moffitt Cancer Center, stated, “These data are important as they mark the first presentation of results from a phase 3 randomized study for the PD-1 immune checkpoint inhibitor class.” He further commented, “the response rate and duration of response in patients treated with Opdivo are consistent with findings from the early phase 1 trial in previously treated advanced melanoma.”12 Dosing and Administration

The recommended dosage of nivolu­ mab is 3 mg/kg administered as an intravenous infusion for 60 minutes every 2 weeks. Nivolumab should be administered until disease progression or until unacceptable toxicity.11 No dose adjustment of nivolumab is required for patients with renal impairment or for patients with mild hepatic impairment, defined as total bilirubin upper limit of normal or less and aspartate aminotransferase (AST) more than

upper limit of normal or total bilirubin <1 to 1.5 times upper limit of normal and any AST.11 Mechanism of Action

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding releases PD-1 pathway-mediated immune responses against tumor cells. Blocking PD-1 activity resulted in decreased tumor growth in syngeneic mouse tumor models.11

Clinical Trial: Checkmate-037

The approval of nivolumab was based on the results of Checkmate-037, a phase 3 randomized, controlled, open-label study of nivolumab versus investigator’s choice chemotherapy in patients with advanced melanoma who previously received ipilimumab.11 A total of 370 patients with previously treated unresectable or metastatic melanoma enrolled in the Checkmate-037 clinical trial.11 All patients’ disease had progressed after previous therapy with ipilimumab and, if the patients were positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.11 These patients were randomized to receive nivolumab 3 mg/kg (N = 268) or investigator’s choice chemotherapy (N = 102) with dacarbazine 1000 mg/m2 every 3 weeks or with carboplatin (area under the curve, 6 mg•min/mL) plus paclitaxel 175 mg/m2 every 3 weeks until disease progression or until unacceptable toxicity.11 The efficacy of nivolumab was evaluated in a single-arm, noncomparative, planned interim analysis of the first 120 patients who received nivolumab in the Checkmate-037 clinical trial and in whom the minimum duration of follow-up was 6 months.11 The primary efficacy end points were confirmed overall response rate according to the Response Evaluation Criteria in Solid Tumors, as assessed by a blinded independent review committee, and duration of response.

Tumor assessments were conducted 9 weeks after randomization, followed by every 6 weeks for the first year, and then every 12 weeks.11 The Checkmate-037 clinical trial excluded patients with an autoimmune disease, medical conditions requiring systemic immunosuppression, ocular melanoma, active brain metastasis, or a Continued on page 34

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Drug Update

Nivolumab (Opdivo): Second PD-1 Inhibitor Receives... history of grade 4 ipilimumab-related adverse reactions (except for endocrinopathies) or grade 3 ipilimumab-related adverse reactions that had not resolved or were inadequately controlled after 12 weeks.11

elected Adverse Reactions in ≥10% of Patients Receiving Nivolumab (and Table S at a Higher Incidence than in the Chemotherapy Arm)

Patient Population

Adverse reaction

Among the 120 patients who received nivolumab, the median age was 58 years.11 The majority of the patients were male (65%) and white (96%). All the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c disease (76%), 2 or more previous therapies for advanced or metastatic disease (68%), elevated lactate dehydrogenase (56%), positive for a BRAF V600 mutation (22%), and a history of brain metastases (18%).11

Safety

The cohort of 268 patients with previously treated unresectable or metastatic melanoma in Checkmate-037 received a median of 8 doses (range, 1-31 doses) of nivolumab (3 mg/kg).11 The patients’ median duration of exposure to nivolumab was 5.3 months (range, ­1 day-9.6 months).11 In this clinical trial, 24% of patients were exposed to nivolumab for more than 6 months, and 3% of patients were exposed to nivolumab for more than 1 year.11 The Table summarizes the adverse reactions that occurred in ≥10% of patients and at a higher incidence rate compared with patients who received chemotherapy.11 Grade 3 and 4 adverse reactions occurred in 42% of nivolumab recipients.11 These events included abdominal pain, hyponatremia, elevated AST levels, and increased lipase levels; these adverse re-

34

Chemotherapy (N = 102) All Grade grades, % 3-4, %

Skin and subcutaneous tissue disorders Rasha

21

0.4

7

0

Pruritus

19

0

3.9

0

17

0

6

0

11

0

2.0

0

0

5

0

Respiratory, thoracic, and mediastinal disorders Cough Infections and infestations Upper respiratory tract infectionb

General disorders and administration site conditions Peripheral edema

10

Including maculopapular, erythematous, pruritic, follicular, macular, papular, pustular, or vesicular rash, and dermatitis acneiform. b Including rhinitis, pharyngitis, and nasopharyngitis.

Source: Opdivo (nivolumab) injection prescribing information; December 2014. a

Efficacy

The planned interim analysis of the Checkmate-037 clinical trial documented a 32% overall response rate for nivolumab 3 mg/kg in patients with unresectable or metastatic melanoma who previously received ipilimumab therapy and, if relevant, a BRAF inhibitor (95% confidence interval, 23%-41%).11 Of the 38 patients whose disease responded to nivolumab therapy, 4 patients achieved complete responses and 34 patients achieved partial responses.11 The majority (87%) of patients responding to nivolumab had ongoing responses with durations ranging from 2.6+ to 10+ months, including 13 patients with ongoing responses of at least 6 months.11 Objective responses were observed in patients with and without BRAF V600 mutation–positive melanoma.11

Nivolumab 3 mg/kg every 2 weeks (N = 268) All Grade grades, % 3-4, %

actions occurred at rates ranging from 2% to <5%.11 Nivolumab was discontinued as a result of adverse reactions in 9% of patients, and 26% of patients who received nivolumab experienced a drug delay for an adverse reaction.11 Nivolumab has no contraindications.

Warnings and Precautions

Immune-mediated pneumonitis.

Overall, 5 (0.9%) fatal cases of pneumonitis occurred among 574 patients with solid tumors who received nivolumab in clinical trials.11 Pneumonitis, including interstitial lung disease, occurred in 3.4% of patients who received nivolu­ mab in the Checkmate-037 clinical trial.11 Immune-mediated pneumonitis, which requires the use of corticosteroids and has no clear alternate etiology, occurred in 6 (2.2%) patients who received nivolumab. The median time to onset for these 6 cases was 2.2 months (range, 25 days-3.5 months).11 Grade 2 pneumonitis led to the interruption or the permanent discontinuation of nivolumab in 4 patients. The other 2 patients discontinued nivolumab for other reasons.

In all 6 patients, immune-mediated pneumonitis improved to grade 0 or 1 with corticosteroids.11 Patients who received nivolumab should be monitored for signs and symptoms of pneumonitis. Corticosteroids should be administered if grade 2 or higher pneumonitis is detected.11 Nivolumab should be withheld for moderate (grade 2) pneumonitis, and permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.11

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Immune-mediated colitis. Colitis or diarrhea occurred in 21% of patients who received nivolumab, and in 18% of patients who received chemotherapy ­­in the Checkmate-037 clinical trial.11 Immune-­mediated colitis was observed in ­­6 patients who received nivolumab.

The median time to onset of immune-­ mediated colitis was 2.5 months.11 Patients who receive nivolumab should be monitored for signs and symptoms of colitis. Corticosteroids should be administered for grade 2 or higher colitis. Nivolumab should be withheld for moderate (grade 2) or severe (grade 3) colitis, and permanently discontinued for life-threatening (grade 4) colitis or recurrent colitis upon restarting nivolumab therapy.11 Immune-mediated hepatitis. An increased incidence of liver test abnormalities was observed in the nivolumab group compared with the chemotherapy group, including increases in AST levels (28% vs 12%, respectively), alkaline phosphatase levels (22% vs 13%, respectively), alanine aminotransferase levels (16% vs 5%, respectively), and total bilirubin levels (9% vs 0%, respectively).11 Overall, 1.1% of patients who received nivolumab had immune-mediated hepatitis, which requires the use of corticosteroids and has no clear alternate etiology.11 Patients who receive nivolumab should be monitored for changes in liver function. Corticosteroids should be administered for grade 2 or higher hepatitis. Nivolumab should be withheld if grade 2 hepatitis is observed, and discontinued for grade 3 and grade 4 immune-mediated hepatitis.11

Continued from page 33

Immune-mediated nephritis and renal dysfunction. An increased incidence of elevated creatinine levels was observed in patients who received nivolumab compared with patients who received chemotherapy (13% vs 9%) in the Checkmate-037 clinical trial.11 ­ Grade 2 or 3 immune-mediated nephritis or renal dysfunction, defined as grade 2 or higher increased creatinine levels, need for corticosteroids, and no clear etiology, occurred in 0.7% of patients after 3.5 months and 6 months of nivolumab therapy, respectively.11 Patients should be monitored for elevated serum creatinine levels before and during treatment with nivolumab.11 If grade 4 elevation in serum creatinine levels is observed, corticosteroid therapy should be tapered and nivolumab should be permanently discontinued. Nivolu­ mab therapy should be withheld if grade 2 or 3 elevation in serum creatinine levels is observed.11 Immune-mediated hypothyroidism and hyperthyroidism. Thyroid function was evaluated for all patients at baseline and during the Checkmate-037 clinical trial.11 Grade 1 or 2 hypothyroidism occurred in 8% of patients who received nivolumab and was not observed among patients who received chemotherapy.

The median time to onset was 2.5 months (range, 24 days-11.7 months).

The majority of patients with hypothyroidism received levothyroxine and restarted nivolumab therapy.11 Grade 1 or 2 hyperthyroidism occurred in 3% of patients who received nivolumab and in 1% of patients who received chemotherapy. The median time to onset in patients who received nivolumab was 1.6 months (range, 0-3.3 months).11 Thyroid function should be monitored before and during treatment ­with nivolumab. Hormone replacement therapy for hypothyroidism should be administered as needed, and hyper­ thyroidism should be controlled. There are ­no recommended dose adjustments for nivolumab.11 Other immune-mediated adverse ­reactions. Other clinically important immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving nivolumab.11 Clinically significant, immune-mediated adverse reactions that were observed in <1% of patients who received nivolumab included pancreatitis, uveitis, demyelination, autoimmune neuropathy, adrenal insufficiency, and facial and abducens nerve paresis.11 When nivolumab was administered at doses of 3 mg/kg and 10 mg/kg, clinically

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Drug Update significant, immune-mediated adverse reactions were observed, including hypophysitis, diabetic ketoacidosis, hypo­ pituitarism, Guillain-Barré syndrome, and myasthenic syndrome.11 If an immune-mediated adverse reaction is suspected, patients who receive nivolumab must be evaluated to exclude other causes.11 Nivolumab therapy should be withheld, and corticosteroid therapy should be administered based on the severity of the reaction. Upon improvement of the immune-mediated adverse reaction to grade 1 or less, a corticosteroid taper can be started and continued for at least 1 month. Depending on the severity of the event, nivolumab can be restarted.11 Embryofetal toxicity. Nivolumab therapy may cause fetal harm when it ­­is administered to a pregnant woman.11 Women of reproductive potential should use effective contraception during nivolumab therapy and for at least 5 months after the last dose. Women who become pregnant while taking nivolu­ mab should be made aware of the potential risk of nivolumab to the fetus.11 Use in Specific Populations

Pediatric patients. The safety and efficacy of nivolumab in pediatric pa-

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tients have not been established.11 Geriatric use. The clinical studies of nivolumab did not include sufficient numbers of patients aged ≥65 years to determine whether they respond differently compared with younger patients.11 Pregnancy. There are no human data to describe the risk associated with nivolumab use during pregnancy. Pregnant women should be advised of the potential risk of nivolumab therapy to the fetus.11 Nursing mothers. It is not known whether nivolumab is present in human milk. Because many drugs, including antibodies, are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from nivolumab, women should be advised to discontinue breastfeeding during treatment with nivolumab.11 Conclusion

Nivolumab is the second PD-1 inhibitor approved by the FDA for the treatment of patients with unresectable or metastatic melanoma. Based on an interim analysis of phase 3 clinical data, this novel agent is an effective and safe alternative for patients with unresectable or metastatic melanoma and disease progression after ipilimumab therapy,

and if the patient is positive for a BRAF V600 mutation, after treatment with a BRAF inhibitor.

Nivolumab was approved under the FDA’s accelerated approval program based on the response rate data. As a condition of accelerated approval, the FDA requires confirmatory trials to verify the agent’s clinical benefit. The Checkmate-037 clinical trial is designed to compare the overall survival rate of patients who receive nivolumab therapy with the overall survival rate of patients who receive chemotherapy. An interim analysis of overall survival was not performed at the time of the response rate analysis.

The efficacy and safety of nivolumab are being evaluated in several other tumors; these include metastatic nonsquamous non–small-cell lung cancer, metastatic breast cancer, metastatic colon cancer, follicular lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma.13 n References

1. Skin Cancer Foundation. What is melanoma? www. skincancer.org/skin-cancer-information/melanoma. Accessed January 23, 2015.

2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer.cancer.gov/statfacts/ html/melan.html. Accessed January 23, 2015.

3. Reed KB, Brewer JD, Lohse CM, et al. Increasing in-

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cidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.

4. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973-2009. Pediatrics. 2013;131:846854.

5. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked database. Appl Health Econ Health Policy. 2009;7:31-41.

6. American Cancer Society. Treatment of melanoma skin cancer by stage. Revised December 23, 2014. www. cancer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-by-stage. Accessed January 23, 2015.

7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/ PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.

8. US Food and Drug Administration. FDA approves Keytruda for advanced melanoma. Press release. September 4, 2014. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm412802.htm. Accessed January 29, 2015.

9. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck & Co; January 2015.

10. US Food and Drug Administration. FDA approves Opdivo for advanced melanoma. Press release. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm 427716.htm. Accessed January 29, 2015.

11. Opdivo (nivolumab) injection [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2014.

12. Bristol-Myers Squibb. Positive phase 3 data for Opdivo (nivolumab) in advanced melanoma patients previously treated with Yervoy (ipilimumab) presented at the ESMO 2014 Congress; first phase 3 results presented for a PD-1 immune checkpoint inhibitor. September 29, 2014. http://news.bms.com/press-release/rd-news/positive-­ phase-3-data-opdivo-nivolumab-advanced-melanoma-­ patients-previously-t. Accessed January 27, 2015.

13. ClinicalTrials.gov. Nivolumab. Search results. http://clinicaltrials.gov/ct2/results?term=nivolumab& Search=Search. Accessed January 27, 2015.

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Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Lukeâ&#x20AC;&#x2122;s Cancer Center

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