AHDB June 2015 Vol 8 No 4 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN ™ JUNE 2015

VOLUME 8, NUMBER 4

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Hematology/Oncology Theme Issue EDITORIAL

The Continuation of Care David B. Nash, MD, MBA

BUSINESS

Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer ™

Lorie A. Ellis, PhD; Marie-Hélène Lafeuille, MA; Laurence Gozalo, PhD; Dominic Pilon, MA; Patrick Lefebvre, MA; Scott McKenzie, MD Stakeholder Perspective: Comparing Cost and Utilization of 2 Therapies for Metastatic Castration-Resistant Prostate Cancer By Matthew Mitchell, PharmD, MBA, FAMCP

Estimating the Costs of Therapy in Patients with Relapsed and/or Refractory Multiple Myeloma: A Model Framework Anuja Roy, PhD, MBA; Jonathan K. Kish, PhD, MPH; Lisa Bloudek, PharmD, MS; David S. Siegel, MD, PhD; Sundar Jagannath, MD; Denise Globe, PhD; Emil T. Kuriakose, MD; Kristen Migliaccio-Walle, BS Stakeholder Perspective: The Rationale for Comparing the Costs of Competing Treatment Options in Oncology By James T. Kenney, Jr, RPh, MBA

INDUSTRY TRENDS

Oncology Innovation and Challenging Choices: Balancing Value and Funding Priorities in Light of an Abundance of New Treatment Options Michael Kleinrock

ONCOLOGY PIPELINE

The 2015 Oncology Drug Pipeline: Innovation Drives the Race to Cure Cancer Dalia Buffery, MA, ABD

8 8

CONTINUING EDUCATION

The Emerging Role of Immuno-oncology in Treating Solid Tumors: A ValueBased Perspective for Managed Care Pharmacists Sanjiv S. Agarwala, MD

www.AHDBonline.com

DISCOVERING HOW FAR THERAPY CAN GO IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections - Fatal and non-fatal infections have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA®. Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly. Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or newonset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification. Second Primary Malignancies - Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

IMBRUVICA® (ibrutinib) is the first and only FDA-approved therapy for use in patients with Waldenström’s macroglobulinemia (WM) IMBRUVICA® is approved for use in 4 indications IMBRUVICA® is indicated for the treatment of patients with Mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Chronic lymphocytic leukemia with 17p deletion. Waldenström’s macroglobulinemia (WM).

Tumor Lysis Syndrome - Tumor lysis syndrome has been reported with IMBRUVICA® therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden).

DRUG INTERACTIONS

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA®. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

CYP3A Inducers - Avoid co-administration with strong CYP3A inducers.

ADVERSE REACTIONS The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, and rash. Seven percent of patients receiving IMBRUVICA® discontinued treatment due to adverse events.

CYP3A Inhibitors - Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA® dose. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit

www.IMBRUVICA.com © Pharmacyclics, Inc. 2015 © Janssen Biotech, Inc. 2015 1/15 PRC-00770

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information]. Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. [See Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly. Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in Full Prescribing Information]. Second Primary Malignancies: Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11 %). Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g. high tumor burden). Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL or WM, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions]

IMBRUVICA® (ibrutinib) capsules Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience: Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1. Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

IMBRUVICA® (ibrutinib) capsules

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia. Approximately five percent of patients receiving IMBRUVICA in Study 1 and Study 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients. Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Respiratory, thoracic and mediastinal disorders Musculoskeletal and connective tissue disorders Nervous system disorders Metabolism and nutrition disorders Neoplasms benign, malignant, unspecified Injury, poisoning and procedural complications Psychiatric disorders Vascular disorders

All Grades (%)

Grade 3 or 4 (%)

Diarrhea Constipation Nausea Stomatitis Vomiting Abdominal pain Dyspepsia Upper respiratory tract infection Sinusitis Skin infection Pneumonia Urinary tract infection Fatigue Pyrexia Peripheral edema Asthenia Chills Bruising Rash Petechiae Cough Oropharyngeal pain Dyspnea Musculoskeletal pain Arthralgia Muscle spasms Dizziness Headache Peripheral neuropathy Decreased appetite

63 23 21 21 19 15 13

4 2 2 0 2 0 0

48 21 17 10 10 31 25 23 13 13 54 27 17 19 15 10 27 23 19 21 19 10 17

2 6 6 8 0 4 2 0 4 0 2 0 0 0 0 0 6 0 2 0 2 0 2

Second malignancies*

10*

Laceration

Anxiety Insomnia Hypertension

10 10 17

0 0 8

Preferred Term

*One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) Platelets Decreased 71 10 Neutrophils Decreased 54 27 Hemoglobin Decreased 44 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2. Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

System Organ Class ADR Term Gastrointestinal disorders Diarrhea Nausea Stomatitis* Constipation Vomiting General disorders and administration site conditions Fatigue Pyrexia Infections and infestations Upper respiratory tract infection Pneumonia* Sinusitis* Urinary tract infection Skin and subcutaneous tissue disorders Rash* Petechiae Bruising* Musculoskeletal and connective tissue disorders Musculoskeletal Pain* Arthralgia Nervous system disorders Headache Dizziness Injury, poisoning and procedural complications Contusion Eye disorders Vision blurred

IMBRUVICA (N=195) All Grade Grades 3 or 4 (%) (%)

Ofatumumab (N=191) All Grade Grades 3 or 4 (%) (%)

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

Subjects with multiple events for a given ADR term are counted once only for each ADR term. The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms

IMBRUVICA® (ibrutinib) capsules

Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

IMBRUVICA (N=195) Grade All 3 or 4 Grades (%) (%) 51 23 52 5 36 0

Ofatumumab (N=191) Grade All 3 or 4 Grades (%) (%) 57 26 45 10 21 0

* Based on laboratory measurements per IWCLL criteria Waldenström’s Macroglobulinemia The data described below reflect exposure to IMBRUVICA in an open label clinical trial that included 63 patients with previously treated WM. The most commonly occurring adverse reactions in the WM trial (≥ 20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue. Six percent of patients receiving IMBRUVICA in the WM trial discontinued treatment due to adverse events. Adverse events leading to dose reduction occurred in 11% of patients. Adverse reactions and laboratory abnormalities described below in Tables 7 and 8 reflect exposure to IMBRUVICA with a median duration of 11.7 months in the WM trial. Table 7: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Waldenström’s Macroglobulinemia (N=63) System Organ Class Gastrointestinal disorders

Skin and subcutaneous tissue disorders General disorders and administrative site conditions Musculoskeletal and connective tissue disorders Infections and infestations

Respiratory, thoracic and mediastinal disorders Nervous system disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps)

All Grades (%) 37 21 16

Grade 3 or 4 (%) 0 0 0

13 22 16 11 21

0 0 0 0 0

Muscle spasms Arthropathy

21 13

0 0

Upper respiratory tract infection Sinusitis Pneumonia* Skin infection* Epistaxis Cough

19 19 14 14 19 13

0 0 6 2 0 0

Dizziness Headache Skin cancer*

14 13 11

0 0 0

Preferred Term Diarrhea Nausea Stomatitis* Gastroesophageal reflux disease Rash* Bruising* Pruritus Fatigue

The system organ class and individual ADR terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 8: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with WM (N=63)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=63) All Grades (%) Grade 3 or 4 (%) 43 13 44 19 13 8

* Based on laboratory measurements.

Postmarketing Experience: The following adverse reactions have been identified during post-approval use of IMBRUVICA. 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. Hypersensitivity reactions including anaphylactic shock (fatal), urticaria, and angioedema have been reported. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg). Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in Full Prescribing Information]. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in Full Prescribing Information]. CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively. Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions]. Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, 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 IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients. Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in Full Prescribing Information]. Of the 63 patients treated for WM, 59% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), and infections (pneumonia and urinary tract infection) occurred more frequently among elderly patients. Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in Full Prescribing Information].

IMBRUVICA® (ibrutinib) capsules Hepatic Impairment: Ibrutinib is metabolized in the liver. In a hepatic impairment study, data showed an increase in ibrutinib exposure. Following single dose administration, the AUC of ibrutinib increased 2.7-, 8.2- and 9.8-fold in subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment compared to subjects with normal liver function. The safety of IMBRUVICA has not been evaluated in patients with hepatic impairment. Monitor patients for signs of IMBRUVICA toxicity and follow dose modification guidance as needed. It is not recommended to administer IMBRUVICA to patients with moderate or severe hepatic impairment (Child-Pugh classes B and C) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. Plasmapheresis: Management of hyperviscosity in patients with WM may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions]. • Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in Full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration. Active ingredient made in China. Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2015 © Janssen Biotech, Inc. 2015 PRC-00786

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Founding Dean, The Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Thomas Jefferson University, Philadelphia, PA DEPUTY EDITORS

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson School of Population Health, Thomas Jefferson University Laura T. Pizzi, PharmD, MPH, RPh Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Gregory Shaeffer, MBA, RPh, FASHP Vice President, Consulting Pharmacy Healthcare Solutions AmerisourceBurgen, Harrisburg, PA Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang T. Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD Vice President and General Manager Aesthetic & Corrective Business Galderma Laboratories, LP Fort Worth, TX HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City

172

Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD, BCACP Staff Vice President HealthCore, Inc., Wilmington, DE David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Byron C. Scott, MD, MBA Medical Director National Clinical Medical Leader Truven Health Analytics, Chicago, IL Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy Presbyterian College, Clinton, SC Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

PAYER-PROVIDER FINANCES

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc, New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia PHARMACOECONOMICS

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Senior 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 Founding Editor-in-Chief Robert E. Henry

Hematology/Oncology Theme Issue EDITORIAL

175 The Continuation of Care David B. Nash, MD, MBA INTRODUCTION

184 Health Economics in Oncology: A Necessary Tool for Value-Based Patient Care BUSINESS

185 Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer Lorie A. Ellis, PhD; Marie-Hélène Lafeuille, MA; Laurence Gozalo, PhD; Dominic Pilon, MA; Patrick Lefebvre, MA; Scott McKenzie, MD 195 Stakeholder Perspective: Comparing Cost and Utilization of 2 Therapies for Metastatic Castration-Resistant Prostate Cancer By Matthew Mitchell, PharmD, MBA, FAMCP 204 Estimating the Costs of Therapy in Patients with Relapsed and/or Refractory Multiple Myeloma: A Model Framework Anuja Roy, PhD, MBA; Jonathan K. Kish, PhD, MPH; Lisa Bloudek, PharmD, MS; David S. Siegel, MD, PhD; Sundar Jagannath, MD; Denise Globe, PhD; Emil T. Kuriakose, MD; Kristen Migliaccio-Walle, BS 214 Stakeholder Perspective: The Rationale for Comparing the Costs of Competing Treatment Options in Oncology By James T. Kenney, Jr, RPh, MBA Continued on page 174

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INDUSTRY TRENDS

196 Oncology Innovation and Challenging Choices: Balancing Value and Funding Priorities in Light of an Abundance of New Treatment Options Michael Kleinrock ONCOLOGY PIPELINE

216 The 2015 Oncology Drug Pipeline: Innovation Drives the Race to Cure Cancer Dalia Buffery, MA, ABD CONTINUING EDUCATION

226 The Emerging Role of Immuno-oncology in Treating Solid Tumors: A ValueBased Perspective for Managed Care Pharmacists Sanjiv S. Agarwala, MD ONLINE FIRST Guiding Employer Management of Specialty Drugs American Health & Drug Benefits is included in the

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EDITORIAL

The Continuation of Care David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Founding Dean, J efferson School of Population Health, Philadelphia, PA

his year marks my 25th anniversary as a faculty member at Thomas Jefferson University, something of which I am extremely proud. It is also the 25th anniversary of my service on our Pharmacy and Therapeutics committee, where I have the privilege of chairing the Medication Quality subcommittee. This editorial is focused on the work of the Pharmacoeconomics and Cost Clinical Effectiveness (PEACE) committee, an important group that I have written about previously.1 A recent project by the PEACE committee that was carried out by very capable members of the Department of Pharmacy at Thomas Jefferson University Hospital (TJUH) deserves further dissemination. Let me explain. When a patient is admitted to TJUH, which occurs 36,000 times annually, the average stay in our hospital is approximately 5 days. On discharge, the vast majority of patients receive multiple prescriptions for the continuation of their care. Here is where the challenge begins. As most of our readers know, third-party payers, managed care companies, and other healthcare groups have programs in place that provide cost-effective pharmacotherapy for their patients. This is often characterized by several key strategies. Let’s first describe these strategies and then connect them back to the discharge process. Managed care programs are designed to rationalize the pharmacotherapy process. This starts with the design and implementation of a formulary—the list of drugs that are paid for by the entity in question. Formularies can be open, closed, or tiered. In an open formulary, nonformulary drugs are available, but usually at a very high out-of-pocket cost to the patient. Generally speaking, a closed formulary means that the payer will not reimburse the pharmacy for nonformulary drugs. In a tiered formulary, patients pay progressively greater copays for the preferred and the nonpreferred brand-name drugs. Yet another strategy is step therapy, which is the practice of beginning drug therapy for a medical condition using the most cost-effective and safest drug, and then stepping up through a series of sequences of alternating drug therapies if the preceding treatment option fails. Typically, as a patient progresses through the therapeutic steps, the drugs become more expensive. Another strategy may be quantity limits, in which the payer will only

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June 2015

pay for a specific quantity or supply of a medication. So, here comes the challenge. On discharge, when physicians provide patients with prescriptions for the drugs they were receiving in the hospital, they typically do so not knowing which restriction strategy may apply to these prescriptions. Simply put, a physician prescribes a drug that he or she deems critical to the patient’s ongoing recovery, without knowing whether (or to what extent) the drug will be covered by the patient’s insurance. This challenge is of critical importance to patients and to physicians. If the drugs are not covered, if they are very expensive, or if they are potentially not even available, we are then setting patients up for a series of potentially dramatic challenges and possible negative health outcomes. Regrettably, many physicians, nurses, and even pharmacists often do not ask patients, while they are still in the inpatient setting, which drugs will be covered by their particular insurance plan upon discharge.

Regrettably, many physicians, nurses, and even pharmacists often do not ask patients, while they are still in the inpatient setting, which drugs will be covered by their particular insurance plan upon discharge. We therefore have to ask the question, “Can our recently discharged patients continue using the medication that was prescribed while they were in the hospital?” One process improvement that may help is for providers to routinely say to patients on their admission to the hospital, “Tell us more about your drugs, and how they are paid for in the outpatient setting.” If the medical team decides that the patient needs a specific prescription while still in the hospital, then the team can also potentially confirm that this drug will be available if needed on discharge. If the provider team discovers that a particular drug is not covered as an outpatient, they can work to provide a suitable substitution before the patient’s discharge from the hospital. Although this means extra work for the harried inpatient provider team, it may avoid problems for the pa-

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EDITORIAL

tient (and a potentially unnecessary readmission) down the road. The PEACE committee examined a handful of clinical examples. I will summarize aspects of their analysis here, after providing a brief context. Local payers in TJUH’s market include Independence Blue Cross and Aetna, which have 3-tiered open formularies. The managed Medicaid payers, all of which have closed formu laries, are Keystone First, HealthPartners, and UnitedHealthcare Community Plan. Perhaps ironically, Jefferson’s self-funded insurance plan, which is implemented through OptumRx, has a 2-tier open formulary.

Burdening our patients with prescriptions that require prior authorization (which may take days after discharge to be approved) or, even worse, giving them a prescription for a drug that is not even on their insurance company’s formulary, is an all too common problem. I am confident that we can do better for our patients. Now that we know the players, let’s review the example of fluticasone plus salmeterol (Advair). Independence Blue Cross and Aetna have a prior authorization program implemented for patients who are prescribed fluticasone plus salmeterol; Keystone First and Health- Partners do not even have fluticasone plus salmeterol on their formulary. For Jefferson employees who happen to be admitted to our own hospital, there are no restrictions on fluticasone plus salmeterol. A second example is celecoxib (Celebrex). Again, Independence Blue Cross and Aetna have a prior authorization program, whereas Keystone First has a step therapy program. Do most providers in our busy university hospital have any knowledge of these restrictions or

regulations regarding a specific medication? I very much doubt it. Let’s consider a potential solution to this very impor tant issue regarding the availability of medications after discharge. I would offer the following multipoint plan: 1. All providers must ask patients about the insurance coverage for their current medications and any drugs that they may plan to take in the near term. This will require teamwork on the part of the physicians, pharmacists, and others to get the answers to these sometimes very complex questions 2. It is incumbent on the care team to facilitate prior authorization while patients are still in the hospital, so that we do not unnecessarily prolong their hospital stay and incur an even larger medical bill 3. There must be greater communication between the inpatient and outpatient teams, such as the admitting physician, hospitalists, and other people caring for patients exclusively in the ambulatory setting. This is particularly critical for patients receiving inpatient and outpatient chemotherapy for cancer. If your institution has a robust program already in place that facilitates the transition of care from the inpatient to the outpatient settings, especially with regard to prescriptions for critical medications, I sure would like to learn more about the progress you are making. Burdening our patients with prescriptions that require prior authorization (which may take days after discharge to be approved) or, even worse, giving them a prescription for a drug that is not even on their insurance company’s formulary, is an all too common problem. I am confident that we can do better for our patients, with a commitment to improving the continuation of care. As always, I am interested in your views, and you can reach me via e-mail at david.nash@jefferson.edu. n

Reference

1. Nash DB. Give PEACE a chance. P T. 2005;30:197.

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Vol 8, No 4

For patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapyâ&#x20AC;Ś

What if You Could Do More?

Expect More. Do More.

Proven Superior Survival With the Only Immuno-Oncology Therapy in Previously Treated Metastatic Squamous NSCLC INDICATION OPDIVO速 (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

SELECT IMPORTANT SAFETY INFORMATION OPDIVO is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, nephritis and renal dysfunction, hypothyroidism, hyperthyroidism, other adverse reactions; and embryofetal toxicity.

For patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy

OPDIVO Demonstrated Superior Survival vs Standard of Care1-5 100

MEDIAN OS 9.2 MONTHS vs 6.0 MONTHS

Probability of Survival (% of Patients)

(95% CI: 7.3-13.3 vs 5.1-7.3) HR=0.59; 95% CI: 0.44-0.79; P=0.00025

70 60 50 40 30 20 10 0 0

Number at risk OPDIVO 135 137 DOCETAXEL

31 14

15 7

7 2

0 0

OS (Months) 113 103

86 68

69 45

52 30

Refer to Figure 1 in the Full Prescribing Information for data on censored patients. CI=confidence interval; HR=hazard ratio; IV=intravenous; OS=overall survival; PD-1=programmed death-1; PD-L1=programmed death ligand 1.

Study design: OPDIVO was evaluated in a randomized (1:1), open-label, phase 3 study of OPDIVO 3 mg/kg IV every 2 weeks (n=135) vs docetaxel 75 mg/m2 IV every 3 weeks (n=137). The primary endpoint of the study was overall survival.1,6 Results were based on the prespecified interim analysis conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the OPDIVO arm and 113 in the docetaxel arm).1 ■

This study included patients regardless of PD-L1 status; PD-L1 testing is not required for a treatment decision

Based on the unprecedented results, OPDIVO achieved the benchmark goal of improving overall survival in metastatic squamous NSCLC The safety of OPDIVO (3 mg/kg IV over 60 minutes every 2 weeks) was evaluated in CHECKMATE 063 (Trial 3), a singlearm study of 117 patients with metastatic squamous NSCLC who had progressed after receiving a platinum-based therapy and at least one additional systemic treatment regimen.1,7 Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction.

Serious Adverse Reactions ■

In Trial 3, serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions ■

The most common adverse reactions (≥20%) reported with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see additional Important Safety Information on the following page.

Responding to Your Needs in 24 Hours or Less

IMPORTANT SAFETY INFORMATION Immune-Mediated Pneumonitis

Severe pneumonitis or interstitial lung disease, including fatal

cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immunemediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO; no cases occurred in Trial 3. In Trial 3, immunemediated pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO including five Grade 3 and two Grade 2 cases. Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids for Grade 2 or greater pneumonitis. Permanently discontinue OPDIVO for Grade 3 or 4 and withhold OPDIVO until resolution for Grade 2.

Immune-Mediated Colitis

In Trial 3, diarrhea occurred in 21% (24/117) of patients receiving

OPDIVO. Grade 3 immune-mediated colitis occurred in 0.9% (1/117) of patients. Monitor patients for immune-mediated colitis. Administer corticosteroids for Grade 2 (of more than 5 days duration), 3, or 4 colitis. Withhold OPDIVO for Grade 2 or 3. Permanently discontinue OPDIVO for Grade 4 colitis or recurrent colitis upon restarting OPDIVO.

Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids for Grade 2 or greater transaminase elevations. Withhold OPDIVO for Grade 2 and permanently discontinue OPDIVO for Grade 3 or 4 immunemediated hepatitis. Immune-Mediated Nephritis and Renal Dysfunction

In Trial 3, the incidence of elevated creatinine was 22%. Immunemediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. Monitor patients for elevated serum creatinine prior to and periodically during treatment. For Grade 2 or 3 serum creatinine elevation, withhold OPDIVO and administer corticosteroids; if worsening or no improvement occurs, permanently discontinue OPDIVO. Administer corticosteroids for Grade 4 serum creatinine elevation and permanently discontinue OPDIVO.

Immune-Mediated Hypothyroidism and Hyperthyroidism

In Trial 3, hypothyroidism occurred in 4.3% (5/117) of patients

receiving OPDIVO. Hyperthyroidism occurred in 1.7% (2/117) of patients including one Grade 2 case. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse

administered at doses 3 mg/kg and 10 mg/kg, additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. Based on the severity of adverse reaction, withhold OPDIVO, administer high-dose corticosteroids, and, if appropriate, initiate hormone-replacement therapy. Embryofetal Toxicity

Based on its mechanism of action, OPDIVO can cause fetal harm

when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO.

Lactation

It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment.

Serious Adverse Reactions

In Trial 3, serious adverse reactions occurred in 59% of patients

receiving OPDIVO. The most frequent serious adverse drug reactions reported in ≥2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain.

Common Adverse Reactions

The most common adverse reactions (≥20%) reported

with OPDIVO in Trial 3 were fatigue (50%), dyspnea (38%), musculoskeletal pain (36%), decreased appetite (35%), cough (32%), nausea (29%), and constipation (24%).

Please see brief summary of Full Prescribing Information on the following pages. References: 1. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015. 2. Taxotere [package insert]. Bridgewater, NJ: sanofi-aventis U.S. LLC; 2014. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.4.2015. ©2015 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 3, 2015. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 4. Garassino MC, Martelli O, Broggini M, et al; on behalf of the TAILOR trialists. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial. Lancet Oncol. 2013;14(10):981-988. 5. Kawaguchi T, Ando M, Asami K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced nonsmall-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol. 2014;32(18):19021908. 6. Bristol-Myers Squibb. Study of BMS-936558 (nivolumab) compared to docetaxel in previously treated advanced or metastatic squamous cell non-small cell lung cancer (NSCLC) (CheckMate 017). Identifier: NCT01642004. https://clinicaltrials.gov/ct2/show/NCT01642004. Updated December 31, 2014. Accessed February 5, 2015. 7. Rizvi NA, Mazières J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16:257-265.

reactions occurred in <2% of OPDIVO-treated patients: adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction and vasculitis. Across clinical trials of OPDIVO OPDIVO® and the related logo are trademarks of Bristol-Myers Squibb Company. ©2015 Bristol-Myers Squibb Company. All rights reserved. Printed in USA. 1506US15BR00482-01-01 03/15

OPDIVO® (nivolumab) injection, for intravenous use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. INDICATIONS AND USAGE OPDIVO® (nivolumab) is indicated for the treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy [see Clinical Studies (14.2) in full Prescribing Information]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Immune-Mediated Pneumonitis Severe pneumonitis or interstitial lung disease, including fatal cases, occurred with OPDIVO treatment. Across the clinical trial experience in 691 patients with solid tumors, fatal immune-mediated pneumonitis occurred in 0.7% (5/691) of patients receiving OPDIVO. No cases of fatal pneumonitis occurred in Trial 3; all five fatal cases occurred in a dose-finding study with OPDIVO doses of 1 mg/kg (two patients), 3 mg/kg (two patients), and 10 mg/kg (one patient). In Trial 3, pneumonitis occurred in 6% (7/117) of patients receiving OPDIVO, including five Grade 3 and two Grade 2 cases, all immune-mediated. The median time to onset was 3.3 months (range: 1.4 to 13.5 months). All seven patients discontinued OPDIVO for pneumonitis or another event and all seven patients experienced complete resolution of pneumonitis following receipt of high-dose corticosteroids (at least 40 mg prednisone equivalents per day). Monitor patients for signs and symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater pneumonitis, followed by corticosteroid taper. Permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) pneumonitis and withhold OPDIVO until resolution for moderate (Grade 2) pneumonitis [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Colitis In Trial 3, diarrhea occurred in 21% (24/117) of patients. Immune-mediated colitis (Grade 3) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 6.7 months. The patient received high-dose corticosteroids and was permanently discontinued from OPDIVO (nivolumab). Complete resolution occurred. Monitor patients for immune-mediated colitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for severe (Grade 3) or life-threatening (Grade 4) colitis. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper for moderate (Grade 2) colitis of more than 5 days duration; if worsening or no improvement occurs despite initiation of corticosteroids, increase dose to 1 to 2 mg/kg/day prednisone equivalents. Withhold OPDIVO for Grade 2 or 3 immune-mediated colitis. Permanently discontinue OPDIVO for Grade 4 colitis or for recurrent colitis upon restarting OPDIVO [see Dosage and Administration (2.2) in full Prescribing Information]. Immune-Mediated Hepatitis In Trial 3, the incidences of increased liver test values were AST (16%), alkaline phosphatase (14%), ALT (12%), and total bilirubin (2.7%). No cases of immunemediated hepatitis occurred in this trial. Monitor patients for abnormal liver tests prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for Grade 2 or greater transaminase elevations, with or without concomitant elevation in total bilirubin. Withhold OPDIVO for moderate (Grade 2) and permanently discontinue OPDIVO for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Nephritis and Renal Dysfunction In Trial 3, the incidence of elevated creatinine was 22%. Immune-mediated renal dysfunction (Grade 2) occurred in 0.9% (1/117) of patients. The time to onset in this patient was 0.8 months. The patient received high-dose corticosteroids. OPDIVO was withheld, and the patient discontinued due to disease progression prior to receiving additional OPDIVO. Immune-mediated renal dysfunction was ongoing. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) serum creatinine elevation and permanently discontinue OPDIVO. For severe (Grade 3) or moderate (Grade 2) serum creatinine elevation, withhold OPDIVO and administer

corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents followed by corticosteroid taper; if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue OPDIVO (nivolumab) [see Dosage and Administration (2.2) in full Prescribing Information and Adverse Reactions]. Immune-Mediated Hypothyroidism and Hyperthyroidism In Trial 3, patients were evaluated for thyroid function at baseline, first day of treatment, and every 6 weeks. Hypothyroidism occurred in 4.3% (5/117) of patients. The median time to onset for these five cases was 4.1 months (range: 1.4 to 4.6 months). All five patients with hypothyroidism received levothyroxine. Complete resolution of hypothyroidism occurred in one patient allowing discontinuation of levothyroxine. Interruption of OPDIVO did not occur in these five patients. Hyperthyroidism occurred in 1.7% (2/117) of patients. One patient experienced Grade 2 hyperthyroidism 5.2 months after the first dose of OPDIVO, requiring treatment with high-dose corticosteroids and methimazole. Thyroid laboratory tests returned to normal 4.7 months later. Monitor thyroid function prior to and periodically during treatment. Administer hormone replacement therapy for hypothyroidism. Initiate medical management for control of hyperthyroidism. There are no recommended dose adjustments of OPDIVO for hypothyroidism or hyperthyroidism. Other Immune-Mediated Adverse Reactions Other clinically significant immune-mediated adverse reactions can occur. Immune-mediated adverse reactions may occur after discontinuation of OPDIVO therapy. The following clinically significant, immune-mediated adverse reactions occurred in less than 2% of OPDIVO-treated patients (n=385): adrenal insufficiency, uveitis, pancreatitis, facial and abducens nerve paresis, demyelination, autoimmune neuropathy, motor dysfunction, and vasculitis. Across clinical trials of OPDIVO administered at doses of 3 mg/kg and 10 mg/kg the following additional clinically significant, immune-mediated adverse reactions were identified: hypophysitis, diabetic ketoacidosis, hypopituitarism, GuillainBarré syndrome, and myasthenic syndrome. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, withhold OPDIVO, administer highdose corticosteroids, and if appropriate, initiate hormone-replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting OPDIVO after completion of corticosteroid taper based on the severity of the event [see Dosage and Administration (2.2) in full Prescribing Information]. Embryofetal Toxicity Based on its mechanism of action and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months after the last dose of OPDIVO [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling. • Immune-Mediated Pneumonitis [see Warnings and Precautions] • Immune-Mediated Colitis [see Warnings and Precautions] • Immune-Mediated Hepatitis [see Warnings and Precautions] • Immune-Mediated Nephritis and Renal Dysfunction [see Warnings and Precautions] • Immune-Mediated Hypothyroidism and Hyperthyroidism [see Warnings and Precautions] • Other Immune-Mediated Adverse Reactions [see Warnings and Precautions] 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. The data described in the WARNINGS and PRECAUTIONS section and below reflect exposure to OPDIVO in Trial 3, a single-arm trial in patients with metastatic squamous non-small cell lung cancer (NSCLC).

Clinically significant adverse reactions were evaluated in a total of 691 patients enrolled in Trials 1, 3, or an additional dose finding study (n=306) administering OPDIVO (nivolumab) at doses of 0.1 to 10 mg/kg every 2 weeks [see Warnings and Precautions]. Metastatic Squamous Non-Small Cell Lung Cancer The safety of OPDIVO was evaluated in Trial 3, a single-arm multinational, multicenter trial in 117 patients with metastatic squamous NSCLC and progression on both a prior platinum-based therapy and at least one additional systemic therapy [see Clinical Studies (14.2) in full Prescribing Information]. Patients received 3 mg/kg of OPDIVO administered intravenously over 60 minutes every 2 weeks. The median duration of therapy was 2.3 months (range: 1 day to 16.1+ months). Patients received a median of 6 doses (range: 1 to 34). Trial 3 excluded patients with active autoimmune disease, symptomatic interstitial lung disease, or untreated brain metastasis. The median age of patients was 65 years (range: 37 to 87) with 50% ≥65 years of age and 14% ≥75 years of age. The majority of patients were male (73%) and white (85%). All patients received two or more prior systemic treatments. Baseline disease characteristics of the population were recurrent Stage IIIb (6%), Stage IV (94%), and brain metastases (1.7%). Baseline ECOG performance status was 0 (22%) or 1 (78%). OPDIVO was discontinued due to adverse reactions in 27% of patients. Twenty-nine percent of patients receiving OPDIVO had a drug delay for an adverse reaction. Serious adverse reactions occurred in 59% of patients receiving OPDIVO. The most frequent serious adverse reactions reported in at least 2% of patients were dyspnea, pneumonia, chronic obstructive pulmonary disease exacerbation, pneumonitis, hypercalcemia, pleural effusion, hemoptysis, and pain. Table 1 summarizes adverse reactions that occurred in at least 10% of patients. The most common adverse reactions (reported in at least 20% of patients) were fatigue, dyspnea, musculoskeletal pain, decreased appetite, cough, nausea, and constipation. Table 1:

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3)

Table 1: (Continued)

Adverse Reactions Occurring in ≥10% of Patients for All NCI CTCAE* Grades or ≥5% for Grades 3-4 (Trial 3) OPDIVO (nivolumab) (n=117)

Adverse Reaction

All Grades

Investigations Decreased weight Infections and Infestations Pneumoniag

0.9

*a National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0.

Includes face edema, peripheral edema, local swelling, localized edema, lymphoedema. Includes chest discomfort and noncardiac chest pain. Includes back pain, bone pain, musculoskeletal chest pain, myalgia, neck pain, pain in extremity, spinal pain. d Includes arthritis and osteoarthritis. e Includes abdominal pain lower, abdominal pain upper, gastrointestinal pain. f Includes maculopapular rash, rash erythematous, erythema, dermatitis, dermatitis exfoliative, and dermatitis acneiform. g Includes lung infection and pneumonia aspiration. b c

Other clinically important adverse reactions in less than 10% of patients in Trial 3 were: General Disorders and Administration Site Conditions: stomatitis Nervous System Disorders: peripheral neuropathy Infections and Infestations: bronchitis, upper respiratory tract infection Table 2:

Laboratory Abnormalities Worsening from Baseline Occurring in ≥10% of Patients for all NCI CTCAE Grades or ≥2% for Grades 3-4 (Trial 3) Percentage of Patients with Worsening Laboratory Test from Baselinea

Grades 3-4

Percentage (%) of Patients General Disorders and Administration Site Conditions Fatigue Asthenia Edemaa Pyrexia Chest painb Pain Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Cough Musculoskeletal and Connective Tissue Disorders Musculoskeletal painc Arthralgiad Metabolism and Nutrition Disorders Decreased appetite Gastrointestinal Disorders Nausea Constipation Vomiting Diarrhea Abdominal paine Skin and Subcutaneous Tissue Disorders Rashf Pruritus

Grades 3-4

Percentage (%) of Patients

OPDIVO (n=117) Adverse Reaction

All Grades

50 19 17 17 13 10

7 1.7 1.7 0 0 2.6

38 32

9 1.7

36 13

6 0

2.6

29 24 19 18 16

1.7 0 0.9 2.6 1.7

16 11

0.9 0.9 (Continued)

Test Chemistry Hyponatremia Increased creatinine Hypercalcemia Hypokalemia Hypomagnesemia Hypocalcemia Hyperkalemia Increased AST Increased alkaline phosphatase Increased ALT Hematology Lymphopenia Anemia Thrombocytopenia a

All Grades

Grades 3-4

38 22 20 20 20 18 18 16 14 12

10 0 2.6 2.6 0 1.8 4.4 0.9 0 0

47 28 14

16 2.6 0

Each test incidence is based on the number of patients who had both baseline and at least one on-study laboratory measurement available (range 111 to 114 patients).

Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Of 281 patients who were treated with OPDIVO 3 mg/kg every 2 weeks and evaluable for the presence of anti-product antibodies, 24 patients (8.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. Neutralizing antibodies were detected in two patients (0.7%). There was no evidence of altered pharmacokinetic profile or toxicity profile with anti-product binding antibody development based on the population pharmacokinetic and exposure-response analyses. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample

collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to OPDIVO (nivolumab) with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No formal pharmacokinetic drug-drug interaction studies have been conducted with OPDIVO. USE IN SPECIFIC POPULATIONS

Hepatic Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended for patients with mild hepatic impairment. OPDIVO (nivolumab) has not been studied in patients with moderate or severe hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE There is no information on overdosage with OPDIVO.

Pregnancy

PATIENT COUNSELING INFORMATION

Risk Summary Based on its mechanism of action [see Clinical Pharmacology (12.1) in full Prescribing Information] and data from animal studies, OPDIVO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) in full Prescribing Information]. In animal reproduction studies, administration of nivolumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased abortion and premature infant death [see Data]. Human IgG4 is known to cross the placental barrier and nivolumab is an immunoglobulin G4 (IgG4); therefore, nivolumab has the potential to be transmitted from the mother to the developing fetus. The effects of OPDIVO are likely to be greater during the second and third trimesters of pregnancy. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data

Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of OPDIVO, including: • Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath [see Warnings and Precautions]. • Colitis: Advise patients to contact their healthcare provider immediately for diarrhea or severe abdominal pain [see Warnings and Precautions]. • Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding [see Warnings and Precautions]. • Nephritis and Renal Dysfunction: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis including decreased urine output, blood in urine, swelling in ankles, loss of appetite, and any other symptoms of renal dysfunction [see Warnings and Precautions]. • Hypothyroidism and Hyperthyroidism: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism and hyperthyroidism [see Warnings and Precautions]. Advise patients of the importance of keeping scheduled appointments for blood work or other laboratory tests [see Warnings and Precautions]. Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions, Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO [see Use in Specific Populations]. Advise women not to breastfeed while taking OPDIVO [see Use in Specific Populations].

Animal Data A central function of the PD-1/PD-L1 pathway is to preserve pregnancy by maintaining maternal immune tolerance to the fetus. Blockade of PD-L1 signaling has been shown in murine models of pregnancy to disrupt tolerance to the fetus and to increase fetal loss. The effects of nivolumab on prenatal and postnatal development were evaluated in monkeys that received nivolumab twice weekly from the onset of organogenesis through delivery, at exposure levels of between 9 and 42 times higher than those observed at the clinical dose of 3 mg/kg of nivolumab (based on AUC). Nivolumab administration resulted in a non-doserelated increase in spontaneous abortion and increased neonatal death. Based on its mechanism of action, fetal exposure to nivolumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. In surviving infants (18 of 32 compared to 11 of 16 vehicle-exposed infants) of cynomolgus monkeys treated with nivolumab, there were no apparent malformations and no effects on neurobehavioral, immunological, or clinical pathology parameters throughout the 6-month postnatal period. Lactation Risk Summary It is not known whether OPDIVO 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 OPDIVO, advise women to discontinue breastfeeding during treatment with OPDIVO. Females and Males of Reproductive Potential Contraception Based on its mechanism of action, OPDIVO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations]. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and for at least 5 months following the last dose of OPDIVO. Pediatric Use The safety and effectiveness of OPDIVO have not been established in pediatric patients. Geriatric Use Clinical studies of OPDIVO did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. Of the 117 patients treated with OPDIVO in Trial 3, 50% of patients were 65 years or older and 14% were 75 years or older. Renal Impairment Based on a population pharmacokinetic analysis, no dose adjustment is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA U.S. License No. 1713 1321663A1

Revised: March 2015 1506US15BR00210-02-01

INTRODUCTION

Health Economics in Oncology: A

Necessary Tool for Value-Based Patient Care Dalia Buffery, MA, ABD Senior Editorial Director, American Health & Drug Benefits

ncology continues to be a major focus for all healthcare stakeholders, attracting intense investments in drug development for new therapies and diagnostics that keep fueling innovation while increasing concerns for the ever-rising cost of cancer care. The call for value-based strategies in oncology has become mainstream, with providers, payers, drug manufacturers, and ultimately patients searching for ways to improve access to new therapies and best practices, implementing clinical pathways, new reimbursement metrics, and patient support services. The growing economic challenges in oncology are taking center stage in medicine. The urgency to consider cost-effective strategies in cancer therapy is of top concern for payers, as is evident in this annual Hematology/ Oncology Theme Issue from American Health & Drug Benefits. Therefore, health economics research features prominently in this issue. Lorie A. Ellis, PhD, and colleagues present a cost analysis and utilization patterns associated with 2 new therapies for patients with metastatic prostate cancer, abir aterone acetate and enzalutamide, which were approved by the US Food and Drug Administration in the past 5 years. Although no head-to-head study has yet been conducted, the authors use real-world claims data to compare these novel therapies in a large patient population. Their analysis can help payers to evaluate differentiating characteristics related to these therapies and guide their “management strategies to promote the use of cost-effective treatment regimens,” suggests Matthew Mitchell, PharmD, MBA, FAMCP, in his perspective on this study. “The ability to evaluate…real-world data, such as in the article by Ellis and colleagues, help[s] payers evaluate coverage decisions for patients with prostate cancer,” he observes. The growing need for economic modeling in oncology can provide insight into the complex pharmacoeconomic concerns in oncology and enhance clinical decision-making based on cost, quality, and value considerations, as was discussed previously in this journal.1 Perhaps responding to that call to action, Anuja Roy, PhD, MBA, and colleagues present a model framework for estimating the costs per patient with multiple myeloma using 7 common treatment regimens, to facilitate further budget impact

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analyses and cost-effectiveness comparisons with these regimens. As James T. Kenney, Jr, RPh, MBA, says in his perspective on this study, “The challenge for health plans is to apply the learning from this research, and to make an effort to assess treatment costs in clinical practice. As pointed out by the authors, clinical trial experience is a good starting point for this analysis; however, real-world evidence is needed to effectively validate the results…. The type of cost analysis presented in this article is critical to the management of future oncology treatments in managed care markets.” Applying the implications of health economics research in oncology into everyday patient care provides new opportunities to improve access to best, and affordable, therapies; enhance clinical outcomes; and reduce overall healthcare costs to patients, payers, and the healthcare system as a whole. Also in this issue, Michael Kleinrock, of IMS Health, reflects on innovation in oncology and continuing challenges outlined in the 2015 oncology report from the IMS Institute for Healthcare Informatics. “Cancer is already the largest clinical area of drug spending in the United States, and a cluster of innovative medicines utilizing new mechanisms of action for patients with a wide variety of tumor types promise to further increase cancer-related spending,” he suggests. In its new report, IMS found that “the total global spending on cancer and supportive care medicines reached the $100 billion threshold globally in 2014,” a full 4 years ahead of its projections last year. Finally, the oncology pipeline article in this issue highlights the many promising therapies in late-stage development that may soon become available for a variety of cancers and hematologic malignancies. Certain themes are apparent in the current oncology pipeline, all pointing toward continuing innovation in cancer drug development and a concomitant urgency to address value and cost-effective therapies on a national level. This theme issue is an invitation to all healthcare stakeholders to join this discussion. n

Reference

1. Miller JD, Foley KA, Russell MW. Current challenges in health economics modeling of cancer therapies: a research inquiry. Am Health Drug Benefits. 2014;7(3):153-162.

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BUSINESS

ORIGINAL RESEARCH

Treatment Sequences and Pharmacy Costs of 2 New Therapies for Metastatic Castration-Resistant Prostate Cancer Lorie A. Ellis, PhD; Marie-Hélène Lafeuille, MA; Laurence Gozalo, PhD; Dominic Pilon, MA; Patrick Lefebvre, MA; Scott McKenzie, MD BACKGROUND: The approval of new therapies for metastatic castration-resistant prostate cancer (mCRPC), including the oral agents abiraterone acetate and enzalutamide, has altered the standard of care for patients with mCRPC. Little information exists regarding the sequences in which new therapies for mCRPC with evidence of survival benefits are used. OBJECTIVE: To describe the sequence of medication use for patients with mCRPC as observed in 3 healthcare data sets. METHODS: Three healthcare claims data sets were used to identify patients with mCRPC who had no previous use of and were newly initiating 1 of the 2 oral study drugs (ie, abiraterone acetate or enzalutamide). The index date was the first study drug claim after September 1, 2012. Patients were followed until the data cutoff or until being lost to follow-up. Descriptive statistics summarized the proportion of patients receiving 1 line of therapy versus ≥2 lines of therapy. The use of a corticosteroid and the mean monthly pharmacy costs of abiraterone acetate or enzalutamide during the follow-up period were compared between the cohorts. RESULTS: A total of 3525 patients with mCRPC were identified from data set 1, 499 patients from data set 2, and 1949 patients from data set 3. The first-line use of abiraterone acetate was observed in 74%, 82%, and 80% of data sets 1, 2, and 3, respectively, and the first-line use of enzalutamide was seen in 26%, 18%, and 20%, respectively, of these same populations. The concomitant use of corticosteroids was observed in patients receiving first-line abiraterone acetate and in patients receiving first-line enzalutamide in all 3 data sets. After September 2012, abiraterone acetate was the most frequently administered therapy for mCRPC among the 2 oral agents, abiraterone acetate and enzalutamide. The monthly pharmacy costs associated with abiraterone acetate were significantly lower than those associated with enzalutamide in all 3 data sets. CONCLUSIONS: Based on the data used in this study, abiraterone acetate was more frequently administered for patients with mCRPC than enzalutamide. The concomitant use of corticosteroids was common in patients receiving first-line abiraterone acetate or first-line enzalutamide therapy. Patients receiving abiraterone acetate had significantly lower monthly pharmacy costs than patients receiving enzalutamide. These findings may facilitate the estimation of the budgetary impact of a treatment mix for population health and for managed care stakeholders. KEY WORDS: abiraterone acetate, enzalutamide, metastatic castration-resistant prostate cancer, first-line treatment, treatment sequencing

rostate cancer is a leading cause of cancer-related morbidity and mortality in the United States.1,2 The American Cancer Society estimated that ap-

Dr Ellis is Associate Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Horsham, PA; Ms Lafeuille is Senior Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Dr Gozalo is Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Mr Pilon is Economist, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Mr Lefebvre is Vice President, Groupe d’analyse, Ltée, Montréal, Québec, Canada; Dr McKenzie is Senior Director, Health Economics and Outcomes Research, Janssen Scientific Affairs, Horsham, PA.

Vol 8, No 4

June 2015

Stakeholder Perspective, page 195

Am Health Drug Benefits. 2015;8(4):185-195 www.AHDBonline.com Received May 1, 2015 Accepted in final form May 14, 2015

Disclosures are at end of text

proximately 1 in 7 men will be diagnosed with prostate cancer during his lifetime. Despite important advances in the treatment of prostate cancer, there will be approximately 220,800 new cases in 2015, resulting in approximately 27,540 deaths from the disease.3 Patients with localized prostate cancer may be initially treated with surgery or with radiation therapy.4 Disease recurrence occurs in approximately 20% to 30% of patients and can include metastases to other organs.5 Typically, androgen- deprivation therapy is prescribed for progressive disease; however, castration resistance or unresponsiveness to androgen-deprivation therapy or to antiandrogens frequently develop over time.2

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BUSINESS

KEY POINTS Although the number of therapies for metastatic castration-resistant prostate cancer (mCRPC) is increasing, little data exist on the sequencing and survival benefits of these new treatments. ➤ This new, claims-based, retrospective study examined the use of the oral agents abiraterone acetate and enzalutamide in patients with mCRPC based on 3 large data sets. ➤ Most patients received a single line of therapy for mCRPC in the observation period. ➤ Approximately 3 times as many patients received abiraterone acetate as those who received enzalutamide. ➤ Abiraterone acetate was the most common first-line therapy used for mCRPC, and abiraterone acetate followed by enzalutamide was the most common treatment sequence in patients receiving ≥2 lines of therapy. ➤ Concomitant corticosteroid use was observed in patients receiving first-line abiraterone acetate or first-line enzalutamide in all 3 data sets. ➤ Patients receiving abiraterone acetate had lower monthly pharmacy costs than those receiving enzalutamide. ➤ These results provide useful insights into real-world oral treatment sequencing with abiraterone acetate or with enzalutamide for patients with mCRPC. ➤

Historically, treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) was limited to palliative care.6 However, recent advances have led to an increase in treatment options that have demonstrated survival benefits in phase 3 clinical trials.6 Docetaxel, a taxane approved by the US Food and Drug Administration (FDA) in 2004 for the treatment of patients with mCRPC, has demonstrated a significant impact on survival.7,8 In the TAX 327 trial, the median survival times for patients receiving docetaxel plus prednisone were 18.9 months (dosed every 3 weeks) and 17.4 months (dosed weekly for 5 of every 6 weeks) compared with 16.5 months in patients receiving mitoxantrone plus prednisone every 3 weeks.7 In the Southwest Oncology Group Intergroup protocol 99-16 trial, the median survival of patients with mCRPC who received docetaxel plus estramustine was 17.5 months compared with 15.6 months in patients receiving mitoxantrone plus prednisone (over a maximum of 12 three-week cycles).8 The treatment options offering survival benefit for patients with mCRPC (ie, advanced prostate cancer)

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have expanded in recent years.6 Cabazitaxel is a tubulin- binding taxane with antitumor activity in docetaxel- resistant patients.9 Given with prednisone, cabazitaxel demonstrated a median overall survival benefit of 2.4 months compared with mitoxantrone plus prednisone (15.1 vs 12.7 months, respectively).9 Sipuleucel-T is an active cellular immunotherapy that showed a 4.1-month improvement in median overall survival compared with placebo (25.8 vs 21.7 months, respectively).5 Abir aterone acetate plus prednisone and enzalutamide are 2 oral treatments for mCRPC with different mechanisms of action. Abiraterone acetate, an androgen biosynthesis inhibitor, is a prodrug of abiraterone and the enzyme cytochrome P450 17alpha-hydroxylase, resulting in reduced androgen production in the testes and adrenal glands, and therefore in the prostate tumor.10 At the time our study was conducted, abiraterone acetate plus prednisone was approved by the FDA for patients who had received previous treatment with chemotherapy and for chemotherapy-naïve patients with mCRPC. Abiraterone acetate plus prednisone was found to have a median overall survival benefit of 3.9 months compared with placebo plus prednisone (14.8 vs 10.9 months, respectively) in patients who had previously received docetaxel,10 and a median overall survival benefit of 4.4 months compared with placebo plus prednisone (34.7 vs 30.3 months, respectively) in chemotherapy-naïve patients.11 Enzalutamide belongs to the androgen receptor inhibitor class, of which bicalutamide and flutamide are also members.12 Androgen receptor inhibitors work by blocking signaling at the androgen receptor. At the time our study was conducted, enzalutamide was indicated by the FDA for patients who had previously received chemotherapy; however, it is now also FDA approved for chemotherapy-naïve patients. Compared with placebo, the use of enzalutamide led to a 4.8-month improvement in median overall survival (18.4 vs 13.6 months, respectively) in patients who previously received chemotherapy,12 and a 4-month improvement in median overall survival (35.3 vs 31.3 months, respectively) in chemotherapy-naïve patients.13 Patients treated with abiraterone acetate plus prednisone receive 1000 mg of abiraterone acetate once daily in combination with 5 mg of prednisone twice daily.14 Patients treated with enzalutamide receive 160 mg of enzalutamide once daily.15 The recent introduction of new treatment paradigms has provided physicians with greater options to treat patients with mCRPC, and has altered the historical treatment patterns that were established with docetaxel.6 In their recent literature review on treatment sequencing for patients with mCRPC based on clinical trial evidence for docetaxel, cabazitaxel, sipuleucel-T, abiraterone acetate,

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Treatment Sequences and Pharmacy Costs of 2 New Therapies

enzalutamide, and radium Ra 223 dichloride, Sartor and Gillessen emphasized that there is still little known about the real-world sequencing of the new therapies in mCRPC and their potential optimal sequences.16 They identified a need for additional data, particularly in the post– abiraterone acetate and post–enzalutamide settings.16 Because the costs of treating cancer are an increasing public concern17 and can be impacted by treatment sequences, it has become important to identify sequences in which new agents are utilized. Using 3 healthcare claims databases, the present study aimed at identifying, in a real-world setting, the sequences in which abir aterone acetate and enzalutamide are most often used with respect to one another and to other treatments for mCRPC, along with their associated treatment costs.

Methods Data Source Three separate databases were used to conduct the analysis—Symphony Health Solutions’ Patient Transactional Datasets (data set 1), the IMS PharMetrics Plus database (data set 2), and the Truven Health Market Scan® Research Databases (data set 3); data used were from June 2009 to October 2013, January 2010 to October 2013, and January 2005 to July 2014, respectively. The Symphony Health Solutions database is comprised of US pharmacy and medical claims submitted by approximately 30,000 pharmacies, 1000 hospitals, 800 outpatient facilities, and 80,000 physician practices. Compared with other claims data sources representing commercially insured populations (eg, data sets 2 and 3 described below), this Symphony Health Solutions database includes claims from patients participating in commercial health plans, as well as a large proportion of claims from patients participating in public insurance programs (eg, Medicaid and Medicare). This database contains approximately 4.8 billion prescription claims representing more than 190 million patients receiving unique prescriptions. Medical claims with International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes are linked to nearly 91 million patients in the database receiving prescription drugs. The IMS PharMetrics Plus database is comprised of adjudicated claims for more than 150 million unique enrollees across the United States. Enrollees with medical and pharmacy coverage in 2012 represent 40 million active lives. The metropolitan statistical areas of the United States are represented, with data coverage from 90% of US hospitals and 80% of all US doctors, and representation from 85% of the Fortune 100 companies. This database notably contains information on inpatient and outpatient diagnoses and procedures, retail and mail order prescription records, and detailed information on

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pharmacy and medical benefits (ie, copayment and deductible). Because of the broad reach of the data, patients in the IMS PharMetrics Plus database are similar to the national commercially insured population in terms of age and sex for persons aged ≤65 years. The Truven Health MarketScan Research Databases combines 2 separate databases—the Commercial Claims and Encounters database, and the Medicare Supplemental and Coordination of Benefits database—to cover all age-groups. These databases contain claims from approximately 100 employers, health plans, and government and public organizations, representing approximately 30 million covered lives. All census regions are represented, but the South and North Central (Midwest) regions of the United States are predominant. The data elements used in the present study include health plan enrollment and clinical activity records, participant demographics, inpatient and outpatient medical services, and outpatient prescription drug dispensing records. All data collected from each database were deidentified in compliance with the patient confidentiality requirements of HIPPA (the Health Insurance Portability and Accountability Act).

Study Design A retrospective longitudinal study design was used, and patients with prostate cancer who received abir aterone acetate or enzalutamide therapy from September 1, 2012, to October 31, 2013, for data sets 1 and 2, and to July 31, 2014, for data set 3, were selected to form the study population. The date of the first dispensing of abiraterone acetate or enzalutamide after September 1, 2012 (the first date when abiraterone acetate and enzalutamide were both commercially available in the United States) was identified as the index date. Enrolled patients were also required to have at least 1 diagnosis of prostate cancer (ICD-9-CM, 185.xx) within 12 months before the index date, be aged ≥18 years, and have at least 12 months of continuous clinical activity (data set 1) or continuous eligibility (data sets 2 and 3) before the index date. Patients with exposure to abiraterone acetate or to enzalutamide before September 2012 and patients with a diagnosis for another type of cancer (ICD9-CM, 140.xx-184, 186.xx-195, 200.xx-209.xx) in the year before the index date were excluded from the study. In each database, patients were separated into 2 cohorts based on their first dispensing of abiraterone acetate or enzalutamide. The observation period spanned from the index date to the earliest between the end of clinical activity or eligibility, or the data cutoff date. The information recorded in the 12 months before the first dispensing of abiraterone acetate or enzalutamide was used to evaluate the patients’ baseline characteristics.

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Study End Points The treatment sequencing of therapies for patients with mCRPC during the observation period was reported. Treatment sequences were defined as successive lines of therapies for mCRPC that were stratified into chemotherapy (which was further stratified into docetaxel, cabazitaxel, or other chemotherapies), immunotherapy (sipuleucel-T), and oral agents (abiraterone acetate or enzalutamide). The lines of therapy were defined, using a common convention,18,19 as the period starting from the date of the first claim for a type of therapy and up to either 90 days without treatment with that therapy, a claim for a different therapy, or the earliest of the end of eligibility or data availability. Patients who were receiving corticosteroids were identified. Payers’ costs for treatment with abiraterone acetate or enzalutamide were also reported. Statistical Analysis Descriptive statistics were used to summarize the baseline characteristics and treatment sequences. Frequency

counts and percentages were used to summarize the categorical variables, and means and standard deviations were used for the continuous variables. The treatment sequences were identified for each patient and were then aggregated and reported for each data set. Of note, because of the descriptive nature of the study, parametric tests or nonparametric tests assessing the statistical inference between treatment sequences were not conducted. Nonetheless, statistical significance was assessed for costs through a Wilcoxon rank-sum test and through a Pearson’s chi-square test for counts of patients receiving corticosteroids. All costs were inflation- adjusted to 2014 US dollars based on the medical care component of the Consumer Price Index.

Results A total of 3525 patients from data set 1 (2611 patients receiving abiraterone acetate and 914 receiving enzalutamide as first-line therapies), 499 patients from data set 2 (407 receiving abiraterone acetate and 92 receiving enzalutamide as first-line therapies), and 1949 patients from data set 3 (1568 receiving abiraterone acetate and

Figure 1 Patient Selection Flowchart Data set 1

Data set 2

Data set 3

Patients with ≥1 diagnoses of prostate cancer (ICD-9, 185.xx) N = 1,232,504

Patients with ≥1 diagnoses of prostate cancer (ICD-9, 185.xx) N = 285,155

Patients with ≥1 diagnoses of prostate cancer (ICD-9, 185.xx) N = 699,385

Patients initiating abiraterone acetate or enzalutamide after September 1, 2012 Abiraterone acetate Enzalutamide N = 4955 N = 1496

Patients initiating abiraterone acetate or enzalutamide after September 1, 2012 Abiraterone acetate Enzalutamide N = 632 N = 149

Patients initiating abiraterone acetate or enzalutamide after September 1, 2012 Abiraterone acetate Enzalutamide N = 2658 N = 724

Patients with ≥1 years of clinical activity before the initiation of abiraterone acetate or enzalutamide (index date) Abiraterone acetate Enzalutamide N = 3744 N = 1216

Patients with ≥1 years of clinical activity before the initiation of abiraterone acetate or enzalutamide (index date) Abiraterone acetate Enzalutamide N = 571 N = 125

Patients with ≥1 years of clinical activity before the initiation of abiraterone acetate or enzalutamide (index date) Abiraterone acetate Enzalutamide N = 2227 N = 552

Patients with ≥1 prostate cancer diagnoses (ICD-9, 185.xx) during the year before the index date Abiraterone acetate Enzalutamide N = 3119 N = 1049

Patients with ≥1 prostate cancer diagnoses (ICD-9, 185.xx) during the year before the index date Abiraterone acetate Enzalutamide N = 567 N = 124

Patients with ≥1 prostate cancer diagnoses (ICD-9, 185.xx) during the year before the index date Abiraterone acetate Enzalutamide N = 2209 N = 546

Patients without a diagnosis for another type of cancera within the year before the index date Abiraterone acetate Enzalutamide N = 2611 N = 914

Patients without a diagnosis for another type of cancera within the year before the index date Abiraterone acetate Enzalutamide N = 407 N = 92

Patients without a diagnosis for another type of cancera within the year before the index date Abiraterone acetate Enzalutamide N = 1568 N = 381

Other cancer diagnoses were identified using the following ICD-9 codes: 140.xx-184.xx, 186.xx-195.xx, and 200.xx-209.xx. ICD-9 indicates International Classification of Diseases, Ninth Revision.

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381 receiving enzalutamide as first-line therapies) were selected (Figure 1). Table 1 presents the baseline characteristics for patients receiving first-line abiraterone acetate or first-line enzalutamide, as well as the overall population of each data set. The mean patient ages were 72.9 years in data set 1, 67.5 years in data set 2, and 73.0 years in data set 3. The proportions of patients participating in a public insurance program (Medicaid or Medicare) were different across the data sets; 61.8% of patients from data set 1 had healthcare claims reimbursed through such a program compared with 12.2% and 75.0% of patients, from data sets 2 and 3, respectively. As expected, hormone treatment for prostate cancer was reported for most patients, 90.2% in data set 1; 95.4% in data set 2; and 96.2% in data set 3. Few patients had treatment with chemotherapy in the preindex periodâ&#x20AC;&#x201D;18.2% of patients in data set 1 (abiraterone acetate, 14.6%; enzalutamide, 28.6%); 27.5% of patients in data set 2 (abiraterone acetate, 21.4%; enzalutamide, 54.3%); and 21.9% in data set 3 (abiraterone acetate, 19.3%; enzalutamide, 32.5%). Overall, 5.4%, 14.2%, and 11.6% of patients from data sets 1, 2, and 3, received sipuleucel-T, respectively.

Observed Lines of Therapy Most patients received only 1 line of therapy during the observation period (ie, the index date to data cutoff or loss to follow-up). As shown in Table 2, a single line of therapy was observed in 86.8% of patients overall (abiraterone acetate, 64.3%; enzalutamide, 22.5%) in data set 1, in 80.4% (abiraterone acetate, 66.7%; enzalutamide, 13.6%) of patients in data set 2, and in 69.6% (abiraterone acetate, 55.3%; enzalutamide, 14.4%) of patients overall in data set 3. A second-line therapy was observed in a subset of patients (13.2% of patients from data set 1, 19.6% from data set 2, and 30.4% from data set 3). The average observation duration times were 212 days, 165 days, and 275 days for data sets 1, 2, and 3, respectively. Treatment Sequences Figure 2 illustrates the proportion of patients who started first-line therapy with abiraterone acetate or with enzalutamide in each data set. The majority of patients were initiated with abiraterone acetate as the first-line agent (74.1% of patients from data set 1, 81.6% of patients from data set 2, and 80.5% of patients from data set 3). Table 2 presents the distribution of first-line and subsequent-line treatment sequences observed from the data. Across all data sets, abiraterone acetate was the most frequently prescribed agent in patients receiving a single

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line of therapy. Multiple lines of therapy were prescribed in 13.2%, 19.6%, and 30.4% of patients in data sets 1, 2, and 3, respectively. In patients receiving multiple lines of therapy, the most common treatment followed by a second-line treatment sequence was abiraterone acetate followed by enzalutamide, which occurred in 5.0% of patients from data set 1, 5.2% of patients from data set 2, and 12.4% of patients from data set 3.

Corticosteroid Use and Costs Table 3 shows the observed concomitant use of corticosteroids and the related costs. The concomitant use of corticosteroids was observed in all cohorts (81.2% of patients receiving first-line abiraterone acetate and 32.1% of patients receiving first-line enzalutamide in data set 1; 86.2% of patients receiving first-line abirÂ aterone acetate and 38.0% of patients receiving first-line enzalutamide in data set 2, and 86.4% of patients receiving first-line abiraterone acetate and 33.6% of patients receiving first-line enzalutamide in data set 3). The monthly pharmacy payer cost of abiraterone acetate therapy was significantly lower than the monthly cost to payers of enzalutamide therapy in all 3 data sets ($5756 for abiraterone acetate vs $6879 for enzalutamide in data set 1; $6171 for abiraterone acetate vs $7549 for enzalutamide in data set 2, and $6412 for abiraterone acetate vs $7661 for enzalutamide in data set 3; P <.0001 for all data sets). Discussion Based on healthcare claims data, this large retrospective analysis of the use of abiraterone acetate and enzalutamide with 3 different commercially available databases reveals that a large majority of patients (approximately 87%, 80%, and 70% in data sets 1, 2, and 3, respectively) received only a single line of therapy during an observation period of 13 to 22 months. The majority of patients receiving a single line of therapy received abiraterone acetate. Among patients with 2 or more lines of treatment, the most frequent sequence observed was first-line abiraterone acetate followed by enzalutamide. Chemotherapy treatment before the use of an oral agent was observed infrequently; however, a higher proportion of patients receiving first-line enzalutamide in this study had a history of chemotherapy use during most of the study period, which is consistent with enzalutamideâ&#x20AC;&#x2122;s indication. To our knowledge, this study is one of the first to investigate the real-world sequencing of oral therapies for mCRPC in a broad population of patients. With the addition of several new treatment options for patients with mCRPC, including, but not limited to,

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72.9 ± 8.0 [70.0]

Age,a mean ± SD [median]

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l 1282 (49.1)

78 (2.2)

516 (14.6)

1236 (35.1)

1694 (48.1)

45-54

55-64

65-74

≥75

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Hypertension

Comorbidities,c N (%)

Quan-Charlson comorbidity index,b,c mean ± SD [median]

2010 (57.0)

1.38 ± 1.69 [1.00]

26 (0.7)

Unknown

224 (6.4)

Intern/family practitioner/PCP

210 (6.0)

586 (16.6)

Urology

Other specialty

2479 (70.3)

Oncology

Physician specialty, N (%)

47 (1.3)

1298 (36.8)

Commercial

Cash, other, or unknown

2180 (61.8)

Public insurance program (Medicare or Medicaid)

Payment type, N (%)

899 (34.4)

1 (0.0)

35-44

1577 (60.4)

1.45 ± 1.70 [1.00]

18 (0.7)

156 (6.0)

182 (7.0)

463 (17.7)

1792 (68.6)

36 (1.4)

968 (37.1)

1607 (61.5)

376 (14.4)

53 (2.0)

1 (0.0)

0 (0.0)

73.1 ± 7.9 [70.0]

215 ± 107 [210]

18-34

Age categories, yrs, N (%)

212 ± 108 [207]

Days in observation period, mean ± SD [median]

433 (47.4)

1.19 ± 1.63 [1.00]

8 (0.9)

54 (5.9)

42 (4.6)

123 (13.5)

687 (75.2)

11 (1.2)

330 (36.1)

573 (62.7)

412 (45.1)

337 (36.9)

140 (15.3)

25 (2.7)

0 (0.0)

72.4 ± 8.1 [70.0]

204 ± 109 [186]

300 (60.1)

1.16 ± 1.47 [1.00]

33 (6.6)

37 (7.4)

63 (12.6)

126 (25.3)

240 (48.1)

5 (1.0)

433 (86.8)

61 (12.2)

134 (26.9)

141 (28.3)

185 (37.1)

37 (7.4)

2 (0.4)

0 (0.0)

67.5 ± 9.6 [66.0]

165 ± 98 [164]

244 (60.0)

1.14 ± 1.41 [1.00]

30 (7.4)

32 (7.9)

55 (13.5)

101 (24.8)

189 (46.4)

4 (1.0)

351 (86.2)

52 (12.8)

114 (28.0)

154 (37.8)

24 (5.9)

1 (0.2)

0 (0.0)

67.9 ± 9.6 [66.0]

162 ± 97 [155]

56 (60.9)

1.28 ± 1.71 [1.00]

3 (3.3)

5 (5.4)

8 (8.7)

25 (27.2)

51 (55.4)

1 (1.1)

82 (89.1)

9 (9.8)

20 (21.7)

27 (29.3)

31 (33.7)

13 (14.1)

1 (1.1)

0 (0.0)

65.9 ± 9.8 [66.0]

180 ± 98 [184]

1203 (61.7)

1.34 ± 1.52 [1.00]

35 (1.8)

119 (6.1)

277 (14.2)

448 (23.0)

1070 (54.9)

0 (0.0)

488 (25.0)

1461 (75.0)

927 (47.6)

527 (27.0)

425 (21.8)

68 (3.5)

2 (0.1)

0 (0.0)

73.0 ± 10.6 [74.0]

275 ± 179 [250]

965 (61.5)

1.34 ± 1.52 [1.00]

26 (1.7)

101 (6.4)

232 (14.8)

356 (22.7)

853 (54.4)

0 (0.0)

385 (24.6)

1183 (75.4)

743 (47.4)

434 (27.7)

338 (21.6)

51 (3.3)

2 (0.1)

0 (0.0)

73.1 ± 10.5 [74.0]

281 ± 178 [258]

238 (62.5)

1.37 ± 1.54 [1.00]

9 (2.4)

18 (4.7)

45 (11.8)

92 (24.1)

217 (57.0)

0 (0.0)

103 (27.0)

278 (73.0)

184 (48.3)

93 (24.4)

87 (22.8)

17 (4.5)

0 (0.0)

72.7 ± 10.8 [74.0]

247 ± 181 [199]

Table 1 P atient Demographics and Clinical Characteristics Data set 1 Data set 2 Data set 3 Abiraterone Abiraterone Abiraterone acetate Enzalutamide acetate Enzalutamide acetate Enzalutamide Overall cohort cohort Overall cohort cohort Overall cohort cohort Patient characteristic (N = 3525) (N = 2611) (N = 914) (N = 499) (N = 407) (N = 92) (N = 1949) (N = 1568) (N = 381)

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Because only age ranges are available in database 1, the mean patient age was approximated as the midpoint of the range for this data set (eg, 70 for the range 65-74). The mean age for patients aged ≥75 years is taken as 80 years. b Based on Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43: 1130-1139. c Evaluated during the baseline period, except for data set 1, for which comorbidities were evaluated at any time before the index date. d Treatments received any time before the index date. e Hormone treatments include LHRH/GnRH, estrogens, antiandrogens, and adrenal androgen blockers. GnRH indicates gonadotropin-releasing hormone; LHRH, luteinizing hormone-releasing hormone; mCRPC, metastatic castration-resistant prostate cancer; PCP, primary care physician; SD, standard deviation.

45 (11.8) 182 (11.6) 227 (11.6) 17 (18.5) 54 (13.3) 71 (14.2) 49 (5.4) 192 (5.4)

Sipuleucel-T

143 (5.5)

3181 (90.2)

Hormone treatmentse

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370 (97.1) 1504 (95.9) 1874 (96.2) 90 (97.8) 386 (94.8) 476 (95.4) 808 (88.4)

427 (21.9) 50 (54.3) 87 (21.4) 137 (27.5) 261 (28.6) 380 (14.6) 641 (18.2)

Chemotherapy

Previous mCRPC treatments,d N (%)

2373 (90.9)

124 (32.5) 303 (19.3)

5 (1.3) 24 (1.5) 29 (1.5) 0 (0.0) 7 (1.7) 7 (1.4) 7 (0.8) 51 (1.4)

Seizure

44 (1.7)

119 (31.2) 398 (25.4) 517 (26.5) 24 (26.1) 93 (22.9) 117 (23.4) 207 (22.6) 931 (26.4)

Diabetes

724 (27.7)

127 (33.3) 486 (31.0) 613 (31.5) 36 (39.1) 102 (25.1) 138 (27.7) 262 (28.7) 1083 (30.7)

Depression/ antidepressants

821 (31.4)

1487 (42.2)

Cardiovascular disease

1152 (44.1)

335 (36.7)

195 (39.1)

153 (37.6)

42 (45.7)

892 (45.8)

714 (45.5)

178 (46.7)

Treatment Sequences and Pharmacy Costs of 2 New Therapies

abiraterone acetate and enzalutamide, the possible treatment-sequencing options for patients with mCRPC have exponentially expanded. Several institutions and individual physicians have tried to provide guidance on treatment sequences based on clinical experience or on literature reviews4,6,20-26; a consensus among these reviews is the need to better understand real-world practices and the associated outcomes to identify the optimal treatment sequence for patients with mCRPC, taking into consideration patient status, such as clinical characteristics, prostate cancer stage and progression criteria, comorbidities, and concomitant medication use.22,27 Although this research does not provide information about why physicians or patients selected certain medication sequences, multiple considerations clearly exist. Clinical guideline recommendations, such as those provided by the National Comprehensive Cancer Network (NCCN), are a primary resource available to guide treatment selection.4 The current guidelines by the NCCN do not discriminate in the sequence for which abiraterone acetate plus prednisone or enzalutamide should be utilized; however, it is well known that providers do not necessarily adhere to the guidelines as strictly as they are written.28 Indeed, a physician may identify treatments for a given patient based on familiarity or experience with a particular medication or medication class, or based on differences in mechanisms of action between several possible treatments (eg, an androgen biosynthesis inhibitor vs an androgen receptor inhibitor in the cases of abiraterone acetate and enzalutamide, respectively). From a physician’s perspective, treatment sequencing for mCRPC may be considered as a strategy for managing the effects of cross-resistance between treatments for mCRPC, particularly among taxanes (eg, docetaxel and cabazitaxel) and androgen inhibitors.29 The physician’s treatment sequence selection observed in this study may be influenced by real-world exploratory or pilot studies suggesting that enzalutamide may demonstrate clinical benefit in patients who do not respond to chemotherapy and to treatment with abiraterone acetate.30,31 Furthermore, with limited understanding of the optimal sequential treatments related to specific patient outcomes, and with uncertainty regarding timing optimization to avoid the effects of cross-resistance, physicians may opt for a single-line treatment for patients with mCRPC. Additional phase 3 trials may provide more information on physicians’ prescribing of treatment.32 The clinical characteristics and preferences of patients, and physicians’ assessment of the risk–benefit profile for patients’ respective therapies may also impact the order in which a treatment is given.20 Corticosteroids have long been used to treat the symptoms of prostate cancer, and concomitant corticosteroid use is not required in patients

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Table 2 D istribution of Treatment Sequences Data set 1 (N = 3525)

Data set 2 (N = 499)

Data set 3 (N = 1949)

2267 (64.3)

333 (66.7)

1077 (55.3)

176 (5.0)

26 (5.2)

241 (12.4)

Abiraterone acetate followed by docetaxel

68 (1.9)

23 (4.6)

63 (3.2)

Abiraterone acetate followed by other chemotherapy

26 (0.7)

5 (1.0)

8 (0.4)

Abiraterone acetate followed by abiraterone acetate

19 (0.5)

1 (0.2)

22 (1.1)

Abiraterone acetate followed by cabazitaxel

17 (0.5)

2 (0.4)

16 (0.8)

Abiraterone acetate followed by cabazitaxel, and followed by enzalutamide

1 (0.0)

3 (0.6)

6 (0.3)

Abiraterone acetate followed by docetaxel, and followed by enzalutamide

6 (0.2)

3 (0.6)

27 (1.4)

Abiraterone acetate followed by enzalutamide, and followed by docetaxel

6 (0.2)

0 (0.0)

13 (0.7)

Abiraterone acetate followed by sipuleucel-T

5 (0.1)

2 (0.4)

13 (0.7)

Abiraterone acetate followed by abiraterone acetate, and followed by enzalutamide

1 (0.0)

0 (0.0)

9 (0.5)

794 (22.5)

68 (13.6)

280 (14.4)

Enzalutamide followed by abiraterone acetate

50 (1.4)

8 (1.6)

33 (1.7)

Enzalutamide followed by cabazitaxel

19 (0.5)

2 (0.4)

10 (0.5)

Enzalutamide followed by other chemotherapy

19 (0.5)

3 (0.6)

4 (0.2)

Treatment sequencesa, N (%) Abiraterone acetate only Abiraterone acetate followed by enzalutamide

Enzalutamide only

Only treatment sequences representing ≥0.5% in one data set are presented.

Figure 2 D istribution of Study Drugs as First-Line Treatment 100 81.6% 80.5%

Proportion of patients, %

74.1%

Data set 1 (N = 3525) Data set 2 (N = 499) Data set 3 (N = 1949)

40 25.9% 18.4% 19.5%

0 Abiraterone acetate

Enzalutamide

NOTE: In data set 1, the average number of observed per-patient days on therapy was 120 for abiraterone acetate and 101 for enzalutamide. In data set 2, the average number of observed per-patient days on therapy was 134 for abiraterone acetate and 142 for enzalutamide. In data set 3, the average number of observed per-patient days on therapy was 199 for abiraterone acetate and 170 for enzalutamide.

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receiving enzalutamide.15 Real-world evidence from our study shows that nearly 40% of patients receiving enzalutamide concomitantly received corticosteroids. Finally, in some cases, the economic considerations imposed by insurance reimbursement and/or by a patient’s financial status may impact the treatment sequences selected. Previous studies have assessed the cost-effectiveness of therapies for mCRPC in chemotherapy-refractory and chemotherapy-naïve patients, and have concluded that abiraterone acetate is a cost- effective treatment option.33-35 By contrast, our study demonstrates that treatment with abiraterone acetate results in significantly lower pharmacy costs than treatment with enzalutamide.

Limitations Our study is subject to several limitations. As is the case with claims databases, the Symphony Health Solutions’ Patient Transactional Datasets, the IMS Phar Metrics Plus database, and the Truven Health Market Scan Research Databases may have contained in accuracies or omissions in procedures, diagnoses, or costs, and no information was provided as to whether the medication was taken as prescribed. There is potential

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Table 3 C orticosteroid Use and Costs Data set 1 (N = 3525)

Data set 2 (N = 499)

Data set 3 (N = 1949)

Abiraterone Abiraterone Abiraterone acetate Enzalutamide acetate Enzalutamide acetate Enzalutamide cohort P cohort P cohort P cohort cohort cohort (N = 2611) (N = 914) valuesa (N = 407) (N = 92) valuesa (N = 1568) (N = 381) valuesa

Treatment variables

Corticosteroid use, N (%) Patients using 2217 (84.9) corticosteroidsb

367 (40.2)

<.0001

360 (88.5)

50 (54.3)

<.0001

1399 (89.2)

174 (45.7)

<.0001

Patients with concomitant corticosteroid usec

293 (32.1)

<.0001

351 (86.2)

35 (38.0)

<.0001

1354 (86.4)

128 (33.6)

<.0001

6171 ± 880 [6390]

7549 ± 979 [7750]

<.0001

6412 ± 774 [6634]

7661 ± 1006 [7868]

<.0001

2119 (81.2)

Treatment cost (2014 US$), mean ± SD [median] Monthly payer costd

5756 ± 1485 [6344]

6879 ± 1725 [7560]

<.0001

P values were calculated using the Wilcoxon rank-sum test for continuous variables and Pearson’s chi-square test for categorical variables. b At any time during the observation period. c Patients had ≥1 claims for a steroid overlapping with a claim for a study drug of interest (abiraterone acetate or enzalutamide). d Monthly payer cost was estimated using the total payer cost for treatment reported to 30 days of supply. SD indicates standard deviation. a

for the 3 data sets to overlap, but the actual overlap cannot be determined, because the databases are not linked. In addition, the 3 databases used in this study are not completely comparable: data set 1 is transactionally based and reflects a higher proportion of patients covered under public insurance programs than data sets 2 and 3, which are insurance based. Instead of combining the data sets, this analysis was conducted on each data set separately. Data set 1 may not contain records on some prescriptions or healthcare services that were processed through different claims transaction networks. Because of this particularity, an apparent treatment interruption observed in the data may, in fact, be a patient receiving healthcare services outside of the networks that were not captured in the database. For data set 2, the small sample size may limit the generalizability of the findings, particularly within the subgroups. Even though the prevalence of prostate cancer has a definite racial influence, which might have impacted the study population,36 the ethnicity distribution was not presented here, because data sets 2 and 3 were lacking the necessary information to do so. Nevertheless, it is unclear if ethnicity distribution has an influence on treatment sequencing in this patient population. Finally, the treatment-sequencing analysis was limited to the described agents of interest (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, or sipuleucel-

) after enzalutamide became available (in September T 2012), and had a limited observation period that may not have been sufficient to capture sequences of treatment that may be used over multiple years. Future research may include other agents used for prostate cancer treatment and a longer follow-up period. However, the consistency of the results across these 3 distinct databases adds to the validity and robustness of the study results.

Conclusions In this large retrospective study, most patients with mCRPC received abiraterone acetate or enzalutamide before the use of chemotherapy. This study also revealed that in a vast majority of cases, patients received monotherapy over the study period, with abiraterone acetate being the most common first-line agent. The concomitant use of a corticosteroid was frequently observed in the abiraterone acetate and the enzalutamide groups. Moreover, patients receiving abiraterone acetate had significantly lower monthly treatment costs than patients receiving enzalutamide. These results can provide useful insights on real-world treatment sequencing for patients with mCRPC who receive abiraterone acetate or enzalutamide. ■ Funding Source This research was funded by Janssen Scientific Affairs. Continued

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BUSINESS

Author Disclosure Statement Dr Ellis is an employee of Janssen Scientific Affairs, and a stockholder of Johnson & Johnson. Ms Lafeuille, Dr Gozalo, Mr Pilon, and Mr Lefebvre are employees of Groupe d’analyse, Ltée, a consulting company that has received research grants from Janssen Scientific Affairs. Dr McKenzie is an employee of Janssen Scientific Affairs, and a stockholder of Johnson & Johnson.

References

1. Kohli M, Tindall DJ. New developments in the medical management of prostate cancer. Mayo Clinic Proc. 2010;85:77-86. 2. Sartor O, Michels RM, Massard C, de Bono JS. Novel therapeutic strategies for metastatic prostate cancer in the post-docetaxel setting. Oncologist. 2011; 16:1487-1497. 3. American Cancer Society. What are the key statistics about prostate cancer? Revised March 12, 2015. www.cancer.org/cancer/prostatecancer/detailedguide/ prostate-cancer-key-statistics. Accessed March 15, 2015. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): prostate cancer. Version 1.2015. October 24, 2014. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed April 7, 2015. 5. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422. 6. Vaishampayan U. Therapeutic options and multifaceted treatment paradigms in metastatic castrate-resistant prostate cancer. Curr Opin Oncol. 2014; 26:265-273. 7. Tannock IF, de Wit R, Berry WR, et al; for the TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-1512. 8. Petrylak DP, Tangen CM, Hussain MHA, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. 9. de Bono JS, Oudard S, Ozguroglu M, et al; for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154. 10. de Bono JS, Logothetis CJ, Molina A, et al; for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995-2005. 11. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COUAA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16:152-160. 12. Scher HI, Fizazi K, Saad F, et al; for the AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 13. Beer T, Bhattacharya S, Bjartell A, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): final overall survival analysis of the phase 3 PREVAIL study. Presented at the European Association of Urology Congress; March 20-24, 2015; Madrid, Spain. 14. Zytiga (abiraterone acetate) tablets [prescribing information]. Horsham, PA: Janssen Biotech, Inc; March 2015. 15. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; September 2014. 16. Sartor O, Gillessen S. Treatment sequencing in metastatic castrate-resistant

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prostate cancer. Asian J Androl. 2014;16:426-431. 17. Appleby J. Insurers push back against growing cost of cancer treatments. WebMD. June 6, 2014. www.webmd.com/health-insurance/20140606/insurerspush-back-against-growing-cost-of-cancer-treatments. Accessed October 31, 2014. 18. Seal B, Chastek B, Kulakodlu M, Valluri S. Differences in survival for patients with metastatic colorectal cancer by lines of treatment received and stage at original diagnosis. Int J Clin Pract. 2015;69:251-258. 19. Obeidat NA, Pradel FG, Zuckerman IH, et al. Outcomes of irinotecan- based chemotherapy regimens in elderly Medicare patients with metastatic colorectal cancer. Am J Geriatr Pharmacother. 2009;7:343-354. 20. Parente P, Parnis F, Gurney H. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer. Asia Pac J Clin Oncol. 2014;10:205-215. 21. Zhang TY, Agarwal N, Sonpavde G, et al. Management of castrate resistant prostate cancer—recent advances and optimal sequence of treatments. Curr Urol Rep. 2013;14:174-183. 22. Loblaw DA, Walker-Dilks C, Winquist E, Hotte SJ; for the Genitourinary Cancer Disease Site Group of Cancer Care Ontario’s Program in Evidence-Based Care. Systemic therapy in men with metastatic castration-resistant prostate cancer: a systematic review. Clin Oncol (R Coll Radiol). 2013;25:406-430. 23. Heidenreich A, Bastian PJ, Bellmunt J, et al; for the European Association of Urology. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467-479. 24. Bracarda S, Sisani M, Marrocolo F, et al. Clinical implications for a treatment algorithm and differential indication to hormone therapy and chemotherapy options in metastatic castrate-resistant prostate cancer: a personal view. Expert Rev Anticancer Ther. 2014;14:1283-1294. 25. Irelli A, Bruera G, Cannita K, et al. Bioclinical parameters driving decision-making of subsequent lines of treatment in metastatic castration-resistant prostate cancer. Biomed Res Int. 2014;2014:909623. 26. Pal SK, Lewis B, Sartor O. Management of docetaxel failures in metastatic castrate-resistant prostate cancer. Urol Clin North Am. 2012;39:583-591. 27. Omlin A, Pezaro C, Gillessen Sommer S. Sequential use of novel therapeutics in advanced prostate cancer following docetaxel chemotherapy. Ther Adv Urol. 2014;6:3-14. 28. Maue SK, Segal R, Kimberlin CL, Lipowski EE. Predicting physician guideline compliance: an assessment of motivators and perceived barriers. Am J Manag Care. 2004;10:383-391. 29. van Soest RJ, van Royen ME, de Morrée ES, et al. Cross-resistance between taxanes and new hormonal agents abiraterone and enzalutamide may affect drug sequence choices in metastatic castration-resistant prostate cancer. Eur J Cancer. 2013;49:3821-3830. 30. Fitzpatrick JM, de Wit R. Taxane mechanisms of action: potential implications for treatment sequencing in metastatic castration-resistant prostate cancer. Eur Urol. 2014;65:1198-1204. 31. Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer. 2014;120:968-975. 32. Leape LL, Weissman JS, Schneider EC, et al. Adherence to practice guidelines: the role of specialty society guidelines. Am Heart J. 2003;145:19-26. 33. Zhong L, Pon V, Srinivas S, et al. Therapeutic options in docetaxel-refractory metastatic castration-resistant prostate cancer: a cost-effectiveness analysis. PLoS One. 2013;8:e64275. 34. Gong CL, Hay JW. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer. J Natl eCompr Canc Netw. 2014;12:1417-1425. 35. Wilson L, Tang J, Zhong L, et al. New therapeutic options in metastatic castration-resistant prostate cancer: can cost-effectiveness analysis help in treatment decisions? J Oncol Pharm Pract. 2014;20:417-425. 36. Centers for Disease Control and Prevention. Prostate cancer rates by race and ethnicity. Updated August 27, 2014. www.cdc.gov/cancer/prostate/statistics/ race.htm. Accessed May 26, 2015.

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Treatment Sequences and Pharmacy Costs of 2 New Therapies

STAKEHOLDER PERSPECTIVE

Comparing Cost and Utilization of 2 Therapies for Metastatic Castration-Resistant Prostate Cancer By Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services, SelectHealth, Murray, UT

PAYERS: Real-world data are always interesting when comparing what payers experience in a real-world environment as opposed to what has been demonstrated in a tightly controlled clinical study. These data may also show utilization patterns of medications, sometimes despite similar recommendations for use in clinical guidelines. One question left from the results of the study by Ellis and colleagues is why abiraterone was used so much more compared with enzalutamide within the treatment sequence of castration-resistant prostate cancer (CRPC).1 There may be several contributing factors to this question. First, abiraterone may be viewed as more effective or may be considered a drug that has fewer side effects than enzalutamide. However, although abiraterone and enzalutamide have not been studied in a head-to-head trial, the pivotal trials for each drug demonstrated similar efficacy. Second, abiraterone was approved first and garnered earlier clinical guideline approval. Abiraterone was approved by the US Food and Drug Administration (FDA) in 2011,2 whereas enzalutamide was approved by the FDA in 2012.3 With earlier data available, providers may have been more comfortable prescribing abiraterone, and it may have been placed within their internal pathways so they would be more used to prescribing it in this sequence. Third, abiraterone gained broader FDA approval and guideline placement for expanded use, including for the treatment of patients with metastatic CRPC who had received previous chemotherapy, as well as for patients who had not received chemotherapy. Fourth, when enzalutamide was approved, it was priced substantially higher than abiraterone. This caught the attention of payers, because enzalutamide had less market experience and had efficacy that was similar to abiraterone. This attention from payers has helped to influence the utilization sequence by influencing treatment pathways, or by directly placing increased coverage restrictions for enzalutamide. In an environment with continuing clinical updates for drugs, as well as pricing changes, payers need to stay abreast of management strategies to help promote the use of cost-effective treatment regimens. The ability to evaluate primary literature, clinical guidelines, other

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drug information resources (eg, Micromedex), direct pathways with contracted oncology groups, and real- world data, such as in the article by Ellis and colleagues, help payers evaluate coverage decisions for patients with prostate cancer. Based on these data, the drug cost was lower for abiraterone than for enzalutamide by $1123 to $1378 monthly, depending on the study being considered. Although future pricing changes are unknown, payers will continue to evaluate pricing and clinical outcomes data to help drive treatment decisions. PROVIDERS: Providers want to help their patients achieve the best outcomes and maintain a good quality of life. What is not available in this article is the difference of effectiveness depending on the sequencing of abiraterone or enzalutamide. Quality of life is hard to determine based on claims analysis. Also not shown in the article is adherence to therapy. A follow-up analysis could evaluate the markers of adherence, such as the portion of days covered, and persistence. An interesting finding within this data analysis is the amount of concomitant corticosteroid use. Although abir aterone is approved by the FDA for use in combination with prednisone, only 81% to 86% of patients had claims for abiraterone as well as for prednisone. The reason for nonuse of the combination is unknown, as well as whether the lack of concomitant therapy altered potential effectiveness. The National Comprehensive Cancer Network places enzalutamide and abiraterone as Category 1 for first-line treatment of patients with CRPC, and labels enzalutamide as Category 1 before docetaxel use, and abiraterone as Category 2A before chemotherapy use.4 Providers need to evaluate these recommendations for use within the appropriated sequence, as well as data for other therapies to help patients use the most appropriate therapy. ■ 1. Ellis LA, Lafeuille MH, Gozalo L, et al. Treatment sequences and pharmacy costs of 2 new therapies for metastatic castration-resistant prostate cancer. Am Health Drug Benefits. 2015;8(4):185-195. 2. Zytiga (abiraterone acetate) tablets [prescribing information]. Horsham, PA: Janssen Biotech, Inc; March 2015. 3. Xtandi (enzalutamide) capsules [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc; September 2014. 4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): prostate cancer. Version 1.2015. October 24, 2014. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed June 12, 2015.

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INDUSTRY TRENDS

Oncology Innovation and Challenging Choices: Balancing

Value and Funding Priorities in Light of an Abundance of New Treatment Options

By Michael Kleinrock Research Director, IMS Institute for Healthcare Informatics, IMS Health, Plymouth Meeting, PA

ancer is already the largest clinical area of drug spending in the United States, and a cluster of innovative medicines utilizing new mechanisms of action for patients with a wide variety of tumor types promise to further increase cancer-related spending. New treatments will replace older ones, and some patients will receive multiple targeted therapies and/or will be adding immunotherapies, which are often determined by biomarkers, with the promise of extending lives and improving survival rates fairly dramatically. There remain substantial challenges for payers and for patients in navigating the increasing maze of cancer treatment options and in addressing affordability at a patient level and at a system level. The concerns about these issues go hand in hand with the growing excitement about new treatments that has escalated in the past few years. The United States is a global leader and can yet learn important lessons from other countries regarding oncology treatments and funding. It is na誰ve to examine the US oncology market in isolation.

Measures of value in oncology continue to be tested by payers and providers who, in some health systems, most notably in the United States, have growing concerns about the financial burden faced by patients with cancer. In cancer care perhaps more than anywhere else, we face the challenge of population health versus individual health, because the costs of treating an individual patient can balloon rapidly, whereas the benefits may be only incremental. Funding unlimited treatment choices is increasingly unsustainable. The consequences of not resolving this divide between the individual health and population health will be severe

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for all stakeholders in the healthcare system, because the gap is only getting wider, and the stakes for 足patients simply do not allow them to consider the common good. The need for personalized medicines and diagnostics to bring greater precision in treatment selection and innovative funding mechanisms continues to escalate. The successes in cancer research are many, but that concentration of the research focus is creating a set of prioritization and funding challenges that have so far escaped the ability of stakeholders to reach consensus.

Increasing Spending on Cancer Drugs Based on the recent report from the IMS Institute for Healthcare Informatics, the total global spending on cancer and supportive care medicines reached the $100-billion threshold globally in 2014 (Figure 1), even as their share of the total pharmaceutical spending increased only modestly.1 Oncology drug spending has risen slightly as a percentage of the total drug spending over the past 5 years in all regions, most notably in the European Union 5 countries (ie, France, Germany, Italy, Spain, and the United Kingdom), where oncology now represents 14.7% of the total drug spending, an increase from 13.3% in 2010.1 In the United States, oncology drug spending has increased more modestly, from 10.7% to 11.3% of the total drug spending over the same period. Future spending on oncology medicines through 2018 is expected to increase 6% to 8% annually (Figure 2) compared with the 6.5% level that was seen over the past 5 years, as growing demand for novel therapeutic options are offset to some extent by a new competition from biosimilars and small-molecule generics after patent expirations.1 Measures of value in oncology continue to be tested by payers and providers who, in some health systems, most notably in the United States, have growing con-

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Oncology Innovation and Challenging Choices

Overall, the monthly treatment costs have increased 39% over the past 10 years in inflation-adjusted terms, similar to the 42% increase in overall response rates and 45% increase in number of months that patients with cancer are receiving therapy. Personalized Medicine The largest area of potential leverage in cancer care is the development of personalized treatments and diagnostics that can identify responding patients who have vastly better outcomes than the norm, as well as avoid wasteful medication use in nonresponsive patients. This diagnostic revolution is, of course, not based on definitive biomarker tests, because multiple tests may be used to identify markers, and their results are likely to vary in specificity and sensitivity. Few diagnostics are as definitive as those available for the diagnosis of the Philadelphia chromosome. The emergence of greater numbers of diagnostics linked to treatments is critical from the perspective of payers and providers as a way to help them navigate the maze of treatment choices, and to help avoid wasteful use of expensive but ultimately ineffective treatments for a particular patient or a cohort of patients.

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Figure 1 Global Oncology Drug Spending 2010-2014 United States Pharmerging

European Union 5 Rest of world

Japan 2010-2014 CAGR Global 6.5%

100

5.9%

Spending, $ (in billions)

15.5% 4.3%

60 5.8% 40

5.3%

2010

2011

2012

2013

2014

Year

NOTE: Oncology includes therapeutic treatments and supportive care, radiotherapy, and immunotherapies. Spending in US dollars with variable exchange rates. Growth in US dollars with constant exchange rates. CAGR indicates compound annual growth rate. Copyright © 2015 from IMS Institute for Healthcare Informatics. Used with permission.

Figure 2 Global Oncology Market Forecast United States Pharmerging Global spending, $ (in billions)

cerns about the financial burden faced by patients with cancer. These concerns are reflected in activity on social media networks, which patients are increasingly relying on for support throughout their cancer journey. These concerns are also reflected in the actions and statements of leading clinicians, who are now calling for oncologists to consider cost when making treatment decisions. As cancer treatment costs continue to rise, physicians must consider their patients’ financial resources at least as important as their clinical considerations. Although survival rates and the prognosis for patients with cancer are continuing to improve as a result of improved treatments and earlier diagnoses, cancer is hundreds of diseases, not one: cancer remains stubbornly resistant to therapies that use a single mechanism of action. Cancer management requires a “team approach” from a clinician perspective and in relation to the drugs, radiotherapy, and surgical options that are being used. Over the next 5 years, we can expect to see an acceleration in the number of combination regimens being launched for the treatment of cancer (Figure 3).

European Union 5 Rest of world

Japan

$117 billion$147 billion

120 $100 billion

100 80

$75 billion

60 40 20 0

2009

2014

CAGR 2010-2014, 7%

2018

CAGR 2014-2018, 6%-8%

NOTE: Spending in US dollars with variable exchange rates. Charted growth from 2009-2014 and 2014-2018, including the impact of exchange rate variability. CAGR indicates compound annual growth rate. Copyright © 2015 from IMS Institute for Healthcare Informatics. Used with permission.

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Figure 3 E xpected Combination Regimen Launches in Oncology 40 34

Expected launches, N

35 30 25 19

15 10

2015

2016

2017

5 0

2014

2018

2019

2020

2021+

Year

NOTE: Excludes some phase 1/1b combinations, non-US studies, and certain early-stage trials that have been approved but not yet enrolled. Timing of launches is based on current phase of clinical development: phase 1, 2020-2021+; phase 1b, 2020; phase 2, 2018-2019; and phase 3, 2016-2017. Copyright © 2015 IMS Institute for Healthcare Informatics. Used with permission.

Access to Care Patient access to oncology medicines varies widely by country, and closer scrutiny is being placed on value by payers and by patients who may face a growing share of the treatment costs. Overall, the monthly treatment costs have increased 39% over the past 10 years in inflation-adjusted terms, similar to the 42% increase in overall response rates and 45% increase in number of months that patients with cancer are receiving therapy, which further contribute to the higher overall spending levels associated with improved survival rates.1 In the United States, patient out-of-pocket costs associated with intravenous cancer drugs have risen steeply as a result of the consolidation of smaller group practices into larger hospital systems, which has triggered higher outpatient facility costs that are shared with patients.1 Because patient costs rise faster than incomes, the number of patients who effectively have access to novel medicines is progressively decreasing. At the very least, these patients are making tougher choices about nonhealthcare versus healthcare costs, and at worst they are forgoing lifesaving treatment because of the costs, assuming their access to care was not already limited by payer or provider decisions.

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Setting Priorities for Innovation As we see the continued pace of innovation in cancer care, and stakeholders consider whether the level of innovation is commensurate with the increases in costs, we must finally begin to grapple with choices regarding which cancer treatments to fund and prioritize. Health technology assessment is increasingly being used to judge value for money, but countries differ substantially on the methods they use. The United Kingdom’s NICE (the National Institute for Health and Care Excellence, previously the National Institute for Clinical Excellence) judges value against a £30,000 per quality-adjusted lifeyear gained by the treatment.1 In isolation, this appears to be a rational approach, but because many cancer drugs do not meet that threshold and yet are strongly desirable from social and political viewpoints, the United Kingdom has created a cancer drugs fund for the expressed purpose of funding access to these drugs, even though NICE has determined them to be too expensive.1 In this important sense, negative assessments of value for money are not the only factor that determines a drug’s value. In Germany, the Arzneimittelmarkt-Neuordnungsgesetz policy assesses drugs to input to reimbursement discussions, and few pharmaceuticals assessed on this basis have achieved the same level of value across countries.1 France, another leader in health technology assessment policy, uses a drug innovation rating system and then bands reimbursement linked to the level of innovation.1

The lack of transparency regarding drug pricing to different purchasers only exacerbates discussions and questions of value. On the face of it, each country’s approach appears reasonable; however, agreement on the value of a drug, or agreement on which methods to use in determining value, is fairly limited. These issues are complicated by the complex nature of cancer treatments that often have one price but differential value in different tumor types; their value often emerges over time, whereas their price is typically set with the initial approval of the drug. The lack of transparency regarding drug pricing to different purchasers only exacerbates discussions and questions of value. In the 4 decades since President Richard Nixon declared war on cancer, rarely has there been a discussion about which cancers to prioritize and which treatments to deem more important. Today, treatments allow multiple lines of therapy for patients, and successive chances to treat their tumors and extend their lives. The cost of

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Oncology Innovation and Challenging Choices

treating a patient with cancer includes longer treatment durations as well as multiple treatment modalities, which sometimes far overstretches the existing cost-sharing and funding models. Patientsâ&#x20AC;&#x2122; share of costs in the United States is often designed to reflect a fair balance, but a percentage coinsurance model, if uncapped, could expose a patient to hundreds of thousands of dollars in costs.

Patientsâ&#x20AC;&#x2122; share of costs in the United States is often designed to reflect a fair balance, but a percentage coinsurance model, if uncapped, could expose a patient to hundreds of thousands of dollars in costs. In a single-payer environment, as exists in Europe, balancing access for some patients to innovative drugs with overall health system funding is forcing societal discussions about the value of treatments. For access to these treatments to be fair and equitable, society must balance the appropriate rewards for innovators to keep the flow of treatments coming, as well as the ability of systems and patients to afford these treatments.

As healthcare funding approaches zero-sum game levels, we must also consider population health issues, such as prioritizing some disease treatments over others.

Tough Choices May Limit Innovation These issues present tough choices, and no single country has addressed these issues of system funding versus patient need. The pressures this will no doubt place on stakeholders will likely result in fewer commercially successful pharmaceutical innovators, and that, in turn, could slow down the flow of innovation. These are trade-offs that stakeholders must consider, but if we were asked 4 decades ago to choose, clearly we all would choose this problem over a lack of treatments. Now we have to decide how to make the fairest and best use of the available dollars and treatments that have emerged from research laboratories. n Author Disclosure Statement Mr Kleinrock is an employee of IMS Health, which serves as a consultant to many pharmaceutical companies.

Reference

1. IMS Institute for Healthcare Informatics. Developments in Cancer Treatments, Market Dynamics, Patient Access and Value: Global Oncology Trend Report 2015. May 2015.

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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For 1 in 4 patients with polycythemia vera (PV), disease remains uncontrolled despite treatment with hydroxyurea (HU)1,2 According to Marchioli et al, 2013, in The New England Journal of Medicine, maintaining control of hematocrit (Hct) levels consistently below 45% is an established target in treatment of PV3

Maintain hematocrit

<45% Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information

Patients who are intolerant of or inadequately responding to HU may be identified by4: Inability to maintain Hct level consistently <45% without phlebotomy Persistent elevation in platelet and leukocyte counts Leg ulcers or other unacceptable non-hematologic toxicities Persistent splenomegaly Polycythemia vera is a chronic, progressive myeloproliferative neoplasm. Of the approximately 100,000 people in the United States with PV, the disease remains uncontrolled in 25,000.2,3,5

evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk-benefit determination

Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose-related effects. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated

Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate

Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly

When discontinuing Jakafi, myeloproliferative neoplasmrelated symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation

Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi,

Non‐melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations

Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery

Advise patients about early signs and symptoms of herpes zoster and to seek early treatment

For your members who have uncontrolled PV despite treatment with HU, Jakafi® (ruxolitinib) may be appropriate therapy The first and only FDA-approved treatment for patients with PV who have had an inadequate response to or are intolerant of HU6 In a phase 3 trial, the primary end point was a composite of Hct control without phlebotomy and ≥35% spleen volume reduction at week 326,7* Significantly more patients treated with Jakafi achieved the composite primary end point compared with best available therapy (BAT) (21% vs 1%; P < 0.0001)6,7

Individual Components of Primary End Point 80 60

Patients (%)

* A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy in 222 patients. Best available therapy included hydroxyurea (60%), interferon/ pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). Patients had been diagnosed with PV for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy, and exhibited splenomegaly. The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both Hct control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value).

60% (n = 66)

38%

40 20 0

The three most frequent non-hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast-feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following pages.

Jakafi (n = 110) BAT (n = 112)

20% (n = 22)

(n = 42)

(n = 1)

Hct Control Without Phlebotomy

≥35% Spleen Volume Reduction

References: 1. Alvarez-Larrán A, Pereira A, Cervantes F, et al. Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood. 2012;119(6):1363-1369. 2. Data on file. Incyte Corporation. Wilmington, DE. 3. Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. 4. Barosi G, Birgegard G, Finazzi G, et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2009;148(6):961-963. 5. Tefferi A. Polycythemia vera: a comprehensive review and clinical recommendations. Mayo Clin Proc. 2003;78(2):174-194. 6. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. 7. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426-435.

Review the clinical trial data at

www.jakafidata.com

BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebocontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse Reactions

a b

c d

e f

All Gradesa Grade 3 (%) (%)

Grade 4 All Grades Grade 3 (%) (%) (%)

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebocontrolled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

Presented values are worst Grade values regardless of baseline

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

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) Adverse Events

Grade 4 (%)

Best Available Therapy (N=111)

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

0 0

Grade 3-4 (%)

Bruisingb

Constipation

Dizzinessc

Cough

Headache

Edemae

Urinary Tract Infectionsd

Arthralgia

Weight Gaine

Asthenia

Flatulence

Epistaxis

Herpes Zosterf

Nausea

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present includes weight increased, abnormal weight gain includes herpes zoster and post-herpetic neuralgia

a b c d e f

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

Other clinically important treatment emergent adverse events observed in less than 6% of patients treated with Jakafi were: Weight gain, hypertension, and urinary tract infections Clinically relevant laboratory abnormalities are shown in Table 4. Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta Jakafi (N=110) Laboratory Parameter

All Gradesb Grade 3 (%) (%)

Best Available Therapy (N=111) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2015 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428

Hematology Anemia

Thrombocytopenia

Neutropenia

Chemistry Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made 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 Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity

Have you ever treated polycythemia vera with hydroxyurea but your patient’s Hct level remained too high? Consider

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea. Summary of Warnings and Precautions1 Jakafi can cause thrombocytopenia, anemia, and neutropenia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. In patients developing cytopenias, manage by dose reduction, interruption, or transfusion Serious infections can occur. Assess patients for signs and symptoms of infection and initiate appropriate treatment promptly. Serious infections should have resolved before starting therapy with Jakafi Some patients have experienced symptom exacerbation following interruption or discontinuation of Jakafi. Manage patients with supportive care and consider resuming treatment with Jakafi Non‐melanoma skin cancers, including basal cell, squamous cell, and Merkel cell carcinoma, have occurred. Perform periodic skin examinations in patients taking Jakafi The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness, and headache Please see the Important Safety Information on previous pages to learn more about these and other risks. Hct, hematocrit. Reference: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation. Jakafi is a registered trademark of Incyte Corporation. © 2015, Incyte Corporation. All rights reserved. RUX-1619 04/15

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ORIGINAL RESEARCH

Stakeholder Perspective, page 214

Am Health Drug Benefits. 2015;8(4):204-215 www.AHDBonline.com Received April 20, 2015 Accepted in final form May 15, 2015

Disclosures are at end of text

BACKGROUND: Multiple myeloma is a progressive cancer for which there is no cure. Despite treatment, almost all patients eventually experience periods of disease relapse and remission. With the increasing use of novel therapies, including bortezomib, lenalidomide, carfilzomib, pomalidomide, and panobinostat, benchmarks for assessing the value of these therapies in treating patients with relapsed or refractory multiple myeloma (RRMM) are needed for physicians and payers alike. OBJECTIVES: To develop a model framework and to calculate an annual estimate of the total costs per patient for the treatment of patients with RRMM using 7 common treatment regimens, including bortezomib plus dexamethasone; panobinostat, bortezomib, and dexamethasone; lenalidomide plus dexamethasone; lenalidomide, bortezomib, and dexamethasone; carfilzomib; carfilzomib, lenalidomide, and dexamethasone; and pomalidomide plus dexamethasone. METHODS: The expenditures for drugs and their administration, for prophylaxis and adverse event monitoring, and for the treatment of grade 3 or 4 adverse events were included in the calculations of the total pharmacy and medical costs. The drug costs were based on published pricing and labeled dosing schedules; the adverse event prophylaxis and monitoring costs were obtained from peer-reviewed publications; and the adverse event incidence rates were obtained from each regimen’s prescribing information and from clinical trials. All the costs were summed over the duration of therapy for which the drugs were administered and were calculated separately for commercial and Medicare plans. The duration of therapy for each regimen was the time for which a patient had to be receiving the regimen to obtain 12 months of progression-free survival based on the duration-of-therapy to progression-free survival ratio observed from published clinical trials and/or the drug’s labeling. RESULTS: The pharmacy costs were highest for pomalidomide plus dexamethasone, whereas the medical costs were highest for the combination of carfilzomib, lenalidomide, and dexamethasone. The total cost associated with available treatments for RRMM was highest for regimens that included lenalidomide (approximate range, $126,000-$256,000). Only bortezomib plus dexamethasone and the combination of panobinostat, bortezomib, and dexamethasone had total costs that were lower than $125,000 per patient. CONCLUSION: This study represents the first model developed to comprehensively estimate the costs of managing RRMM with all currently approved and guideline-recommended regimens in the United States. As such, it provides the framework and basis for further budget impact analyses and for cost- effectiveness comparisons with these regimens. KEY WORDS: costs, progression-free survival, relapsed/refractory multiple myeloma, histone deacetylase inhibitor, proteasome inhibitor, immunomodulatory drug, model framework

Dr Roy is Associate Director, Health Economics and Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Dr Kish is Manager, Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL; Dr Bloudek is Assistant Director, Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL; Dr Siegel is Chief of the Myeloma Division, Hackensack University Medical Center, NJ; Dr Jagannath is Director of the Multiple Myeloma Program and Professor of Medicine, Hematology and Medical Oncology, Tisch Cancer Institute, Mount Sinai Hospital, New York; Dr Globe is Executive Director, US Health Economics and Outcomes Research, Novartis Pharmaceuticals, East Hanover, NJ; Dr Kuriakose is Medical Director, Novartis Pharmaceuticals, East Hanover, NJ; Ms Migliaccio-Walle is Director, Global Health Economics and Outcomes Research, Xcenda, Palm Harbor, FL.

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June 2015

Vol 8, No 4

Estimating the Costs of Therapy in Patients with Multiple Myeloma

ultiple myeloma is a malignant B-cell neoplasm of terminally differentiated plasma cells that accumulate in the bone marrow and frequently invade the adjacent bone, leading to bone destruction and marrow failure.1,2 Multiple myeloma accounts for 10% of all blood cancers3 and 1.6% of all new cancer cases in the United States.4 Among the general population, the lifetime risk for multiple myeloma is 0.7%.4 Multiple myeloma has no cure and, despite treatment, almost all patients experience periods of relapse and remission.1 Relapsed multiple myeloma is defined as disease that has previously responded to therapy and subsequently progressed beyond 60 days of the last therapy.5 Refractory multiple myeloma is defined as “disease that is nonresponsive while on primary or salvage therapy, or progresses within 60 days of last therapy.” 5 For patients with relapsed or refractory multiple myeloma (RRMM), there is no published standard of care. Treatment guidelines for RRMM offer many therapeutic options; as such, a wide variety of anticancer regimens and sequencing patterns are used in the real-world clinical practice.2 Novel agents approved for the treatment of RRMM— including bortezomib, a proteasome inhibitor; carfilzomib, a second-generation proteasome inhibitor; and lenalidomide and pomalidomide, which are immunomodulatory drugs (IMiDs)—are used at different points throughout the course of treatment.6 In US clinical practice, regimens based on bortezomib form the cornerstone of therapy for multiple myeloma, and bortezomib is used as either firstline therapy or for retreatment in patients who had achieved a durable response before disease relapse.7 Similarly, treatment with lenalidomide in induction and as maintenance therapy has gained widespread use.8 With each successive line of treatment, however, therapeutic options become increasingly limited, and patients experience lower rates of clinical response and shorter progression-free survival (PFS); that is, the time between the start of treatment and progressive disease or death, on each subsequent disease relapse.9,10 The total direct medical costs associated with cancer treatment in the United States were estimated to be $124.6 billion in 2010.11 Multiple myeloma accounts for a small percentage (1%) of all patients with cancer12; however, the associated costs over the course of the disease may be disproportionately high compared with other cancers that have metastasized to the bone.13 Moreover, these costs are expected to rise with the aging of the US population and with extended patient survival from newer and improved therapies. Improvements in available treatment regimens have enabled patients with RRMM to live longer, and overall survival has increased from a median of 4.6 years in 2001-2005 to 6.1 years in 2006-2010.14 Patients are liv-

Vol 8, No 4

June 2015

KEY POINTS Almost all patients with multiple myeloma, a progressive cancer for which there is no cure and no standard of care, experience periods of disease relapse despite treatment. ➤ This is the first US model to comprehensively estimate the costs of treatment for relapsed or refractory multiple myeloma (RRMM) based on all currently approved and guideline- recommended regimens. ➤ The analysis focused on the annual per-patient treatment cost with 7 regimens. ➤ The pharmacy and medical costs were highest for regimens that included lenalidomide (approximate total cost range, $126,000-$256,000). ➤ Only bortezomib plus dexamethasone and the combination of panobinostat, bortezomib, and dexamethasone had total per-patient treatment costs of <$125,000. ➤ Bortezomib plus dexamethasone had the lowest annual per-patient cost ($90,616); carfilzomib plus lenalidomide and dexamethasone had the highest ($256,416) in commercially insured patients. ➤ The total treatment cost was highest ($148,326) for the combination of carfilzomib, lenalidomide, and dexamethasone in patients with commercial insurance. ➤ The total pharmacy cost was highest ($135,774) for pomalidomide plus dexamethasone. ➤ This study provides a framework that can be used for further budget impact analyses and costeffectiveness comparisons with these regimens. ➤

ing longer because they are receiving more lines of therapy and are achieving longer PFS. More lines of therapy, however, result in greater costs per patient, especially because physicians are prescribing newer therapies that are, in most cases, more expensive. As survival in patients with RRMM is extended and treatment is prolonged, the costs of therapy have become increasingly important to payers and to patients.15 Although drug costs form a conspicuous portion of treatment costs in multiple myeloma, myeloma-related healthcare costs are also significantly driven by disease complications, which result in inpatient hospitalizations, hospital readmissions, and medical procedures.12,16,17 For example, the Healthcare Cost and Utilization Project Nationwide Inpatient Sample found an estimated mean cost of $28,700 per patient with multiple myeloma per hospital stay (among the highest of all cancers) and a

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eported Median Duration of Therapy to Achieve 12 Table 1 R Months of Progression-Free Survival Median DOT, mo

Median PFS, mo

DOT to yield 12 months of PFS, mo

Panobinostat, bortezomib, dexamethasone22,23

5.0

12.0

5.0

Bortezomib + dexamethasone22,23

6.1

8.0

9.2

Lenalidomide + dexamethasone24

10.1

11.1

10.9

Lenalidomide, bortezomib, dexamethasone25

8.0

9.5

10.1

Carfilzomib, lenalidomide, dexamethasone26

20.5

26.3

9.4

Carfilzomib27

3.0

3.7

9.7

Pomalidomide + dexamethasone28,29

3.7

4.0

11.1

Regimen/source of data

DOT indicates duration of therapy; PFS, progression-free survival.

total cost of $522 million (based on 18,200 discharges) in 2009.18 Moreover, the average length of hospital stay (mean, 11.6 days) associated with multiple myeloma was among the longest of the cancers that were evaluated,18 and 28.4% of patients who were hospitalized were readmitted within 30 days of their initial hospitalization.16 Thus, the avoidance of hospitalizations may be an important approach to control costs in this disease and to enhance patient lives. Prolonging the duration of remission and/or lengthening PFS are the primary goals of therapy for patients with multiple myeloma and may lead to the avoidance of hospitalizations and other outcomes associated with significant costs.10 Patients often experience their best response to novel agents when they are used early in the course of therapy after the first disease relapse; however, retreatment with bortezomib or an IMiD after the first relapse with the same regimen or in combination with other drugs has demonstrated efficacy.10 Two trials—VISTA19 and RETRIEVE20—successfully demonstrated overall response rates (ie, at least a partial response) of 47% and 40% for patients with previous bortezomib exposure and subsequent retreatment, respectively. The response rates observed were not significantly different from the overall response rates that were seen in the respective bortezomib-naïve arms. Thus, an attractive option after a second relapse, particularly in patients who were previously exposed to

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bortezomib and an IMiD and who are being considered for retreatment with bortezomib, may be the addition of a drug with a novel mechanism of action in combination with other agents. This approach may mitigate the tangible direct medical costs and the intangible, and bothersome, effects of disease progression and its treatment. To understand the costs of treatment across the current spectrum of regimens for patients with RRMM, a Microsoft Excel–based treatment regimen cost estimator was developed. A review of published studies in 2011 found that, despite advances in therapy for multiple myeloma, the literature at the time was still lacking economic comparisons of novel therapies, specifically cost-effectiveness studies.21 Since that time, 1 study evaluating the costs of care of multiple myeloma has been published.15 Durie and colleagues developed an economic model to evaluate the total treatment costs and the monthly costs without progression associated with lenalidomide plus dexamethasone (Rd) versus bortezomib plus dexamethasone.15 The results of this model demonstrated that the drug and medical costs associated with bortezomib were more than $17,000 higher than those for patients treated with lenalidomide.15 Although these results provided a baseline for comparison, the model did not include any treatment regimens that were more recently approved for RRMM (specifically panobinostat, carfilzomib, and pomalidomide), and it contained a limited list of adverse events. To address these gaps, the treatment regimen cost estimator described in this article was developed. The objectives of this article are (1) to describe the framework of the cost estimator in terms of the cost inputs, assumptions, and calculations; and (2) to calculate the estimated total Medicare and commercial payer cost per patient to achieve 12 months of PFS with US Food and Drug Administration (FDA)-approved and/or National Comprehensive Cancer Network (NCCN)- recommended therapies for RRMM.

Methods Treatment Regimens and Clinical Inputs An Excel-based treatment regimen cost estimator was developed with the primary objective of estimating the costs of treatment with RRMM regimens from US commercial and Medicare perspectives. All costs are reported in 2015 US dollars either directly or inflation adjusted from earlier estimates using the medical component of the US Bureau of Labor Statistics Consumer Price Index. The treatment regimens considered were approved by the FDA or were recommended by the NCCN, or involved therapies used in real-world settings for RRMM. These include the combination of panobinostat, bortezomib, and dexamethasone; bortezomib plus dexa-

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Table 2 Total Number of Doses During the Course of Treatment to Attain 12 Months of Progression-Free Survival PAN, BTZ, BTZ + LEN + LEN, BTZ, CFZ, LEN, CFZ, POM + Drug dose DEX, N DEX, N DEX, N DEX, N DEX, N N DEX, N Panobinostat 20 mg

Bortezomib 1.3 mg

Dexamethasone 10 mg Dexamethasone 20 mg

43 86

46 80

28 64

Dexamethasone 40 mg

Lenalidomide 15 mg Lenalidomide 25 mg

210 252

217

Carfilzomib 20 mg

Carfilzomib 27 mg

Pomalidomide 4 mg

252

BTZ indicates bortezomib; CFZ, carfilzomib; DEX, dexamethasone; LEN, lenalidomide; PAN, panobinostat; POM, pomalidomide.

methasone; Rd; lenalidomide, bortezomib, and dexamethasone (RVD); and the combination of carfilzomib, lenalidomide, and dexamethasone (CRd). Although they were used later in treatment and among patients with a worse prognosis and previous exposure to a proteasome inhibitor and IMiD based on their FDA-approved label, carfilzomib monotherapy and pomalidomide plus dexamethasone were also considered in the cost analysis. The costs for a drug (oral or intravenous) and its administration (intravenous only), adverse event prophylaxis and monitoring costs, and grades 3 and 4 adverse event costs (monthly rate of therapy multiplied by the costs of treatment) were summed over the duration of a treatment interval to calculate the total costs. The total costs of therapy per patient were calculated using the total duration of therapy that was theoretically needed to achieve 12 months of PFS. The 12-month time horizon was chosen to reflect the typical budgetary interval for hospitals or for pharmacies. The total time of therapy duration was calculated based on the ratio of median duration of treatment to median PFS. To calculate the costs that are relevant to a typical 1-year payer time horizon, the model assumes that after completing a course of therapy at the median duration of therapy, patients remain without disease progression until reaching the median PFS that was reported in the pivotal clinical trial for each drug or treatment regimen. The patients are then assumed to be subsequently retreated with the same regimen. This method of determining time duration of therapy was chosen to allow for fair comparisons across the treatment regimens with large variability in PFS (range, 3.723.6 months), although this may not always be the case in a real-world clinical setting. In addition, in any typical 12-month period, some patients will begin therapy,

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whereas others may be mid-regimen or may be carried over from the previous year. As such, the total duration of therapy theoretically needed to achieve 12 months of PFS based on the median duration of therapy and the PFS reported from pivotal clinical trials of the respective regimens was assumed to be a fair and balanced representation of the duration for which an average or typical patient can be assumed to continue using therapy in a given year. The data on PFS and duration of therapy were obtained from published clinical trials and/or from drug labeling information and are presented in Table 1, along with the total number of months required to obtain a PFS of 12 months.22-29

Drug Costs The costs for each drug and its administration were calculated as the sum of the total cost per dose over the duration of therapy. The costs to commercial and 足Medicare plans for oral drugs were based on their wholesale acquisition costs as reported in Red Book.30 For drugs administered by intravenous infusion, the Medicare drug cost was based on the average sales price plus 6%,31 whereas for commercial intravenous drugs, the cost was estimated at 123.5% of the Medicare cost.32 The Medicare cost for each agent was $6860 per package of 6 capsules for panobinostat, $2134 per vial of bortezomib, $9855 per package of 21 capsules for lenalidomide, $2392 per vial for carfilzomib, $11,414 per package of 21 capsules for pomalidomide, and $11 per package for dexamethasone. The medical costs related to intravenous drug administration, hydration, and physician office visits were included. The costs of administration were estimated from Current Procedural Terminology (CPT) code 99212 (level

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Table 3 C osts of Adverse Event Prophylaxis and Monitoring Prophylactic Applicable therapy treatment regimens

Cost, $a

Cost source

IV hydration

Bortezomib- and carfilzomib-containing regimens

57.92 (Medicare) 71.53 (commercial)

References 18, 19

Electrocardiogram

Panobinostat- and carfilzomib-containing regimens

17.16 (Medicare) 21.19 (commercial)

References 18, 19

Herpes zoster

Bortezomib- and carfilzomib-containing regimens

5.34 weekly Acyclovir (400 mg twice daily)

Cost based on WAC of $0.3814 per tablet17

Deep-vein thrombosis/ pulmonary embolism

Lenalidomide-containing regimens

22.00 weekly Enoxaparin (40 mg daily)

Cost based on WAC of $220 per 10 syringes17

Renal toxicity, tumor lysis syndrome

Carfilzomib-containing regimens

2.20 weekly Allopurinol (200 mg daily)

Cost based on WAC of $31.41 per 100 allopurinol 100-mg tablets17

Infusion reactions

Carfilzomib-containing regimens

0.11 per carfilzomib dose Dexamethasone (4 mg per carfilzomib dose)

Cost based on WAC of $11.41 per 4 100-mg tablets17

Inflation adjusted to 2015 US dollars. IV indicates intravenous; WAC, wholesale acquisition cost.

2 established office visit) and CPT code 96409 (chemotherapy administration, intravenous push, single drug). The costs included for Medicare and commercial insurance calculations were $43.98 and $54.31, respectively, for physician office visits; $111.20 and $137.33, respectively, for intravenous administration; and $57.92 and $71.53, respectively, for the intravenous administration of hydration. The model accounted for typical conventions for patient cost-sharing by using a tier 4 copayment rate of $100 for orally administered drugs (ie, panobinostat, lenalidomide, and pomalidomide). A 20% coinsurance was assumed for drugs administered intravenously (ie, carfilzomib and bortezomib). Cost-sharing for dexamethasone was assumed to be tier 1 at a rate of $10.30 The number of drug doses over the duration of therapy was calculated based on the dosing schedules provided in the drug’s prescribing information or in a pivotal clinical trial for each drug for the base case reported here. Table 2 illustrates the base-case number of administered doses of each drug by treatment regimen over the duration of therapy needed to achieve 12 months of PFS. Patients were assumed to be adherent to all therapies over the entire duration of therapy, with no skipped doses, dose escalation, or de-escalation. The median duration of therapy was selected, because it is frequently reported in clinical trials, as well as to account for variability in patient adherence that may be expected in real-world settings.

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Cost of Prophylaxis and Adverse Event Monitoring The costs of prophylaxis and monitoring for adverse events are provided in Table 3. Specific adverse event prophylaxis measures and monitoring procedures were recommended for some treatment regimens, and a complete blood count with autodifferential was included for all regimens15 at a cost of $48.14 for Medicare and $59.45 for a commercial plan. The costs associated with medical services, such as intravenous hydration, electrocardiogram, and the management of adverse events, were taken from published literature and were inflated to 2015 US dollars (Table 3). Cost of Adverse Events The costs related to grade 3 or 4 adverse event profiles for each regimen were calculated using the adverse event rates collected from clinical trials and from the drug labels (Table 4). The adverse events considered were those occurring in ≥5% of the treatment arm of any regimen, as was reported in each drug’s prescribing information or in a pivotal clinical trial. In addition, the costs related to monitoring for arrhythmia and atrial fibrillation were included for panobinostat-, lenalidomide-, and carfilzomib-containing regimens. The unit costs for adverse events were obtained from published sources and were inflated to 2015 US dollars using the medical care component of the US Bureau of Labor Statistics Consumer Price Index.33 Because the median duration of exposure differs across studies, the adverse event rates were first standardized to

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1287

1155

Herpes zoster

Hypocalcemia

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166

Lymphopenia

Neutropenia

Thrombocytopenia

Inflation adjusted to 2015 US dollars.

166

Hyponatremia

166

Hyperglycemia

Hypophosphatemia

783

Peripheral neuropathy

Leukopenia

924

901

Hypomagnesemia

Urinary tract infection

1.00

0.20

3.60

13.48

6.90

10.76

4.60

4.00

2.60

0.00

3.52

0.00

1.00

1707

Hypokalemia

0.47

3.60

5220

Upper respiratory infection

0.60

4.78

5.10

0.16

0.47

1.10

1.46

0.10

0.20

2.52

0.00

971

6998

Arrhythmia/atrial fibrillation

Anemia

9738

10,728

Back pain

8437

10,886

Dyspnea

Diarrhea

11,934

Nausea

Asthenia/fatigue

12,316

13,261

Febrile neutropenia

11,934

14,855

Pneumonia

Renal failure

31,645

Deep-vein thrombosis/ pulmonary embolism

Vomiting

Unit cost,a $

Grade 3 or 4 adverse event

Treatment regimen

5.15

1.87

6.65

1.31

1.97

1.15

0.00

2.39

0.00

0.16

3.13

0.33

0.31

1.15

0.26

0.00

1.96

1.31

0.22

0.39

0.09

0.21

0.00

0.08

1.69

0.00

1.19

3.25

0.27

0.39

0.25

0.00

0.14

0.00

0.96

0.36

0.00

0.47

0.14

0.36

0.66

0.30

0.00

0.17

0.00

0.22

0.83

1.19

2.75

3.75

0.00

1.17

0.98

1.17

0.38

0.00

0.25

0.00

0.39

0.59

0.38

0.00

0.25

0.81

1.44

0.00

0.13

0.00

0.83

0.00

0.46

0.00

0.37

0.19

0.00

0.14

0.00

0.16

0.00

0.09

Monthly events during therapy, %

Panobinostat, Bortezomib Lenalidomide Lenalidomide, Carfilzomib, bortezomib, + + bortezomib, lenalidomide, dexamethasone dexamethasone dexamethasone dexamethasone dexamethasone

Table 4 Grade 3 or 4 Adverse Event Rates (Monthly Incidence) and Unit Costs

6.27

2.76

4.85

1.77

2.15

1.20

0.37

0.00

0.13

8.00

0.00

0.05

1.08

0.76

3.36

0.27

0.95

1.65

0.44

0.27

1.84

0.27

2.81

0.00

Carfilzomib

4.07

9.21

1.50

2.10

0.00

1.72

0.00

4.50

0.19

0.00

0.36

0.00

5.17

0.21

1.91

2.68

0.14

0.00

1.34

0.64

4.93

0.00

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a monthly percentage (based on the observed rates during the course of treatment reported in the clinical trials) and were then multiplied by the median duration of therapy for each treatment regimen (Table 1). The model assumes that grade 3 or 4 adverse events occur with equal distribution of risk across the duration of therTable 5 T otal Cost of Treatment Regimens (per Patient) in Medicare and Commercial Health Plans Cost inputsa Grade 3 or 4 adverse event prophylaxis and Regimen Pharmacy, $ Medical, $ management, $ Commercial Panobinostat, bortezomib, dexamethasone

50,704

55,805

12,236

Bortezomib + dexamethasone

79,988

10,623

Lenalidomide + dexamethasone

117,069

9083

Lenalidomide, bortezomib, dexamethasone

97,554

85,568

6161

Carfilzomib, lenalidomide, dexamethasone

100,811

148,326

7279

136,878

21,670

135,774

24,372

Panobinostat, bortezomib, dexamethasone

50,704

45,187

11,855

Bortezomib + dexamethasone

64,768

10,024

Lenalidomide + dexamethasone

117,069

8906

Lenalidomide, bortezomib, dexamethasone

97,554

69,286

5507

Carfilzomib, lenalidomide, dexamethasone

100,811

120,102

6240

110,833

20,599

135,774

24,176

Carfilzomib Pomalidomide + dexamethasone Medicare

Carfilzomib Pomalidomide + dexamethasone

Total costs based on data that were either reported in or inflation adjusted to 2015 US dollars.

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apy (ie, adverse events are equally likely to occur at any given week of therapy).

Results The drug costs, medical costs, and grade 3 or 4 adverse event prophylaxis and management costs associated with each treatment regimen are shown in Table 5. From the commercial payer perspective, the costs for prophylaxis and the management of grade 3 or 4 adverse events were highest for carfilzomib monotherapy ($21,670) and for combination therapy with pomalidomide and dexamethasone ($24,372). The medical costs were highest for the CRd treatment regimen ($148,326), whereas 2 regimens (Rd, and pomalidomide plus dexamethasone) incurred no medical costs. The pharmacy costs were highest for pomalidomide plus dexamethasone ($135,774) and were lowest for bortezomib plus dexamethasone ($6), followed by the combination of panobinostat, bortezomib, and dexamethasone ($33,804). The pharmacy costs for lenalidomide-based regimens ranged from $97,554 (RVD) to $117,069 (Rd). All carfilzomib-related costs were medical, and therefore there were no pharmacy costs. The total cost per patient and the monthly total cost per patient receiving treatment are presented in Figure 1 and Figure 2 for the commercial and Medicare plans. The pharmacy and medical costs were highest for regimens that included lenalidomide. The lowest-cost lenalidomide-based therapy was Rd at $126,153 (commercial) and $125,976 (Medicare). The total cost per patient over the course of 12 months of PFS ranged from approximately $90,600 (bortezomib plus dexamethasone) to approximately $260,000 (CRd). Bortezomib and dexamethasone had the lowest total annual cost per patient per 12 months of PFS gained at $90,616; the combination of panobinostat, bortezomib, and dexamethasone followed at $118,745. The total monthly cost per patient receiving therapy (eg, the number of months to achieve 12 months of PFS; Table 1) was highest from the commercial plan perspective for CRd at $27,422 and was lowest for bortezomib plus dexamethasone at $9903. For the Medicare plan, the highest monthly cost per patient receiving therapy was for carfilzomib ($24,293), and the lowest cost was for bortezomib plus dexamethasone ($8175). Discussion This study presents a framework and foundation for estimating the economic impact of novel therapies for the management of RRMM. Although this model adopted a similar approach to a previously published cost study

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$159,950

$160,146

$131,432

$158,549

$189,283 $125,976

$126,153

$90,616

100,000

$74,798

150,000

$107,746

200,000 $118,745

Cost estimate, $

250,000

$172,347

Commercial Medicare

300,000

$227,152

$256,416

ost Estimation Model Total: Cost Comparisons for Treatment Regimens for Relapsed or Refractory Figure 1 C Multiple Myeloma in Medicare and Commercial Health Plans

50,000 0

Panobinostat, bortezomib, dexamethasone

Bortezomib Lenalidomide Lenalidomide, + + bortezomib, dexamethasone dexamethasone dexamethasone

Carfilzomib, lenalidomide, dexamethasone

Carfilzomib

Pomalidomide + dexamethasone

10,000

$14,410

$14,428

$16,295

$13,508

$27,422 $17,055

$11,537

$11,554

$9903

15,000

$8175

$20,369

20,000

$18,169

Cost estimate, $

25,000

$18,731

Commercial Medicare

30,000

$24,293

ost Estimation Model: Total Costs per Patient per Month with Treatment Regimens for Relapsed or Figure 2 C Refractory Multiple Myeloma in Medicare and Commercial Health Plans a

5000 0

Panobinostat, bortezomib, dexamethasone

Bortezomib Lenalidomide Lenalidomide, + + bortezomib, dexamethasone dexamethasone dexamethasone

Carfilzomib, lenalidomide, dexamethasone

Carfilzomib

Pomalidomide + dexamethasone

Monthly cost per patient receiving therapy is the total cost divided by the median duration of therapy needed to obtain 12 months of progression-free survival. a

in patients with RRMM,15 it builds on the existing literature by evaluating all the frequently used regimens, and by incorporating a broader list of adverse events within a single framework. Many of the cost and resource components that were included in our study are the same as those previously evaluated, including drug costs, medical costs (ie, prophylaxis, monitoring), and grade 3 or 4 adverse event costs.

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The specific adverse events considered from one study to the next were generally the same; however, as new therapies and combination regimens have emerged, the adverse event profile has changed, necessitating a broader inclusion of potentially relevant adverse events to consider when evaluating the total cost. Our model projected a total 1-year cost for Rd of approximately $126,000 for Medicare and commercially

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insured patients, representing a monthly therapy cost of approximately $11,500. In the previous cost study, the total 1-year cost of treatment with Rd was estimated at $103,871 in 2011 US dollars ($116,295 when inflated to 2015 US dollars using the medical care component of the Consumer Price Index).15 This is lower than our estimate of $126,153 (2015 US dollars), a difference that was primarily driven by an increase in cost for lenalidomide since the study was published and by the choice of using wholesale acquisition cost in our study ($465 daily) versus average wholesale price minus 16% ($360 daily) as in the previous analysis. The previous analysis also calculated the monthly cost without progression and showed generally similar results to our analysis when the difference in the estimated price of lenalidomide is considered ($8949 for Rd and $10,105 for bortezomib plus dexamethasone), even when using median time to progression (where deaths are censored observations) rather than median PFS (including progression and death as outcomes, leading to a more conservative estimate of efficacy) to inform this calculation. Another study evaluating an administrative claims database showed a monthly cost estimate of $6911 for Rd in 2010 US dollars ($7964 in 2015 US dollars).34 The higher costs in our model may result from including a more robust adverse event profile and increased drug, pharmacy, and medical costs since the publication of the previous studies. The lower costs may reflect the study’s design elements; administrative claims analyses, such as that carried out by Binder and colleagues,34 may not capture all of the clinically relevant adverse events (eg, fatigue or nausea). The duration of therapy to PFS ratio is one method to determine regimen value relative to its cost. A lower- cost treatment regimen combined with a lower duration of therapy to PFS ratio would be valuable from a payer budget perspective. Thus, to assess the relative value of therapies with very different duration of therapy and PFS profiles, the total costs of therapy were determined over an interval that was potentially relevant to payers and physicians alike: the number of treatment months necessary for a patient to remain free of disease progression for 12 months. The comparison of new therapies for RRMM by their cost per unit of clinical outcome (in this case, 12 months of PFS) allows for fair comparisons across the treatment regimens for several reasons. The median PFS is a generally reported primary or secondary clinical end point, and the median duration of therapy is often reported for clinical trials. Because PFS is a common outcome reported across all comparator regimens, using the PFS to duration of therapy ratio was deemed to be a representative way of standardizing across multiple diverse treatments

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to estimate the total patient costs.35-37 Moreover, the only other recent cost analysis of RRMM presented the monthly cost of PFS to provide a balanced comparison across the regimens.15 Second, there exists a large variability in median PFS (range, 8.0-23.6 months) and median duration of therapy (range, 3.0-20.5 months), which was adjusted in our analysis by estimating the number of treatment months required to achieve 12 months of PFS. Finally, a smaller duration of therapy to PFS ratio also implies the potential for a longer overall treatment-free interval. A longer treatment-free interval may translate into less treatment-related toxicity and fewer treatment-related adverse events and medical visits, in turn resulting in an improved patient experience and value from the healthcare that is delivered.38-40

Limitations As with any modeling study, there are several limitations to this research that should be considered. First, the model uses data derived from clinical trials, including duration of therapy, treatment adherence, and dosing schedules, that may differ in a real-world practice. In addition, in clinical practice, patients will be free of progression for intervals that are shorter or longer than the 12 months used in our model. Moreover, the heterogeneity of populations between trials may affect the observed duration of therapy and PFS. For example, in the pomalidomide and carfilzomib monotherapy trials, patients were required to have previously failed a proteasome inhibitor and an IMiD, which represents a population with a worse disease prognosis in comparison to the trials of panobinostat or lenalidomide (patients received between 1 and 3 previous treatment regimens and were not required to have failed previous treatment with a proteasome inhibitor and an IMiD). The purpose of this model was to create a framework to assess the cost of therapy and cost per 12 months of PFS, and was not intended to compare directly the efficacy of various treatment regimens. Second, the model assumes patient adherence to therapy over the course of the median duration of therapy; gaps in treatment resulting from toxicities and drug “holidays” are not included; however, in using the median duration of therapy, any potential impact of discontinuation is implicitly accounted for. The rates for grade 3 or 4 adverse events are taken from either the drug labeling or from clinical trial results and are standardized to a monthly percentage to facilitate comparison across the treatment regimens. It is assumed that adverse events occur uniformly throughout the treatment duration (ie, adverse events are equally likely at any week of therapy). To account for these limitations, we have used the median PFS and the median duration of therapy. By using

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the median, patients who discontinue therapy either early or late as a result of adverse events have been accounted for as the median, in contrast to the mean, because a measure of central tendency is less reflexive to outliers. In addition, for modeling purposes, the patients were assumed to be treated for the number of months necessary to achieve 12 months of PFS based on the median PFS and the median duration of therapy reported in the literature. This calculation is explicitly not intended to suggest that treating an individual patient for a shorter or longer period than recommended is appropriate and/or will result in linear gains in PFS in clinical practice. Finally, on disease progression, the model assumes that patients return to their original treatment regimen. Although physicians and some clinical guidelines recommend that patients should be retreated with the same treatment regimen if they do not have refractory disease,10,41 this may not always reflect the individualized patient treatment pathways that are used in real-world practice. However, the ability to model detailed treatment pathways, as they relate to very specific patient profiles, is limited by the availability of data.

Conclusion The present study represents the first treatment regimen cost estimator developed to comprehensively pro ject the costs of managing patients with RRMM with all currently approved and recommended regimens in the United States, as of 2015. As such, our study provides the framework and basis for further budget impact analyses and for cost-effectiveness comparisons with the regimens included in this analysis. ■ Funding Source This research was sponsored by Novartis Pharmaceuticals. Author Disclosure Statement Dr Roy is an employee of Novartis. Dr Kish, Dr Bloudek, and Ms Migliaccio-Walle are employees of Xcenda, a consulting company contracted by Novartis to provide consulting services. Dr Siegel is on the advisory boards and speaker’s bureau of Celgene, Onyx/Amgen, Millennium/Takeda, and Novartis, and on the advisory boards of Merck. Dr Jagannath is a consultant to Sanofi and to Celgene. Dr Globe and Dr Kuriakose are employees of Novartis.

References

1. Katzel JA, Hari P, Vesole DH. Multiple myeloma: charging toward a bright future. CA Cancer J Clin. 2007;57:301-318. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 4.2015. www. nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 15, 2015. 3. Dimopoulos MA, Terpos E. Multiple myeloma. Ann Oncol. 2010;21(suppl 7):vii143-vii150. 4. National Cancer Institute. SEER stat fact sheets: myeloma. http://seer.cancer. gov/statfacts/html/mulmy.html. Accessed March 15, 2015.

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5. Rajkumar SV, Harousseau JL, Durie B, et al; for the International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117:4691-4695. 6. Madan S, Lacy M, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory compounds in patients receiving initial therapy for newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 1964. 7. Petrucci MT, Giraldo P, Corradini P, et al. A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013;160:649-659. 8. Kim Y, Schmidt-Wolf IG. Lenalidomide in multiple myeloma. Expert Rev Anticancer Ther. 2015;15:491-497. 9. Kumar SK, Therneau TM, Gertz MA, et al. Clinical course of patients with relapsed multiple myeloma. Mayo Clin Proc. 2004;79:867-874. 10. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Treatment strategies in relapsed and refractory multiple myeloma: a focus on drug sequencing and ‘retreatment’ approaches in the era of novel agents. Leukemia. 2012;26:73-85. 11. National Cancer Institute. Cancer trends progress report–2011/2012 update. August 22, 2014. http://progressreport.cancer.gov/sites/default/files/archive/ report2011.pdf. Accessed March 15, 2015. 12. Cook R. Economic and clinical impact of multiple myeloma to managed care. J Manag Care Pharm. 2008;14(7 suppl):S19-S25. 13. Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007;109:2334-2342. 14. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia. 2014;28:1122-1128. 15. Durie B, Binder G, Pashos C, et al. Total cost comparison in relapsed/refractory multiple myeloma. J Med Econ. 2013;16:614-622. 16. Elixhauser A, Steiner C. Readmissions to U.S. hospitals by diagnosis, 2010. Statistical brief #153. April 2013. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality (US). www.hcup-us.ahrq.gov/reports/statbriefs/sb153.pdf. Accessed March 15, 2015. 17. Teitelbaum A, Ba-Mancini A, Huang H, Henk HJ. Health care costs and resource utilization, including patient burden, associated with novel-agentbased treatment versus other therapies for multiple myeloma: findings using real-world claims data. Oncologist. 2013;18:37-45. 18. Anhang Price R, Stranges E, Elixhauser A. Cancer hospitalizations for adults, 2009. Statistical brief #125. February 2012. In: Healthcare Cost and Utilization Project (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Quality (US). www.hcup-us.ahrq.gov/reports/statbriefs/ sb125.pdf. Accessed March 15, 2015. 19. 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;28:2259-2266. 20. Petrucci T, Blau I, Corradini P, et al. Efficacy and safety of retreatment with bortezomib in patients with multiple myeloma: interim results from RETRIEVE, a prospective international phase 2 study. Haematologica. 2010;95 (suppl 2). Abstract 0377. 21. Messori A, Maratea D, Nozzoli C, Bosi A. The role of bortezomib, thalidomide and lenalidomide in the management of multiple myeloma: an overview of clincial and economic information. Pharmacoeconomics. 2011;29:269-285. 22. San-Miguel JF, Hungria VTM, Yoon S-S, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15:11951206. Erratum in: Lancet Oncol. 2015;16:e6. 23. Farydak (panobinostat) capsules [prescribing information]. East Hanover, NJ: Novartis; February 2015. 24. Dimopoulos MA, Chen C, Spencer A, et al. Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma. Leukemia. 2009;23:2147-2152. 25. Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/ refractory myeloma. Blood. 2014;123:1461-1469. 26. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. 27. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent car filzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817-2825.

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28. Pomalyst (pomalidomide) capsules [prescribing information]. Summit, NJ: Celgene Corporation; April 2015. 29. San Miguel J, Weisel K, Moreau P, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055-1066. 30. RED BOOK Online. Truven Health Analytics; 2015. www.redbook.com/ redbook/online/. Accessed March 15, 2015. 31. Centers for Medicare & Medicaid Services. Payment allowance limits for Medicare Part B drugs: effective January 1, 2015 through March 31, 2015. www. cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvg SalesPrice/2015ASPFiles.html. Accessed January 26, 2015. 32. Medicare Payment Advisory Commission. Report to the Congress: Medicare payment policy. March 2014. www.medpac.gov/documents/reports/ mar14_entirereport.pdf?sfvrsn=0. Accessed October 21, 2014. 33. US Bureau of Labor Statistics. Consumer Price Index. www.bls.gov/cpi/. Accessed March 15, 2015. 34. Binder G, Harwin WN, Stemkowski S, et al. Drug resource use and costs for novel agents in multiple myeloma. J Clin Oncol. 2012;30(15 suppl). Abstract e18560. 35. Anderson KC, Kyle RA, Rajkumar SV, et al; for the ASH/FDA Panel on Clinical Endpoints in Multiple Myeloma. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22:231-239.

36. Niesvizky R, Richardson PG, Rajkumar SV, et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol. 2008;143:46-53. 37. Lonial S, Roy A, Globe D, et al. Estimating cost per month of progression free survival (PFS) from a payer perspective: comparing commonly used treatment regimens for previously treated relapsed and/or refractory multiple myeloma (RRMM). Presented at: Academy of Managed Care Pharmacy 2015 Annual Meeting & Expo; April 7-10, 2015; San Diego, CA. Abstract D6. 38. Petrucci MT, Finsinger P, Chisini M, Gentilini F. Subcutaneous bortezomib for multiple myeloma treatment: patientsâ&#x20AC;&#x2122; benefits. Patient Prefer Adherence. 2014;8:939-946. 39. Acaster S, Gaugris S, Velikova G, et al. Impact of the treatment-free interval on health-related quality of life in patients with multiple myeloma: a UK cross-sectional survey. Support Care Cancer. 2013;21:599-607. 40. Harousseau JL, Palumbo A, Richardson PG, et al. Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone. Blood. 2010;Â116:3743-3750. 41. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood. 2011;118:1763-1765.

STAKEHOLDER PERSPECTIVE

The Rationale for Comparing the Costs of Competing Treatment Options in Oncology James T. Kenney, Jr, RPh, MBA Manager, Specialty and Pharmacy Contracts, Harvard Pilgrim Health Care, Wellesley, MA

PAYERS: Historically, health plans have not focused a lot of attention on the cost of cancer treatments, regardless of disease stage or severity. The primary reasons for this lack of focus and management have been restrictive legislative mandates, the emotional nature of cancer treatments, and the lack of reasonable clinical alternatives for these difficult cases. Multiple myeloma is no exception to this rule, because of the complex nature of the disease and the significant variation in treatment approaches by oncologists in this particular type of cancer. The lack of a recognized standard of care in the treatment of multiple myeloma makes any consideration of management a challenge to operationalize.1 The need to effectively identify the clinical differences among the various treatments is typically left to the treating oncologist; however, cost is not usually considered as part of this process. In their current article in this issue of American Health & Drug Benefits, Dr Roy and colleagues provide a very interesting perspective that allows for an informed review of the cost differences among competing treatment options for relapsed or refractory multiple myeloma.2 The recent approvals of a number of new therapies to treat multiple myeloma, including panobinostat, poma-

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lidomide, and carfilzomib, increase the need for sound clinical and financial reviews of the potential treatment options and the myriad of possible combinations that may be offered to patients.3 Although multiple myeloma represents approximately 1% of the cancer population, the cost of the various regimens makes multiple myeloma one of the most expensive cancers to treat for the typical health plan.4,5 The evaluation of a number of treatment approaches using 12 months of progression-free survival as the target for comparing regimens is a reasonable approach. The use of wholesale acquisition cost (WAC) pricing eliminates any confusion or upcharges seen when average wholesale price is used in an analysis. Health plans do not typically receive any price concessions from drug manufacturers for oncologics, which further supports a WAC-based analysis. It was important for these researchers to include all of the potential costs of treatment, including for grade 3 or 4 side effects and other disease-related costs outside of the individual drug costs.2 RESEARCHERS/PAYERS: The challenge for health plans is to apply the learning from this research, and to make an effort to assess treatment costs in clinical

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Estimating the Costs of Therapy in Patients with Multiple Myeloma

STAKEHOLDER PERSPECTIVE Continued practice. As pointed out by the authors, clinical trial experience is a good starting point for this analysis2; however, real-world evidence is needed to effectively validate the results. Adherence to therapy is critical to achieve success, and the compliance rates in clinical trials are usually quite good. PATIENTS: Most health plans note a significant decrease in adherence from clinical trials to real practice, and strategies to improve or maintain adherence are needed, and are often driven through specialty pharmacy providers who often supply the self-administered drugs to these patients under restricted network distribution arrangements with health plans. MANAGED MARKETS: The type of cost analysis presented in this article is critical to the management of future oncology treatments in managed care markets. The improvements in information technology at health plans, including data warehouses that combine all the critical data elements to perform intelligent analyses of

all disease states, will support additional research on the true costs of managing patients with all types of cancer. The significant differences—as much as $100,000— among the treatment options for multiple myeloma reviewed in this research will lead to additional data extraction and analysis by health plans that are looking to apply this research to pharmacy practice. ■ 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 4.2015. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March 15, 2015. 2. Roy A, Kish JK, Bloudek L, et al. Estimating the costs of therapy in patients with relapsed and/or refractory multiple myeloma: a model framework. Am Health Drug Benefits. 2015;8(4):204-215. 3. Madan S, Lacy M, Dispenzieri A, et al. Efficacy of retreatment with immunomodulatory compounds in patients receiving initial therapy for newly diagnosed multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2010;116. Abstract 1964. 4. Cook R. Economic and clinical impact of multiple myeloma to managed care. J Manag Care Pharm. 2008;14(7 suppl):S19-S25. 5. Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007;109:2334-2342.

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ONCOLOGY PIPELINE

The 2015 Oncology Drug Pipeline: Innovation Drives the Race to Cure Cancer By Dalia Buffery, MA, ABD Editorial Director, American Health & Drug Benefits

“I

nnovation drives progress,” suggests the US Food and Drug Administration (FDA) in its report on the 41 new molecular entities and new biologic pharmaceuticals that were approved in 2014.1 This perspective is echoed by the FDA’s Center for Drug Evaluation and Research (CDER) as the rationale for its support for innovation in the pharmaceutical industry. The CDER states, “The availability of new drugs and biological products often means new treatment options for patients and advances in health care for the American public. For this reason, CDER supports innovation and plays a key role in helping to advance new drug development.” 1 More recently, in a provocative article published in this journal and titled “Breaking the Bank: Three Financing Models for Addressing the Drug Innovation Cost Crisis,” Kleinke and McGee argue that drug innovation is key to medical advances, especially in deadly diseases such as cancer: to ensure continuing innovation in drug therapies, what is needed is not to halt funding innovation but rather to find a new way to pay for drugs. “Innovative new treatments designed to address serious diseases in targeted patient populations represent the future of medicine. Traditional payment methodologies need to change to keep pace with medical innovation,” Kleinke and McGee propose, offering 3 models for consideration that will help pay for drugs in a novel way and allow drug innovation to continue in its path.2 Reflecting on oncology drugs in its 2014 report, the IMS Institute for Healthcare Informatics (henceforth, IMS) highlighted innovation as a key feature in the oncology pipeline. According to that report, “Developers have brought innovation across cancer types and therapeutic approaches, including preventive vaccines. Pharmaceutical company investments remain high and cancer therapies account for more than 30% of all preclinical and phase 1 clinical development, with 21 new molecular entities being launched and reaching patients in the last two years alone. These new medicines have increased the complexity of treating cancer, leading to more combination therapies and additional lines of therapy.” 3

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The Financial Challenge of Innovation Innovation indeed remains particularly evident in the oncology arena, where exciting new medications have been entering the market at an accelerated pace since early 2014 and through the first half 2015, with many more drugs currently in various phases of development. But innovation comes with a cost, and the cost of cancer drugs continues to be a significant hurdle for patients and for payers. Advising that innovation in oncology will continue to lead the way in the pipeline in its last year’s report, the IMS predicted that “the surge in cancer drug innovation over recent years will continue to contribute to global spending on all oncology drugs, reaching about $100 billion in 2018.” 3 This prediction, alas, was much too timid. One year later, in its latest report released in May 2015, the IMS observes that that $100 billion threshold was already reached in 2014, a full 4 years ahead of its prediction 1 year earlier. Explaining this accelerated rate, the IMS noted, “The landscape is shifting rapidly, bringing new complexity to oncologists, payers and governments….Earlier diagnosis, longer treatment duration and increased effectiveness of drug therapies are contributing to rising levels of spending on medicines for cancer care. Total global spending on such medicines reached the $100 billion threshold in 2014, even as their share of total medicine spending increased only modestly.” 4 Yet this escalation in global spending on oncology drugs represents a lower rate of growth in the United States. According to the IMS, “Global spending on oncology medicines…increased 10.3% in 2014 and reached $100 billion, up from $75 billion five years earlier. The compound average growth rate over the past five years was 6.5% globally on a constant exchange rate basis, though only 5.3% in the U.S.” 4 The growing costs to a large extent reflect the high cost of targeted therapies, which dominate the oncology pipeline. Last year, the IMS report noted, “The high number of new targeted therapies launched and available for cancer patients has also escalated payer scrutiny of

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Table 1 C ancer Drugs Approved by Mid-May 2015 Drug trade name (generic) Manufacturer

Indication/therapeutic class/route

Approval date/ comment

Imbruvica (ibrutinib)

Pharmacyclics

For Waldenström’s macroglobulinemia; Bruton’s tyrosine kinase inhibitor; oral

New indication: 1/29/15

Ibrance (palbociclib)

Pfizer

In combination with letrozole for postmenopausal women with estrogen receptor– positive, human EGFR 2–negative advanced breast cancer; cyclin-dependent kinase 4 and 6 inhibitor; oral

2/3/15 (accelerated approval)

Lenvima (lenvatinib)

Eisai

For locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer; receptor tyrosine kinase; oral

2/13/15

Novartis

In combination with bortezomib and dexamethasone for patients with multiple myeloma who have received at least 2 previous regimens, including bortezomib and an immunomodulatory agent; histone deacetylase inhibitor; oral

2/23/15 (accelerated approval)

Bristol-Myers Squibb

For metastatic squamous NSCLC that has progressed with or after platinum-based chemotherapy; PD-1–blocking antibody; IV

New indication: 3/4/15

Zarxio (filgrastim-sndz)

Sandoz

First biosimilar to Neupogen approved for all the indications for which Neupogen is approved; leukocyte growth factor; subcutaneous/IV

3/6/15

Unituxin (dinutuximab)

United Therapeutics

In combination with granulocyte-macrophage colony-stimulating factor, IL-2, and 13- cis-retinoic acid, for pediatric patients at high risk for neuroblastoma who achieve a partial response or more to first-line multiagent, multimodality therapy; chimeric monoclonal antibody; IV

3/10/15

Cyramza (ramucirumab)

Eli Lilly

In combination with FOLFIRI for metastatic colorectal cancer that has progressed with firstline bevacizumab-, oxaliplatin-, and fluoropyrimidine-containing regimens; human VEGF receptor 2 antagonist; IV

New indication: 4/24/15

Farydak (panobinostat)

Opdivo (nivolumab)

EGFR indicates epidermal growth factor receptor; IL, interleukin; IV, intravenous; NSCLC, non–small-cell lung cancer; PD-1, programmed cell death receptor-1; VEGF, vascular endothelial growth factor.

their value relative to their incremental benefits compared to existing treatments. The average cost per month of branded oncology drug…is now about $10,000, up from an average of $5,000 a decade ago.” 3 And in its most recent report, the IMS observes, “Targeted therapies now account for almost 50% of total spending and they have been growing at a compound average growth rate of 14.6% over the past five years.” 4 That this high cost of cancer drugs presents a continuing challenge for patients with cancer as well as for payers is not really news; the real issue, as Kleinke and McGee suggest, is how to pay for these drugs in a way that will sustain innovation and improve patient outcomes.2

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Still, neither the cost nor the slowing rate of growth of cancer drugs has trumped the prominent place of oncology in the pipeline. Despite the reduction in cancer-related death rate, the 2015 annual report of the American Cancer Society indicates that cancer remains the second most common cause of death in the United States, accounting for approximately 1 in 4 deaths, and the total number of cancer cases is growing.5 In 2015, an estimated 1,658,370 new cases of patients with cancer were projected to be diagnosed in the United States, with an estimated 589,430 deaths,5 potentially because of the aging of the US population and other demographic trends.

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Fast Pace of Cancer Drug Approvals Continues into 2015 By mid-May 2015, 4 new molecular entities or new biologics have already received FDA approval for various tumor types, as well as 2 new indications for drugs that were initially approved by the FDA ≤1 year earlier, as listed in Table 1. Of these, 2 approvals were for rare diseases with few treatment options. One of these new approvals came on the heels of the other. On January 29, 2015, ibrutinib (Imbruvica) was the first cancer drug to receive a new indication this year, representing the first-ever medication to receive FDA approval for Waldenström’s macroglobulinemia, a rare disease with few treatment options. On February 3, a new tyrosine kinase inhibitor (TKI), palbociclib (Ibrance), was approved for metastatic breast cancer. On February 13, lenvatinib (Lenvima) became the newest TKI option for differentiated thyroid cancer, another rare disease. On February 17, lenalidomide (Revlimid) received a new indication for the first-line treatment of patients with multiple myeloma. On February 23, panobin ostat (Farydak) became the first-ever histone deacetylase (HDAC) inhibitor to receive FDA approval, also for multiple myeloma. On March 4, another immunotherapy, the first programmed cell death (PD)-1–blocking antibody, nivolu mab (Opdivo), was approved by the FDA for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC). This is a breathtaking list of new anticancer therapies, with promising outcomes demonstrated in early-stage clinical trials, and with many of the drugs receiving accelerated or priority regulatory reviews to facilitate early access to patients who may benefit from these promising therapies. It may be safe to presume that many of the cancer drugs approved last year will continue to receive second or third indications, or even more, and some will be further approved to facilitate enhanced outcomes within a combination regimen. Of course, more new cancer drugs are expected to be approved in 2015. Of the 771 cancer drugs currently in development,6 several drugs are farther along in the process and are expected to be reviewed by the FDA between now and the end of 2015. These drugs potentially are: • Trabectedin (Yondelis), for chemotherapy-experienced soft-tissue sarcoma, is scheduled to be reviewed by the FDA for approval in July 2015 • Cobimetinib, for melanoma, is scheduled for approval in August 2015 • Gefitinib (Iressa), for first-line advanced or metastatic NSCLC with EGFR mutation; approval expected in September 2015 • Sonidegib, for advanced basal-cell carcinoma, with

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approval expected in September 2015 • Talimogene laherparepvec (T-VEC), for regionally or distally metastatic melanoma, is scheduled for approval in October • Necitumumab, for the first-line treatment of squamous NSCLC, with a scheduled date of December 2015 • Trifluridine and tipiracil, for third-line therapy of refractory metastatic colorectal cancer, with approval expected by the end of the year.

Oncology Drugs Still a Pipeline Priority According to the Pharmaceutical Research and Manufacturers of America (PhRMA), 771 new drugs and vaccines are in development by US companies; these agents are currently in clinical trials or have been submitted to the FDA for review.6 According to PhRMA, of the 771 drugs and vaccines currently in the pipeline6: • 98 are being developed for lung cancer • 87 for leukemia • 78 for lymphoma • 73 for breast cancer • 56 for skin cancer • 48 for ovarian cancer. Overall, 3137 clinical trials for cancer drugs are being conducted in the United States. Of these, 1313 are ongoing and are no longer enrolling new patients.6 Again, an impressive list of therapies, some with new mechanisms of action that may bring significant changes to cancer care. Certain trends seen in the FDA approvals in 2014 appear to be continuing in 2015. Of the 41 new molecular entities and new biologics approved last year, 9 were for cancer drugs, including 5 new molecular entities and 4 new biologics. Moreover, several of the new drugs received a second indication in 2014 soon after their initial approval, with some receiving 2 or 3 new indications in succession within a few months. If the first half of 2015 is any indication, this approval trend may linger into 2016 and beyond, with increasing numbers of cancer drugs introducing new mechanisms of action, first-inclass options, or new options for rare cancers. Several tumor types have attracted significant attention among pharmaceutical developers in recent years, resulting in a concentration of new therapies in the pipeline for specific cancers. Among the categories currently leading the race for FDA approval of new cancer therapies are melanoma, breast cancer, and lung cancer (Table 2) and hematologic malignancies (Table 3). In addition, several important emerging drugs are in a variety of other tumor types as shown in Table 4. All these drugs are currently in late stages of development, and many drug manufacturers have already submitted New Drug Applications to the FDA for these

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ONCOLOGY PIPELINE

Table 2 P romising Late-Phase Drugs for Melanoma, Breast, and Lung Cancers Drug trade name (generic) Manufacturer Expected indication/therapeutic class/route

Development stage/comments (expected approval)

Melanoma Talimogene laherparepvec (T-VEC)

Amgen

For metastatic melanoma that is not resectable; oncolytic immunotherapy; intralesional injection

NDA submitted PDUFA: 7/28/15 Submitted to EMA: 9/2014

Cobimetinib (GDC-0973)

Genentech/ Exelixis

For advanced melanoma with BRAF V600 mutation; a MEK inhibitor for use in combination with vemurafenib (Zelboraf), a BRAF inhibitor; oral

NDA: priority review PDUFA: 8/11/15

Binimetinib

Array BioPharma

For metastatic melanoma with NRAS mutation; MEK inhibitor; oral

Phase 3 trials Est. NDA: mid-2016

Selumetinib

Array BioPharma

For metastatic uveal melanoma; ATP inhibitor; oral

Phase 3 trials

Entinostat

Syndax Pharmaceuticals

In combination with exemestane (Afinitor) for ERpositive metastatic breast cancer; HDAC inhibitor

Phase 3 trials BT: 9/12/13

Veliparib (ABT-888)

AbbVie

PARP inhibitor for advanced BRCA1 or BRCA2 breast cancer, in combination with chemotherapy; oral

Phase 3 trials

Puma Biotechnology

For early-/late-stage HER2-positive breast cancer; TKI; oral

Phase 3 trials

Eli Lilly

For advanced squamous NSCLC (in combination with gemcitabine plus cisplatin); recombinant human antiEGFR immunoglobulin G1 monoclonal antibody

Est. approval 12/2015 FDA panel to discuss NDA: 7/9/15

AstraZeneca

For first-line monotherapy of NSCLC with EGFR mutation; TKI; oral

NDA: 12/2/14 Est. approval 9/2015

Clovis Oncology

For NSCLC with the EGFR T790M mutation after progression with anti-EGFR therapy; EGFR inhibitor TKI; oral

BT: 5/19/14 Est. NDA: mid-2015

Genentech

For patients with PD-1–positive NSCLC; PD-1–blocking immunotherapy

BT: 2/1/15 Phase 3 trials BT for metastatic bladder cancer: 2014

GlaxoSmithKline

For metastatic NSCLC with BRAF V600E mutation; a kinase inhibitor; oral

BT for NSCLC: 1/13/14 Phase 2 trials FDA approved for metastatic melanoma

Roche

For ALK-positive NSCLC that progressed with crizotinib; second-generation ALK inhibitor; oral

BT: 6/2013 Phase 2 trials Approved in Japan: 7/7/14

Brigatinib (AP26113)

ARIAD Pharmaceuticals

For ALK-positive metastatic NSCLC resistant to crizotinib; a dual ALK/EGFR inhibitor; oral

BT: 10/2/14 NDA: mid-2016

AZD-9291

AstraZeneca

For patients with advanced NSCLC with EGFR mutation resistant to EGFR TKI therapy (ie, Iressa); EGFR inhibitor

Phase 2 trials: promising results Est. approval 2/2016

Patritumab

Daiichi Sankyo

Human anti-HER3 antibody for the treatment of NSCLC; oral

Phase 2 trials

Breast cancer

Neratinib Lung cancer Necitumumab (IMC-11F8) Iressa (gefitinib) Rociletinib (CO-1686) Atezolizumab (MPDL3280A)

Tafinlar (dabrafenib)

Alectinib

ATP indicates adenosine triphosphate; BT, breakthrough therapy; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; ER, estrogen receptor; Est., estimated; FDA, US Food and Drug Administration; HDAC, histone deacetylase; NDA, New Drug Application; NSCLC, non–small-cell lung cancer; PARP, poly (ADP-ribose) polymerase; PD-1, programmed cell death receptor-1; PDUFA, Prescription Drug User Fee Act; TKI, tyrosine kinase inhibitor.

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Table 3 P romising Late-Phase Drugs for Hematologic Malignancies Drug trade name (generic) Manufacturer Expected indication/therapeutic class/route Daratumumab

Development stage/comments (expected approval)

Janssen Biotech

For relapsed/refractory multiple myeloma; anti-CD38 monoclonal antibody (immunotherapy); IV

BT: 5/1/13 Phase 3 trials

Ixazomib (MLN9708)

Takeda Oncology

For relapsed/refractory multiple myeloma (systemic light-chain amyloidosis); proteasome inhibitor; oral

BT: 1/12/14 Phase 3 trials

Elotuzumab

Bristol-Myers Squibb

In combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received ≥1 previous therapies; humanized immunoglobulin G1 monoclonal antibody; IV

BT: 5/19/14 Phase 3 trials

Boehringer Ingelheim

For patients aged ≥65 years with previously untreated AML who are ineligible for intensive remission induction therapy; PLK inhibitor; IV

BT: 9/17/13 Phase 2 trials Orphan drug: 5/13/14

CTL019

Novartis

For relapsed/refractory ALL in pediatric or adult patients; CAR T-cell therapy; IV

BT: 7/7/14 Phase 1/2 trials

JCAR015

Juno Therapeutics

For relapsed/refractory B-cell ALL; CAR T-cell therapy; IV

BT: 11/24/14 Phase 1/2 trials Orphan drug: 11/18/14

Venetoclax (ABT-199/ RG7601)

AbbVie/Roche

Oral, selective B-cell lymphoma 2 inhibitor, in combination with chemotherapy, for relapsed/refractory CLL

BT: 5/6/15 Phase 3 trials

Pracinostat

MEI Pharma

Oral HDAC inhibitor for myelodysplastic syndrome

Phase 2/3 trials

Vosaroxin

Sunesis Pharmaceuticals

First-in-class quinolone derivative for relapsed/refractory AML; IV

Phase 3 trials

Quizartinib

Ambit Biosciences

Treatment of newly diagnosed patients and patients with relapsed or refractory FLT3-ITD–positive and FLT3ITD–negative AML; tyrosine kinase inhibitor; oral

Phase 3 trials

Volasertib

ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; BT, breakthrough therapy; CAR, chimeric antibody receptor; CLL, chronic lymphocytic leukemia; HDAC, histone deacetylase; IV, intravenous; PLK, polo-like kinase.

agents, with an overall estimated approval date anticipated within the next 1 to 2 years.

Breakthrough Therapy Designation Increasing in Oncology As shown in Table 2 through Table 4, the list of cancer drugs in the pipeline that have already received a breakthrough therapy designation is extensive. A few medications received the designation based on early results from phase 1 or phase 2 clinical trials. According to the FDA, the expressed goal of a breakthrough therapy designation is to support the expedited development process of a drug that has shown significant benefits over therapies that are currently available to patients with a serious or life-threatening disease, such as cancer, and to facilitate the expedited approval of the drug to allow more patients to benefit from such promising therapies.7 Therefore, drugs that have received a breakthrough therapy designation are usually reviewed by the FDA for final approval under its priority review and/or accelerated review program, which facilitates the expedited pro-

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cessing of the FDA’s review of drugs that treat serious conditions with evidence indicating that their approval would provide significant improvement in safety or effectiveness over current treatment options. As was seen in the past year, the FDA may expedite the approval of therapies that received breakthrough designation a few months ahead of their scheduled approval to allow patients to benefit from these promising therapies as soon as possible.

Abundance of Immunotherapies Much of the excitement today in cancer drug development involves immunotherapies, which have the potential to bring significant improvements in outcomes, prolonged survival, and progression-free survival, as well as reduced side effects. Many of the drugs in late stages of development or those that have received a breakthrough therapy designation are different types of immunotherapy, which come in various forms and a variety of mechanisms of action, and make up a large proportion of the current pipeline of new therapies coming to market.

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Vol 8, No 4

ONCOLOGY PIPELINE

Oncology continues to dominate the specialty drug pipeline, with recently introduced immunotherapies representing a variety of mechanisms of action, including the PD-1 antibodies; several anti-CD monoclonal antibodies; new HDAC inhibitors; novel agents targeting different proteins and mutations; new TKIs; and other multikinase inhibitors. Therefore, despite the rising costs of cancer therapies, there is palpable excitement among those involved in cancer research, with a renewed sense that using human biology to fight cancer-producing cells may eventually move cancer from a death sentence and into the realm of chronic diseases, as in the case of HIV/AIDS. Perhaps not surprising, and similar to the case of HIV/AIDS, therapies that combine ≥2 drugs with several mechanisms of action are gaining more attention in cancer

drug development. Combination therapies may indeed be the way of the future for cancer care, with the FDA continuing to approve new combination regimens that improve outcomes and prolong patients’ lives. But challenges remain with immunotherapies. Elaborating on the growing understanding of the role of immunotherapies in cancer care, Alise Reicin, Vice President of Clinical Research, Merck & Co, said, “We think the immune system does recognize cancer, and there is probably something called immune-editing going on, where the immune system finds the cancer and begins the process of trying to kill the tumor. But we’re learning that tumors have developed ways to cloak themselves and deactivate the immune system. Tumors start to express a protein PD-L1 or PD-L2. These proteins interact with the protein on the T-cells, and they are

Table 4 P romising Late-Phase Drugs for Various Patient Populations and Tumor Types Drug trade name (generic) Manufacturer Expected indication/therapeutic class/route Rolapitant

Development stage/comments (expected approval)

Tesaro

For the prevention of chemotherapy-induced nausea and vomiting; selective NK-1 receptor agonist; oral

NDA: 9/2014 Est. PDUFA: 9/5/15 IV formulation in phase 3 trials

Yondelis (trabectedin)

Janssen Pharmaceuticals

For advanced soft-tissue sarcoma, including liposarcoma and leiomyosarcoma; multimodal therapy; IV infusion

NDA: 11/25/14 Priority review: 2/3/15 Est. PDUFA: 11/24/15

TAS-102 (trifluridine + tipiracil hydrochloride)

Taiho Oncology

For third- or fourth-line treatment of refractory metastatic colorectal cancer; combination of antineoplastic nucleoside analog and a hydrochloride

NDA: 2/23/15 PDUFA: 12/19/15

Rindopepimut

Celldex Therapeutics

Immunotherapy for EGFRvIII-positive glioblastoma; intradermal

BT for glioblastoma: 1/23/15 Phase 3 trials

MM-398 (irinotecan liposome)

Merrimack Pharmaceuticals

For second-line treatment of metastatic pancreatic cancer; nanotherapeutic derivative of irinotecan; IV

NDA: 4/27/15 Fast track: 11/19/14

Sonidegib (LDE225)

Novartis

For advanced basal-cell carcinoma; selective smoothened inhibitor; oral

NDA: 10/2014 Est. approval: 9/2015

PLX3397

Plexxikon

Recurrent glioblastoma; also in combination with pembrolizumab for advanced melanoma and multiple other solid tumors; tyrosine kinase inhibitor; oral

Phase 2 trials

Tivantinib

ArQule

Treatment of c-MET diagnostic-high inoperable hepatocellular carcinoma treated with 1 previous sorafenib therapy; c-MET inhibitor; oral

Phase 3 trials

Niraparib

Tesaro

For ovarian cancer; PARP inhibitor; oral

Phase 3 trials

Active Biotech Research

For castration-resistant prostate cancer; allosteric modulator of HDAC4; oral

Phase 3 trials

NewLink Genetics

Immunotherapy vaccine for resectable or locally advanced unresectable pancreatic cancer; intradermal injection

Phase 3 trials

Tasquinimod Algenpantucel-L

BT indicates breakthrough therapy; EGFR, epidermal growth factor receptor; Est., estimated; HDAC, histone deacetylase; IV, intravenous; NDA, New Drug Application (submitted); NK, neurokinin; PARP, poly (ADP-ribose) polymerase; PDUFA, Prescription Drug User Fee Act.

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able to deactivate the T-cells so that it no longer recognizes or kills the tumor.” 8 It may, therefore, take some time before the full potential for harnessing the various mechanisms of immunotherapy to kill cancer cells is fully realized and could be successfully translated into cure. Nevertheless, great progress can be seen in the oncology pipeline and in new therapies approved by the FDA for multiple indications in great succession. Immunotherapies against cancer are helping to chart new ways to tame cancer cells and change the outlook for patients.

A true collaboration among government, drug manufacturers, payers, employers, and patients is needed to advance the discussion and bring new solutions to the table. Everyone has a stake in ensuring that patients have access to life-saving drugs, not only drug manufacturers. Oncology Leading the Biosimilars Buzz It is perhaps not surprising that the first-ever biosimilar to receive FDA approval (in March 2015) was a cancer drug, Zarxio (filgrastim-sndz), a biosimilar of the original drug Neupogen. What this means to curbing the costs of cancer care remains to be seen, but this approval has finally opened the way for biosimilar entry into the United States, trailing by several years behind Europe. Several oncology biosimilars are currently in the pipeline and are expected to receive FDA approval in 2015, including: • Neupeg (pegfilgrastim), a biosimilar to Neulasta, is expected to be approved in August or September of this year • Grastofil, a second biosimilar to Neupogen, is expected to be approved in October • Retacrit (epoetin alfa), a biosimilar to Epogen and to Procrit, could be approved later in 2015. This is likely just the beginning. Conclusion With all the excitement and continuing innovation in oncology drugs in the pipeline, and with the new FDA approvals in recent months, serious challenges remain in the oncology pipeline. To sustain innovation, the US healthcare industry must find a way to pay for targeted

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cancer drugs that have the potential to change the face of this deadly disease, which is to a large degree not related to lifestyle choices. But how to do so remains a major challenge to all healthcare stakeholders, not just patients and payers. Furthermore, whether the new biosimilars coming soon to market can help in terms of cost containment and expanded access to care is unclear at this point. Even if the anticipated 20% reduction in cost is materialized, this will not be sufficient to change cancer care in any real sense. A true collaboration among government, drug manufacturers, payers, employers, and patients is needed to advance the discussion and bring new solutions to the table. Everyone has a stake in ensuring that patients have access to life-saving drugs, not only drug manufacturers. For now, despite ongoing and serious concerns over the increasing costs of cancer drugs, new scientific discoveries and new milestones reached with novel drug therapies will likely continue to fuel innovation in oncology drug development, and may eventually chart a way for a new payment system that will ensure continuing innovation and continued improvement in outcomes. This, in turn, will benefit everyone’s ultimate goal of transforming cancer from a deadly disease into the chronic disease arena, and potentially even finding a cure for cancer. What only a few years ago seemed an impossible dream no longer appears so, with some cancers already reaching a chronic disease status and cure for many patients. n

References

1. US Food and Drug Administration. New Drugs at FDA: CDER’s New Molecular Entities and New Therapeutic Biological Products. Updated February 2, 2015. www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm 20025676.htm. Accessed March 12, 2015. 2. Kleinke JD, McGee N. Breaking the bank: three financing models for addressing the drug innovation cost crisis. Am Health Drug Benefits. 2015;8:118-126. 3. IMS Institute for Healthcare Informatics. Innovation in Cancer Care and Implications for Health Systems. May 2014. www.obroncology.com/imshealth/ content/IMSH_Oncology_Trend_Report_020514F4_screen.pdf. Accessed March 10, 2015. 4. IMS Institute for Healthcare Informatics. Development in Cancer Treatments, Market Dynamics, Patient Access, and Value: Global Oncology Trend Report 2015. May 2015. www.theimsinstitute.org. Accessed May 15, 2015. 5. American Cancer Society. Cancer Facts & Figures 2015. www.cancer.org/ research/cancerfactsstatistics/cancerfactsfigures2015/index. Accessed June 9, 2015. 6. Pharmaceutical Research and Manufacturers of America. Nearly 800 New Medicines in Development to Help in the Fight Against Cancer. October 6, 2014. www.phrma.org/research/cancer. Accessed March 12, 2015. 7. US Food and Drug Administration. Fact Sheet: Breakthrough Therapies. Updated December 10, 2014. www.fda.gov/RegulatoryInformation/Legislation/ FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDC Act/FDASIA/ucm329491.htm. Accessed May 10, 2015. 8. Myshko D, Robinson R, Grom T. Detangling Oncology. February 2015. www.pharmavoice.com/article/detangling-oncology/. Accessed March 12, 2015.

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What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+MP provided an OS advantage over MP that was not regained with subsequent therapies Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration. Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR §II

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE adjacent to this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE-HCP.com.

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.

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Brief Summary

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. 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-12-0306a All rights reserved. Printed in USA V-14-0258

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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.

Call for Papers Cardiometabolic Health Theme Issue American Health & Drug Benefits will be publishing a theme issue on Cardiometabolic Health in September 2015

Readers are invited to submit articles for publication in this theme issue on topics relevant to the clinical, business, and policy aspects of cardiometabolic health and wellness. Original research, comparative effectiveness analyses, cost-effective analyses, evidence-based systematic reviews, and case studies are of particular interest. All articles will undergo the journal’s rigorous peer-review process and acceptance is contingent on that review. Topics of high interest include: • Benefit designs to improve cardiometabolic outcomes

• Insulin resistance and type 2 diabetes • Lifestyle strategies and cardiometabolic health and wellness

• Best practices in insulin control, lipid management, blood pressure control

• Lipid management in patients with diabetes

• Cardiovascular disease: diagnosis and treatment

• Medication adherence

• Comparative effectiveness analyses • Cost-effective analyses of current therapies

• New biomarkers for assessing cardiometabolic risk

• Current recommendations for optimizing A1c target outcomes

• New therapies for diabetes, cardiovascular disease, or obesity

• Diabetes management and prevention

• Optimal therapies for cardiovascular disease, diabetes, and/or obesity

• Employers’ strategies to enhance employees’ cardiometabolic wellness

• Pharmacoeconomic analyses

• Health plan initiatives for cardiometabolic health and prevention

• Prevention strategies for cardiovascular disease

• Hot topics in diabetes management

• Wellness programs for patients with heart disease, diabetes, obesity

Submission deadline: July 24, 2015 Submit articles at www.AHDBonline.com or e-mail to editorial@engagehc.com. Articles must follow the Manuscript Instructions for Authors, available online.

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Supplement

The Emerging Role of Immuno-oncology in Treating Solid Tumors: A Value-Based Perspective for Managed Care Pharmacists Faculty Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Release date: June 15, 2015 Expiration date: June 30, 2016 Estimated time to complete activity: 0.75 hours Target Audience This activity is directed toward pharmacists who are involved in the management of patients with solid tumors. Educational Objectives After completing this activity, the participant should be better able to: • Describe the pathophysiologic basis for immunotherapy of melanoma, non–small-cell lung cancer, and breast cancer • Incorporate the safety and efficacy data on recently approved and emerging immunotherapies in the treatment of patients with melanoma, non–small-cell lung cancer, and breast cancer • Describe the patient selection process for immunologically based therapy of patients with melanoma, non–small-cell lung cancer, and breast cancer • Incorporate the pharmacoeconomic data on current and emerging immunotherapies into the value-based management of melanoma, non–small-cell lung cancer, and breast cancer • Provide accurate and appropriate counsel as part of the treatment team. Faculty Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA Pharmacist Continuing Education Accreditation Statement Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Postgraduate Institute for Medicine designates this continuing education activity for 0.75 contact hour(s) (0.075 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 0809-9999-15-211-H01-P) Type of Activity: knowledge System Requirements PC Windows 7 or above

MAC MAC OS X 10.6 or higher

Flash Player v10.0 or higher Internet Explorer v9.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

Flash Player v10.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

*Required to view printable (PDF) version of the lesson. Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/ CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Name of Faculty or Presenter

Reported Financial Relationship

Sanjiv S. Agarwala, MD Nothing to disclose. The following PIM planners and managers—Judi SmelkerMitchek, RN, BSN; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Center of Excellence Media, LLC: Susan Berry and Sy Schlager, MD, PhD, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Disclosure of Unlabeled Use This educational activity may contain discussion of published

and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Instructions for Credit There is no fee for this activity. To receive credit after reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme.com/COE193. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. If you have any questions regarding the CE certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930. Pharmacists: Upon successfully completing the posttest with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks. Media: Printed report

To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

This activity is supported by an independent educational grant from Bristol-Myers Squibb. Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

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n April 8, 2015, a satellite symposium was held during the Academy of Managed Care Pharmacy’s 27th Annual Meeting & Expo held in San Diego, CA. The symposium explored the emerging role of immuno-oncology in cancer, including a discussion on immunologically mediated therapies for such solid tumors as breast cancer, melanoma, non–small-cell lung cancer (NSCLC), colorectal cancer (CRC), and prostate cancer. In addition, value-based issues regarding the use of immune-mediated therapies for the treatment of patients with cancer were presented at a panel discussion during the program. The panelists included Douglas Burgoyne, PharmD, President of VRx Pharmacy Services, in Salt Lake City, UT; Sanjiv S. Agarwala, MD, Professor of Medicine, Temple University School of Medicine, and Chief, Medical Oncology and Hematology, St. Luke’s Cancer Center, in Bethlehem, PA; and Sandip Patel, MD, Assistant Professor, Cancer Immunotherapy Program, Division of Hematology and Oncology and Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center. This monograph provides an overview of the presentations and discussions at this live symposium.

Immune Checkpoint Therapy in Solid Tumors According to Andrew Baum of Citigroup Research/ Global Markets, “Immunotherapies will likely become the treatment backbone in up to 60% of cancers over the next 10 years, compared with less than 3% today.” If his prediction is correct, it is important for all members of the team involved in the delivery of medical care to patients to understand the role played by immunology in cancer and how immunologically mediated therapies work.

Immunotherapies will likely become the treatment backbone in up to 60% of cancers over the next 10 years, compared with less than 3% today. Figure 1 depicts an overview of the immune system and its interactions with tumor cells.1 The goal of cancer immunotherapy is to boost or restore the ability of the immune system to detect and destroy cancer cells by overcoming the mechanisms by which tumors evade and suppress the immune response, thereby proliferating and metastasizing.2 In this regard, tumor cells have tumor-specific antigens that are recognized as foreign by dendritic cells (so-called antigen-presenting cells), which, in turn, process and present the antigens to resting T lymphocytes. The T cells are then activated to infiltrate and kill the tumor cells.

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Figure 1 A Road Map of Immunotherapy Agents in the Cancer–Immune System Interaction Resting T cell

Activated T cell TUMOR Killing of cancer cells: anti–PD-1, anti–PD-L1 Release of cancer cell Tumor antigen antigens: chemotherapy, radiation, targeted therapy

Cancer antigen presentation: vaccines

LYMPH NODE TCR

CD28

MHC B7 Priming and activation: anti–CTLA-4

Dendritic cell

CD28 indicates cluster of differentiation 28; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-L1, programmed death ligand 1; TCR, T-cell receptor. Source: Courtesy of Sanjiv S. Agarwala, MD.

Numerous inhibitory pathways, collectively referred to as immune checkpoints, are built into the immune system to maintain self-tolerance and homeostasis.3 The primary role of immune checkpoints is to protect tissues from damage when the immune system is responding to pathogens and to maintain tolerance to self-antigens (ie, prevent autoimmunity). This is achieved primarily by downregulating T-cell activation or effector functions. A growing body of evidence demonstrates that a primary mechanism by which tumors evade the immune system is by engaging immune checkpoints. This has spurred the development of many novel agents that modulate or inhibit immune checkpoints or other costimulatory receptors, to allow a robust antitumor immune response. Immune checkpoint inhibitors have generated excitement, because these agents appear to overcome the mechanisms that tumors hijack in order to suppress the antitumor immune response. Some of these modalities have been tested clinically for decades, whereas others are new. In fact, several of the older strategies are being revisited with new twists based on our current understanding of immuno-oncology. The first checkpoint receptor to be successfully targeted as an immunotherapy is cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4),4 which is expressed on activated T cells. The primary function of CTLA-4 is to downregulate the extent of T-cell activation by counteracting the costimulatory signal delivered by CD28 (see Figure 1).5-7 The critical role played by CTLA-4 is to keep T-cell activation in check. Ipilimumab, an anti–CTLA-4 monoclonal antibody, was the first immune checkpoint inhibitor to

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Figure 2 Blocking CTLA-4 and PD-1

CD28 indicates cluster of differentiation 28; CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; MHC, major histocompatibility complex; PD-1, programmed cell death protein-1; PD-L1, programmed cell death ligand 1; TCR, T-cell receptor. Source: Courtesy of Jedd D. Wolchok, MD.

receive US Food and Drug Administration (FDA) approval for the treatment of patients with unresectable or metastatic melanoma.8 Tremelimumab, another anti– CTLA-4 monoclonal antibody, is in phase 2 development for the treatment of patients with mesothelioma and a variety of other solid tumors. These antibodies bind to CTLA-4 and block its immunosuppressive signal. As a result, activated T cells, including those activated by tumor antigens, can continue to proliferate, produce cytokines, and exert their cytotoxic effector functions in the tumor microenvironment. The biologic activity of anti– CTLA-4 antibodies, however, can sometimes lead to undesirable immune-related adverse events caused by an autoimmune reaction to normal tissues. For example, adverse events typically observed with ipilimumab use include rash, pruritus, liver toxicity, diarrhea, colitis, and hypophysitis, beginning 3.5 to 6.5 weeks after the initiation of therapy and lasting for 14 weeks or longer.9 Targeting programmed cell death protein-1 (PD-1), another immune checkpoint receptor, and its ligands— programmed cell death ligand 1 (PD-L1) and PD-L2—is also emerging as a promising immunotherapeutic modality.4 Similar to CTLA-4, PD-1 plays a key role in regulating and maintaining the balance between T-cell activation and immune tolerance (Figure 1).10,11 Unlike CTLA-4, however, PD-1 is broadly expressed and can be found on T cells, B cells, and natural killer cells.12,13 Whereas CTLA-4 regulates primarily T-cell activation in the lymphatic tissues, the main role of PD-1 is to limit T-cell activity in peripheral tissues during a cell-mediated or in-

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flammatory immune response.10,11,13-18 PD-L1 is commonly upregulated on several human solid carcinomas, including melanoma; lung, colon, and ovarian tumors; and gliomas.19,20 Monoclonal antibodies that target PD-1 (nivolumab, pidilizumab, and lambrolizumab) and PD-L1 (BMS-936559, MPDL3280A, MSB0010718C, and MEDI4736) are in various stages of clinical development. Clinical studies to date have yielded encouraging results, with significant durable response rates reported in several tumor types, particularly melanoma, renal-cell carcinoma, and lung cancer. Thus far, the anti–PD-1 antibodies pembrolizumab21 and nivolumab22 have received FDA approval for the treatment of patients with malignant melanoma, and lambrolizumab23 has received FDA breakthrough therapy designation for this malignancy. In addition, MPDL3280A, an anti–PDL-1 antibody, was just granted FDA breakthrough therapy designation for the treatment of patients with NSCLC.24

Immuno-oncology in Solid Tumors: Data Update Immune checkpoint inhibitors have been particularly effective in treating patients with malignant melanoma and NSCLC. For example, approximately 20% of patients with malignant melanoma derived a long-term overall survival (OS) benefit from treatment with the anti–CTLA-4 agent ipilimumab,25,26 but only about an 11% overall response rate (ORR) was reported in patients treated with this agent.25 Moreover, when the anti–PD-1 agent pembrolizumab was used in ipilimumab-refractory patients with melanoma, the ORR was 26%, with a 51% disease control rate and long-term durable responses past 50 weeks.27 Similarly, treatment with nivolumab resulted in a 32% ORR (4 complete responses [CRs] and 34 partial responses [PRs]) in ipilimumab-refractory patients (n = 120), compared with an 11% ORR (0 CR and 5 PRs) in patients receiving standard chemotherapy (n = 47).28

Similar to CTLA-4, PD-1 plays a key role in regulating and maintaining the balance between T-cell activation and immune tolerance. As front line therapy for advanced melanoma, treatment with nivolumab was associated with a 40% ORR, compared with 14% with dacarbazine; 1-year OS with nivolumab was 73%, versus 42% with dacarbazine (P <.001).29 Similarly, in the KEYNOTE-006 trial, which was recently stopped early, pembrolizumab demonstrated superior OS and progression-free survival (PFS) com-

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pared with ipilimumab in ipilimumab-naïve patients with advanced melanoma.30 There is a rationale for combining an anti–CTLA-4 antibody with an anti–PD-1 agent, since the activity of these 2 types of agents occurs at different sites in the T-cell activation cascade and they may provide synergistic effects (Figure 2).31 Indeed, in ipilimumab-naïve patients with advanced melanoma, ipilimumab-plus-nivolumab combination therapy was associated with a higher ORR (53%) compared with ipilimumab alone (7%) or nivolumab alone (28%).31 The limiting factors for the use of this combination are cost and toxicity. Similarly, anti–PD-1 therapy has been shown to be effective in patients with squamous and non–squamous NSCLC. For example, nivolumab monotherapy demonstrated an acceptable safety profile, resulting in an ORR of 16.7% and a median OS of 9.2 months in patients with squamous NSCLC who had been treated with at least 1 previous round of chemotherapy.32 Comparable results were observed in those with nonsquamous NSCLC, with an ORR of 17.6% and a median OS of 10.1 months.32 In addition, in January 2015, CheckMate-017, a phase 3, randomized, open-label study evaluating nivolumab versus docetaxel in previously treated patients with advanced or metastatic squamous NSCLC, was stopped early because an assessment conducted by the independent Data Monitoring Committee concluded that the study met its end point, demonstrating superior OS in patients receiving nivolumab compared with those in the control arm.33 Similarly, in patients with advanced NSCLC, pembrolizumab demonstrated an acceptable safety profile and an ORR of 19.4%, with a median duration of response of 12.5 months.34 In this study, the median PFS was 3.7 months and the median OS was 12.0 months.34 Among patients with ≥50% PD-1–positive NSCLC cells, the ORR was 45.2% and the median PFS was 6.3 months; median OS was not reached.34 Patients with metastatic breast cancer, metastatic colorectal cancer (mCRC), and metastatic castrate-resistant prostate cancer (mCRPC) also have been successfully treated with immunologically based therapies. Although breast cancer traditionally has not been considered an immunogenic cancer, it is known that patients with human epidermal growth factor receptor-2–positive breast cancer who have stromal tumor-infiltrating lymphocytes (S-TILs) have a better prognosis and a more robust response to chemotherapy than do those without S-TILs.35 Indeed, patients with metastatic breast cancer and high S-TILs had a 10-year recurrence-free survival rate of 91%, compared with 64% in those with low S-TILs.35 Similarly, in the difficult-to-treat patients with triple-negative breast cancer, every 10% increase in S-TILs was associated with a 15% reduced risk for relapse

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and a 17% reduced risk for death.36 Together with the recognition of increased expression of PD-L1 in triple-negative breast cancer, this led to clinical trials with anti–PD-1 in patients with this form of the disease. In a phase 1b study, 32 patients with treatment-refractory triple-negative breast cancer and PD-L1–positive tumors were treated with pembrolizumab; ORR was 18.5% and 60% of the responses lasted for >11 months.37 In another study with an investigational anti–PD-L1 agent, MPDL3280A, of 12 patients with metastatic, treatment-refractory, triple-negative breast cancer, 1 patient experienced a CR, 2 had PRs, 1 achieved disease stabilization, and 8 demonstrated disease progression.38 The current challenge is the lack of reliable biomarkers that can predict which patients with metastatic breast cancer are more likely to respond to immunotherapy. Once molecular or immunologic biomarkers are discovered, it should be easier to identify those patients who will benefit most from immunologically based therapies.

The current challenge is the lack of reliable biomarkers that can predict which patients with metastatic breast cancer are more likely to respond to immunotherapy. As with breast cancer, mCRC is often characterized by lymphocytic infiltration, which is associated with a high rate of microsatellite instability and PD-L1 expression. Anti–PD-1 therapy in this patient population, however, has been disappointing. For example, in a phase 1 trial, no major responses were reported among 17 patients with mCRC who were treated with nivolumab (ORR, 0%).39 Similarly, MPDL3280A treatment in 4 patients with mCRC was associated with 1 PR, 1 patient with stable disease, and 2 patients with disease progression.40 It may be worthwhile to reserve immunotherapy in CRC for the microsatellite instability subset of patients who are more likely to respond. The story is very different in patients with mCRPC, in whom immunotherapy has been used successfully for quite some time. mCRPC is amenable to a vaccine immunotherapy strategy because of the unique cell surface expression on prostate cancer cells of prostate-specific membrane antigen. This has led to the development of sipuleucel-T, a type of therapeutic cancer vaccine that consists of autologous peripheral blood mononuclear cells, including antigen-presenting cells, that have been activated ex vivo with a recombinant fusion protein (PA2024).41 PA2024 consists of a prostate antigen— prostatic acid phosphatase—that is fused to granulo-

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cyte-macrophage colony-stimulating factor, which is an immune-cell activator.41 In a double-blind, placebo-controlled, multicenter, phase 3 trial in which 512 patients with mCRPC were treated with sipuleucel-T or placebo, a 22% relative reduction in the risk for death was reported in the sipuleucel-T group compared with the placebo group (hazard ratio [HR], 0.78; 95% confidence interval, 0.61-0.98; P = .03).41 This reduction represented a 4.1month improvement in median survival (25.8 months in the sipuleucel-T arm vs 21.7 months in the placebo arm).41 The 36-month survival probability was 31.7% in the sipuleucel-T group compared with 23.0% in the placebo group.41 Adverse events reported more frequently in the sipuleucel-T group than in the placebo group included chills, fever, and headache.41

It is important to develop molecular biomarkers that can identify those patients who are most likely to benefit from a specific immunotherapy. Treatment of patients with mCRPC with other forms of immunotherapy, including nivolumab39,42 and ipilimumab,43 however, has not been successful, except in those patients without visceral metastases. Indeed, patients with docetaxel-resistant mCRPC and no visceral metastases who were treated with ipilimumab demonstrated an OS benefit compared with placebo (HR, 0.62; P = .0038).43 This trial is now being extended only in those patients with mCRPC who have no visceral metastases.44

Value-Based Perspective on the Use of Immunooncology in Solid Tumors From a managed care pharmacy perspective, the clinical management of solid tumors with immuno-oncology approaches requires the consideration of several issues, including prior authorization (and whether this should depend on FDA-approved indications and/or National Comprehensive Cancer Network [NCCN] guidelines), coordination with care managers, and involvement of specialty pharmacies. The panelists agreed that in the field of oncology, therapy is highly data-driven, and the best approach is to use immuno-oncology agents only for those indications that are FDA approved. Some payers, however, do use NCCN guidelines to direct their course of action with respect to reimbursement. Cost is another important issue in immuno-oncology. Ipilimumab can cost $120,000 for a course of therapy (based on the approved dosing regimen of 3 mg/kg every 3 weeks for 4 doses),45 pembrolizumab costs approximate-

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ly $150,000 per year,46 and nivolumab is expected to cost $143,000 annually.47 Moreover, according to the data presented at this symposium, combining these agents may be beneficial, especially in patients with metastatic melanoma. This prompts the question of how do we achieve value-based care in immuno-oncology. During the discussion among the panelists, several suggestions were offered, including using Quality-Adjusted Life Years data to determine whether to use or pay for a specific immunotherapeutic agent. It also was proposed that the way pharmaceutical companies are paid for their drugs may need to change, possibly to a capitated model with a fixed price. All of the panelists agreed that in the area of immunooncology, this is a complicated issue. Another consideration is a clinical question related to value-based care: What is the appropriate clinical end point for immunotherapy—PFS, OS, ORR, or some other surrogate measure? The clinicians agreed that OS is the best clinical end point, both from an FDA perspective and in a real-life clinical setting. It is important to develop molecular biomarkers that can identify those patients who are most likely to benefit from a specific immunotherapy, as well as to be able to determine when the maximum benefit from a particular therapy has been derived so that it would be safe to stop the treatment. The other major question regarding immunotherapies is when to use them in the sequence of treating patients. For example, in patients with melanoma, should immunotherapy be used after standard chemotherapy and BRAF inhibitors, or as first-line treatment? This is a complex issue that involves FDA labels, NCCN guidelines, and clinical judgment. ■

Acknowledgment Sy Schlager, MD, PhD, contributed to the development of this article. References

1. Courtesy of Dr. Sanjiv Agarwala, Professor of Medicine, Temple University School of Medicine; Chief, Oncology and Hematology, St. Luke’s Cancer Center; Bethlehem, Pennsylvania. 2. Disis ML. Mechanism of action of immunotherapy. Semin Oncol. 2014;41(suppl 5):S3-S13. 3. Bauzon M, Hermiston T. Armed therapeutic viruses – a disruptive therapy on the horizon of cancer immunotherapy. Front Immunol. 2014;5:74. 4. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252-264. 5. Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/ BB1 in interleukin-2 production and immunotherapy. Cell. 1992;71:1065-1068. 6. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol. 1996;14:233-258. 7. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev. 2009;229:12-26. 8. Yervoy (ipilimumab) injection for intravenous infusion [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; December 2013. 9. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:2691-2697. 10. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027-1034.

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