Page 1

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN ™ FEBRUARY 2015 VOL 8 I SPECIAL ISSUE

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

PAYERS’ PERSPECTIVES IN ONCOLOGY Including ASH 2014 Highlights*

Value and Cost-Effectiveness Immunotherapy with PD-1 Analyses Should Be Included Inhibitors the Newest Break­­ Reimbursement Decisions through in Hodgkin Lymphoma in By Kate Smith By Wayne Kuznar

© Lushpix www.fotosearch.com.

San Francisco, CA—Drug reimbursement decisions should incorporate value and cost-effectiveness, suggested Andreas Laupacis, MD, MSc, a palliative care specialist and Executive Director of the Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, Ontario, Canada, during the Special Symposium on Quality at ASH 2014. Dr Laupacis has chaired many drug reimbursement committees in Canada. He called cost-effectiveness “an ethical although admittedly imperfect tool

with which to make tough policy decisions.” Such calculations are “often messy,” because they usually lack validated surro- Andreas Laupacis, MD, MSc gate markers of long-term clinical outcomes, they are based on assumptions of a drug’s efficacy outside of clinical trials, and they involve modeling and sensitivity analyses. Continued on page 7

Computerized immune response: white blood cells attacking a cancer cell (blue).

San Francisco, CA—Two programmed-cell death receptor-1 (PD-1) inhibitors— the investigational drug nivo­lumab and the recently approved pem­bro­lizumab (Keytruda)—produced dramatic responses in patients with Hodg­kin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of Continued on page 25

Psychological Distress and Financial Burden Impact Adherence to CML Treatment By Phoebe Starr San Francisco, CA—The era of tyrosine kinase inhibitors (TKIs) has transformed chronic myeloid leukemia

(CML) from an often fatal disease to a chronic disease with ongoing treatment. Joanne S. Buzaglo, PhD, Senior Continued on page 23

*This publication is neither endorsed by nor associated with the American Society of Hematology.

The Hematology Pipeline Is Abundant By Kate Smith and Wayne Kuznar San Francisco, CA—With new signaling pathways being explored, established drug classes expanding across the tumor spectrum, and immunotherapies investigated across tumor types, the hematology pipeline is abundant. Here are some of the most promising compounds in development presented at ASH 2014. Leukemia and Myelodysplastic Syndrome

ABT-199, an oral selective BCL-2

Continued on page 16

IN TH IS IS S U E HEALTH ECONOMICS. . . . . . . . . . . Cancer therapies targeting small populations dictate drug prices Financial toxicity impacts adherence

7

FDA APPROVALS . . . . . . . . . . . . 14 Ibrutinib approved for Waldenström’s macroglobulinemia Blinatumomab for B-cell ALL MULTIPLE MYELOMA. . . . . . . . . 18 Monoclonal antibodies poised to be “blockbusters” New ixazomib data support long-term maintenance with oral therapy © 2015 Engage Healthcare Communications, LLC

inhibitor, had considerable clinical activity in patients with poor-prognosis acute myeloid leukemia (AML). ABT199 is designed to selectively bind to and inhibit BCL-2, a critical regulator of apoptosis. AG-221, an oral selective inhibitor of the IDH2 gene, showed preliminary efficacy in patients with IDH2-positive AML or myelodysplastic syndrome (MDS). AG-221 was used in 45 patients with IDH2-mutated AML or MDS at

LEUKEMIA . . . . . . . . . . . . . . . . . . Sorafenib prolongs survival in ALL High remission rate with CAR-T in pediatric ALL Pediatric regimen new standard in young adults with ALL LYMPHOMA. . . . . . . . . . . . . . . . . Stem-cell transplant safe in HIV-­­ related lymphoma Brentuximab cost-effective after transplant

21

24

PAYERS’ PERSPECTIVE. . . . . . . 26 Value of drugs and treatment adherence in hematologic cancers


NEW PHASE 3 DATA

IMBRUVICA® demonstrated single-agent survival in previously treated CLL INDICATIONS: IMBRUVICA® is a first-in-class Bruton’s tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with: • Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy • CLL with 17p deletion

Significantly improved overall survival (OS)—secondary endpoint • 57% statistically significant reduction in the risk of death for patients in the IMBRUVICA® arm (HR=0.43; 95% CI: 0.24, 0.79) • Median OS not yet reached in either treatment arm • 29% of ofatumumab patients crossed over to receive IMBRUVICA® upon progression

Significantly extended progression-free survival (PFS)—primary endpoint 78% statistically significant reduction in the risk of death or progression (independent review) 100

PFS (%)

80 60 40 Hazard ratio (HR) for progression or death: 0.22 (95% CI: 0.15, 0.32) P<0.0001 by log-rank test

20 0

0

3

6

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

12

15

38 15

7 1

0 0

Results from the randomized, multicenter, open-label, Phase 3 RESONATE™ trial of IMBRUVICA® vs ofatumumab in patients with previously treated CLL. Patients (N=391) were randomized 1:1 to receive either IMBRUVICA® 420 mg orally daily until disease progression or unacceptable toxicity or IV ofatumumab at an initial dose of 300 mg, followed 1 week later by a dose of 2000 mg weekly for 7 doses, and then every 4 weeks for 4 additional doses. Fifty-seven patients randomized to ofatumumab crossed over following Independent Review Committee-confirmed progression to receive IMBRUVICA®. Primary endpoint: PFS as assessed by an Independent Review Committee (IRC) according to modified International Workshop on CLL Criteria.

Significantly improved PFS in patients with previously treated del 17p CLL • 75% reduced risk of progression or death (HR=0.25; 95% CI: 0.14, 0.45) — Median PFS not reached with IMBRUVICA® vs 5.8 months with ofatumumab

In CLL studies, approximately 5% of patients discontinued due to adverse events Please review the Important Safety Information on adjacent page.


ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - 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 anti-platelet or anti-coagulant 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®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly. Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 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 new-onset 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 10%) including carcinomas (range, 1 to 3%) have occurred in

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 07/14 PRC-00483

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%). 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. ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® 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. DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose. CYP3A Inducers - Avoid co-administration with strong CYP3A inducers. SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment. Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com


Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

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. Improvements in survival or disease-related symptoms have not been established. 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]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: 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. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 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 10%) including 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 8%). 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, 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] 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. 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

Preferred Term Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis

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

0 3 7 5 1

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued) System Organ Class

Preferred Term

General disorders and administrative site conditions

Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%)

Grade 3 or 4 (%)

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

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

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* 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. 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 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

Preferred Term 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

Metabolism and nutrition disorders Neoplasms benign, malignant, Second malignancies* unspecified Injury, poisoning and Laceration procedural complications Psychiatric disorders Anxiety Insomnia Vascular disorders Hypertension *One patient death due to histiocytic sarcoma.

All Grades (%) 63 23 21 21 19 15 13

Grade 3 or 4 (%) 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

10*

0

10

2

10 10 17

0 0 8


IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules 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].

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 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* 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 Grades Grade 3 or 4 (%) (%)

Ofatumumab (N=191) All Grades Grade 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

11

0

3

0

10

0

3

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

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

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

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

* Based on laboratory measurements per IWCLL criteria 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.

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 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]. 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]. Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see 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]. 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) 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]. • 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. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14


PAYERS’ PERSPECTIVES IN ONCOLOGY

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

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 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 Engage Healthcare Communications 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo­metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and edi­ torial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2015 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright.com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

6

HEALTH ECONOMICS Value and cost-effectiveness analyses should factor in reimbursement Value of survival gains for MDS could exceed $100 billion US orphan drug spending expected to stabilize More….. RECENT FDA APPROVALS Ibrutinib for Waldenström’s macroglobulinemia Blinatumomab for B-cell ALL Ruxolitinib for polycythemia vera EMERGING THERAPIES The hematology pipeline is abundant MULTIPLE MYELOMA Oprozomib shows promise New ixazomib data support maintenance with oral therapy More…..

LEUKEMIA Psychological distress and financial burden impact adherence to CML treatment Pediatric regimen new standard in young adults with ALL More….. LYMPHOMA Immunotherapy with PD-1 inhibitors newest breakthrough in Hodgkin lymphoma Posttransplant brentuximab new standard in Hodgkin lymphoma Brentuximab cost-effective after transplant More….. PAYERS’ PERSPECTIVE Value of pharmaceuticals and treatment adherence in hematologic cancers

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 AmerisourceBergen, 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 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 Operating Partner, Spindletop Capital Austin, 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

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

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 Associate Professor, School of Pharmacy University of the Sciences, Philadelphia 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 PAYER-PROVIDER FINANCES

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

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

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

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 SPECIALTY PHARMACY

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

VOL. 8

I

SPECIAL ISSUE


Health Economics

Value and Cost-Effectiveness Analyses... Nevertheless, Dr Laupacis said that cost-effectiveness is an important component of reimbursement decisions.

cer, Dr Laupacis indicated. Cost-effectiveness determinations help committees allocate resources fair-

“If we pay for a very expensive drug or any intervention with very little value, we won’t be able to pay for something else with potentially more value…. We have to ask how much value we are getting for the additional cost.” —Andreas Laupacis, MD, MSc

Using cost-effectiveness calculations, Canadian drug reimbursement committees decide whether to pay for a drug out of the public purse, to decline to pay because the drug is not cost-­ effective, or to pay for a restricted indication, such as a certain stage of can-

ly, he explained. “Resource allocation decisions must be made, ad hoc or in a planned manner. Doing so in a planned manner is better,” Dr Laupacis said. “If we pay for a very expensive drug or any intervention with very little value, we won’t be able to pay for something

Continued from page 1

else with potentially more value,” he noted. “In the vast majority of circumstances, we have to ask how much value we are getting for the additional cost.” In the United States, payers can dictate their reimbursement based on reliable cost-effective analyses. Negotiating Cost with Manufacturers

As of the past few years, Canadian drug reimbursement committees have been able to negotiate prices with manufacturers. This has been an improvement over the previous structure, in which the manufacturer submitted a price for consideration, with no opportunity for adjustment. “This meant we often suggested that drugs not be funded, because at the price they charged, the drugs were not cost-effective,” Dr Laupacis said. “That changed recently, and if a drug is not felt to be cost-effective at the price submitted by the manufacturer, we have the ability to negotiate in an

attempt to find a price at which it becomes cost-effective,” he indicated. “Unfortunately, that price is not made public, and I find that unacceptable,” Dr Laupacis added. “People can find out what I charge for a consult, but we don’t know the price our government has negotiated with the manufacturer.” Regardless of a drug’s cost-effectiveness and perhaps a reasonable price, which is negotiated with the manufacturer, Dr Laupacis acknowledged that drug prices are still “massively higher” than they used to be, and are “generally not massively better” than the current best treatments. “For the way forward, there are no easy solutions,” Dr Laupacis concluded. His suggestions for payers are to: • Focus on getting high-quality information about effectiveness of drugs to accurately drive cost-effectiveness ratios • Negotiate prices aggressively based on­ cost-effectiveness • Use tools such as value-based discounts • I nvolve patients in the dialogue. n

American-Style Capitalism Drives Drug Development: Cancer Therapies Targeting Small Subpopulations Dictate Prices By Kate Smith San Francisco, CA—There is no way around the fact that American-style capitalism is at the root of drug development, and the costs associated with that endeavor, according to Alex W. Bastian, MBA, Vice President of Market Access, GfK Bridgehead, San Francisco, CA. GfK provides consulting services to pharmaceutical, biotechnology, medical device, and diagnostics industries. Speaking at the special session on drug pricing during ASH 2014, Mr Bastian asked the audience to “open its mind” to some concepts that are “realworld, practical, and deal with actual considerations that take place.” “Unfortunately, this is American-­ style capitalism,” he said. “Alternative pricing models are very difficult to implement.” Discussions about the cost of drugs have been a “constant theme” over the past century, and the problem is not unique to America, Mr Bastian said. “This is a global problem. The problems facing the United States in terms of cost are seen around the globe. It is not isolated to our cost of drugs alone.” Mr Bastian acknowledged, how­ ever, that in cancer drugs, “costs are increasing, especially as we are going

VOL. 8

I

SPECIAL ISSUE

after smaller niche populations.” The investment community must aim for a robust return on its money, and this gets trickier as tumors become more molecularly classified, he said. Potential markets for cancer drugs become smaller, as ever-more targeted treatments are required.

“This is American-style capitalism….We are frontloading cost, and the question is whether that is right. I can’t answer that. A healthy discussion is important.” —Alex W. Bastian, MBA

“For a population with very low prevalence rates, and high mortality, to justify investment by tumor types and subtumor types, we are talking fractions and subfractions,” Mr Bastian said. “Developing drugs is difficult for these populations.” Investors must justify their investments, he said, and they face “grave unintended consequences” if they advo-

cate for “hypertension-like drug prices” in the oncology arena. Mr Bastian acknowledged that patent protections are an important means of assuring the manufacturer a continuing profit for its efforts, but he pointed out that patents on a number of common agents will soon expire, and biosimilars will also begin appearing in the marketplace. “The days when Gleevec will cost cents on the dollar are close,” Mr Bastian said. Value-Based Pricing Is Needed

He suggests that the focus be on “value” rather than on cost. In hematology, value has clearly been proved by the doubling and even tripling of survival times in lymphoma, multiple myeloma, and some leukemia, as a result of novel agents. Nevertheless, Mr Bastian added that the treatment armamentarium is much weaker for hematologic cancers than for solid tumors, which highlights the difficulties in developing drugs in this setting. Since 1998, some 249 drugs in the hematology pipeline have failed to make it to market. “I don’t know at what price, but it is a lot,” Mr Bastian said. “The number of approvals is much less in comparison to other cancers.”

KEY POINTS ➤ The costs of cancer drugs are increasing in large part because they target smaller and smaller subpopulations of patients ➤ High prices and healthy margins justify the continued investment in future therapies ➤ The United States bears the bulk of the high cost; whether this is right requires an open discussion

The need for new agents keeps the pipeline flowing, he said. The point is not that current treatments must be priced high to justify past investments, but that high prices and healthy margins justify the continued investment in future therapeutics, Mr Bastian said. Meanwhile, he acknowledged, “We are front-loading cost, and the question is whether that is right. I can’t answer that. A healthy discussion is important.” This discussion should examine total benefits, as well as costs, Mr Bastian emphasized, and must include “a rounded point of view.” n

FEBRUARY 2015

I

www.AHDBonline.com

7


Introducing Introducing the thefirst first and and FDA-approved FDA-approved treatment treatment

patients patientswith withpolycythemia polycythemiavera vera aninadequate inadequateresponse responsetotoor orare are an In a phase 3 trial of Jakafi® (ruxolitinib) vs best available therapy: 21% of patients receiving Jakafi achieved the primary composite end point of hematocrit (Hct) control and spleen volume reduction compared with <1% of patients on best available therapy at week 32 (P < 0.0001)*

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

Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, 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 Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment When discontinuing Jakafi, myeloproliferative neoplasm-related 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

Jakafi is a registered trademark of Incyte Corporation. © 2014, Incyte Corporation. All rights reserved. RUX-1451 12/14


only for

who have had intolerant of hydroxyurea

1

Visit www.jakafi.com/HCP 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 Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations 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 page.

to see Full Prescribing Information and learn more about Jakafi for use in PV

* 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%). 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). Reference: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.


Health Economics

Financial Toxicity Impacts Treatment Adherence Oncologists must address costs with their patients By Kate Smith San Francisco, CA—The cost of paying for cancer impacts the efficacy of treatment, according to S. Yousuf Zafar, MD, MHS, Associate Professor of Medicine, Duke Cancer Institute,

Durham, NC. High patient cost burden is associated with a 70% higher likelihood of a patient’s nonadherence to treatment, Dr Zafar said at the ASH 2014 special session on

drug pricing. Dr Zafar coined the now-familiar concept of “financial toxicity,” which, he says, is as important as drug toxicity when it comes to patients

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

10

All Gradesa Grade 3 (%) (%)

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

with cancer. A patient’s inability to afford the cost of cancer therapy is as important to the patient’s health as potential drug toxicity. Therefore, Dr Zafar urges oncolo-

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

70

9

4

31

1

0

Anemia

96

34

11

87

16

3

Neutropenia

19

5

2

4

<1

1

a b

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

16

<1

19

<1

Abdominal Painb

15

<1

15

<1

Diarrhea

15

0

7

<1

Dizzinessc

15

0

13

0

Fatigue

15

0

15

3

Pruritus

14

<1

23

4

Dyspnead

13

3

4

0

Muscle Spasms

12

<1

5

0

Nasopharyngitis

9

0

8

0

Constipation

8

0

3

0

Cough

8

0

5

0

7

0

Grade 3-4 (%)

Bruisingb

23

<1

0

15

0

0

Edemae

8

0

Dizzinessc

18

<1

0

7

0

0

Arthralgia

7

0

6

<1

Headache

15

0

0

5

0

0

Asthenia

7

0

11

2

Urinary Tract Infectionsd

9

0

0

5

<1

<1

Epistaxis

6

0

3

0

Weight Gaine

7

<1

0

1

<1

0

Herpes Zosterf

6

<1

0

0

Nausea

6

0

4

0

Flatulence

5

0

0

<1

0

0

Herpes Zosterf

2

0

0

<1

0

0

a b

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

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 c includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site d hematoma, increased tendency to bruise, petechiae, purpura e includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis f includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, Other clinically important treatment emergent adverse events observed in less than 6% of patients bacteria urine identified, nitrite urine present treated with Jakafi were: Weight gain, hypertension, and urinary tract infections includes weight increased, abnormal weight gain Clinically relevant laboratory abnormalities are shown in Table 4. includes herpes zoster and post-herpetic neuralgia

30051_incjak_fa3_pv_ahdbppo.indd 3

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

VOL. 8

I

1/9/15 3:37 PM

SPECIAL ISSUE


Health Economics gists to discuss costs with their patients to improve outcomes. Patient–physician communication about the cost reduces out-of-pocket (OOP) costs to patients, even in oncology, where treatment options are often limited, he says. “It’s important for physicians to recognize that some patients are at risk for financial toxicity,” he said. His position is supported by the fol-

lowing statistics related to cancer care: • 50% of Medicare beneficiaries pay 10% of the cost OOP •  28% of Medicare beneficiaries spend >20% OOP • Nearly 50% of patients take money from their savings and cut back on basics to pay for care • The average patient spends approximately $5000 OOP

• The average insurance deductible has risen from $584 in 2006 to $1217 in 2014 • Since 2006, the cost of insurance premiums has risen by 182%, and employees’ contributions have gone up 128% • A cancer diagnosis raises the risk for bankruptcy nearly 3-fold. Contributing to the rising cost for patients are 4-tiered formular-

ies, which have become increasingly common. There were no fourth-tier drugs in 2003, but by 2013, approximately 23% of drugs were in the fourth tier. This usually includes all oral chemotherapy agents. The cumulative cost of treatment to the patients not only impacts their emotional and financial health, but it can also compromise clinical outcomes, according to Dr Zafar. Patient–Physician Discussions About Cost

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 (%)

<1

<1

58

0

0

Hematology Anemia

72

Thrombocytopenia

27

5

<1

24

3

<1

Neutropenia

3

0

<1

10

<1

0

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 © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428

Chemistry Hypercholesterolemia

35

0

0

8

0

0

Elevated ALT

25

<1

0

16

0

0

Elevated AST

23

0

0

23

<1

0

Hypertriglyceridemia

15

0

0

13

0

0

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 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

30051_incjak_fa3_pv_ahdbppo.indd 4

VOL. 8

In prospective, longitudinal studies of patients with cancer, Dr Zafar and colleagues have found that 52% of patients want to discuss treatment-related OOP costs with their oncologist, and 51% want their oncologist to take cost into account when making treatment decisions, but only 19% of patients have actually discussed these things with their doctors.

I

SPECIAL ISSUE

“It’s important for physicians to recognize that some patients are at risk for financial toxicity.… We have to involve patients. I do this in the clinic every day.” —S. Yousuf Zafar, MD, MHS

Among patients who did discuss costs, 57% report having lower OOP costs as a result, mainly because they were referred to a financial assistance organization (53%). Other reasons for lower costs include physicians negotiating with insurance companies on the patient’s behalf (25%), patients switching to less expensive medications (19%), tests altered (13%), and office visits scaled back (6%), Dr Zafar said. He emphasizes that cost issues do not get resolved in the absence of price transparency and discussions with patients. “We have to involve patients” in their care, Dr Zafar said. “I do this in the clinic every day.” n 1/9/15 3:37 PM

FEBRUARY 2015

I

www.AHDBonline.com

11


Health Economics

Stem-Cell Mobilization More Cost-Effective with Plerixafor By Kate Smith San Francisco, CA—The upfront use of plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem-cell mobilization is more cost-effective than the more widely used cyclophosphamide plus G-CSF regimen, according to a cost analysis from Memorial Sloan Kettering Cancer Center investigators that was presented at ASH 2014. “Phase 3 trials demonstrated higher stem-cell collection efficiency with plerixafor plus G-CSF, and plerixafor can rescue patients failing mobilization with G-CSF with or without cyclophosphamide. But despite the proven efficacy of plerixafor plus G-CSF, its upfront use has been limited, mostly due to concerns of the high cost of the drug,” said Salma Afifi, PharmD, of the Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York. “As a measure to contain cost, ‘on-demand’ plerixafor has been used in patients anticipated to be poor mobilizers with G-CSF with or without cyclophosphamide,” Dr Afifi said. The assumption is that using plerixafor plus G-CSF upfront will promote cost-effectiveness by limiting the use of plerixafor; however, a comprehensive comparison has not been done. This retrospective study is the first to compare the mobilization and cost-­ effectiveness of cyclophosphamide plus

G-CSF versus plerixafor plus G-CSF as upfront mobilization regimens. Dr Afifi and colleagues identified 223 patients with multiple myeloma undergoing upfront mobilization, with 111 patients receiving cyclophosphamide plus G-CSF and 112 patients receiving plerixafor plus G-CSF. Patients collecting <5 × 106 CD34+ cells/kg were considered mobilization failures and had a second attempt using an alternate approach. Mobilization costs included upfront mobilization, salvage mobilization, and complications directly related to the mobilization procedures. All costs were calculated using the institution’s ratio of cost to charges, and were normalized and adjusted based on institutional charges and costs for 2012. Differences in Outcomes Favor Plerixafor

Plerixafor was associated with re­­ duced use of G-CSF, fewer toxicities and related hospitalizations, and a lower rate of mobilization failure and its need for salvage mobilization associated with plerixafor plus G-CSF. The mean apheresis sessions were 2.3 with plerixafor and 2.6 with cyclophosphamide (P = .06). The median CD34+ cells/kg were 11.4 × 106 and 10.9 × 106, respectively (P = .29).

A successful total yield was achieved by 105 (94%) patients receiving pler­ ixafor plus G-CSF versus 92 (83%) pa­ tients receiving cyclophosphamide plus G-CSF (P = .01).

“This single institution study provides additional rationale for the standard use of plerixafor plus G-CSF as an upfront mobilization regimen in multiple myeloma patients.” —Salma Afifi, PharmD, and colleagues

Approximately 85% of each group went to transplant. Platelet engraftment and neutrophil engraftment were achieved by 100% of patients in each group. Overall, 13 (12%) patients were rehospitalized as a result of complications after receiving cyclophosphamide plus G-CSF, with an average hospital stay of 6.5 days. No patients in the plerixafor plus G-CSF arm were hospitalized. Of the patients in the cyclophosphamide plus G-CSF group, 19 (17%) failed first mobilization com-

pared with 7 (6.2%) patients receiving plerixafor plus G-CSF upfront. Plerixafor plus G-CSF More Cost-Effective

“Plerixafor plus G-CSF was more cost-effective than cyclophosphamide plus G-CSF,” Dr Afifi concluded. The average charges were $74,884 in the cyclophosphamide plus G-CSF cohort versus $59,127 in the plerixafor plus G-CSF cohort (P = .004). The average cost of stem-cell collection per patient was 22% higher in the cyclophosphamide group than in the plerixafor group (P = .017), Dr Afifi reported. “When the costs associated with salvage pheresis was discounted for the 19 patients in the cyclophosphamide plus G-CSF upfront group who failed first stem-cell mobilization, assuming that these patients could have been salvaged by plerixafor on demand, the cost per patient in the cyclophosphamide plus G-CSF group remains 1.26 times greater [P = .019] than that of the plerixafor plus G-CSF group,” Dr Afifi and her colleagues noted. “Overall, this single institution study provides additional rationale for the standard use of plerixafor plus G-CSF as an upfront mobilization regimen in multiple myeloma patients,” Dr Afifi concluded. n

High Cancer Drug Prices Hurt Patients San Francisco, CA—Hagop M. Kantarjian, MD, Professor and Chair of Leukemia, M.D. Anderson Cancer Center, Houston, TX, did not mince words during his talk at the ASH 2014 special session on drug pricing. “Drug prices are definitely too high, and this is harming our patients….We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability,” Dr Kantarjian said. Disputing the claim that rising prices is not a new concern, he pointed out that before 2000, the average cost of an oncology drug was less than $10,000 annually. Since then, prices have risen 10-fold, while the average household income has diminished by 8%. This disparity has compromised the financial and emotional security of many patients with cancer, whose outof-pocket expenses are simply unaffordable, Dr Kantarjian said. The end result, he suggested, is a “medical Darwinian system” in which

12

“Drug prices are definitely too high, and this is harming our patients…. We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability.” —Hagop M. Kantarjian, MD

“if you can pay, you live, and if you cannot, you may die from your disease.” Although the concept of cost-sharing (ie, giving patients “skin in the game”) aims to facilitate value-based treatment choices, this holds true only for less expensive drugs and generics, and is not applicable to most cancer treatments, Dr Kantarjian said. “In cancer, new drugs are patented,

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

and patients don’t have this choice. Having skin in the game is only harmful to them,” he said. Rebutting Common Arguments

Dr Kantarjian took exception to the arguments made to support high prices: that prices reflect the high cost of research and the cost–benefit ratio of the drug, that market forces will set pric-

es at reasonable levels, and that price control will stifle innovation. “None of these are true, morally justifiable, or defensible,” Dr Kantarjian maintains. He took exception to the argument that price reflects benefit, noting that some drugs prolong life by years and others by days, yet the near-universal annual cost of new agents is approximately $100,000. Market forces cannot correct price imbalances, he says, because drug companies do not compete on the basis of cost. In addition, drug companies set their own prices for the Medicare system. Although manufacturers indicate that they set prices by calculating cost–­ benefit ratio, examining the competitive marketplace, and estimating the potential market for the drug, Dr Kantarjian suggests that “companies look at the price of an existing drug and put a 20% higher price tag on the new one.” “Making progress in drug development in the long run is not a reason to increase prices to a profiteering level,” he concluded.—KS n

VOL. 8

I

SPECIAL ISSUE


Health Economics

Once Off Patent, Imatinib Will Be the Most CostEffective Treatment for Newly Diagnosed CML By Wayne Kuznar San Francisco, CA—Once Gleevec loses patent exclusivity in 2016, imatinib will become the most cost-effective initial treatment strategy for patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, said Richard A. Larson, MD, Director, Hematologic Malignancies Clinical Research Program, University of Chicago, IL, at ASH 2014. Dr Larson’s analysis showed an incremental cost-effectiveness ratio of $291,000 per quality-adjusted life-year (QALY) when generic imatinib was used as the initial therapy in a step therapy regimen. Lifelong treatment with a tyrosine

KEY POINTS ➤ Once it loses patent exclusivity in 2016, imatinib will be the most cost-effective treatment for newly diagnosed chronicphase CML ➤ Generic imatinib had an incremental cost-effectiveness ratio of $291,000 per QALY when used as the initial therapy in a step therapy regimen ➤ In a 12-month CCyR model, step therapy was shown to cost less and offer clinically equivalent use compared with physician’s choice over the first 5 years of therapy

kinase inhibitor (TKI) is recommended for patients with chronic-phase CML, and although out-of-pocket costs vary within and between health systems, they may be considerable, and costs influence daily adherence and outcomes, Dr Larson said. Currently, imatinib, dasatinib, and nilotinib are approved by the FDA as frontline therapies for chronic-phase CML. “When imatinib loses patent exclusivity in early 2016, 6 to 8 manufacturers are expected to enter the generic imatinib market,” said Dr Larson. In evaluating the clinical outcomes and economic costs of imatinib versus second-generation TKIs as initial treatment for patients with newly diagnosed CML, Dr Larson’s group applied “value of information” as an outgrowth of comparative effectiveness methods to prospectively assess step therapy and physician’s choice. In step therapy, all patients begin with imatinib but are switched for intolerance or failure of efficacy. In the physician’s choice model, imatinib, dasatinib, and nilotinib were prescribed equally for initial therapy. “I believe this currently reflects the situation in the United States,” said Dr Larson. The results were evaluated from a commercial payer perspective, with comparison of treatment costs and outcomes over the first 5 years of therapy. The end points used for this analysis were complete cytogenetic response (CCyR) at 12 months and

“When imatinib loses patent exclusivity in early 2016, 6 to 8 manufacturers are expected to enter the generic imatinib market.” —Richard A. Larson, MD

overall survival. In the step therapy model, if imatinib failed or was not tolerated as the initial choice, patients were switched to dasatinib or to nilotinib in equal proportions. In the physician’s choice model, if the initial second-generation TKI failed, patients were switched to an alternate second-generation TKI (with a small percentage switched to imatinib). Patients with CCyR by 12 months continued to receive initial TKI ther-

apy up to complete remission and were assumed to survive for 5 years. It was assumed that patients without CCyR by 12 months were switched to an alternate TKI and also survived for 5 years. Patients who progressed to accelerated-phase CML or blast crisis CML (an estimated 5% of patients) received allogeneic transplantation, assuming a 1-year survival of 50%. The model assumed an annual cost of $60,390 for imatinib, $95,338 for dasatinib, and $91,644 for nilotinib. The cost of imatinib was assumed to decrease with its availability as a generic, remaining at 100% of the branded-­ drug price for the first 6 months, 60% to 80% of the branded-drug price in the second 6 months, and 10% to 30% thereafter. The 12-month CCyR model showed that step therapy costs less and offers clinically equivalent utility compared with physician’s choice over the first 5 years (with step therapy at approximately $184,000 vs physician’s choice at $216,000). The QALYs remained similar between step therapy and physician’s choice (3.25 vs 3.36, respectively). Step therapy was estimated to have an incremental cost-effectiveness ratio of $291,000 per QALY. Multivariate probabilistic sensitivity analyses found step therapy to be cost-effective in 73.3% of 10,000 Monte Carlo simulations, with the currently accepted willingness-to-pay threshold of $100,000 per QALY. n

Economic Value of Survival Gains for MDS Could Exceed $100 Billion By Chase Doyle San Francisco, CA—The introduction of the 3 targeted therapies—lenalidomide, decitabine, and azacitidine—for myelodysplastic syndrome (MDS) has resulted in a 74% increase in median survival and generates more than $100 billion in value resulting from survival gains for current and future patients, reported Joanna P. MacEwan, PhD, Associate Research Economist, Precision Health Economics, San Francisco, CA, at ASH 2014. Despite improvement in cancer survival since the 1970s, critics have argued that newer cancer treatments offer minimal survival gains, at high costs. Noting the lack of economic

VOL. 8

I

SPECIAL ISSUE

analyses, Dr MacEwan and colleagues studied the value of MDS treatments relative to their cost. Building on an existing analytic

survival analysis, the value of survival gains, and value appropriation. Cox proportional hazards models were applied to estimate the increase

“The annual value of survival gains associated with these innovative treatments—roughly $208,000 per year—equaled the estimated amount a patient would be willing to pay for the higher survival profile associated with new therapies.” —Joanna P. MacEwan, PhD

framework using data on survival and prescription drug claims, the researchers conducted 3 subanalyses, including

in survival associated with the introduction of new therapies for MDS in 38,085 patients with MDS diagnosed

KEY POINTS ➤ Treatment with lenalidomide, decitabine, or azacitidine showed an increase in median survival from 33 months to 57.5 months, representing a 74% improvement ➤ The annual survival gain associated with these treatments was roughly $208,000

between 2001 and 2011. The results showed that patients diagnosed with

FEBRUARY 2015

Continued on page 14

I

www.AHDBonline.com

13


Health Economics

Orphan Drug Expenditures in the United States Expected to Stabilize By Wayne Kuznar San Francisco, CA—The increase in orphan drug expenditures is expected to slow, said Victoria Divino, Senior Consultant at IMS Health, at ASH 2014. Ms Divino and colleagues evaluated the trends in orphan drug expenditures over time in the United States, calculating the total expenditures for branded orphan drugs from 2007 to 2013 and projected drug expenditures for ­2014 to 2018. “Future trend analysis suggests that while orphan drug expenditures in 2014 to 2018 will increase, there will be a slowing down in growth, and growth will remain fairly stable as a proportion of total drug expenditures,” said Ms Divino. “Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified,” she emphasized. Orphan drug development is increasing in hematologic malignancies. “Despite the clinical value of orphan drugs, payer sensitivity to orphan drugs is increasing, due to the perceived potential impact on payers’ drug budgets,” Ms Divino said. “Little evidence and data have been generated as to the actual burden of orphan drug expenditures in the United States.” Of the 356 branded orphan drugs analyzed, 291 (82%) “orphan-only” drugs were included in a primary analysis. In a secondary analysis, expenditures were adjusted for 65 (18.3%) of the 356 orphan drugs, which were identified as “partial orphans,” because they are approved for orphan and for nonorphan indications. Study Details

In the primary analysis of orphan-­

only drugs, the expenditures represented 4.3% to 7.7% of the total US drug expenditures from 2007 to 2013. Overall, the orphan drug expenditures totaled $15 billion to $30 billion, representing 4.8% to 8.9% of the total US drug expenditures from 2007 to 2013.

“Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified.” —Victoria Divino

“While we observe a trend for increasing costs, it’s also important to note that the number of drug approvals has increased over time,” said Ms Divino. There was a total of 210 unique orphan drugs in 2007, which increased to 286 drugs in 2013.

Economic Value of Survival Gains for MDS Could Exceed... Continued from page 13 MDS since 2006 (when all 3 therapies were available) had an approximate 10% lower mortality risk than patients diagnosed between 2001 and 2003 (hazard ratio, 0.901; P <.10). The median survival in patients with MDS who received lenalidomide, decitabine, or azacitidine (approximately 25%) increased from 33 months to 57.5 months, representing a 7­4% improvement. “The annual value of survival gains associated with these innovative treatments—roughly $208,000 per year—equaled the estimated amount a patient would be willing to pay for ­­ the higher survival profile

14

associated with new therapies,” Dr MacEwan suggested. This value was estimated to exceed the cost of therapy, with an annual net benefit of $68,200 to patients with MDS and a lifetime benefit of $238,700. The present value of survival gains for all current and future cohorts was determined to be $101.5 billion. Based on estimates of patent expiration and price decreases after the patent expirations, the investigators concluded that 85% of the value of survival gains created by novel therapies ($86.5 billion) will accrue to patients with MDS, with the remaining 15% accruing to the drugs’ manufacturers. n

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

In addition, oncology was the most common therapeutic class of orphan drug approved, with 101 (32.0%) of the total 356 orphan drugs with an orphan indication for oncology. In 2007, $15.08 billion was spent on orphan drugs, with 29.3% representing cancer-related orphan drugs compared with $30.08 billion in 2013, of which 40.7% was for cancer-related orphan drugs. Using sales data from 2007 to 2013, the investigators estimated the orphan drug expenditures to be $33.5 billion to $44.2 billion for 2014 to 2018, representing 8.8% to 9.5% of the total US drug expenditures. The future costs were estimated as the number of new approvals times the average cost per drug annually added to the previous year’s total orphan drug sales. Orphan drug expenditures of $34.9 billion to $54.9 billion were estimated for 2014 to 2018, representing 9.2% to 11.8% of the total US drug costs. Although select orphan drugs may be costly, the population using these orphan drugs is small. The adjusted drug expenditures for 64 partial orphan drugs represented 0.5% to 1.2% of the total US drug sales from 2007 to 2013. A disease-factoring analysis suggested that most unadjusted partial orphan drug sales were for nonorphan indications. “Following adjustment, orphan indication costs were minimal and represented only 7.2% to 10.5% of total unadjusted partial orphan drug expenditures in 2007 to 2013, respectively,” Ms Divino said.

KEY POINTS ➤ Based on a new analysis, the concern that growth in orphan drugs will cause unsustainable spending is unjustified ➤ The total US drug expenditures for orphan drugs increased by 0.5% to 1.2% from 2007-2013 to 2014-2018, but the growth in orphan drugs is expected to slow ➤ Orphan drugs are often costly, in part because they serve a small patient population ➤ The total spending on orphan drugs is low compared with spending on all drugs ➤ Orphan drugs often benefit patients with previously underserved rare conditions

“While associated orphan drug expenditures have increased, these drugs benefit many patients with previously underserved rare conditions. While this study examined drug expenditures, it’s important to consider the value of orphan drugs to both patients and society, such as health and quality-of-life improvements, reductions in costly hospitalizations, increased productivity, and the ability to go back to work,” said Ms Divino. “The annual expenditures on orphan drugs are small relative to the total pharma drug expenditures,” she ­concluded. n

RECENT FDA APPROVALS Ibrutinib Gets New Indication for Waldenström’s Macroglobulinemia

On January 29, 2015, the US Food and Drug Administration (FDA) ap­­ proved a new indication for ibrutinib (Imbruvica; Pharmacyclics) under its priority review process for the treatment of patients with Waldenström’s macroglobulinemia (WM), a rare type of non-Hodgkin lymphoma. Ibrutinib had previously received a breakthrough therapy designation by the FDA for this use. WM progresses gradually over time, resulting from the overproduction of B-cells within the bone marrow, lymph nodes, liver, and spleen. These B-cells

also overproduce immunoglobulin M, which may lead to bleeding and vision and nervous system problems. Ibrutinib inhibits the abnormal activity of these B-cells to fight WM. The approval was based on a clinical study of 63 previously treated patients with WM. The patients received 420 mg of oral ibrutinib daily until disease progression or until side effects became intolerable. The overall response rate to the drug was 62%, with a response duration ranging from 2.8 months to approximately 18.8 months. The most common adverse events with ibrutinib are thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nauContinued on page 23

VOL. 8

I

SPECIAL ISSUE


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.


Emerging Therapies

The Hematology Pipeline Is... escalating doses. Responses were seen in 56% of patients, including 15 complete responses (CRs) and 10 partial responses. Responses were durable, with CRs lasting up to 8 cycles; many patients continue to receive AG-221, reported Eytan M. Stein, MD, of Memorial

Sloan Kettering Cancer Center, New York. Dr Stein called the 56% response rate “a very big deal” in this hard-totreat population. The targeting of a specific genotype will increase efficacy, he said, and potentially “extend life spans and minimize toxicity.” S:7”

Continued from page 1

Olaptesed pegol, a novel L-stereoisomer RNA aptamer that binds and neutralizes CXCL 12/SDF-1, produced an 82% overall response rate (ORR) when combined with bendamustine and rituximab in an open-label study of 28 patients with relapsed or refractory

Brief Summary

16

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

AMERICAN HEALTH & DRUG BENEFITS

I

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-14-0258 All rights reserved. Printed in USA

FEBRUARY 2015

8/14

8/27/13 4:54 PM

S:10”

INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

chronic lymphocytic leukemia (CLL). The ORR of bendamustine plus rituximab without olaptesed has historically been 59%. Olaptesed in combination with bendamustine and rituximab was safe and well-tolerated. XmAb5574, a novel humanized immunoglobulin G1 CD19 monoclonal antibody with an engineered Fc region to enhance Fc gamma receptor binding affinity, showed promising preliminary efficacy in high-risk patients with heavily pretreated CLL. Responses were reported in 67% of 16 patients who received XmAb5574. The results with this drug compare favorably with single-agent CD20 antibodies in relapsed CLL. Current studies are investigating XmAb5574 in combination with other agents. Another anti-CD19 antibody agent, MEDI-551, was evaluated in combination with bendamustine versus rituximab and bendamustine in 147 patients with relapsed or refractory CLL in a phase 2 trial that was presented by Douglas E. Gladstone, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. The preliminary results showed clinical activity, with comparable safety observed between the MEDI-551 and rituximab arms. The investigators may also have identified a biomarker of response—low baseline levels of a microRNA signature. Pracinostat, an investigational oral histone deacetylase (HDAC) inhibitor, resulted in a rate of 45% for the composite end point of CR and CR with incomplete blood count recovery and morphologic leukemia-free status when combined with azacitadine in a phase 2 trial of 33 patients with AML and intermediate- or unfavorable-risk cytogenetics (see article, page 21). Vosaroxin, a first-in-class anticancer quinolone derivative, in combination with cytarabine improved the median overall survival compared with placebo plus cytarabine (7.5 months vs 6.1 months, respectively) in a phase 3 study of patients with relapsed or refractory AML. CTL019, a chimeric antigen receptor targeting CD19, achieved durable remission in children with relapsed or refractory acute lymphocytic leukemia who were given T-cells engineered with CTL019 (see article, page 22). In patients with MDS, rigosertib did not meet the primary end point in the phase 3 ONTIME trial; however, it did improve survival in several subgroups, including patients whose disease progressed with or failed to respond to previous treatment with hypomethylating agents, patients at very high risk, and patients with certain karyotypic abnor-

VOL. 8

I

SPECIAL ISSUE


Emerging Therapies

malities. “Patients in these subgroups have a very poor prognosis, and currently there is no approved drug available to treat their disease, once they have failed hypomethylating agents,” said Guiller­­mo Garcia-Manero, MD, of M.D. Anderson Cancer Center, Houston. Dr Garcia-Manero also presented findings for SGI-110, a novel subcutaneous hypomethylating agent, in 102 patients with MDS and chronic myelo­ monocytic leukemia (CMML). CRs plus minor CRs were reported in 19% to 22% of patients, depending on the dose used. Transfusion independence for ≥8 weeks was reported in approximately 33% of patients in total, and in 50% of the treatment-naïve patients. The investigators noted that SGI-110 was well-tolerated and showed biological and clinical activity in intermediate- and high-risk patients with MDS and CMML. SGI-110 has “particularly promising activity” in patients who previously received azacitidine or decitabine, the researchers noted. Sotatercept (ACE-011), a first-inclass activin type-2A receptor fusion protein, may have a role in patients with MDS and anemia, especially when their disease does not respond to erythropoiesis-stimulating agents. In a phase 2 study from the Moffitt Cancer Center, 45% of 54 patients receiving intravenous sotatercept demonstrated a reduced need for transfusion or an increase in hemoglobin level. Non-Hodgkin Lymphoma

Polatuzumab vedotin and pinatuzumab vedotin, 2 antibody-drug conjugates, showed activity and tolerability in a phase 2 randomized trial of patients with relapsed or refractory non-Hodg­kin lymphoma (NHL). In the ROMULUS trial, patients received polatuzumab or pinatuzumab, plus rituximab. Both regimens were generally well-tolerated, with similar toxicity profiles. Neutropenia, peripheral neuropathy, and diarrhea were the principal toxicities. In patients with diffuse large B-cell lymphoma (DLBCL), the ORRs were 56% with polatuzumab and 57% with pinatuzumab (plus rituximab), and the CRs were 15% and 24%, respectively. In follicular lymphoma, the ORRs were 70% and 62%, and the CRs were 40% and 10%, respectively. The higher CR rate with polatuzumab plus rituximab compared with pinatuzumab plus rituximab suggests that polatuzumab may have greater clinical activity in this patient population. Combination studies of polatuzumab plus rituximab with chemotherapy and with antibody-­ drug conjugate schedules to reduce peripheral neuropathy are ongoing or in planning.

VOL. 8

I

SPECIAL ISSUE

MOR00208, an Fc-engineered hu­­­ manized anti-CD19 antibody, was evaluated as a single agent in a phase 2a study of patients with relapsed or refractory B-cell NHL. Among the first 51 patients in the trial, the response rate was 24%. The drug was well-tolerated, without significant toxicity from the infusion. Accrual to the study i­s continuing. Alisertib (MLN8237), an oral Aurora A kinase inhibitor, was investigated alone and in combination with rituximab in a phase 2 study of 11 patients with high-risk relapsed or refractory B-cell NHL. Alisertib was well-tolerated, wi th 1 patient responding and able to proceed to transplant. Enrollment ­­is continuing.

Nivolumab and pembrolizumab, the 2 most recently approved programmed-cell death receptor (PD)-1 inhibitors approved for patients with melanoma, showed exciting findings in patients with classic Hodgkin lymphoma. Copanlisib, a novel PI3K inhibitor, was explored in 33 patients with indolent NHL or with CLL. The ORR in both patient populations was 44%; when divided by disease state, the ORR was 48% in patients with NHL and 38% in patients with CLL. The combined median duration of response was 390 days, and the median progression-free survival was 288 days. Grade ≥3 events included hypertension (48%), neutropenia (33%), hyperglycemia (30%), anemia (15%), and thrombocytopenia (15%). The investigators noted that copanlisib is active as a single agent in heavily pretreated patients with advanced refractory or relapsed follicular NHL, marginal zone lymphoma, small lymphocytic lymphoma, and CLL, and its toxicity level is acceptable. Based on these results, a phase 2b study in patients with relapsed or refractory indolent NHL has been initiated. DLBCL is a particularly aggressive subtype of NHL, and novel treatments are clearly needed. A number of novel agents were presented at ASH 2014, but their efficacy was modest. Buparli­ sib (BKM120), an oral pan-class I PI3K inhibitor, was active among 64 patients with relapsed or refractory DLBCL NHL in a phase 2 study presented by Anas Younes, MD, of Memorial Sloan Ket-

tering Cancer Center. Tumor reduction was observed in 67% of heavily pretreated patients; durable CRs were seen in 31% and 88% of the DLBCL and follicular lymphoma subsets, respectively; however, the primary objective of ORR was not met in either cohort. The investigators indicated that “targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL.” Barasertib, a potent Aurora B kinase inhibitor, showed promising results in a phase 2 trial of patients with relapsed or refractory DLBCL. In 15 patients, the response rate was 20%, and 33% attained stable disease. The median PFS was 60 days. The study provided proof of concept that Aurora B kinase is a valid target in DLBCL. Mogamulizumab, a humanized mono­­ clonal antibody targeting the CC chemokine receptor 4 (CCR4), achieved stable disease or better in 46% of patients (11% responses) with peripheral T-cell lymphoma, with an acceptable safety profile, in a multicenter phase 2 study of heavily pretreated relapsed or refractory patients. The CCR4 is expressed on 30% to 65% of tumor cells in patients with peripheral T-cell lymphoma, whose prognosis is generally poor. Mogamulizumab binds to CCR4. The drug is already approved outside of the United States for this patient population.

tumor reduction. The median response duration was approximately 6 months. MK2206 was well-tolerated; rash was the main toxicity. Multiple Myeloma

Monoclonal antibodies may be poised to be the “rituximab of myeloma,” experts predicted at ASH 2014. Elotuzumab (which received breakthrough therapy designation for myeloma in May 2014), in combination with lenalidomide and dexamethasone, induced an 84% ORR in a phase 1b/2 study of patients with relapsed or refractory myeloma (see article, page 18). The data were less mature but were at least as impressive for the 2 antiCD38 antibodies, SAR650984 and daratumumab. SAR650984 yielded a 63% response rate in optimally treated patients with myeloma. Daratumumab (which received a breakthrough therapy designation for myeloma in 2013) showed impressive results in combination with standard regimens, yielding a 100% response rate in some cohorts (see article, page 18). Ricolinostat (ACY-1215), a selective oral HDAC6 inhibitor, is in early-stage studies but is of particular interest to myeloma specialists. In a phase 1b study of 42 patients with relapsed or refractory myeloma, ricolinostat, in combination with bortezomib and dexamethasone, was well-tolerated, with diarrhea Hodgkin Lymphoma as the only dose-related side effect. Nivolumab and pembrolizumab, the The response rate was 44%, and only 2 most recently approved programmed-­ 3 patients showed progressive disease. cell death receptor (PD)-1 inhibitors Responses were seen even in bortezoapproved for patients with melanoma, mib-refractory patients. showed exciting findings in patients with Panobinostat, another HDAC inhibclassic Hodgkin lymphoma. Although itor, is in phase 3 development. Jatin the results for these 2 PD-1 inhibitors Shah, MD, of M.D. Anderson Cancer came from small, phase 1 studies in Center, presented data for panobinospatients with Hodgkin lymphoma, they tat in combination with bortezomib, earned spots at press conferences at the lenalidomide, and dexamethasone in 31 meeting and drew large attendance at newly diagnosed patients with myeloASH 2014 sessions. In this patient popu- ma. He reported an ORR of 95%, lation, the ORR was 87% for nivolumab including 50% CRs or near-CRs. Dr and 66% for pembrolizumab in patients Shah pronounced the regimen “very with disease progression with standard well-tolerated,” with limited grade 3 therapies (see article, page 25). or 4 toxicity. Panobin­ ostat was also MK2206, an oral AKT inhibitor, combined with carfilz­omib in a phase 1 induced response in patients with classic study of 28 heavily pretreated patients Hodgkin lymphoma and indolent lym- with relapsed or refractory myeloma. phoma; however, its single-agent activ- Jonathan L. Kaufman, MD, of Emory ity was low in patients with DLBCL, University, reported an ORR of 46% T-cell lymphoma, or mantle-cell lym- (44% in patients refractory to bortezophoma in a phase 2 study of 50 patients mib) and no unexpected toxicities. The with refractory disease. MK2206 is median PFS was 11.4 months. the first oral non-ATP competitive Ixazomib and oprozomib, 2 novel allosteric inhibitor of the AKT path- oral proteasome inhibitors, have way 1, 2, and 3 that is currently in clin- shown promising results in myeloma. ical development. Objective responses Long-term data were presented for were observed in 14% of patients (20% ixazomib; oprozomib is in earlier-stage among patients with Hodgkin lympho- development (see articles, page 19 and ma), and 40% of patients showed some page 20). n

FEBRUARY 2015

I

www.AHDBonline.com

17


Multiple Myeloma

By Kate Smith San Francisco, CA—Monoclonal antibodies may be to multiple myeloma what rituximab has been to lymphoma, according to myeloma experts who expressed enthusiasm over these emerging agents at an education session at ASH 2014. “Monoclonal antibodies present an attractive therapeutic strategy,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston. “Monoclonal antibodies have activity in high-risk disease and represent truly novel mechanisms of action.” “Elotuzumab is the most advanced in development, and is currently in phase 3 testing in both the upfront and relapsed/refractory settings and primarily in combination. Daratumumab and SAR650984 show promise. Numerous other potential targets in the myeloma plasma cells have been identified, and a number of other monoclonal antibodies are in development as well,” Dr Richardson said. Elotuzumab

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody that targets the signaling lymphocytic activation molecule F7. The regimen of elotuzumab plus lenalidomide and dexamethasone demonstrated encour-

Elotuzumab is the most advanced in development.” —Paul G. Richardson, MD

aging efficacy in a phase 1b/2 study of patients with relapsed or refractory disease. “What was particularly exciting was that we saw a remarkable response rate in this relapsed/refractory population, recognizing that they were lenalidomide-naïve,” said Dr Richardson, who presented the final results from a randomized phase 2 cohort of 73 patients. The overall response rate was 84%. A complete response (CR) or stringent CR was achieved by 14% of patients. The median duration of response was 20.8 months, which is reflected by the long progression-free survival (PFS)— 29 months, and 32.5 months with the highest dose of elotuzumab. Approximately 66% of patients had diarrhea and muscle spasms, and nearly 50% reported constipation, nausea, and upper respiratory tract infection. The

© American Society of Hematology. All rights reserved.

Monoclonal Antibodies Poised to Be “Blockbusters” in Myeloma

“Anti-CD38 monoclonal antibodies…will be.” —Thomas G. Martin, III, MD

most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, lymphopenia, and anemia. Infusion reactions occurred in 11% of patients. “It’s important to judge safety in the context of the duration of treatment; patients were on therapy for a number of years,” said Dr Richardson. Anti-CD38 Monoclonal Antibodies

The data were slightly less mature but at least as impressive for the antiCD38 antibodies SAR650984 and daratumumab. “These anti-CD38 monoclonal antibodies, I believe, will be blockbuster drugs and will be an important component to multiple myeloma treatment,” predicted Thomas G. Martin, III, MD, Associate Director, Myeloma Program, University of California, ­San Francisco.

Dr Martin led a study of SAR650984 given in combination with lenalidomide and dexamethasone in 31 heavily pretreated patients with relapsed or refractory disease. The combination produced responses in 58% of patients overall, rising to 63% in the highest-dose cohort. The median PFS was 6.2 months, but it had not been reached in the least pretreated patients. “SAR650984 in combination with lenalidomide and dexamethasone showed encouraging activity in this heavily pretreated population,” without increasing toxicity, Dr Martin said. The other anti-CD38 antibody, daratumumab, was evaluated in combination with standard regimens in the MMY1001 study of 18 patients with newly diagnosed disease and 7 patients with relapsed or refractory disease. Backbone regimens included bortezomib/dexamethasone (VD), bortezomib/ thalidomide/dexamethasone (VTD), bortezomib/melphalan/prednisone (VMP), and pomalidomide/dexamethasone (POM-DEX). For daratumumab combined with VD, VMP, and VTD in the upfront setting in patients with newly diagnosed myeloma, 100% of the patients responded. With POM-DEX, in patients with relapsed or refractory disease, 50% responded and 1 of these patients had a stringent CR, reported Philippe Moreau, MD, of Nantes University Hospital, France. n

Pomalidomide plus Low-Dose Dexamethasone Combination Likely to Be Cost-Effective San Francisco, CA—Pomalidomide plus low-dose dexamethasone is “likely to be a cost-effective use of healthcare resources,” according to researchers from the United Kingdom, who presented a pharmacoeconomic analysis at ASH 2014. Although the incremental cost-effectiveness ratio (ICER) for quality-adjusted life-years (QALYs) gained slightly exceeded $100,000, which is the often-cited willingness-to-pay threshold, Steve Schey, MD, of King’s College London, and colleagues suggested in their poster that “end-of-life drugs that significantly improve survival and health-related quality of life and address unmet needs can be considered to be cost-effective at a higher willingness-to-pay threshold.” The pomalidomide plus low-dose dexamethasone regimen demonstrated a significant overall survival ben-

18

efit versus high-dose dexamethasone in the pivotal phase 3 MM-003 study, when adjusted for crossover (12.7 vs 5.7 months, respectively; P <.001). The investigators explored the cost-­ effectiveness of the pomalidomide/ dexamethasone regimen versus current care from UK and Irish healthcare payer perspectives. Current care included in the economic model consisted of retreatment with bortezomib (intravenous or subcutaneous), bortezomib in combination with lenalidomide, and bendamustine regimens. The costs and outcomes were modeled to estimate the cost per lifeyear and cost per QALY gained over a lifetime horizon (25 years). The efficacy data were obtained from a systemic review of the regimen in patients who had previously been treated with bortezomib and lenalidomide. Three studies relevant to ques-

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

tion of pomalidomide/dexamethasone versus current practice were included in the analysis. The economic evaluation included the cost of treatment, administration, monitoring, tests, the management of adverse events, blood

“End-of-life drugs that significantly improve survival and healthrelated quality of life and address unmet needs can be considered to be cost-effective at a higher willingness-to-pay threshold.” —Steve Schey, MD, and colleagues

transfusions, concomitant medication, and terminal care. The medical costs were presented in US dollars. Survival and Quality of Life

The model predicted that patients who receive pomalidomide/dexamethasone live for a mean of 2.2 years compared with 1.2 years with current care; the QALYs were 1.3 versus 0.7, respectively, representing an additional 0.6 QALYs. In the base-case analysis, pomalidomide/dexamethasone was associated with a total incremental cost of $59,250 per patient over a lifetime horizon compared with current care. The model predicted an ICER of $100,920 per QALY compared with current care. The probabilistic ICER obtained through 1000 probabilistic model runs was consistent, at $101,947 per QALY, Dr Schey reported. —KS n

VOL. 8

I

SPECIAL ISSUE


Multiple Myeloma

Weekly Carfilzomib Safe and Effective By Kate Smith San Francisco, CA—The weekly administration of carfilzomib may be equivalent to the current practice of twice-weekly injections, according to an abstract presented at ASH 2014 by Antonio Palumbo, MD, of the University of Turin, Italy, and colleagues. “With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy,” Dr Palumbo said in an interview. The phase 1/2 study evaluated the safety and efficacy of weekly carfilzomib in elderly patients newly diagnosed with myeloma (median age, 74 years) and determined the maximum tolerated dose for weekly administration of the drug. The rationale for studying weekly carfilzomib came from the observation that the weekly administration of bortezomib has proved safe and efficacious. “We have previously seen that with once-weekly administration of bortezomib, the risk of adverse events, especially peripheral neuropathy, was diminished significantly,” Dr Palumbo said. To evaluate once-weekly carfilzomib, Dr Palumbo and colleagues enrolled 12 patients in a dose-finding phase of the trial and then added 18

patients for phase 2 of the study. The escalating doses started at 45 mg/m2; the maximal planned dose was 70 mg/m2. Carfilzomib was given on days 1, 8, and 15, along with oral cyclophosphamide

“With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy.” —Antonio Palumbo, MD

and oral dexamethasone. Of the 30 patients in the trial, 21 received the maximum tolerated dose (70 mg/m2) ­of carfilzomib. After the completion of 9 cycles, patients received 28-day maintenance cycles with carfilzomib at the maximum tolerated dose until disease progression or intolerance. The median relative dose intensity was 100% for carfilzomib, 100% for cyclophosphamide, and 96% for dexamethasone. At the time of the analysis, 77% of patients had received at least 4 cycles.

No Increase in Toxicity, High Response Rates

Dr Palumbo reported that the “grade 3/4 adverse events were very rare and very low” with once-weekly higher-dose carfilzomib, and they were not increased over what has been observed with twice-weekly dosing. Dose reductions also appeared to be required less frequently (10%) with once-weekly dosing than with twice-weekly dosing (21%). Grade 3/4 hematologic events were observed in 23% of patients in this study compared with 27% in studies of twice-weekly dosing; grade 3/4 nonhematologic events were seen in 30% and 29% of patients, respectively. With once-weekly dosing, grade 3/4 adverse events were primarily grade 3 neutropenia (10%), anemia (10%), and cardiac toxicity (7%), and grade 4 cardiac toxicity (7%) and pulmonary embolism (3%). Grade ≥3 thrombocytopenia, fatigue/fever, gastrointestinal toxicity, infection, and venous thromboembolism occurred in fewer than 5% of patients each. Showing data from a study of twice-weekly carfilzomib (36 mg/m2), he noted that toxicity numbers were “superimposed with ours,” a finding that Dr Palumbo called “reassuring.”

Deep Responses Achieved

The preliminary response data showed an overall response rate of 86%, with 64% of patients having at least a very good partial response, 41% achieving at least a near-complete response (CR), and 25% achieving a CR, stringent CR, or near-CR. By cycle 9, a very good partial response or better was achieved by 91% of patients receiving weekly carfilzomib compared with 77% of patients receiving the drug twice weekly at 36 mg/m2 in previous studies. A nearCR was reached by cycle 9 in 41% of patients with once-weekly dosing and by 47% of patients on the twice-weekly schedule. The median time to first response (at least a partial response) was 1 month, and the median duration of response was not reached in the study. Dr Palumbo indicated that the response rates will improve over time. “We need at least 6 cycles to maximize response,” he pointed out. “We start seeing stringent CRs at 8 cycles. Some patients improved their response beyond induction, into maintenance. With prolonged treatment, we will increase the percentage of patients with more profound CRs.” n

Novel Oral Proteasome Inhibitor Oprozomib Shows Promise in Myeloma San Francisco, CA—The oral anti­ myeloma proteasome inhibitor oprozomib, given as a single agent in a dose-escalation study, “showed promising antitumor activity,” which included responses even in patients with carfilzomib-refractory multiple myeloma, according to Ravi Vij, MD, of Washington University in St Louis, MO. Oprozomib binds selectively and irreversibly to its target, resulting in sustained cancer-cell inhibition. At ASH 2014, Dr Vij presented data from an ongoing multicenter open-­label phase 1b/2 study of 129 patients with hematologic malignancies, including 87 patients with relapsed and/or refractory multiple myeloma. “The majority of patients had seen bortezomib and carfilzomib, and quite a few were refractory to both these drugs,” he noted. Patients received oprozomib in various schedules and dose levels in 2-week cycles. During the phase 1b of the study, the formulation of oprozomib was changed from powder in a capsule to an extended-­ release tablet; in phase 2, step-up dosing was

VOL. 8

I

SPECIAL ISSUE

introduced. These amendments appeared to improve the drug’s tolerability. Clinical Benefit of 50%

In the phase 1b cohort of patients receiving 150 to 330 mg daily for 2 of every 7 days (2/7 schedule), the objective response rate was 31.3% and the clinical benefit rate was 50%. In the patients in the phase 1b/2 of the trial who received 150- to 270-mg daily for 5 of 14 days (5/14 schedule), the response rate was 23.3% and the clinical benefit rate was 32.6%. Of note, these response rates were observed before the step-up dosing schedule was initiated. The response data were not presented for the step-up cohorts, because of limited treatment exposure (approximately 7 weeks). Responses were achieved by 18.2% of patients with carfilzomib-­refractory disease, Dr Vij added. The recommended phase 2 dose and schedules were the 2/7 step-up schedule at 240 to 300 mg daily and the 5/14 step-up schedule at 150 to 180 mg daily.

Improved Tolerability

In the cohorts that did not benefit from step-up dosing, the most common grade ≥3 nonhematologic adverse events were diarrhea, nausea, and vomiting. With step-up dosing, these events were uncommon.

“Our preliminary data suggest that step-up dosing is associated with improved tolerability.” —Ravi Vij, MD

In the 240- to 300-mg daily step-up cohorts in phase 2, grade ≥3 nausea and diarrhea were observed in only 10% of patients each. Hematologic toxicities grade ≥3 were limited to anemia (11%) in the 240- to 300-mg daily cohort and neutropenia (10%) in the 150- to ­180-mg daily cohort. Treatment-emergent peripheral neuropathy was rare, occurring in only 6% of patients, with only 1 case of grade 3.

Rash was reported in 7% of patients, with no grade ≥3. A total of 3 deaths were reported in the 5/14 dosing cohort before step-up dosing was instituted; 2 from upper gastrointestinal bleeding and 1 from disease progression. “Our preliminary data suggest that step-up dosing is associated with im­­ proved tolerability, with fewer gastrointestinal adverse events observed, and less hematologic toxicity, although the numbers are small,” Dr Vij reported. “With the phase 2 step-up dose of 150-180 mg daily, we have seen no grade 3 gastrointestinal toxicity. There’s also a hint that dose reductions and discontinuations for adverse events are less.” Enrollment in the 2/7 and 5/14 schedules is continuing. The target enrollment for the phase 2 portion of the myeloma cohort is 94 patients. All current and newly enrolled patients are receiving extended-release tablets of oprozomib. Most patients receive premedication with antidiarrheal and antiemetic agents.—KS n

FEBRUARY 2015

I

www.AHDBonline.com

19


Multiple Myeloma

New Data on Ixazomib Maintenance Support LongTerm Oral Therapy in Patients with Myeloma By Kate Smith Dr Kumar reported. The rate of CRs plus near-CRs increased from 24% after induction to 62%, with 71% being very

ing maintenance therapy at the time of the report. The estimated percentage of patients surviving without progression

“Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience…. Single-agent ixazomib maintenance for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem-cell transplant.”

© American Society of Hematology. All rights reserved.

San Francisco, CA—Data from a phase 1/2 clinical trial support further evaluation of the investigational oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. Approval of this drug would introduce an all-oral treatment regimen for this disease. In a study reported at ASH 2014 by Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, MN, long-term maintenance with ixazomib improved the depth of response after induction in patients with treatment-naïve myeloma. The overall response rate was 90%; complete response (CR) rate was 22% in patients after induction, which increased to 52% by the end of maintenance. Of the 65 patients enrolled, 25 entered the maintenance phase and received a median of 31 total cycles (induction and maintenance) and 19 maintenance cycles. “With maintenance, we saw a deepening of response in 48% of patients,”

—Shaji K. Kumar, MD

good partial responses or better. Ixa­ zomib maintenance contributed to the durable responses, he said. Half of the patients were still receiv-

at 2 years was 57%. Serious adverse events were observed in 4 (19%) patients during maintenance with ixazomib, none of which were considered

to be related to treatment. Ixazomib is the first oral proteasome inhibitor and has physiochemical properties distinct from bortezomib. The triplet of bortezomib, lenalidomide, and dexamethasone has been shown to produce high response rates, and increasing evidence suggests that extended treatment may add benefit to conventional induction strategies. “Agents for continuous therapy, however, need to be convenient and well-tolerated,” Dr Kumar suggested. “Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience.” “Single-agent ixazomib maintenance for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem-cell transplant,” he said. “New-onset toxicity during single-agent ixazomib maintenance was limited.” Phase 3 trials that include patients who are newly diagnosed with myeloma and patients with relapsed myeloma are under way. n

Dissecting the Treatment Costs of Newly Diagnosed Myeloma in First 2 Years San Francisco, CA—In the treatment of patients newly diagnosed with multiple myeloma, medical, nondrug costs, particularly outpatient costs, account for approximately 75% of the total expenditures for the first 2 years after diagnosis, according to a new analysis of a large US claims database presented at ASH 2014. Recent studies have suggested that medical costs, such as hospital admissions, are the main contributors to overall cost during first-line treatment of patients with relapsed or refractory myeloma using novel agents, said X. Henry Hu of Global Health and Patient Outcomes Research, a division of Celgene Corporation. “We need to understand the full range of costs associated with the management of myeloma patients,” said Mr Hu. Mr Hu and colleagues examined the MarketScan database of 6238 patients with newly diagnosed myeloma to analyze the healthcare expenditures for inpatient care, outpatient services, and prescription drugs. Overall, the total healthcare expenditures were $65,607

20

per patient annually for the first 2 years after diagnosis. The smallest proportion of costs was attributed to drugs compared with outpatient and inpatient costs during that period. When analyzed by transplantation status, the total annual costs were $182,061 per patient undergoing stemcell transplant versus $50,840 for other patients (Table). “Outpatient costs accounted for the greatest proportion of overall costs for both patient groups,” he said. The distribution of total costs during the first 2 years after diagnosis was fairly

similar for the transplant and nontransplant groups.

“We need to understand the full range of costs associated with the management of myeloma patients….Changes were most marked in the stemcell transplant patients.” —X. Henry Hu

Table Overall Costs in the First 2 Years After Diagnosis Nontransplant, $ (N = 5536)

Received transplant, $ (N = 702)

Inpatient

11,719

61,802

Outpatient

27,438

83,320

Drug

11,683

36,939

Overall

50,840

182,061

Annual cost per patient

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

Overall, the healthcare costs de­­ creased for both patient groups during the second year. The decreases were seen in inpatient and outpatient costs; however, drug costs increased in both groups. “Changes were most marked in the stem-cell transplant patients,” Mr Hu noted. “Transplant costs were considerably higher during the first year following diagnosis than in the subsequent year.” In year 2, the transplant group had 63% lower inpatient costs and 50% lower outpatient costs, but the drug costs increased by 28%. For the nontransplant group, the inpatient costs were 46% lower, the outpatient costs were 29% lower, and the drug costs were increased by only 4% in year 2 versus in year 1 after the diagnosis. The investigators concluded that outpatient costs account for most expenditures, and that stem-cell transplant is associated with markedly higher healthcare expenditures, particularly with respect to inpatient costs, particularly in year 1.—KS n

VOL. 8

I

SPECIAL ISSUE


Leukemia

Pracinostat-Azacitidine Combination Generates Responses in Older Adults with Acute Myeloid Leukemia By Wayne Kuznar San Francisco, CA—Nearly 50% of elderly patients with newly diagnosed acute myeloid leukemia (AML) who received pracinostat, an investigational HDAC (histone deacetylase) inhibitor, in combination with azacitidine had responses in an ongoing phase 2 clinical trial. Furthermore, “no patient who achieved a clinical response has progressed,” according to lead investigator Guillermo Garcia-Manero, MD, Chief, Section of Myelodysplastic Syndromes, Department of Leukemia, M.D. Anderson Cancer Center, Houston, and colleagues. Previously, pracinostat demonstrated clinical evidence of single-agent activity in patients with AML and myelofibrosis. In a phase 1 dose-escalation study of 14 evaluable patients with AML, 2 patients achieved a complete response (CR)—1 lasting more than 206 days and 1 lasting more than 362 days.

Study Details

The interim phase 2 data presented at ASH 2014 come from the ongoing MEI-004 trial investigating the effectiveness and safety of the pracinostat and azacitidine combination in treatment-naïve older patients with AML.

“No patient who achieved a clinical response has progressed….Most clinical responses occur within the first 2 cycles and continue to improve with ongoing therapy.” —Guillermo Garcia-Manero, MD, and colleagues

The study is enrolling patients aged ≥65 years with newly diagnosed de novo (N = 29), secondary disease (N = 12) or

treatment-related AML with intermediate- or unfavorable-risk cytogenetics and ≥20% bone marrow blasts. Overall, 80% of the patients had an ECOG performance status of 0 to 1; the remaining 20% had an ECOG status of 2. Patients received pracinostat 60 mg orally 3 days weekly for 21 days of a 28-day cycle. Azacitidine was given subcutaneously or intravenously on days 1 to 7, or days 1 to 5 and 8 and 9 (based on site determinations) of each 28-day cycle. The main end point is CR and full response with incomplete blood count recovery, along with morphologic leukemia-free state. At study evaluation, 41 patients were registered at 15 centers; enrollment has been continuing since the end of 2013, and 25 patients are still active in the study. Reasons for study discontinuation included progressive disease (N = 6), adverse events (N = 6), or other (N = 4). Interim efficacy data in 33 patients

show that 45% achieved the primary end point. “Most clinical responses occur within the first 2 cycles and continue to improve with ongoing therapy,” according to the researchers. “The observed response rate may increase with longer follow-up of patients achieving partial response or stable disease.” In addition, 3 patients had a partial response or a partial response with incomplete blood count recovery, and 4 had stable disease; 4 patients had no clinical benefit. The most common treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, nausea, anemia, and fatigue. Adverse events resulting in dose reductions were uncommon. Six patients have received pracinostat beyond 230 days, which attests to its long-term tolerability. These data support definitive development of pracinostat in combination with azacitidine as treatment for older patients with AML. n

Sorafenib Prolongs Event- and Relapse-Free Survival in Acute Myeloid Leukemia

VOL. 8

I

SPECIAL ISSUE

Sorafenib is a multikinase inhibitor with activity against several oncogenic kinases that may play a role in AML. The drug is approved for the treatment of several types of solid tumors, including thyroid, liver, and kidney cancer. In this study, patients aged 18 to 60 years with newly diagnosed AML

© American Society of Hematology. All rights reserved.

San Francisco, CA—Sorafenib added to standard therapy significantly im­­ proves event-free survival (EFS) and relapse-free survival compared with standard chemotherapy alone in younger patients with newly diagnosed acute myeloid leukemia (AML). In a phase 2 clinical trial of 267 patients with AML aged ≤60 years, sorafenib extended median EFS by 20.5 months versus 9.2 months with placebo, but it did not improve overall survival (OS), reported Christoph Röllig, MD, MSc, Universitätsklinikum Dresden, Germany, at ASH 2014. “These data constitute the first randomized evidence that kinase inhibitors work in AML,” Dr Röllig said. “Based on these results, we cannot call sorafenib a standard treatment for AML yet. It would be nice to have a second confirmatory trial, and we would like to see what happens to overall survival after a longer period of follow-up.” Nevertheless, the improvement in EFS is clinically meaningful, he said.

received daunorubicin 60 mg/m2 on days 3 to 5 plus cytarabine 100 mg/ m2 continuous intravenous infusion on days 1 to 7 for 2 cycles, followed by cytarabine 3 g/m2 twice daily on days 1, 3, and 5 for 3 cycles. Nonresponders

received second induction with cytarabine plus mitoxantrone. Allogeneic stem-cell transplant was scheduled for intermediate- or high-risk patients. Patients were randomized to sorafenib 800 mg daily or to placebo in addition to standard chemotherapy on days 10 to 19 of induction, from day 8 of each

“These data constitute the first randomized evidence that kinase inhibitors work in AML.” —Christoph Röllig, MD, MSc

consolidation until 3 days before the start of the next consolidation, and as maintenance for 12 months after consolidation. Complete response was 59% in the placebo arm versus 60% in the sorafenib

arm (P = .764). With a median follow-up of 3 years, the median EFS was 20.5 months with sorafenib and 9.2 months with placebo; the 3-year EFS rate was 40% versus 22%, respectively (P = .013). The median relapse-free survival was 23 months in the placebo arm but has not yet been reached in the sorafenib arm, corresponding to a 3-year relapsefree survival of 38% with placebo versus 56% for sorafenib (P = .017). The median OS had not yet been reached for either arm, but the 3-year OS rates are 56% and 63% for placebo and sorafenib, respectively. Toxicity was much more likely with sorafenib compared with placebo. Hazard ratios with sorafenib were 3.61 for bleeding, 3.84 for rash, 3.36 for liver toxicity, and 3.53 for fever. Hand-foot syndrome occurred only in the sorafenib arm. The most common reported grade ≥3 adverse events were fever (40%), infections (22%), and bleeding events (2%).—WK n

FEBRUARY 2015

I

www.AHDBonline.com

21


Leukemia

CAR-T Achieves High Rate of Remission in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia By Wayne Kuznar It also allows activation of the T-cell, which causes significant proliferation. More than 130 patients at the University of Pennsylvania and the Children’s Hospital of Philadelphia, encompassing ALL, chronic lymphocytic

CR was achieved in 36 (92%) patients 28 days after T-cell infusion. There have been 10 relapses, 50% related to disappearance of the engineered T-cells (ie, CD19-positive relapse) and 50% related to antigen escape

“About two thirds of the patients retain their T-cells for 6 months or longer. It’s a key point in terms of maintaining remission in these patients.”

© American Society of Hematology. All rights reserved.

San Francisco, CA—Administration of T-cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) persist over the long-term and induce durable remissions in children with relapsed or refractory acute lymphoblastic leukemia (ALL). In this phase 1/2 study, 92% of patients achieved complete responses (CRs) with CTL019, reported Stephan A. Grupp, MD, PhD, Director of Translational Research, Center for Childhood Cancer Research, the Children’s Hospital of Philadelphia, at ASH 2014. In July 2014, CTL019 received breakthrough therapy designation from the US Food and Drug Administration as a treatment for pediatric and adult patients with relapsed or refractory ALL. The CAR process uses genetically modified T-cells to target cancer, explained Dr Grupp. This genetic modification allows the expression of a CAR protein on the surface of the T-cell. The T-cell receptor gains this new recognition capability through the CAR protein, which allows interaction with the cancer cell, with the intent of killing it.

—Stephan A. Grupp, MD, PhD

leukemia, and non-Hodgkin lymphoma, have been treated with CTL019. Dr Grupp’s report focused on 39 pediatric patients with relapsed, treatment-resistant ALL, who received CTL019 at a median of 3.6 × 106 cells/kg during 1 to 3 days. One week before CTL019 treatment, 87% of patients received lymphodepleting chemotherapy.

(ie, CD19-negative relapse). Of the patients who relapsed with CD19-positive disease after achieving CR, 40% had disease refractory to previous treatment with blinatumomab. The median follow-up has been 6 months, but 15 patients have been followed for ≥1 year, with the longest being 31 months. Only 3 patients

have subsequently undergone stemcell transplant. Response seems to be independent of the disease burden. In patients with >50% bone marrow blasts by minimal residual disease, the overall response rate was 82%, similar to the response rate of 88% in patients with >5% blasts. The significant risk of treatment is a cytokine-release syndrome, which is higher in patients with high disease burden, although all patients have some degree of cytokine-release syndrome at peak T-cell expansion. “Patients who have <50% bone marrow blasts essentially do not have significant degrees of cytokine-release syndrome,” Dr Grupp noted. “About two thirds of the patients retain their T-cells for 6 months or longer,” Dr Grupp said. “It’s a key point in terms of maintaining remission in these patients.” The duration of response has been favorable: 76% of the patients remain in remission if they reach 6-months remission. The event-free survival rate at 6 months is 70%, and the overall survival rate is 75%. n

Pediatric Regimen a New Standard for Adolescents and Young Adults with Acute Lymphoblastic Leukemia By Alice Goodman San Francisco, CA—Early results of the large, prospective Intergroup C10403 trial demonstrate that a high-intensity pediatric-inspired regimen improves event-free survival (EFS) and overall survival (OS) in adolescent and young adults with acute lymphoblastic leukemia (ALL). Many smaller studies have shown that adolescent and young adults have improved outcomes on pediatric regimens, but this is the first large data set to validate this practice. The 2-year EFS was 66% and the 2-year OS was 79%. “These results are a major improvement compared with 34% and 39%, respectively, in historical controls. This is a clear opportunity to improve care in adolescent and young adults with ALL,” said lead investigator Wendy Stock, MD, University of Chicago Medical Center, Chicago, IL. The study showed that the presence of a BCR-Abl1–like signature and aberrant CRLF2 expression were associated

22

with worse EFS and OS rates and are considered factors for increased risk in this patient population. Patients without these clinical features had excellent EFS and OS, Dr Stock told listeners at ASH 2014.

“These results are a major improvement compared with 34% and 39%, respectively, in historical controls. This is a clear opportunity to improve care in adolescent and young adults with ALL.” —Wendy Stock, MD

The Intergroup C10403 trial was undertaken by cooperative groups in North America to evaluate treatment with a pediatric intensive regimen

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

delivered by hematologists/oncologists treating adult patients. Dr Stock presented the main results of the trial. Additional analysis of adherence and outcomes based on psychosocial factors will be presented in the future. A total of 296 adolescent and young adults (median age, 25 years) with ALL were treated between 2007 and 2013. Overall, 75% of the patients had B-precursor ALL and 24% had T-precursor ALL. In addition, 31% of the patients were obese, with body mass index >30 kg/m2, and 7% were morbidly obese. The backbone of the pediatric-­ inspired regimen included intensified glucocorticoid, vincristine, and asparaginase and more maintenance therapy. The regimen included induction, consolidation, interim maintenance, delayed intensification, and prolonged maintenance (2 years for girls and 3 years for boys). The EFS rate was similar among

the treatment groups, regardless of the age-group or a precursor B- or T-­ lineage. The OS was significantly worse in the obese patients, and significantly improved in patients with undetectable minimal residual disease. Dr Stock and colleagues will propose a successor US Intergroup trial that should begin in 2015. The plans include the use of the molecular signature of the disease to stratify patients and to add a novel antibody or a targeted kinase inhibitor to eradicate any minimal residual disease and improve outcomes. “This is a phenomenal achievement,” said Yoav Messinger, MD, Pediatric Oncologist at Children’s Hospital and Clinics of Minnesota, Minneapolis, chair of the session where these data were presented. “We have been waiting for a long time for these data, which put what we already know into a formalized protocol on a large-scale basis.” n

VOL. 8

I

SPECIAL ISSUE


Leukemia

Psychological Distress and Financial Burden Impact Adherence to CML... Continued from page 1

Vice President of Research and Training at the Cancer Support Community, presented results from a patient survey of patients with CML at ASH 2014, indicating that the treatment of CML imposes a significant economic burden on patients and increases psychosocial distress, which together lead to reduced adherence to treatment. The survey data “suggest that psychosocial distress and financial burden may have a greater impact on treatment adherence than financial burden alone,” said Dr Buzaglo. Several other studies have reported that the financial burden associated with CML treatment is negatively affecting treatment adherence. Studies have reported significant decreases in 5-year event-free survival with poor adherence to TKIs, and poor adherence occurs more frequently than physicians recognize. Patient-Reported Outcomes

The Cancer Support Community, in partnership with the Leukemia & Lymphoma Society, registered 484 patients living with CML to the Cancer Experience Registry. Of the registrants, 81% (N = 393) responded to this survey that included questions about the financial burden of CML and cancer-related distress.

• 10% skipped dosages of their CML medication. In total, 31% of the patients were defined as having poor drug adherence.

Stress and anxiety over managing the financial impact of CML was measured with the Impact of Event Scale, and 15 items from a validated distress

The survey data “suggest that psychosocial distress and financial burden may have a greater impact on treatment adherence than financial burden alone.” —Joanne S. Buzaglo, PhD, and colleagues

screener were calculated to create a score for overall distress; of this, 4 items were summed to indicate risk for depression. The analysis included 327 US-based patients with a median age of 59 years. The annual income of patients surveyed was <$40,000 in 32% of patients; $40,000 to $79,000 in 31% of patients; and ≥$80,000 in 37% of patients. Impact of Cost of Care on Medication Adherence

• 19% of patients reported missing a dose of oral medication for their CML at least once monthly • 14% reported postponing prescription

Nearly 50% of the patients reported out-of-pocket (OOP) costs of ≥$100 related to CML monthly, 27% spent ≥$250, 15% spent ≥$500, and 5% spent ≥$1000. Moreover, 38% said they had to use copay assistance because of the medical costs of CML treatment, 35% had to cut grocery expenses, 33% depleted their savings, 30% used pharmaceutical assistance programs, 18% sold personal property, 17% asked their healthcare provider for a less expensive treatment, 13% had liquidated their assets, 6% went into bankruptcy, and 4% foreclosed on their homes.

Psychological Distress

To reduce the costs associated with CML, 23% of patients postponed seeking psychological support, 17% delayed follow-up on recommendations for complementary treatment (ie, physical therapy), 16% postponed doctors’ appointments, and 12% postponed follow-up screening and/or blood work. Approximately 45% of patients were at risk for depression and 37% reported clinically high levels of stress-related intrusive ideation about the financial cost of cancer. Greater OOP costs were associated with higher overall distress (P <.001) and increased risk for depression (P <.001), adjusting for income. Among those at risk for depression, financial burden increased the odds of poorer drug adherence by more than 7-fold. Among those not at risk for depression, financial burden had a modest impact on drug adherence (odds ratio, 1.3; P = .60). “Implications for future research and practice so that patients fully benefit from CML therapy include the development and evaluation of interventions that enhance patient–clinician communications, psychosocial distress screening and referral, and financial counseling and assistance,” concluded Dr Buzaglo. n

RECENT FDA APPROVALS Ibrutinib Gets New Indication for... Continued from page 14

sea, upper respiratory tract infection, ­and rash. Ibrutinib was initially approved by the FDA in November 2013 for the treatment of patients with mantle-cell lymphoma; in February 2014, it was approved for patients with previously treated chronic lymphocytic leukemia (CLL), and in July 2014, for patients with CLL and a deletion in chromosome 17. Ruxolitinib Gets New Indication for Polycythemia Vera

On December 14, 2014, the FDA approved ruxolitinib (Jakafi; Incyte) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The approval was based on a randomized, multicenter, open-label, active-control trial of 222 patients with PV.

VOL. 8

I

SPECIAL ISSUE

The composite end point was durable hematocrit control and spleen volume reduction, and a durable hematocrit control that obviated the need for regular phlebotomy. Ruxolitinib was significantly better than best-available therapy in durable hematocrit control and in spleen volume reduction by week 32 (21% vs 1%; P <.001) and week 48 (19% vs 1%; ­­­P <.001), and had a 55% rate of durable hematocrit control by week 48. The most common (incidence >20%) hematologic adverse reactions through week 32 were thrombocytopenia and anemia. The most common (incidence >10%) nonhematologic adverse events were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms. Overall, 4% of patients discontinued therapy because of adverse events. The recommended starting dose of ruxolitinib is 10 mg twice daily, with modifications in some patient populations.

Blinatumomab First Immunotherapy Approved by the FDA for B-Cell ALL

On December 3, 2014, the FDA approved blinatumomab (Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia. The drug acts as a connector between the CD19 protein (which is found on the surface of most B-cell lymphoblasts) and the CD3 protein found on T-cell lymphocytes, using the body’s T-cells to destroy the leukemia cells. The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated programs for this approval. The FDA is now requiring the manufac-

turer to conduct a new clinical trial to show a survival benefit with blinatumomab in patients with relapsed or refractory Ph-negative precursor B-cell ALL. The approval was based on a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumomab for at least 4 weeks. Overall, 32% of patients had complete remission lasting approximately 6.7 months. The trial was not designed to show improvement in survival. Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system events. It was approved with a Risk Evaluation and Mitigation Strategy program and has a boxed warning regarding these risks. The most common side effects reported were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor. n

FEBRUARY 2015

I

www.AHDBonline.com

23


Lymphoma

Posttransplant Brentuximab: New Standard in Hodgkin Lymphoma? By Phoebe Starr San Francisco, CA—Early posttransplant consolidation with brentuximab vedotin (Adcetris) significantly improved progression-free survival (PFS) compared with placebo in patients with Hodgkin lymphoma who are at risk for disease progression in the placebo-controlled phase 3 AETHERA trial. AETHERA is the first placebo-­ controlled trial to compare brentuximab and placebo in patients with Hodgkin lymphoma after transplant. The results of the study were presented at the 2014 American Society of Hematology annual meeting. The median PFS was 43 months for the group receiving brentuximab versus 24 months for the group receiving placebo (P = .001), representing a 43% reduction in the risk for disease progression. The 2-year PFS rates were 65% and 45%, respectively, for the cohorts. “In my opinion, once this study is published, brentuximab should be the standard of care for patients with risk factors for disease progression,” namely, with remission duration <1 year, extranodal

disease, B symptoms, 2 or more previous salvage therapies, and primary refractory disease, stated lead investigator Craig H. Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York. Dr Moskowitz called the 20% difference in 2-year PFS “unprecedented” in any lymphoma. Autologous stem-cell transplant (ASCT) cures approximately 50% of patients with relapsed or refractory Hodgkin lymphoma. The other 50% will relapse after transplant. Before this study, no investigational regimen had improved posttransplant outcomes. Brentuximab is an antibody-drug conjugate directed to CD30, which is typically expressed in classic Hodg­kin lymphoma cells. Although brentuximab has been approved by the FDA for the treatment of relapsed or refractory Hodgkin lymphoma and for systemic anaplastic large-cell lymphoma, it is not approved for posttransplant consolidation.

“Once this study is published, brentuximab should be the standard of care for patients with risk factors for disease progression.” The 20% difference in 2-year PFS is “unprecedented” in any lymphoma. —Craig H. Moskowitz, MD Study Details

The international multicenter trial enrolled 329 patients with Hodgkin lymphoma who had at least 1 risk factor for relapse. Approximately 50% of the patients had ≥3 risk factors for disease progression at baseline. After ASCT, patients were randomized to 16 cycles of treatment with brentuximab or placebo. Of patients in the place-

bo group who progressed, 85% were crossed over to brentuximab. Brentuximab achieved superior PFS in all prespecified subgroups, including primary refractory patients who relapsed within 12 months of frontline therapy and patients who relapsed after 12 months with extranodal disease. The overall survival (OS) was no different between the 2 treatment arms in the interim analysis at 2 years, which could be attributed to the high percentage of patients receiving placebo who crossed over to the active treatment arm. The final OS analysis will be presented in 2016. The most common adverse events in the brentuximab arm included peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%). Dose reductions of brentuximab effectively alleviated peripheral neuropathy in the majority of patients. n

Stem-Cell Transplant Safe in HIV-Related Lymphoma By Phoebe Starr

24

Alvarnas, MD, Director of Medical Quality at City of Hope, Duarte, CA. © American Society of Hematology. All rights reserved.

San Francisco, CA—Patients with HIV-­related lymphoma should not be excluded from clinical trials of autol­ ogous hematopoietic-cell transplant (AHCT). Moreover, they should be offered AHCT as a standard treatment option, according to the results of a phase 2 trial reported at the 2014 American Society of Hematology meeting. The concern has been that immunocompromised patients, such as those with HIV infection, are at greater risk for serious infections. Thus, they are typically not considered candidates for AHCT, which is a curative therapy for lymphoma. Despite effective antiretroviral therapy, HIV infection (AIDS) persists as a risk factor for lymphoma. “Chemotherapy-sensitive patients with relapsed/refractory HIV-related lymphoma may successfully undergo AHCT with favorable outcomes. Our study shows that exclusion from clinical trials on the basis of HIV infection alone is no longer justified. In fact, in clinical practice, patients with controlled HIV infection—with emphasis on the word ‘controlled’—should be receiving transplants as standard of care,” said lead study investigator Joseph

Single-Arm Clinical Trial

“Exclusion from clinical trials on the basis of HIV infection alone is no longer justified….Payers should also recognize that this treatment [AHCT] should now be the standard of care for these patients.” —Joseph Alvarnas, MD

“These results are an important advancement for patients and their

AMERICAN HEALTH & DRUG BENEFITS

physicians seeking access to effective treatments. Payers should also recognize that this treatment should now be the standard of care for these patients,” Dr Alvarnas stated.

I

FEBRUARY 2015

The single-arm, multi-institutional trial was conducted jointly by the Blood and Marrow Transplant Clinical Trials Network and the AIDS Malignancy Clinical Trials Consortium. The results should be generalizable to a broader spectrum of centers, because the 16 transplant centers included in the study do not specialize in the treatment of HIV and AIDS. The single-arm study showed that AHCT achieved an estimated 1-year overall survival rate of 86.6% and a progression-free survival rate of 82.3% in patients with HIV-related lymphoma. The estimated rate of disease progression at 1 year was 12.5% and the estimated mortality rate was 5%. The study included 40 HIV-infected patients with lymphoma who had at least 1 risk factor for disease progression; approximately 50% had ≥3 risk factors for disease progression. Patients underwent AHCT with a modified

KEY POINTS ➤ For chemotherapy-sensitive patients with relapsed/ refractory HIV-related lymphoma, AHCT should now be the standard of care ➤ Excluding patients from clinical trials on the basis of HIV infection is no longer justified ➤ AHCT resulted in an estimated 1-year OS rate of 86.6% and PFS of 82.3% in these patients

BEAM (carmustine, etoposide [Toposar], cytarabine [Depocyt], melphalan [Alkeran]) regimen. Patients did not receive antiretro­ viral therapy during the preparative regimen; that therapy was resumed after the resolution of gastrointestinal toxicities. All patients received standard institutional supportive care after transplant. At a press conference, Dr Alvarnas noted that a case-control study of 151 matched patients with lymphoma who did not have HIV infection showed similar mortality outcomes to the patients in the present study. n

VOL. 8

I

SPECIAL ISSUE


Lymphoma

patients who had exhausted other treatment options, providing solid evidence that targeting the immune system can be effective in hematologic malignancies, similar to solid tumors. The data were presented at the 2014 American Society of Hematology meeting. “Strategies that target tumor cells using the immune system are extremely exciting,” said Catherine M. Bollard, MBChB, MD, Blood and Marrow Transplant Specialist, Children’s National Health System, and Professor of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC. “I see this as a way forward in how we will revolutionize treatments in hematology.” Nivolumab

Nivolumab was tested in 23 patients with Hodgkin lymphoma, 87% of whom had received previous treatment with at least 3 regimens, including stem-cell transplant and brentuximab vedotin (Adcetris). In all, 35% of the patients had received at least 6 previous regimens. All tumors had genetic abnormalities involving 9p24.1, leading to overexpression of the PD-1 ligands. Nivolumab 3 mg/kg was administered every 2 weeks until disease progression or severe toxicity. “Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” said lead investigator Philippe Armand, MD, PhD, Senior Physician,

© American Society of Hematology. All rights reserved.

Immunotherapy with PD-1 Inhibitors the Newest...

“Treatment [with nivolumab] resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated.” —Philippe Armand, MD, PhD

data assessment, 48% of the responses were ongoing, and 43% of patients were still receiving treatment. Some patients have been in remission for >1 year, said Dr Armand. The safety profile of nivolumab mirrored that in solid tumors. Overall, 22% of patients had grade 3 drug-related adverse events (AEs); no deaths or drug-related grade 4 AEs were reported. Two patients discontinued treatment as a result of AEs. “There was no apparent increase in lung toxicity, which we worry about, because many patients had other treatments that can cause lung injury,” Dr Armand said. In May of this year, the FDA granted nivo­lumab a breakthrough therapy designation for relapsed Hodgkin lymphoma. Pembrolizumab

Pembrolizumab was evaluated in 29 heavily pretreated patients with Hematologic Malignancies, Dana-­ classic Hodgkin lymphoma who had progressed after treatment with brenFarber Cancer Institute, Boston. Responses were seen in 100% of tuximab vedotin. Craig H. Mosko­ patients who had not undergone a witz, MD, Clinical Director, Division stem-cell transplant and in 80% who of Hematologic Oncology, Memorial had a transplant but did not receive Sloan Kettering Cancer Center, New brentuximab. At an average of 40 York, presented the results of the trial weeks, the complete response rate was at the meeting. The response rate was 66%, reported 17% overall, and 60% in brentuximab-naïve patients. Another 13% of Dr Moskowitz, with complete responses in 21% of the patients and partial patients had stable disease. The progression-free survival rate responses in 45%. Responses occurred was 86% at 24 weeks. At the time of in 75% of the patients with previous

Continued from page 1

stem-cell transplant and in 44% of those who were transplant-ineligible or who had refused transplant. The median time to response was 12 weeks, and the median duration of response was not reached. “Almost all patients had some evidence of tumor shrinkage,” Dr Moskowitz said. The clinical benefit rate, which includes stable disease, was 86%. “Many patients had stable disease on pembro­ lizumab. In fact, some who have been on treatment the longest had stable disease,” he said. Pembrolizumab 10 mg/kg was administered every 2 weeks until progressive disease, excessive toxicity, or the completion of 24 months of therapy. Overall, 52% of the patients had received at least 5 previous lines of treatment. All patients had previously failed therapy with brentuximab, and 69% had stemcell transplant failure. There were 4 treatment-related grade ≥3 AEs—1 patient each with axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 AEs or treatment-related deaths. Pembrolizumab and nivolumab have individually demonstrated single-­ agent activity in patients with Hodgkin lymphoma, said Dr Moskowitz, commenting on these results. He noted that future evaluations in combination with standard therapies, or even as maintenance treatment to enhance the posttransplant immune response will be important. n

Brentuximab Cost-Effective After Transplant By Chase Doyle San Francisco, CA—The use of brentuximab vedotin (Adcetris) to prevent progression after autologous stem-cell transplantation (ASCT) in patients with Hodgkin lymphoma is expected to increase survival and be cost-effective, according to a cost-effectiveness analysis presented at ASH 2014. Relapsed or refractory Hodgkin lymphoma after ASCT carries an unfavorable prognosis, with a median overall survival of less than 2 years. It is also very costly to treat. Novel agents that reduce the risk for disease progression and the need for further treatment, including ASCT, offer the potential to be not only clinically effective but also cost-effective, noted Joshua A. Roth, PhD, MHA, of the Hutchinson Institute for Cancer Outcomes Research, Seattle, WA. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, significantly improved progression-free survival when given after ASCT in the AETHERA trial (see article, page 26).

VOL. 8

I

SPECIAL ISSUE

Cost-Effective

The objective of the current analysis was to evaluate the cost-effectiveness of brentuximab treatment strategy after ASCT to prevent or delay disease progression in patients with Hodgkin lymphoma compared with best supportive care. The investigators constructed a decision model evaluating the potential cost-effectiveness of brentuximab vedotin versus best supportive care. Adults with relapsed or refractory Hodgkin lymphoma “enter” the model immediately after receiving ASCT, and then receive brentuximab vedotin plus best supportive care or best supportive care alone. After treatment, patients are tracked in monthly cycles through the 5 health states of remission, relapse/salvage therapy, relapse/palliative care, second remission, and death, with transition probabilities derived from peer-reviewed literature, bone marrow transplant registry data, and US life tables.

When used after ASCT to prevent progression, brentuximab vedotin has the potential to be cost-effective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma. —Joshua A. Roth, PhD, MHA

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

of $50,000, $100,000, and $150,000 per QALY, respectively. The investigators concluded that when used after ASCT to prevent progression, brentuximab has the potential to be cost-effective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma. Dr Roth also noted that the results of the forthcoming phase 3 AETHERA trial would provide definitive evidence of the efficacy of brentuximab in this setting and, consequently, more precise evidence of the cost-effectiveness of this strategy. n

FEBRUARY 2015

I

www.AHDBonline.com

25


Payers’ Perspective

The Value of Pharmaceuticals and Adherence to Therapy in the Management of Hematologic Cancers Atheer A. Kaddis, PharmD Senior Vice President, Sales and Industry Relations Diplomat Specialty Pharmacy

C

onsistent with past meetings, the 2014 annual meeting of the American Society of Hematology (ASH) included very insightful and educational presentations on the value of pharmaceuticals, cost implications, and the importance of adherence to therapy that can help guide policy decisions for pharmacy and medical directors. This is especially impor­ tant considering the impact of the new treatments for hematologic cancers that have been introduced to the market over the past 12 months. Novel therapies for hematologic cancers are a major area of focus for payers. In 2014, the US Food and Drug Administration approved 4 new molecular entities for the treatment of hematologic cancers, impacting the medical and pharmacy budgets for payers. These 4 drugs include belinostat for relapsed or refractory peripheral T-cell lymphoma; blinatumomab for Philadelphia chromosome–negative relapsed or refractory precursor acute lymphoblastic leukemia; ibrutinib for several indications, including mantle-cell lymphoma and chronic lymphocytic leukemia (CLL); and idel­ alisib for several indications, including CLL, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma.1 Of these novel therapies, 2 are administered intravenously (belinostat and blinatumomab) and 2 are administered orally (ibrutinib and idelalisib), with direct implications for payers. Cancer care, including hematologic cancers, is a major area of focus in the current drug development arena, and is one of the leading contributors to the overall growth in spending for payers. This highlights the importance of evaluating the information presented at the recent ASH meeting as well as other developments in hematologic cancers. Reimbursement, Value, and Cost-Effectiveness

At a special symposium on quality care and discussed in this special issue (see article on page 1), Andreas Laupacis, MD, MSc, suggested that drug reimbursement decisions should incorporate value and cost-effectiveness. Dr Laupacis is actively involved in drug reimbursement committee decisions in Canada. Focusing on cost-effectiveness, Canadian drug reimbursement committees decide whether to pay for particular drugs, decline to pay because of a lack

26

of cost-effectiveness, or to pay for a restricted indication using public funds. Even though we do not have nationalized healthcare in the United States, Dr Laupacis suggests that private payers in the United States can still dictate their reimbursement policies based on reliable cost-effective analyses. His suggestions for payers include: • Focusing on getting high-quality information about the effectiveness of drugs to accurately drive cost-effectiveness ratios • Negotiating drug prices aggressively based on cost-effectiveness • Using tools such as value-based discounts • Involving patients in the care dialogue. Given these suggestions, and considering that more than $1 billion in additional funding was appropriated to comparative effectiveness research in the Affordable Care Act,2 we are likely to see more focus on value in healthcare, cost-effectiveness, and comparative effectiveness research in the near future. Economic Burden and Adherence to Therapy

Several presentations at ASH 2014 focused on the cost of care for hematologic cancers and the impact of these costs on patient medication adherence. Decreased adherence to therapy can have a detrimental effect on patient morbidity and mortality, especially for cancer diagnoses. Joanne S. Buzaglo, PhD, studied the economic burden on patients diagnosed with chronic myeloid leukemia (CML). The availability of new breakthrough therapies for the treatment of CML has transformed this condition from an often fatal disease to a chronic disease that requires ongoing treatment. The Cancer Support Community, in partnership with the Leukemia & Lymphoma Society, registered 484 patients living with CML to the Cancer Experience Registry. Overall, 81% of patients responded to a survey about the financial burden of CML and cancer-related psychological distress. Among these patients with CML, 19% reported missing a dose of their oral CML medication at least once monthly, 14% reported postponing prescriptions, and 10% said they skipped dosages of their prescribed CML medication. By these measures, 31% of the patients with CML were

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

Cancer care, including hematologic cancers, is a major area of focus in the current drug development arena, and is one of the leading contributors to the overall growth in spending for payers. defined as having poor medication adherence (see article on page 1). In addition, nearly 50% of the patients reported out-of-pocket (OOP) costs of ≥$100 related to CML, 27% spent ≥$250 monthly, 15% spent ≥$500, and 5% of patients spent ≥$1000. To be able to pay for their CML medication, 38% of patients said that they had to use copay assistance, 35% had to cut grocery expenses, 33% depleted their savings, 30% used pharmaceutical assistance programs, 18% sold personal property, 17% asked their healthcare provider for a less expensive treatment, 13% had liquidated their assets, 6% went into bankruptcy, and 4% of patients foreclosed on their homes. Other studies have also shown that cancer treatments can lead to rates of bankruptcy that are more than double the rate among people without cancer.3 These statistics are very concerning, and Dr Buzaglo concluded that “implications for future research and practice so that patients fully benefit from CML therapy include the development and evaluation of interventions that enhance patient–clinician communications, psychosocial distress screening and referral, and financial counseling and assistance.” S. Yousuf Zafar, MD, MHS, who had coined the term “financial toxicity,” has been pointing at different occasions how

the cost of paying for cancer impacts the efficacy of treatment. At ASH 2014, Dr Zafar said that a high patient cost burden is associated with a 70% higher likelihood of nonadherence to treatment. He stated that financial toxicity is as important as drug toxicity when it comes to the management of patients with cancer (see article on page 10). Some of the statistics supporting the concept of “financial toxicity” in regard to the treatment of cancer include that 50% of Medicare beneficiaries pay 10% of the cost of OOP therapy, 28% of Medicare beneficiaries spend >20% of the cost of OOP treatment, and nearly 50% of patients take money from their savings and cut back on basics to pay for care. In prospective, longitudinal studies of patients with cancer, Dr Zafar and colleagues found that 52% of patients want to discuss treatment-related OOP costs with their oncologist, and 51% want their oncologist to take cost into account when making treatment decisions, but only 19% of patients have actually discussed this with their oncologist, leaving a gap in treatment that can result in patient nonadherence. By contrast, among patients who did discuss costs with their oncologist, 57% reported having lower OOP costs, primarily a result of being referred to a financial assistance organization. This is very interesting, considering that financial assistance programs and organizations contribute millions of dollars in aid annually to patients who cannot afford their medications. Specialty pharmacies are particularly adept at helping patients obtain this financial support when needed. In addition to presenting data on the value of pharmaceuticals and adherence to therapy in the treatment of hematologic cancers, many studies were presented at ASH 2014 related to new advances in the treatment of hematologic cancers, advances in treatment regimens, and updates on the cost of treatment. ASH should be commended for another insightful and educational meeting. n References

1. CenterWatch. FDA approved drugs. www.center watch.com/drug-information/fda-approved-drugs/ year/2014. Accessed February 6, 2015. 2. Donnelly J. Health policy briefs: Comparative effectiveness research. Health Affairs. Updated October 8, 2010. www.healthaffairs.org/healthpolicybriefs/brief. php?brief_id=27. Accessed February 6, 2015. 3. Ramsey S, Blough R, Kirchoff A, et al. Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Aff (Millwood). 2013;32:1143-1152.

VOL. 8

I

SPECIAL ISSUE


TH

BestANPractices RSARY VE NI

ANNUAL CONFERENCE

Monday, May 4, 2015 Co-chairs:

John Fox, MD, MHA Senior Medical Director Associate Vice President Medical Affairs Priority Health Alex Jung Principal, Global Strategic Advisory Services Ernst & Young LLP

Tuesday, May 5, 2015 Co-chairs:

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

2 0 15

Barbara L. McAneny, MD Chair, Board of Trustees American Medical Association

REGISTER TODAY

MAY 3-6, 2015

Omni Shoreham Hotel Washington, DC HELD IN PARTNERSHIP WITH

Wednesday, May 6, 2015 Co-chairs:

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc.

F. Randy Vogenberg, PhD, RPh Principal Institute for Integrated Healthcare (IIH)

AVBCC2015KsizeAd012215

VOL. 8

I

AVBCConline.org/conference

SPECIAL ISSUE

FEBRUARY 2015

I

www.AHDBonline.com

27


Best Practices

For reliability and quality,

our roots go deep

At Amgen, we pour commitment, passion, and a drive for perfection into every biologic medicine we make. From innovative biotechnology to extensive experience in biologic manufacturing, see how Amgen strives to deliver on its commitment to your patients.

Take a deeper look at our reliability and quality

Our Roots Go Deep

visit biotechnologybyamgen.com Download the LAYAR app on your smartphone and scan this page.

28

Š2014 Amgen Inc. All rights reserved. 80012-R2-V1

AMERICAN HEALTH & DRUG BENEFITS

I

FEBRUARY 2015

VOL. 8

I

SPECIAL ISSUE

February 2015 Vol 8, Special Issue: Payers' Perspectives in Oncology  
Read more
Read more
Similar to
Popular now
Just for you