AHDB August 2014, Payers' Perspectives in Oncology

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ august 2014 Vol 7 I SPECIAL ISSUE

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Payers’ Perspectives in Oncology Including ASCO 2014 Highlights

Federal Spending on Cancer Research and Access to Care Woefully Inadequate

By Wayne Kuznar

By Wayne Kuznar

O

of the Breast Medicine Service at Memorial Sloan Kettering Cancer Center, New York City, in his presidential address at ASCO 2014.

He called for the achievement of “social justice in cancer care” through Continued on page 7

Ibrutinib Outperforms Ofatumumab in Patients with Relapsed/Refractory CLL

By Caroline Helwick

F

or the second-line treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or with small lymphocytic leuke-

Ezekiel J. Emanuel, MD, PhD

ncologists should become value-­based providers by eliminating unnecessary tests, prescribing cheaper alternatives when therapeutic equivalents exist, and keep calling for payment reform, said Ezekiel J. Emanuel, MD, PhD, Chair of the Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia, at ASCO 2014.

These measures will add value as a bridge to payment reform, which is the ultimate change that will bring value to cancer care, Dr Emanuel emphasized.

Photo by ©ASCO/Phil McCarten 2014

T

he impact of federal budget cuts on cancer research is threatening progress in cancer therapy and access to increasing demand for cancer services, said ASCO president Clifford Hudis, MD, Chief

Payment Reform Key to Value-Based Cancer Care

mia (SLL), ibrutinib improved progression-free survival (PFS), overall survival (OS), and overall response rate ORR compared with ofatumumab, results of

Continued on page 28

Social and Economic Costs Dr Emanuel started his discussion on value in oncology by stating that the $3 trillion that the United States

Continued on page 21

2014 Oncology Pipeline Looks Impressive

By Caroline Helwick and Wayne Kuznar

T

he cancer drug pipeline continues to boast many new therapies, reinforcing the recent trends of new and improved monoclonal antibodies and other classes of targeted therapies for different types of tumors. At ASCO 2014, researchers presented findings for many of these drugs, with immunotherapies leading the way in current drug development in oncology.

Lung Cancer

Anti–PD-1 Antibodies The future looks particularly bright for the anti–programmed death (PD)1 monoclonal antibodies, which are being evaluated in several solid tumors. Strong results were reported for both nivolumab and pembroliz­ umab (MK-3475; formerly lambroliz­ umab) in phase 1 and 2 studies of patients with non–small-cell lung Continued on page 14

in th is is s u e VALUE IN ONCOLOGY . . . . . . . .

ASCO beginning to address value What makes a treatment clinically meaningful?

21

14

2014 FDA APPROVALS. . . . . . . .

Cancer drugs approved this year

26 29

19

MYELOMA . . . . . . . . . . . . . . . . . .

Novel drug classes in multiple myeloma

Health Economics . . . . . . . . . . .

Patients with cancer not asking for costly treatments ASCO workgroup proposes consolidated payments EMERGING THERAPIES. . . . . . .

Enthusiasm high for anti–PD-1 agents in cancer PROSTATE CANCER. . . . . . . . . .

Upfront docetaxel markedly improves survival LUNG CANCER. . . . . . . . . . . . . .

Necitumumab extends survival

© 2014 Engage Healthcare Communications, LLC

“We need to do more at a faster pace to fundamentally change the payment system,” advised Dr Emanuel. ”That and that alone—making it neutral for us whether we give more, test more, or care more for the patient—will be the important item that will change how we practice, and make sure that it is value-based.”

7

20

PAYERS’ PERSPECTIVE. . . . . . . 30 Stakeholder integration needed to fix flawed payment system

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 Real-World 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 Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino 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

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6

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EMERGING THERAPIES 2014 oncology pipeline looks impressive More…..

PROSTATE CANCER Upfront docetaxel improves survival, reduces cost LUNG CANCER Necitumumab extends survival in squamous lung cancer More…..

VALUE IN ONCOLOGY Payment reform key to value-based care ASCO beginning to address value More…..

2014 FDA APPROVALS Ofatumumab approved for CLL More…..

BREAST CANCER Dual HER2 blockade no better than monotherapy More…..

LEUKEMIA Ibrutinib outperforms ofatumumab More…..

PAYERS’ PERSPECTIVE Stakeholder integration needed to fix a flawed reimbursement system

EDITORIAL BOARD Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia 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 Past Chair, NCCN Board of Directors 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

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

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC 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 Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA 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 Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

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

Jeffrey A. Bourret, PharmD, MS, RPh, 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

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine 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 Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

American health & drug benefits

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

Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services 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 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 University of Missouri, Kansas City 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

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

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

PHARMACOECONOMICs

SPECIALTY PHARMACY

Personalized medicine

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

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

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Health Economics

Federal Spending on Cancer Research and Access to Care... loosening the purse strings for research and assuring better access to high-quality care. The meeting was attended by approximately 33,000 oncologists, representing more than 100 countries.

Dr Hudis implored legislators to “understand the price our patients pay for inaction and gridlock on this issue.” In keeping with the “Science and Society” theme of the meeting, he said that the 40% projected increase in cancer cases and survivors suggests the need for expanding clinical resources “if we are to achieve our goal of assuring that every patient has access to high-quality cancer care.”

He added, “If we intend to achieve social justice in cancer care, we simply need more public and private resources.”

The current federal budget allocates 0.1% to spending on cancer research.

“We need societal awareness of the fact that an investment of 0.1% of our federal budget cannot begin to address the problem we face,” said Dr Hudis. “Research on a disease that affects one third to one half of all

Americans garners less than $1 of every $1000 spent federally.”

“We need to control payment reform and our focus on the quality of care we deliver, or others will quickly step in and define all of this for us.”

—Clifford Hudis, MD The impact of these cuts is felt directly or indirectly every day by oncologists and by patients. “We must raise awareness of the remarkable return all of society receives on its investment in federal research,” he said.

In addition to sustaining innovation through a robust national cancer research program, specific investments are needed in the development and testing of new healthcare delivery and

payment models designed to preserve access to high-quality care in local communities, where most cancer care is delivered.

Rewarding Value “Our goal with these models is to reward value as opposed to volume,” said Dr Hudis. “We need to control payment reform and our focus on the quality of care we deliver, or others will quickly step in and define all of this for us. We must end persistent financial threats to clinical practice, especially in vulnerable communities, that are caused by sequester-related cuts and the flawed sustainable growth rate formula that drives physician payment.”

The goal is to help oncologists and patients more fully understand the elements of each treatment. “By understanding the full range of choices­ —their expected benefit, toxicities, as well as cost—patients can make choices that best suit their personal circumstances,” he said.

To achieve social justice in cancer care, “value in cancer care” must be

Continued from page 1

defined to optimally use society’s previous resources, Dr Hudis pointed out. When breakthroughs in care are available, as in the United States, the rising cost of care is having predictable negative consequences—patients bear more of this cost, leading to declines in compliance.

“Ask yourselves where it could ever make sense to have a copay for an oral cancer treatment that saves and extends life and avoids more toxic and expensive alternatives,” he said.

“A financial disincentive for compliance is irrational, no matter how you look at it.”

One key issue is the lack of a rational relationship between pricing and value. The challenge lies in preserving innovation while improving access and affordability.

The potential for industry and providers to collaborate to identify a productive way forward is great. “One that preserves capital flow and reward for innovators, but that provides even more access to care,” said Dr Hudis.

“We must be creative and innovative, and we can if we work together.” n

Patients with Cancer Are Not Asking for Costly, Excessive Treatments

By Wayne Kuznar

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as oncologists and the public, believe that healthcare costs are, to some extent, propelled by patients seeking unnecessary treatments, she said.

Study Details For the study, oncologists and NPs at 2 sites affiliated with an academic cancer center were questioned soon after patient visits to measure how often patients demanded potentially unnecessary treatments, whether the demands were acceptable to providers, whether physicians followed through on the requests, and why the providers chose to agree to certain tests.

Of the 2050 encounters assessed, 73.1% of patients were white, 42% had stage IV or refractory disease, and 66.3% were receiving active therapy. A total of 26 clinicians were surveyed.

In 177 (8.6%) encounters, the patients requested some form of testing.

Clinicians were recommended to rank the appropriateness of patient requests on a 10-point Likert scale (1 = not at all appropriate, 10 = extremely appropriate). Clinicians viewed requests by patients as inappropriate in only 24 (13.6%) encounters.

More than 80% of the requests were

Photo Courtesy © ASCO/Todd Buchanan 2013

C

ontrary to belief, there appears to be little demand on the part of patients with cancer for unsuitable, high-cost, low-value tests or therapies. Furthermore, oncologists and nurse practitioners (NPs) are not frequently ordering such services, found Keerthi Gogineni, MD, MSHP, an oncologist at the Abramson Cancer Center, University of Pennsylvania, Philadelphia.

Data from a large survey of oncologists and NPs revealed that “the frequency of requested testing was unusual in itself. In only about 9% of 3800 encounters did a patient ask for something,” she said. “The likelihood of acting on inappropriate requests was even lower. When we asked the providers to rank the appropriateness of that request, it was pretty infrequent that even they thought it was an inappropriate request, and even less likely that they would act on an inappropriate request.”

Dr Gogineni and colleagues assessed whether and how often patients are seeking expensive or low-value therapies and treatments from their providers. Past studies have indicated that many patients with cancer, as well

“The frequency of requested testing was unusual in itself. In only about 9% of 3800 encounters did a patient ask for something.”

—Keerthi Gogineni, MD, MSHP categorized as appropriate. These included requests for imaging, blood work, and treatments for pain or nausea. Providers denied patients’ requests in 32 (18.1%) cases; for 27 of

these instances, physicians reported that they declined the test or therapy, because they viewed it as unnecessary or saw no clinical advantage to doing it. In 4 of the 2050 (<1%) encounters, the provider requested a test or therapy that was considered unsuitable.

Patients with early-stage cancer were more likely to make an inappropriate request, said Dr Gogineni. Patients with late-stage disease who were undergoing surveillance were nearly twice as likely to make an inappropriate request compared with patients receiving treatment.

Of note, patients who were being treated with a goal to cure were more often seeking unnecessary treatments than patients who received palliative care.

To limit low-value care, the researchers suggest educating patients on evidence-based surveillance, because patients with early-stage cancer who are under observation are often more likely to seek inadvisable treatments or therapies. In this survey, patients undergoing observation were 9 times more likely to make inappropriate requests than patients with advanced-­ stage cancer. n

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Health Economics

ASCO Workgroup Proposes Consolidated Payments

By Caroline Helwick

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alling the current fee-for-­ service (FFS) reimbursement model “medicine’s dark secret”­ —one that has jeopardized value-based cancer care—a member of the ASCO Workgroup on Payment Reform presented a novel proposal for consolidated cancer care at the Community Oncology Town Hall during ASCO 2014.

“Working towards a better payment system for oncology care, instead of just complaining about the one that we have, has been liberating and exhilarating,” said Jeffery Ward, MD, the immediate past chair of ASCO’s Clinical Practice Committee and an oncologist at the Swedish Cancer Institute in Seattle, WA. The diverse group had as its premise the need to hear voices from across the clinical oncology spectrum, the goal being “a uniform re-formation of oncology care that can be applied to all cancer care settings.”

Need to Depart from Fee-forService Approach The concept moves the reimbursement system away from FFS. “Fee-forservice medicine is a barrier to personalized care. It’s an antiquated reimbursement system that only pays for care when it involves physician ‘touches’ and the infusion of drugs,” Dr Ward said.

“It only pays for some services, failing to reimburse at all for other essential services provided in oncology offices and clinics. It fails to reward decision-making that brings greater

quality, efficacy, or value to the care equation, and conversely it incentivizes inefficiency and the overuse of the most expensive services to maximize reimbursed service,” he continued.

At its heart, he said, FFS medicine takes the focus of the patient and centers care on the physician, failing to achieve the personalized care that is the general aim in oncology now.

“What we developed has at its core monthly bundled payments that are adjusted for (ie, rewarded for) quality, pathway utilization, resource utilization and clinical trial participation.”

—Jeffery Ward, MD “It’s time to open the current model to scrutiny, recognize how incongruent it is to the future on cancer care and replace it,” he maintained.

The Workgroup’s Proposal The group explored numerous concepts for payment reform, and ultimately crafted and released (in May 2014) a consolidated payment,

patient-centered model.

“We asked our committee members, if you could throw out all you know and start over—and not just tweak a broken system—how would you like to be paid for what you do?” he said.

“What we developed has at its core monthly bundled payments that are adjusted for (ie, rewarded for) quality, pathway utilization, resource utilization and clinical trial participation.”

The model does not ignore the importance of drug purchasing, but contains a vehicle for integrating the current 6% margin into the reimbursement mix, “which will remove the stigma of drug margins from our profession.”

Monthly Payment Tiers At the model’s core are monthly payments that vary according to the treatment activity of the patient. These payments are developed by taking the gross revenue for typical clinical services and combining them into a lump sum. “It’s forgetting where the revenue came from, and rearranging it into these payments,” Dr Ward explained.

“We believe ASP +6% could be folded into this bucket and added to ‘treatment month’ payments once an alternative to buy-and-bill is developed and sufficiently tested,” he said.

The new payments would not track directly with existing Current Procedural Terminology (CPT) codes; they are intended to cover services that are not compensated today. New aggregate revenue would be no less than the aggregate amount of current reve-

nue, for typical oncology practices.

The relative sizes of payments would reflect the relative amount of time and cost incurred for the activities in the payment period.

These distinct periods include: • New patient payments • Treatment month payments • Active monitoring month payments • Transition-of-treatment payments.

These monthly payments would be phased in over time, and some components of FFS would be continued, such as laboratory tests, imaging, bone marrow biopsy, and transplant.

Expected Impact of This Proposal The adoption of this model should give practices flexibility to build innovative processes of care that will allow them to assume accountability for quality and value of the care they give. Ultimately, the model would also remove the current financial penalty for using lower-cost drugs or for treating with oral drugs. It would also simplify billing by replacing 63 CPT codes with 9 codes.

The end result should be cost-savings through reductions in the use of the hospital and emergency department, in testing and surveillance, and in the administration of oncolytics and supportive drugs. Oncologists should be rewarded for participating in these savings.

In closing, Dr Ward indicated, “ASCO is not wedded to this plan….

We plan to refine it and may offer other alternative payment plans.” n

Even When Adjusting for Improved Survival, Newer Cancer Drugs More Expensive Than Older Ones

By Wayne Kuznar

E

ven after adjusting for improved outcomes, newer anticancer drugs are more expensive than older agents, said Rena Conti, PhD, Assistant Professor of Health Policy and Economics, University of Chicago, at ASCO 2014.

This conclusion came from an examination of the prices of 56 anticancer drugs approved between 1995 and 2013. The analysis measured the launch prices of the drugs using Medicare prices for oral and intravenous drugs, and adjusted the price (in 2013 dollars) based on survival data obtained from phase 3 clinical trials.

For drugs approved on the basis of single-arm trials, modeling studies

“Drug prices, after adjusting for survival, appear to be going up approximately 5% to 7% per year over time….The only other consumer goods that we see that have this type of price trajectory appear to be luxury products.”

—Rena Conti, PhD were used to estimate the survival benefit. The prices of the drugs represent the cost of a course of therapy

based on the median duration of treatment in the clinical trials submitted to gain approval.

“The reason we did this study was to examine exactly how and if the launch prices of these were increasing at a rate over and above inflation, and also over and above their benefit in terms of survival,” said Dr Conti.

For each drug, the annual price of additional survival was calculated as the price per course of therapy divided by the survival benefit in years.

The average drug price in the sample was $78,600, and the average survival benefit was 0.45 years. Therefore, the average annual price of survival benefit was $185,000.

“We found that drug prices, after adjusting for survival, appear to be going up approximately 5% to 7% per Continued on page 9

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Should Oncologists Consider Interests of Society at Large When Treating the Individual Patient?

By Wayne Kuznar

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ith finite healthcare resources, do physicians have a duty to serve society broadly by being responsible stewards of those shared resources, or is their obligation to the patients before them incompatible with any rationing? The balance of duties to patients and to society was the subject of a debate at ASCO 2014.

Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital, Boston, set the stage by noting that therapy for cancer amounts to approximately 5% to 11% of the total healthcare budget and is the most rapidly growing segment of healthcare.

The costs of targeted therapy range from $500 to >$30,000 monthly or per cycle. These ballooning costs present an ethical dilemma. The professional norm that says that the first and foremost responsibility of oncologists is to do what is best for their patients is eroding in the face of the ever-increasing growth of healthcare costs, said Dr Moy. “Oncology providers are faced with balancing their duties to individual patients and society.”

Reshma Jagsi, MD, DPhil, Department of Radiation Oncology, University of Michigan, Ann Arbor, argued that physicians’ moral duty to their patients is paramount in any clinical encounter, but in their privileged professional role, they “have an obligation to serve society more broadly.”

Healthcare spending can crowd out other spending that is essential to promote health, she said. The question is not whether to ration resources, but how to ration them.

“Physicians owe it to society to help ensure that resources are allocated in a way that is congruent with broader

“Oncology providers are faced with balancing their duties to individual patients and society.”

—Beverly Moy, MD, MPH moral intuitions, as well as to reduce waste to maximize the value of our interventions,” said Dr Jagsi. “Physician stewardship of society’s scarce re­ sources is best accomplished at the so-

evidence base for the assessment of value, including studies to identify situations of overdiagnosis and overtreatment in healthcare,” she added.

Recent studies on the financial burden of cancer care highlight how prescribing costly care can hurt the individual patient. When strong evidence suggests that clinical benefit is not compromised by a more efficient approach to treatment, physicians have a duty to consider cost, Dr Jagsi advised.

The “Choosing Wisely” campaign has engaged professional organizations in identifying practices that may represent the inappropriate use of finite societal resources. To this end, ASCO has issued “Top 5” lists of opportunities to improve the quality and value of cancer care, she noted.

The professional ethic of medicine is patient-centered, countered Daniel P. Sulmasy, MD, PhD, Associate Director of the MacLean Center for Clinical Medical Ethics, University of Chicago, in which the goal of the clinical encounter is to promote the good of the individual

“Physicians owe it to society to help ensure that resources are allocated in a way that is congruent with broader moral intuitions, as well as to reduce waste to maximize the value of our interventions.”

—Reshma Jagsi, MD, DPhil

cietal level rather than the individual level.” Physicians must call attention to general areas of waste and develop solutions to improve efficiency, as well as “lead the development of a robust

patient. Patients must trust that physicians will do the best for them in light of the available resources. “Questions of justice might arise regarding the unequal distribution of medical resources

across the globe, but such questions are not answered in the immediacy of the bedside encounter, with the individual patient in a particular society,” he said.

“Such questions are not answered in the immediacy of the bedside encounter, with the individual patient in a particular society.”

—Daniel P. Sulmasy, MD, PhD

Economists suggest that medicine is a public good, Dr Sulmasy said, given the necessity of health for access to many other goods. “The existential situation of sickness demands that patients be able to trust that their doctors are applying this public good for their individual benefit, not the physician’s personal benefit or the good of society at large,” said Dr Sulmasy.

Bedside rationing of care undermines trust, “disrupts the balance between profession, market, and state, and is likely to be idiosyncratic and unjust to individual patients,” he suggested. n

Even When Adjusting for Improved Survival... Continued from page 8 year over time. These are inflation-­ adjusted prices,” she said. “The only other consumer goods that we see that have this type of price trajectory appear to be luxury products, such as art and jewelry, but also college tuition.”

The price of an additional month of survival increased by $600 annually, Dr Conti noted. The model predicted that the launch price of a drug that extended median survival by 5 months would be $37,000 in 1995, but the same drug launched in 2010 would have been $84,000. A sensitivity analysis found no VOL. 7

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Key Points ➤ Drug prices, after adjusting for survival, are going up approximately 5% to 7% annually over time ➤ The price of an additional month of survival increased by $600 annually change in the results when controlling for side effects or quality of life.

Manufacturers are pricing their anticancer drugs as high as the market is

➤ Based on this analysis, a drug launched in 1995 that extended median survival by 5 months would cost $37,000; the same drug launched in 2010 would cost $84,000 willing to bear, with little pushback from insurers, hospitals, or physicians, Dr Conti said. “These are list prices,” she pointed out. “It reflects what insur-

ers will pay, and also what patients will pay for these therapies. This is not what physicians, hospitals, and pharmacies pay to acquire these drugs, and we believe that there are quite substantial discounts in the marketplace for these therapies that are then baked into the list price over time.”

Expansion of the 340b drug pricing programs, which requires manufacturers to give discounts to eligible buyers, may have contributed to price increases for noneligible buyers, she added. n

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Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred

in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension.

Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery.

Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1 MAJOR OUTCOME MEASURE

OS PROBABILITY

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Major efficacy outcome measure was overall survival. Supportive efficacy outcome measure was progression-free survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

238 117

5

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

4

154 66

92 34

49 20

17 7

7 4

3 2

37%

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for antiramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting antiramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant.

• Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89001 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

CYRAMZATM (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information.

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

Infusion Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single-agent in clinical trials experienced gastrointestinal perforation.

Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed.

Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

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

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates.

Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels.

Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single-agent.

Geriatric Use Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility.

Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes.

Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion.

Dose Modifications Infusion Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management.

• Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy.

Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 5 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours.

• Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome.

Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed.

Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness.

• Of increased risk of an arterial thromboembolic event.

• To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.

• To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain.

• That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider.

• Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment.

Additional information can be found at www.CYRAMZAhcp.com.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading.

DRUG INTERACTIONS No formal drug interaction studies have been conducted.

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Health Economics

Financial Distress Experienced by 40% of Patients with Cancer

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By Caroline Helwick early 40% of patients with cancer experienced a higher financial burden than they expected, but the duration of their chemotherapy did not correlate with financial distress, according to a study of 300 patients by Duke University researchers.

There was no evidence of a correlation between subjective financial distress and the amount of time that a patient received treatment (P = .893), according to Lena Van Nimwegen, a third-year medical student at Duke.

The senior investigator was S. Yousuf Zafar, MD, MHS, an oncologist at Duke.

Ms Van Nimwegen noted that although objective financial burden is known to correlate with treatment course, less is known about whether patients’ subjective report of financial distress follows similar trends during the course of treatment.

“Finding a trend in patients’ finan-

cial distress could help providers implement timely interventions to provide aid and relieve distress,” she suggested.

Financial distress related to cancer care often has far-ranging consequences, including nonadherence to treatment; the use of savings to pay for care; bankruptcy; and decreased spending on food, clothing, and leisure activities, she noted.

Cross-Sectional Study of 300 Adults In this cross-sectional study of 300 insured adults with solid tumors receiving treatment for at least 1 month, most of the patients had incurable disease, at a referral center and 3 rural oncology clinics. Using a validated measure of financial distress, the researchers also asked about out-ofpocket expenses and extracted medical records.

On study enrollment, all patients (median age, 60 years) were insured, although 40% were underinsured; 97% had prescription drug coverage.

The patients’ annual median household income was $60,000.

The patients’ time on treatment ranged from 1 month to >10 years. All participants were receiving chemotherapy or hormonal therapy at the time of the survey; 72% were receiving intravenous chemotherapy, 6% were receiving oral drugs, and 22% were receiving both.

Most Patients Report “Moderate” Financial Distress The patients’ median monthly outof-pocket cost was $591 for a median of 4.6 months. Their median financial distress score was 7.4 (on a scale of 1 to 10), corresponding to moderate distress, Ms Van Nimwegen reported.

Almost 40% of the patients reported experiencing a higher financial burden than they expected, and 16% reported “high or overwhelming” financial distress.

The main predictor of high financial distress was early-stage disease (ie, potentially curable cancer), which carried an odds ratio (OR) of 2.56 (P = .02).

Factors associated with not reporting financial distress included: • Increasing age: OR, 0.77 (P = .01) • Employed versus unemployed: OR, 0.36 (P = .03) • Married versus unmarried: OR, 0.23 (P = .01) • Prescription drug coverage: OR, 0.11 (P = .03).

The group’s next steps are to further examine the various risk factors for financial distress during treatment and to find a way to monitor this “to ensure timely intervention,” she noted. n

Generic Docetaxel Increases Risk of Neutropenia, Costs

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he use of generic docetaxel instead of branded docetaxel was associated with a significantly higher rate of neutropenia and increased healthcare cost during the 6 months after drug initiation, according to a US Oncology study presented at ASCO 2014.

Patients with breast cancer who received generic docetaxel were approximately 40% more likely to have a medical claim for neutropenia than patients receiving branded docetaxel.

This cost the healthcare system an additional $9000 per patient, reported Stephen E. Jones, MD, Medical Director, US Oncology Research, Houston, TX, and colleagues.

Dr Jones and colleagues compared the disease burden and resource utilization of 1955 patients with breast cancer who received the generic or branded docetaxel between 2011 and 2012.

Emerging differences between generic and branded formulations during the 6 months after the initiation of docetaxel were examined with a hierarchical mixed-effects model by the adjustment of patient characteristics during the 6 months before starting the drug.

The final analysis included 360 patients whose baseline characteristics were similar, including the use of anthracyclines, cyclophosphamide, and

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growth factors, as well as comorbidities and previous neutropenia.

More Problems with Generics at 6-Month Follow-Up During the 6-month follow-up, the generic-receiving cohort showed a higher rate of claims for neutropenia (67.3% vs 48.9%; P <.01) and malaise and fatigue (22.4% vs 13.7%; P <.05) versus the branded-receiving cohort.

The branded cohort had higher rates of nausea and vomiting (43.5% vs 29.6%; P = .02).

The baseline variables that were adjusted for the estimation of neutropenia included age, baseline neutropenia, inpatient admission, total healthcare costs, adjuvant therapy, comorbidities, the use of granulocyte colony-stimulating factor (G-CSF) and fosaprepitant, and the number of treatment cycles. Fosaprepitant is indicated for the prevention of delayed vomiting and can cause neutropenia (<1% of patients).

After these adjustments, the rate of neutropenia remained higher with generic than with branded docetaxel (73.9% vs 52.8%; P <.01), even after accounting for history of neutropenia and the baseline use of G-CSF or fosaprepitant.

Further investigation showed that the difference in neutropenia between generic and branded docetaxel was

observed only in patients without a history of neutropenia (58.4% vs 35.4%; P = .003) and was not present in patients with a diagnosis for neutropenia at baseline. In the latter group, the risk was approximately 98%, regardless of the drug used.

It has been reported that 90% of the generic docetaxel formulations contain an insufficient amount of active drug or high levels of impurities, which can affect efficacy and safety.

Generic Costs Were Higher Excluding the cost of branded docetaxel, the mean outpatient cost after initiating treatment was significantly higher for patients receiving generic docetaxel in the unadjusted model and the model adjusted for age, comorbidities, inpatient admissions, total costs, and adjuvant therapy at baseline.

In the unadjusted model, the mean cost was $50,243 for the branded cohort and $59,177 (P = .009) for the generic cohort, and remained significantly higher after adjustments for

baseline healthcare costs, inpatient admissions, and other baseline patient characteristics ($46,698 vs $54,282; P = .03). The mean total healthcare costs in the unadjusted model after initiating treatment were $74,832 with branded docetaxel and $83,982 with generic docetaxel (P = .05) versus $70,736 and $76,454, respectively, in the adjusted model (P = .22).

“The cost differential seems more than offsetting the potential difference in acquisition costs relative to the branded docetaxel,” the authors suggested in a poster.

William M. Sikov, MD, Clinical Associate Professor of Medicine, Brown University, Portland, ME, commented that he found the poster’s results interesting and surprising. He mentioned that, in his center, he is not aware of whether his patients receive branded or generic drugs. Dr Sikov said that he has often questioned whether generic agents may, indeed, be equivalent, and has had some concerns.

“At times, I have tried to influence the pharmacy to buy a brand name when the cost differential is minimal but have been told that I am not allowed [to request that],” Dr Sikov said. “I wonder if the pharmacokinetics are really the same? We are given assurances by the FDA, but we don’t know how extensively they are really tested.”—CH n

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2014 Oncology Pipeline Looks Impressive cancer (NSCLC; see article, page 15), melanoma, and renal-cell carcinoma.

The durability of responses to these agents is perhaps more impressive than the response rates themselves.

The majority of responders continue to demonstrate responses at the time of the study analyses.

The monoclonal antibody ramu­ cirumab, which is already approved for the treatment of advanced gastric cancer, is being investigated in NSCLC. Ramucirumab improved overall survival (OS) when added to docetaxel versus chemotherapy alone in a phase 3 trial of 1253 patients with stage IV NSCLC, although the median OS was prolonged by only 1.4 months (see article, page 20).

Other Agents CO-1686 is a selective, oral tyrosine kinase inhibitor (TKI) that specifically targets EGFR mutations in patients with NSCLC. The efficacy of other EGFR inhibitors has been limited by acquired resistance, most frequently a second T790M mutation.

The proposed solution to this challenge is to create drugs that can inhibit these newly mutated targets. At ASCO 2014, investigators reported early data on 3 drugs that successfully target T790M. In a phase 1/2 dose-finding trial of CO-1686, responses were achieved by 58% of 72 heavily pretreated patients with T790M mutations; in a phase 2 extension study of 40 patients, median progression-free survival (PFS) was not reached and was estimated to exceed 12 months. Activity against metastases in the central nervous system was observed. The most common toxicity was elevated glucose, which was well-managed with oral hypoglycemic and/or dose reduction.

In a phase 1 trial of AZD9291 in 199 heavily pretreated patients with EGFR mutation, the objective response rate (ORR) was 51%, rising to 64% among the 89 patients with a T790M mutation. Among T790M-negative patients, the response rate was 23%.

Nearly all patients were still responding at the data cutoff, with the longest response lasting more than 8 months.

AZD9291 is also associated with less skin toxicity than other EGFR inhibitors. Because greater efficacy is seen in patients with the T790M mutation, future studies of this drug will be limited to this subgroup.

Although they are still in clinical testing, AZD9291 and CO-1686 have already received breakthrough therapy designation from the FDA. Both drugs are in phase 3 clinical trials.

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The oral CDK 4/6 inhibitor abe­ maciclib (LY2835219), given twice daily, showed evidence of single-agent activity in heavily pretreated patients with NSCLC in a phase 1 study. The study enrolled 57 patients whose disease progressed or relapsed after a median of 4 previous treatments.

KRAS mutations were present in 29 of the patients. The disease control rate was 49%, including 2 partial responses and 26 patients with stable disease.

The disease control rate was higher for patients with KRAS mutation (55%) compared with the wild-type KRAS (38%).

The human anti-EGFR monoclonal antibody necitimumab improved median OS by approximately 2 months when added to standard chemotherapy in a phase 3 trial of patients with stage IV NSCLC of squamous histology (see article, page 20).

Myeloma In the international phase 3 PANORAMA 1 trial in multiple myeloma (MM), the addition of the oral pan-histone deacetylase (HDAC) inhibitor panobinostat to a bortezomib-containing regimen led to a statistically and clinically significant 4-month increase in median PFS, meeting the study’s primary end point. The study enrolled 768 patients who had received 1 to 3 previous lines of treatment but their disease was not refractory to bortezomib.

The ORRs were similar between the arms—60.7% with panobinostat and 54.6% with placebo (P = .087)— but the active combination was associated with almost a doubling in the rate of complete responses (CRs) and near CRs—27.6% versus 15.7%, respectively (P = .006). The median PFS was significantly improved, from 8.1 months with placebo to 12 months with panobinostat (P <.001), a 37% reduction in risk. After 28 months of follow-up, the median OS remained comparable at 33.6 months in the panobinostat arm and 30.4 months in the placebo arm (P = .87).

In May 2014, the FDA granted priority review status to panobinostat. Other panobinostat-containing combinations and additional HDAC inhibitors are currently in clinical trials.

31 patients with refractory disease who had received 6 previous treatments for MM showed strong antitumor activity and good tolerability.

The ORR was 58% but rose to 63% among patients receiving the highest dose (10 mg/kg given every other week), with 25% of patients achieving a very good partial response.

Antitumor activity for the second monoclonal antibody, daratumumab, as a single agent was shown in a phase 2 study of 50 heavily pretreated patients with relapsed/refractory MM. The ORRs for the single agent were 35% with the 16-mg/kg dose and 10% with the 8-mg/kg dose. The median PFS times were 23 weeks in the 16-mg/kg group and 15 weeks in the 8-mg/kg cohort, although the investigators noted that the PFS analysis is still immature.

Lymphoma Favorable findings from the STARLYTE phase 2 trial were reported for coltuximab ravtansine (SAR3419), a CD19-targeting antibody drug conjugate, in diffuse large B-cell lymphoma.

Study investigators reported achievement of proof of concept, with a 43.9% ORR in 55 patients with relapsed and/ or refractory disease who received the single agent, including responses among patients whose disease had not responded to previous therapy. There were few treatment-related grade 3/4 adverse events. This was a “Best of ASCO” abstract.

Leukemia Blinatumomab is an investigational bispecific T-cell–engaging antibody developed using bispecific T-cell engager technology designed to bring the T-cells into closer contact with the tumor cells, thereby promoting T-cell– mediated lysis of tumor cells.

A large phase 2 study presented at the meeting confirmed the antileukemic activity of single-agent blinatumomab in a difficult-to-treat population of 189 patients with relapsed and/or refractory acute lymphocytic leukemia. Treatment with blinatumomab resulted in a 43% CR/complete hematologic response rate during the first 2 cycles. The median relapse-free survival was 5.9 months, and the median OS was 6.1 months.

Anti-CD38 Monoclonal Antibodies ABT-199 (GDC-0199), an investigaImpressive data from small early-­ tional B-cell lymphoma 2–selective phase studies were presented for 2 inhibitor, in combination with rituxmonoclonal antibodies that target imab produced an ORR of 84% in an the CD38 protein—SAR650984 and open-label phase 1b study of 45 padaratumumab. In a phase 1b study, tients with relapsed and/or refractory the combination of SAR650984 and chronic lymphocytic leukemia (CLL). lenalidomide plus dexamethasone in In a separate phase 1 study of ABT-

American health & drug benefits

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199/GDC-0199 as monotherapy in patients with relapsed and/or refractory CLL, the ORR was 77% in 78 evaluable patients, with 23% of the patients achieving a CR. The ORRs for the 19 patients with 17p deletion and the 41 patients with fludarabine-refractory CLL were 79% and 76%, respectively. The median duration of response has not been reached. This same monotherapy trial enrolled 124 patients with various subtypes of non-Hodgkin lymphoma, where the ORR was 48% in the 59 patients who were evaluable for efficacy.

Thyroid Cancer For the treatment of metastatic differentiated radioiodine-refractory thyroid cancer, treatment with the multi-TKI lenvatinib reduced disease progression by 79% versus placebo in the phase 3 SELECT trial. The median PFS (the primary end point) was improved by 14.7 months. Patients receiving lenvatinib had a median PFS of 18.3 months, whereas in patients receiving placebo the PFS was only 3.6 months (P <.001). Toxicity could be challenging, and 6 treatment-related deaths were reported.

Disease progression at 2 years was reported in 41% of patients in the lenvatinib arm versus 86% of patients in the placebo arm.

The ORR was 65% with lenvatinib versus 2% with placebo (P <.001). The median OS has not been reached in either arm; because of the expected crossover on disease progression, this end point may be hard to interpret.

Receipt of previous anti–vascular endothelial growth factor therapy did not adversely affect outcomes.

Breast Cancer The poly (ADP-ribose) polymerase inhibitor veliparib demonstrated activity in a phase 2 trial of 41 patients with metastatic breast cancer and BRCA1 or BRCA2 mutation. At enrollment, the patients received a median of 3 previous chemotherapy regimens. The partial remission rate in patients receiving at least 4 cycles of follow-up was 17% (2 of 12 patients) with BRCA1 mutations and 23% (3 of 13 patients) with BRCA2 mutations.

The time to failure while receiving veliparib was 2 months and 5.1 months, respectively. In all, 20 patients are still alive from the group receiving veliparib; 10 patients proceeded to postprogression therapy with veliparib and carboplatin, with 1 partial response in a patient with a BRCA1 mutation. n

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Emerging Therapies

Enthusiasm Sky High for Immunotherapy with Anti–PD-1 Agents in Cancer See also page 19

By Caroline Helwick

Nivolumab plus Ipilimumab Many melanoma experts predict that the best way to use the immune checkpoint inhibitors will be in combination. In a study presented by Mario Sznol, MD, of Yale School of Medicine, New Haven, CT, this double hit paid off.

The concurrent treatment of nivolumab and the anti–cytotoxic T-lymphocyte antigen (CTLA)-1 antibody ipilimumab led to a 2-year OS rate of 79%, and 88% of responders had ongoing responses at the time of analysis. Grade 3/4 toxicity rate was 62%, but this was manageable with the proper education of clinicians.

“While this is a small trial, that is very impressive 2-year survival data,” Dr Sznol said. “Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”

Dr Sznol reported updated data for the initial 53 patients who received concurrent combination treatment regimens in the phase 1 CA209-004 trial that he reported at ASCO last year. He announced preliminary reVOL. 7

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The most common grade 3/4 toxicities were increased lipase and amylase—reversible laboratory abnormalities. One drug-related death occurred

“Concurrent therapy with nivolumab and ipilimumab results in what I believe to be an unprecedented 2-year survival.”

“For the original 53 patients, 2-year survival is 79%. In metastatic melanoma, it doesn’t get any better than that.”

—Mario Sznol, MD melanoma and could have received up to 3 previous systemic therapies, although 55% of patients received no previous systemic treatments.

In the original cohort, the 1-year OS rate was 85%, and the 2-year survival rate was 79%. The overall response rate was 42%, with confirmed complete responses increasing from 10% to 17%. To accommodate patients who had “unconventional” responses (ie, immune-related partial responses and stable disease), the researchers used an “aggregate clinical activity rate,” which was 70%.

In the new 41-patient cohort, the objective response rate was 43%, with 10% complete responses; the aggregate clinical activity rate was 53%. Altogether, 82% of responses were ongoing at the time of analysis.

Now with 2 cohorts evaluated, Dr Sznol said, “We feel very confident that the activity of this combination regimen is real.”

Combining ipilimumab with nivolumab did result in increased toxicity compared with either single agent, and grade 3/4 side effects occurred in 62% of the 94 patients. These events, however, “were manageable and reversible with algorithms that were established for ipilimumab,” Dr Sznol pointed out.

—Jeffrey S. Weber, MD, PhD in the latest cohort, which resulted from colitis.

Discussing the combination, Dr Weber noted that, “The responses were outstanding. Eight of 9 patients in cohort 2 remain in response, as do 16 of 17 in the most recent cohort. And for the original 53 patients, 2-year survival is 79%. In metastatic melanoma, it doesn’t get any better than that…I cannot help but be impressed.”

Enrollment has been completed for a phase 3 trial comparing nivolumab

Photo by © ASCO/Todd Buchanan 2014

Data on Nivolumab Maturing The long-term follow-up of the pivotal phase 1 trial of nivolumab showed ongoing responses in 56% of 107 patients treated with the single agent. At a median follow-up of 22 months, the median overall survival (OS) was 17.3 months. The OS rates were 63% at 1 year, 48% at 2 years, and 41% at 3 years. In the subset of patients receiving the optimal dose of nivolumab, 3 mg/kg, the median progression-free survival (PFS) was 9.7 months and the median OS was 20.3 months, reported F. Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston.

Jeffrey S. Weber, MD, PhD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, who discussed the results, commented, “For the totality of patients, many with 3 and 4 prior regimens, and some with performance status 2, these are very good data.”

sponse data for a new cohort of 41 patients receiving the regimen being used in the subsequent phase 2/3 trials. All 94 patients had stage III or IV

Photo by © ASCO/Zach Boyden-Holmes 2014

J

udging by the high attendance at sessions where data on the anti– programmed death (PD)-1 antibodies were presented, oncologists can hardly wait to have these immunotherapies in the clinic. The key data from ASCO 2014 regarding stage III/IV melanoma are presented here.

mab (MK-3475), whose activity in the phase 1 KEYNOTE-001 dose-finding study was impressive enough to earn a spot at the ASCO 2014 press briefing. In May 2014, the US Food and Drug Administration granted pembrolizumab (formerly lambrolizu­ mab) a priority review designation.

“These are early data, but they tell us we are on to something really important,” noted Antoni Ribas, MD, PhD, Professor of Medicine at the David Geffen School of Medicine, University of California, Los Angeles.

At the press briefing, Steven O’Day, MD, of the University of Southern California, Keck School of Medicine, Los Angeles, agreed, noting the “remarkable” finding that almost 90% of patients achieve durable responses, with a toxicity profile that is “almost unheard of in metastatic cancer.”

In the dose-finding trial of 411 patients, pembrolizumab produced responses in 34% of patients, including 28% whose disease progressed with ipilimumab therapy. At 1 year, 88% of responders were continuing to respond, with the longest response so far being 76 weeks. The median PFS was 5.5 months, and the estimated OS rate at 1 year was 69%. The median OS was not reached at the time of analysis.

The tolerability of the drug was also noteworthy. “This is one of the most benign therapies I’ve ever used in my clinic,” Dr Ribas noted, reporting a rate of grade 3/4 events of 10% to 12%.

Pidilizumab The data were less impressive for another investigational anti–PD-1 anti-

“These are early data, but they tell us we are on to something really important….This is one of the most benign therapies I’ve ever used in my clinic.”

—Antoni Ribas, MD, PhD

plus ipilimumab versus nivolumab or ipilimumab alone, as well as a phase 2 trial comparing nivolumab plus ipi­ limumab versus ipilimumab alone.

Pembrolizumab Hits the Mark The newest agent is pembrolizu­

body, pidilizumab, which produced responses in only 5% to 6% of pretreated patients, although the 1-year OS rate was encouraging at 64.5%. A subset of patients received subsequent treatment with ipilimumab, and their survival rate rose to 80%. n

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

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.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival 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 overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1585 per 3.5-mg vial as of July 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ 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 on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, 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. *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.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous.

Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome

(RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia.

Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

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 postimplantation loss and a decreased number of live fetuses.

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.

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 previouslytreated 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 Please see full Prescribing Information for VELCADE at of VELCADE administered intravenously in combination with VELCADEHCP.com. 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%), VELCADE, MILLENNIUM and are registered trademarks of Millennium vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Pharmaceuticals, Inc., Cambridge, MA 02139 vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia Millennium Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306a (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), All rights reserved. Printed in USA

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Prostate Cancer

Upfront Docetaxel Markedly Improves Survival in Metastatic Prostate Cancer, at Reduced Cost

By Wayne Kuznar

T

he upfront addition of docetaxel to androgen deprivation therapy (ADT) adds more than 1 year to overall survival compared with ADT alone in men with newly diagnosed hormone-sensitive prostate cancer, according to findings from a phase 3 study funded by the National Cancer Institute.

The survival benefit was even greater for the subset of men with high-volume disease, reported Christopher Sweeney, MBBS, a medical oncologist at the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston.

“The benefit is substantial and warrants this being a new standard treatment for men who have high-extent disease and are fit for chemotherapy,” he said. Docetaxel is typically initiated only after disease progression despite ADT. The study randomized 790 men with newly diagnosed metastatic prostate cancer to either ADT alone or to ADT with docetaxel over 18 weeks.

Approximately 66% of patients had high-volume disease.

“The benefit is substantial and warrants this being a new standard treatment for men who have highextent disease and are fit for chemotherapy.”

—Christopher Sweeney, MBBS At a median follow-up of 29 months, 136 deaths occurred in the ADT-alone group compared with 101 in the group receiving ADT plus docetaxel. Overall survival was improved by 13 months with upfront docetaxel: 44 months in the ADT group versus 57.6 months in the group receiving ADT plus docetaxel, for a relative improvement of 39% (P = .003).

In men with high-volume disease, the median overall survival was 49.2 months with docetaxel plus ADT compared with 32.2 months with ADT, corresponding to a 40% reduction in the risk of death with the addi-

tion of docetaxel (P = .006). In men with low-volume disease, the median overall survival had not been reached at the time of the analysis.

Docetaxel also delayed disease progression, assessed by either a rise in the level of prostate-specific antigen (PSA) or the appearance of new metastases or symptom worsening. At 1 year, the proportion of patients with PSA levels of <0.2 ng/mL was 11.7% in the ADT group versus 22.7% in the group receiving ADT plus docetaxel. The median time to clinical progression was 19.8 months in the ADT group compared with 32.7 months in the group receiving ADT plus docetaxel (P <.001).

Median time to castration-resistant prostate cancer was also significantly improved with the addition of docetaxel compared with ADT alone (20.7 months vs 14.7 months; P <.001).

At disease progression, 129 (approximately 75%) of the 174 patients in the ADT-alone arm subsequently received docetaxel, Dr Sweeney said.

Adverse effects in the men assigned to docetaxel included febrile neutropenia (6%) and significant effects on sensory nerves (1%) and on motor nerves (1%).

“Docetaxel is going to cost less than our newer therapies.”

—Michael J. Morris, MD Immediate past president of ASCO, Clifford A. Hudis, MD, remarked, “In prostate cancer, I’m not aware of a historical study that ever offered up this magnitude of improvement in survival. Across all solid tumors, this is all almost unprecedented improvement in median survival.”

Michael J. Morris, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, said that the study results bear on the ongoing dialogue regarding cost versus value in cancer care.

“Docetaxel is going to cost less than our newer therapies,” Dr Morris said.

“I estimate that using docetaxel in castration-resistant prostate cancer gains 81 days of life for $15,000 of drug costs at wholesale prices. If docetaxel is applied in castration-sensitive disease, it gains 476 days of life at a cost of $9000 for 6 cycles.” n

Emerging Therapies

Anti–PD-1 Antibodies for NSCLC and Renal Carcinoma

S

By Caroline Helwick everal presentations at ASCO 2014 focused on the use of the anti–programmed death (PD)-1 monoclonal antibodies in non–small-cell lung cancer (NSCLC) and in renal-cell carcinoma.

Nivolumab plus Ipilimumab The phase 1 multicohort CA209-012 trial evaluated nivolumab as a single agent and in combination with ipilimumab, chemotherapy, and erlotinib.

Nivolumab monotherapy in the firstline setting produced responses in 30% of patients, but the median duration of response was not reached. “Responses are ongoing in 4 of 6.

The progression-free survival (PFS) at 24 weeks was 60%, and the median PFS was 47.2 weeks in patients with nonsquamous histology and 15.1 weeks in patients with squamous tumors; the 1-year overall survival (OS) rate was 75%. The median OS was not reached at the time of analysis.

All of the responders expressed the PD-L1 ligand, which may possibly serve as a biomarker of activity. In this subgroup, the results were most impressive, with a 1-year OS rate of 80%.

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Could 2 immune checkpoint inhibitors be better than 1? That question was asked in a cohort of the CA209-012 trial involving 49 chemotherapy-naïve patients receiving nivolumab plus ipilimumab and followed by nivolu­mab monotherapy until progression. Responses were ongoing in 75% of responders at the time of the analysis.

At 24 weeks, the median PFS ranged from 20% to 51%, and the median PFS was 14.4 weeks to 16.1 weeks. The median OS was 44 weeks in 1 subset and was not reached in the other arms.

“The findings suggest this combination may be suitable for PD-L1–positive and –negative patients,” said Scott J. Antonia, MD, of H. Lee Moffitt Cancer Center, Tampa, FL. Pembrolizumab (MK-3475) in Previously Treated Patients A phase 1 study of 217 patients with previously treated NSCLC showed strong antitumor activity for pembrolizumab, especially among patients expressing PD-L1. The objective response rate was 20% and was higher among patients expressing PD-L1

(23%) than in those who did not (9%).

Of the former patients who responded, 82% continue to receive treatment.

Nivolumab in Renal-Cell Carcinoma Results from the phase 2 CheckMate-010 trial in advanced kidney cancer showed that single-agent nivolu­ mab produced responses in 20% to 22% of patients and yielded 1-year survival rates of 63% to 72%. In previously treated patients, the median OS was 25 months with 2-mg/kg dosing.

In a phase 1b trial of previously treated as well as treatment-naïve patients, nivolumab combined with ipilimumab produced responses in 43% to 48% of patients and was associated with a 24-week PFS rate of 65%.

“These data are encouraging as we seek to identify new treatments for patients, particularly those who pro­ gress following treatment with antiangiogenic therapy,” said Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York City.

Tolerability of Anti–PD-1 Agents The toxicities associated with anti–

PD-1 agents are primarily immune-­ related and transient, although some can be concerning. As a single agent, nivolumab was associated with adverse events in 85% of patients, but only 20% were grade 3/4. For the combination of nivolumab and ipilimumab, grade 3/4 adverse events were reported by 49% of patients across the arms, primarily during induction and not maintenance. Serious diarrhea and colitis occurred in 8% of patients, and liver enzymes were elevated in 6% of patients. Approximately 33% of patients discontinued treatment as a result of adverse events, and 3 patients died as a result of drug-related toxicities (1 each from colitis, pulmonary hemorrhage, and toxic epidermal necrolysis).

When given with chemotherapy, treatment-related grade 3/4 adverse events occurred in 45% of patients receiving anti–PD-1.

With pembrolizumab, almost 66% of patients had at least 1 drug-related adverse event of any grade, and 10% of patients had grade 3/4 toxicity.

Grade 3/4 pneumonitis was observed in 4 patients. n

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Lung Cancer

Necitumumab Extends Survival of Patients with Squamous Lung Cancer

By Wayne Kuznar

N

ecitumumab, a human im­ munoglobulin G1 anti-EGFR monoclonal antibody, added to standard chemotherapy significantly improved survival compared with chemotherapy alone as first-line treatment of patients with stage IV non– small-cell lung cancer (NSCLC) of squamous histology.

The median overall survival (OS) was extended by 1.6 months in patients randomized to the arm receiving necitumumab plus gemcitabine and cisplatin in the phase 3 clinical trial, said Nick Thatcher, MD, PhD, Professor in Medical Oncology, University of Manchester, Christie Hospital NHS Foundation Trust, United Kingdom, at ASCO 2014.

Although the results were criticized because of the less-than-2-month improvement in survival, Dr Thatcher remarked, “It’s the first time that we’ve seen benefit in this group of patients over the last 20 or 25 years.”

Progress in the treatment of squamous NSCLC has been minimal over

the past 2 decades compared with nonsquamous NSCLC, noted Dr Thatcher.

The main reason is the lack of relevant oncogenic drivers to inform treatment decisions. Necitumumab was chosen as an add-on to standard gemcitabine plus cisplatin because EGFR expression is detectable in most advanced squamous NSCLC tumors.

“It’s the first time that we’ve seen benefit in this group of patients over the last 20 or 25 years.”

—Nick Thatcher, MD, PhD The open-label multicenter study randomized 1093 patients with stage IV squamous NSCLC to gemcitabine 1250 mg/m2 on days 1 and 8 and intravenous cisplatin 75 mg/m2 on day 1 plus necitumumab 800 mg on days 1 and 8, or to gemcitabine plus cisplatin alone, administered every 21 days for up to 6 cycles.

Patients assigned to gemcitabine plus cisplatin and necitumumab who had no disease progression continued to receive necitumumab alone until disease progression or intolerable toxicity. Overall, 51% of the patients randomized to necitumumab plus chemotherapy continued to receive necitumumab monotherapy for a median of 4 additional cycles.

The primary end point, median OS, was 11.5 months in the arm receiving necitumumab plus chemotherapy versus 9.9 months in the arm receiving chemotherapy alone (P = .012).

The 1-year survival rate was 47.7% and the 2-year survival rate was 19.9% in the necitumumab plus chemotherapy arm compared with 42.8% and 16.5%, respectively, in the chemotherapy-­alone arm.

The median progression-free survival (PFS) was extended from 5.5 months in the chemotherapy arm to 5.7 months in the necitumumab plus chemotherapy arm (P = .02).

The need for systemic therapy after the study was similar in the 2 treatment groups: 47.3% in the necitumu­ mab plus chemotherapy arm versus

44.7% in the chemotherapy-alone arm.

A preplanned exploratory analysis of the EGFR H-score, a potential predictive biomarker, using a prespecified cut point of 200, showed no association between it and the OS or PFS by cut-point interaction.

Adverse event rates leading to the study discontinuation were 31.2% in the necitumumab plus chemotherapy arm and 24.6% in the chemotherapy-alone arm; adverse event rates leading to death were 12.3% and 10.5%, respectively. Grade ≥3 adverse events that occurred significantly more often in the necitumumab arm were hypomagnesemia (9.3% vs 1.1%, respectively), skin rash (7.1% vs 0.4%, respectively), and venous thromboembolic events (5% vs 2.6%, respectively).

Although statistically significant, the improvement in OS did not meet ASCO’s threshold for a clinically meaningful difference of 2.5 months to 3 months in squamous NSCLC, noted Julie R. Brahmer, MD, Associate Professor of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore. n

Ramucirumab Shows Survival Benefit in NSCLC

T

he investigational monoclonal antibody ramucirumab improved overall survival (OS) when added to docetaxel versus chemotherapy alone in patients with stage IV non– small-cell lung cancer (NSCLC), according to a phase 3 trial highlighted in a press briefing at ASCO 2014.

“This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC, and the first treatment in approximately a decade to improve outcomes in the second-line setting,” said Maurice Pérol, MD, of the Département de Cancérologie Médicale, Centre Léon-Bérard, Lyon, France.

Ramucirumab, which was recently approved by the US Food and Drug Administration (FDA) for advanced gastric cancer, targets vascular endothelial growth factor receptor 2 and thus blocks the formation of new blood vessels to feed the tumor.

“This study met the primary end point of OS, reducing the risk of death by 14% and prolonging median survival by 1.4 months,” Dr Pérol reported. The combination reduced the risk of disease progression by 24%.

“Ramucirumab represents a potential new option for treatment in the second-line setting,” Dr Pérol suggested.

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If further studies validate these findings, and the drug is approved by the FDA for this new indication, it would be the first antiangiogenic drug approved for the second-line treatment of patients with NSCLC. The improvement in survival was demonstrated in patients with squamous histology and in patients with nonsquamous histology, but the median OS benefit, although significant, was quite modest. Nevertheless, Dr Pérol said that the drug could be useful in patients lacking a specific mutation (EGFR, ALK) that would make them candidates for targeted therapy.

In patients with NSCLC and EGFR mutation, the currently approved second-line chemotherapy agents include docetaxel, pemetrexed, and erlotinib, and the median OS with these drugs is between 7 months and 9 months.

REVEL Study Details The double-blind, placebo-controlled, phase 3 REVEL clinical trial enrolled 1253 patients with stage IV NSCLC (26% of whom had squamous histology) whose disease progressed with standard platinum-based therapy. Patients were randomized to ramucirumab plus docetaxel or to docetaxel plus placebo.

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Photo by © ASCO/Scott Morgan 2014

By Caroline Helwick

“This is the first treatment to have shown a significant survival advantage over chemotherapy alone in second-line therapy of NSCLC.” —Maurice Pérol, MD

The active combination significantly improved response rate, progression-free survival (PFS), and OS compared with docetaxel alone. The median PFS times were 4.5 months with ramucirumab versus 3 months without (P <.001), and the median OS times were 10.5 months versus 9.1 months (P = .0235), respectively.

The safety profile was in line with other angiogenesis inhibitors. No increase in pulmonary hemorrhage was observed with the combination.

“This combination shows good activity in the difficult-to-treat second-line setting of NSCLC,” said Gregory A. Masters, MD, Director, Medical

Oncology Fellowship, Helen F. Graham Cancer Center, Newark, DE, who moderated the press briefing.

Dr Masters was asked whether 1.4 months of additional survival represented “value,” especially in light of ASCO’s recommendation that new NSCLC treatments (in the first-line setting) extend survival by at least 3 months.

Dr Masters responded that the drug may be a small step along the pathway that ultimately constitutes improvement. “Progress is slow and step-wise, and we build one step at a time. The cumulative progress is what we find encouraging….A study like REVEL may not change the way we treat NSCLC, but it can influence our design of further studies,” he said, adding that there is a mandate to “balance benefit with cost, and figure out how best to treat patients.”

Don S. Dizon, MD, Assistant in Medicine, Medical Gynecologic Oncology, Massachusetts General Hospital, Boston, commented that ASCO’s 3-month OS threshold is “guidance” but is not the “be all and end all” for investigational studies. “When we decide that a treatment has value, we consider 3 key things: efficacy, toxicity, and cost,” Dr Dizon noted. n

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Value in Oncology

Payment Reform Key to Value-Based Cancer...

Key Points ➤ Achieving value-based care in oncology requires a quick and fundamental change in the payment system ➤ Unnecessary testing and use of expensive therapies are the result of the current reimbursement system ➤ When a therapeutic equivalent exists at a lower cost, oncologists must use it

mesylate has tripled since its introduction, even though there are newly approved drugs in the same drug category, he noted. Part of the problem is the large sums of money being spent on cancer drugs for a few additional months of survival.

switched from average wholesale price to average sales price plus 6%, the use of more expensive treatments for lung cancer increased. In radiation oncology, per guidelines from the American Society for Radiation Oncology, a single dose of radiation for

“We need to do more at a faster pace to fundamentally change the payment system.

That and that alone—making it neutral for us whether we give more, test more, or care more for the patient—will be the important item that will change how we practice, and make sure that it is value-based.”

Photo Courtesy © ASCO/Todd Buchanan 2006

spent on healthcare in 2013 is more than the entire economy of France, which is the fifth largest economy in the world. The amount spent on cancer care represents approximately 50% more than what will be spent on expanding health insurance coverage under the Affordable Care Act, he noted. Yet, the median household income is only $51,371.

“One drug for cancer care can wipe out the median income of a household,” Dr Emanuel said.

The annual health insurance premium for a family in the United States in 2013 was $16,000, or approximately 30% of the median household income.

Even if most of the cost of premiums is coming from employers, this amount comes out of workers’ paychecks.

“We need to keep these numbers in mind every time we talk about value,” said Dr Emanuel.

Some drugs with high price tags are not adding value, he pointed out.

For example, the price of imatinib

—Ezekiel J. Emanuel, MD, PhD But even drugs that provide cures, such as sofosbuvir for the treatment of hepatitis C infection, are coming under scrutiny for their high costs.

The $84,000 price tag for sofosbuvir “seems like a good value to me for a one-time treatment over a few months, and yet we’re having a lot of consternation about it, because of the cost,” he said. “We’re concerned about value, but we’re also concerned about absolute total cost.”

Reimbursement Drives Clinical Decisions When Medicare reimbursement

palliation of bone pain from a bone metastasis in an otherwise incurable patient is equivalent to 10 or more fractions for the same bone metastasis.

Yet, single-dose radiation is used less than 5% of the time for this purpose in the United States.

The same applies to hypofractionated radiation for breast cancer, which has been shown to be clinically equivalent to, but only 65% to 70% of the cost of, standard radiation treatment.

Unnecessary testing also contributes to increased cost, said Dr Emanuel. One example is positron emission tomography/computed tomography

Continued from page 1

(PET/CT) in patients with early-stage breast cancer. Despite not being indicated for this patient population, its use varies considerably, ranging from almost 1 PET/CT scan per patient with breast cancer to 0.10 PET/CT scan per patient.

Eliminating incentives to use drugs outside of the evidence base can help to curtail their use, Dr Emanuel said.

For example, when UnitedHealthcare indicated that it would only pay for bevacizumab if its use was endorsed by a guideline from a major medical society, the use of the drug decreased by 60%.

Therapeutic Equivalence In addition to avoiding unnecessary testing, a second obligation is to prescribe the lowest-cost treatment when therapeutically equivalent ones exist. “We have lots of places in cancer where we have therapeutic equivalent and wide variation in cost,” Dr Emanuel pointed out. “Advanced gastric cancer is a very good example. There is a 50-fold difference in price among the preferred options on the National Comprehensive Cancer Network list. In that circumstance, we have an obligation to prescribe the lowest-cost treatment.”

Perhaps the most important obligation for oncologists is a collective one to “rapidly advance off the treadmill system of fee for service,” Dr Emanuel concluded. “We should want to get out of that system, so we can focus on our patients as we claim to want to be.” n

ASCO Beginning to Address Value in Oncology

By Caroline Helwick

A

SCO is starting to address the issue of value in cancer care, “moving the needle” away from cost alone, according to Lowell E. Schnipper, MD, the Berenson Professor in Medicine, Harvard Medical School, Boston, and Chair of the ASCO Task Force on Value in Cancer Care. This is not about the absolute dollars expended, but about what these dollars buy for patients who may be experiencing financial, as well as physical, toxicity, Dr Schnipper said at ASCO 2014.

The issue is not just about cost.

“Cost demeans the purpose for which we are all gathered here, which is to improve patient care,” he said, noting that the task force is focusing on “patient-centeredness.”

“We chose not to take a macroeco-

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nomic incentive, but to consider the doctor and patient, and how they are thinking about the variables that we take into account every day in cancer care,” he added.

Professor at Harvard Business School, and a leading proponent of value-based care: value should be defined around the customer. The creation of value for patients determines

“We are wrestling with data like these to provide a value system that would provide some degree of nuance and distinguishability among regimens.”

—Lowell E. Schnipper, MD

Dr Schnipper referred to the concepts put forth by Michael E. Porter, Bishop William Lawrence University

“the rewards” for all other actors in the healthcare system, and the success of a value-based treatment is mea-

sured through outcomes, not by the volume of services delivered.

“Porter makes the point that patient-centeredness is one of the key elements as we think about the value equation,” he said. “It’s appropriate for a physician to use all health-related resources in an appropriate manner that is resource-efficient. This implies doing our best for our patients, and understanding that doing so will positively impact the body politic.”

Variables Affecting Value The Task Force on Value in Cancer Care has identified 5 common practices that are not evidence-based, and it recommended that they not be routinely used. These 5 elements include: • Unwanted variation in quality and outcome

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Value in Oncology

What Makes a Treatment Clinically Meaningful?

By Caroline Helwick

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wo presentations at ASCO 2014 struck Jennifer Malin, MD, PhD, Medical Director of Oncology at WellPoint, Inc, as good examples of value in cancer care, but many other studies did not make the value-based list. Dr Malin described these studies at an ASCO Highlights of the Day session.

Proposed Criteria for Clinically Meaningful Outcomes Dr Malin’s perspective was based on new criteria recently proposed by ASCO as a means of evaluating clinical trial results in terms of “clinically meaningful outcomes” (Ellis LM, et al. J Clin Oncol. 2014;32:1277-1280). De­ pending on the tumor and previous treatment, any new regimen for metastatic disease should convey improvement in median overall survival (OS) of at least 2.5 months to 6 months.

“Powering studies to achieve these end points would be worth consideration. It would ensure that we make advances that provide clinically meaningful outcomes to patients, and it would also lead to smaller trial designs and would speed up innovation,” she predicted.

Studies Showing Value Among studies presented at the meeting that clearly have clinical meaningfulness were 1 study of a subset of patients with lymphoma whose prognosis was poor and 1 study of patients with early-stage, HER2-positive breast cancer.

The phase 2 study of 64 patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) showed that the addition of lenalidomide to R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone; R2CHOP) reduced the negative prognostic significance of the non–germinal center B-cell (GCB) phenotype (a subset of DLBCL). At 2

years, progression-free survival (PFS) for this subset of patients was 50%, and OS was 75% with the “R2CHOP” regimen, mirroring the outcomes in the patients with GCB.

“This regimen improves OS in patients previously known to have a poor prognosis. This is definitely a clinically meaningful improvement in outcome and provides great value.”

—Jennifer Malin, MD, PhD This represented a 2-year relative increase of 30% in OS, at an estimated total drug cost of $73,682, and an incremental drug cost (for adding lenalidomide to R-CHOP) of $26,540.

“This regimen improves OS in patients previously known to have a poor prognosis. This is definitely a clinically meaningful improvement in outcome and provides great value, certainly in comparison to many other studies presented at ASCO,” Dr Malin commented.

A second study was a meta-analysis of 5 randomized trials of adjuvant trastuzumab. The analysis focused on 4220 HER2-positive patients with tumors ≤2 cm (mostly lymph node–pos-

itive), a group for whom the benefit of trastuzumab has not clearly been established.

Ciara C. O’Sullivan, MD, of the National Cancer Institute, Bethesda, MD, reported that trastuzumab reduced disease recurrences and deaths by approximately 30% in all groups, except for patients with 1 or no positive lymph nodes, whose mortality risk was reduced by only 2%.

“Trastuzumab clearly provides tremendous value for these patients, at a total drug cost of $81,336 and incremental cost of $76,601,” Dr Malin said.

“It may have limited value, however, in the group with 0 to 1 positive nodes.”

taxel and trastuzumab in patients with HER2-positive advanced breast cancer in a phase 1b study. Although the median PFS was approximately 18 months, which was deemed encouraging by the investigators, the estimated total drug and incremental drug costs—$325,530 and $170,000, respectively—gave Dr Malin pause.

“When our new drugs cost $170,000, we need to look for significant improvements in outcomes,” she commented.

“When our new drugs cost $170,000, we need to look for significant improvements in outcomes.”

Examples of Lack of Value Dr Malin then described several studies that illustrated a lack of clinically meaningful outcomes, and therefore a lack of value. One was a phase 1 study of escalating doses of cabozantinib plus abiraterone in castration-­ resistant prostate cancer in which a prostate-specific antigen decline of >75% was observed in 63% of men with the 20-mg dose and in 13% with the 40-mg dose. The investigators noted the combination’s tolerability and preliminary efficacy, which they claimed “support the investigation of this combination for further clinical development.”

According to Dr Malin, however, the findings indicated “limited to no improvement in outcomes,” and carried a total drug cost of $92,410 and an incremental drug cost of $32,521.

Another study evaluated the benefit of adding bevacizumab to trastuzumab plus docetaxel in the neoadjuvant breast cancer setting, finding a 20% relative increase in the rate of pathologic complete response. For this, the total drug cost was $103,976, and the incremental cost was $77,267.

The novel agent trebananib was evaluated in combination with pacli-

Can Data Like These Guide Conversations?

Oncologists could use data such as these to have more meaningful conversations with patients about treatment options, Dr Malin suggested.

“There are often discussions with patients about what are meaningful outcomes, and these ‘value’ discussions often end up in debates as to whether a week, a month, a year is meaningful,” she said.

A pivotal study (Weeks JC, et al. N Engl J Med. 2012;367:1616-1625) revealed that 25% of patients with advanced lung cancer and approximately 35% of patients with metastatic breast cancer believed it was “very likely” their treatments could cure them.

“I posit that patients are looking for cures. If they understood the more marginal benefits that our treatments bring, they may be more likely to understand the tradeoffs in toxicity and cost, and be more likely not to want them,” she said. n

os, treatments, benefits, toxicities, and costs related to cancer care and ascribe each treatment as having no value, low value, medium value, or high value. In patients with non–small-cell lung cancer (NSCLC), for example, the value parameters will include treatment regimen, median overall survival (OS), hazard ratio, progression-free survival, palliative data, time to next treatment, toxicity, and the total cost of care.

For example, for the first-line treat-

ment of NSCLC, carboplatin plus paclitaxel yields a median OS of 8.2 months and costs $374; cisplatin plus pemetrexed offers 10.3-month survival and costs $6183; the combination of paclitaxel, carboplatin, and bevaciz­ umab results in a 12.3-month survival and costs $8329.

“We are wrestling with data like these to provide a value system that would provide some degree of nuance and distinguishability among regimens,” Dr Schnipper said. n

—Jennifer Malin, MD, PhD

ASCO Beginning to Address... Continued from page 21 • Harm to patients • Waste and failure to maximize value • Health disparities • Failure to prevent disease.

The Quality Oncology Practice Initiative should help reveal the degree of variation in clinical practice, which ties into safety. Experimental models of payment reform are being tested.

Usable Tool for Oncologists The goal is to create a transparent, clinically driven, methodologically

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sound method for defining and assessing the relative value of care options in oncology, which ultimately would “drive change” among payers and industry and encourage the promotion of high-value care, Dr Schnipper said.

“We want to give oncology providers the skills and tools to assess the relative value of therapies, and use these in discussing treatment options with patients,” he said. The tool would describe the different clinical scenari-

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Value in Oncology

Value-Based Insurance Not Such an Easy Sell

By Caroline Helwick

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he need to design insurance coverage that promotes value in cancer care is no longer a matter of debate, but how to accomplish it remains a huge challenge, according to Lee N. Newcomer, MD, UnitedHealthcare Senior Vice President of Oncology, Women’s Health and Genetics, who discussed value in cancer care from the payer’s perspective at ASCO 2014.

Dr Newcomer spoke at a session, “Can We Find Common Ground?

Stakeholder Perspectives on Value in Cancer Care.” He began by reminding attendees “why we are having this discussion.” The average US household income is currently approximately $50,000, and 50% of this goes to pay for insurance premiums and out-of-pocket expenses. Even worse, given the current trend, by 2028, the average US household will spend 100% of its income on healthcare expenses.

“This is a trend that cannot be sustained. We have to start having discussions about value, and we are going to have to say that there are certain things that should not be covered. The issue is how to do this in a way that will be rational and fair,” he said.

Value-Based Design Challenges Insurance benefits are not based on value; most are designed around structures, he said. The idea behind copayment or coinsurance “is for the patient to pause and ask, ‘is this worth the money?’ Copays were never intended to be large enough to keep people from getting important,

“We have to start having discussions about value, and we are going to have to say that there are certain things that should not be covered. The issue is how to do this in a way that will be rational and fair.”

—Lee N. Newcomer, MD high-value care, but to keep them from selecting lower-value care if they have to pay the first $50 or a percentage,” Dr Newcomer said.

“Unfortunately, this is not discriminatory based on the procedure,” he continued. “It’s simply discriminatory based on price.”

To be successful, a value-based insurance program needs a nonbiased external reference that will create a fair differential between high-value and low-value services. A high-value service may offer complete coverage, with no requirement for patient participation, whereas a low-value service would mandate participation—33%, 50%, or even 100% participation.

“It will be difficult for consumers to understand this for every service they will receive,” Dr Newcomer said.

These thresholds must be set externally, because payers “will always be

perceived as making these decisions on a financial basis only,” he suggested. “It doesn’t matter how high-integrity the process is, the bias is real in the consumer mind.” Dr Newcomer noted that ASCO has started “wrestling with this issue” through the Choosing Wisely campaign. “Having ASCO set references would be a key to getting these in place,” he said.

Consumer education will also be critical to the success of value-based design, because the insured population is already unclear about their benefits. “In a value-based program, we are asking consumers to take on an increasingly large amount of information that may be even harder to digest,” Dr Newcomer said. “For a consumer to sort out a 2-month versus 4-month survival benefit, or grade 5 versus grade 4 toxicities could be overwhelming.”

“Trying to make this concept easily accessible to consumers, and helping them find out the value of a given treatment, is a daunting task and has been a major barrier to getting value-based insurance in place,” he noted.

Issues for Payers Equally overwhelming for systems programmers within a payer system will be sorting out the different diagnoses and treatment regimens and assigning different coinsurance amounts to these. The number of permutations could overwhelm any computer system, Dr Newcomer added.

Furthermore, who decides, and how will it be determined what the

patient participation will be for each of these scenarios? “Where do we draw the line? Where we say one thing should be free and another should have 30% participation?” he posed. “No matter where we draw the line, someone will be unhappy.”

On the positive side, once these thresholds are determined it will be easier for payers to set prices. The more generous the benefit, the higher the overall price of the premium, and this should help consumers begin to understand the concept of value, Dr Newcomer predicted.

“The thing that’s the hardest is simply not paying for anything at all,” he continued. For example, in its Choosing Wisely campaign, the American Society of Clinical Oncology has already recommended that patients with metastatic breast cancer receive only single-agent chemotherapy (except under certain circumstances), but insurance carriers restricting payment to single agents would elicit strong public reaction.

“The immediate perception of value-based insurance is that it’s simply being done to save money,” he posed.

“Putting these programs in place will have to be a gradual process accompanied by education.”

In closing, Dr Newcomer emphasized that decisions about high- versus low-value services must be made in the setting of limited resources.

“Payers need reliable information on value, and so do patients,” he said, “so they can apply their preferences and make smart decisions.” n

Site of Service Influences Value

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he growing affiliation of community oncology practices with hospitals and other networks is an obstacle to achieving value in cancer care, according to Lee N. Newcomer, MD, UnitedHealthcare Senior Vice President of Oncology, Women’s Health and Genetics.

At ASCO 2014, Dr Newcomer referred to the wide difference between what payers spend for cancer care delivered in freestanding oncology offices and what they pay for the same services in the hospital setting.

UnitedHealthcare, he said, pays the Centers for Medicare & Medicaid Services (CMS) rate + 22% for chemotherapy delivered in the oncologist’s office. Should the same chemotherapy be delivered by the same oncologist practicing in a hospital-owned

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facility, the company pays CMS rate +146%. “This is 6.6 times more money for exactly the same service,” Dr Newcomer noted.

“Here’s a vivid example,” he continued. “A Midwest practice with a large volume with our insurance company was acquired by a hospital system. Overnight, we had a new fee schedule. The same treatments by the same doctors increased our cost by $5 million a year. This was a single acquisition by a single institution.”

Dr Newcomer predicted that employers will react to such changes by mandating substantially higher copays and establishing financial penalties for seeking care in institutions with higher fee schedules in the absence of additional value.

Under these circumstances, it is im-

portant to distinguish institutions that conduct research, and therefore need additional funding, from hospitals without a research mission “but that are simply charging more money and are making a profit from the cancer center to support other parts of the hospital,” Dr Newcomer said.

Patients and consumers may inhabit the same body but hold 2 different perspectives on their health insurance. “We have to pay attention to how the consumer thinks, because the consumer is our customer,” he said.

“But while a consumer buys a health plan, a patient uses that health plan.”

Patterns of compliance suggest that even when patients derive great value from their plans, they still consider them expensive. “In our specialty pharmacy program for oral drugs, we

have increased treatment compliance by 50% through our pharmacy teams.

But with only a $50-a-month copay for a drug worth $5000 a month, compliance is still only 58%,” Dr Newcomer noted.

“Consumers are saying, ‘we are not sure healthcare is worth spending our money on,’ and that’s concerning to me,” he remarked.

A plan proposed by some opinion leaders is provocative. “The insurer would say to the patient, ‘You now have metastatic disease. We are about to spend $100,000 taking care of you,’” Dr Newcomer said. “‘Should we do that? Or should we just give you the check?’ This would certainly have patients looking at the concept of value more closely than they do today.”—CH n

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MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia.

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 • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

Jakafi is a registered trademark of Incyte Corporation. © 2014, Incyte Corporation. All rights reserved. RUX-1329a 01/14

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis.

If PML is suspected, stop Jakafi and evaluate

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

50

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

40

Patients (%)

50

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

0

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors 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.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information.

Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al.

N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

FDA Update First Drug Combination Approved for Unresectable or Metastatic Melanoma On January 8, 2014, the US Food and Drug Administration (FDA) approved the use of dabrafenib (Tafinlar; GlaxoSmithKline) plus trametinib (Mekinist; GlaxoSmithKline) as a new

combination therapy for the treatment of patients with advanced melanoma that is unresectable or metastatic. The 2 drugs were individually approved by the FDA in 2013 for melanoma.

Each of the 2 drugs blocks molecular signaling in different sites of the same pathway that promotes cancer-cell

growth. Dabrafenib was initially approved for patients with melanoma whose tumors express the BRAF V600E mutation. The dabrafenib-trametinib combination is indicated for patients with melanoma who also have the BRAF V600E or BRAF V600K mutation. Approximately 50% of skin mel-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.

Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in 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 teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. 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 Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 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 Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

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 (0.3%) 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 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% 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 (16.5% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% 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 placebo-controlled study.

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 moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) 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 any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information].

Jakafi is a registered trademark of Incyte Corporation. All rights reserved.

U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved.

Issued: November 2013 RUX-1326

anomas have a BRAF mutation.

The FDA approval was based on the results of a clinical trial of 162 patients with unresectable or metastatic melanoma with the BRAF V600E or BRAF V600K mutation; the majority of the patients were treatment-naïve. They received dabrafenib as a single agent until their disease progressed or until their side effects became intolerable, at which point they began using the combination. Overall, 76% of patients receiving the combination had an objective response for an average of 10.5 months compared with 54% of patients receiving dabrafenib alone who had an objective response lasting 5.6 months.

Clinical trials are ongoing to determine whether this combination will also result in improved survival.

The side effects reported with the combination are similar to those reported with each individual drug.

Ibrutinib Approved for CLL On January 12, 2014, the FDA approved a new indication for ibrutinib (Imbruvica; Pharmacyclics) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least 1 previous therapy, using the agency’s accelerated approval process.

The drug also received an orphan drug designation from the FDA. The approval of ibrutinib for CLL is based on the results from a clinical trial with 48 patients who had received 4 previous therapies. Patients received oral ibrutinib until disease progression or until unacceptable toxicity. Overall response was nearly 58%, with a response duration of 5.6 months to 24.2 months during the study. No improvement in survival or disease-related symptoms has been established.

The most common side effects reported with ibrutinib include thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, mouth sores, sinusitis, and dizziness.

Expanded indication. On July 28, 2014, the FDA expanded the indication of ibrutinib for patients with CLL who have a deletion in chromosome 17 (17p deletion), which leads to poor response to standard CLL therapies.

With this new indication, the FDA also approved a new labeling for the drug to reflect that the clinical benefit of ibrutinib for the treatment of CLL has been verified based on new trial results. These results confirmed the progression-free survival (PFS) and overall survival (OS) benefits associated with ibrutinib.

The expanded indication for patients with 17p deletion is based on a Continued on page 31

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Breast Cancer

ALTTO: Dual Anti-HER2 Adjuvant Therapy No Better than Trastuzumab Alone See also page 28 Largest trial ever in this setting provides new insights

survival rates were 94%, 95%, and 95%, respectively.

These results were unexpected, because the previous NeoALTTO trial, which evaluated the combination in the neoadjuvant setting, showed improved pathologic complete response rates with 2 agents versus 1 agent, which correlated with better clinical outcomes.

Photo by © GMG/Phil McCarten 2011

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he addition of lapatinib (Tykerb) to trastuzumab (Herceptin) to create dual HER2 blockade was no better than trastuzumab alone in the adjuvant treatment of patients with HER2 breast cancer in the global phase 3 ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation) trial, reported Martine J. Piccart-Gebhart, MD, PhD, Chair, Breast International Group, Brussels, Belgium, at a plenary session at ASCO 2014.

More than 8000 patients with early breast cancer were randomized after surgery to concurrent use of trastuzumab and lapatinib, to the sequential use of trastuzumab followed by lapatinib, or to trastuzumab alone for 1 year. A lapatinib-only arm was closed early because of futility. The majority (N = 4613) of patients received anti-­ HER2 agents after completing chemotherapy. Patients with hormone receptor–positive disease also received appropriate hormonal therapy.

At a median follow-up of 4.5 years, dual targeting, either concurrently or sequentially, was associated with slight numerical (but insignificant) reductions in progression versus trastuzumab alone.

“The ALTTO trial did not meet its end points,” Dr Piccart-Gebhart said.

The disease-free survival rates at 4 years were 86% with trastuzumab, 88% with concurrent HER2-directed treatment, and 87% in the sequential arm. Similarly, the median overall

“The study’s failure tells us, at a simple level, that we won’t be using lapatinib in the adjuvant setting.”

—George W. Sledge, Jr, MD However, “the doubling in pathologic complete response observed with lapatinib plus trastuzumab in NeoALTTO did not translate into improved survival outcomes in ALTTO,”

Dr Piccart-Gebhart said.

Furthermore, “lapatinib was also associated with significant increases in adverse events of special interest— diarrhea, skin rash or erythema, and hepatobiliary problems,” Dr Piccart-­ Gebhart added. Only 60% to 78% of patients in the lapatinib-containing arms received at least 85% of the protocol-specified dose. The rates of serious cardiotoxicity, however, were less than 1%, although 97% of women received anthracyclines.

ALTTO was the largest-ever adjuvant clinical trial in HER2-positive breast cancer, involving 8381 women from 946 centers in 44 countries.

A Disappointment George W. Sledge, Jr, MD, Chief, Division of Oncology, Stanford University Medical Center, CA, and past president of ASCO, called the findings “a serious disappointment, not only to investigators but for the entire field….

The study’s failure tells us, at a simple level, that we won’t be using lapatinib in the adjuvant setting.”

Dr Sledge added that the fact that ALTTO did not corroborate findings from the NeoALTTO trial seriously calls into question the use of pathologic complete response rate as a surrogate end point for survival and as an end point that can be used in drug approvals, suggesting the need to “rethink our approach to the development of new drugs for early breast cancer.”

Photo by © ASCO/Silas Crews 2014

By Phoebe Starr

“Another way of looking at this study is that the patients overall did pretty well—better than anticipated.”

—Edith A. Perez, MD

A Different Perspective The one aspect of good news to come from ALTTO, according to coprincipal investigator Edith A. Perez, MD, Deputy Director at Large, Mayo Clinic Cancer Center, Jacksonville, FL, was that the 555 relapse events that occurred at 4.5 years were far less than the 850 events that were anticipated. “Another way of looking at this study is that the patients overall did pretty well—better than anticipated,” said Dr Perez. n

Less May Be “More” with Zoledronic Acid

By Caroline Helwick

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n patients with breast cancer and bone metastasis, less frequent in­ fusion of zoledronic acid was as effective as the standard monthly dose in the randomized OPTIMIZE-2 study.

“We found that less frequent treatment may reduce the risk of serious side effects, with the additional benefits of reduced inconvenience to the patient and less cost,” said Gabriel N. Hortobagyi, MD, Professor of Medicine at M.D. Anderson Cancer Center, Houston, at ASCO 2014.

Zoledronic acid 4 mg given every 3 months was as effective as infusions given every 3 to 4 weeks, which is the FDA-approved schedule.

OPTIMIZE-2 compared the 2 schedules in 403 women with breast cancer

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and bone metastases who had received at least 9 doses of an intravenous bisphosphonate (either zole-

“We found that less frequent treatment may reduce the risk of serious side effects, with the additional benefits of reduced inconvenience to the patient and less cost.”

—Gabriel N. Hortobagyi, MD dronic acid or pamidronate) before enrolling in the study.

The rates of skeletal-related events

were 22% in the monthly group and 23.2% in the every-12-week group, indicating that less frequent dosing is not inferior. Other efficacy measures, such as time to first skeletal-related event and bone turnover markers, were also similar between the 2 arms, as well as the safety profiles.

Patricia Ganz, MD, a supportive care specialist from the University of California, Los Angeles, commented, “It’s not necessary for women to come in every 4 weeks.”

These data are important, because there are no evidence-based guidelines for the optimal treatment schedule after 1 year of treatment.

Of note, less frequent dosing ameliorated some of the safety concerns

for bisphosphonates as a class. Like all agents in the class, “zoledronic acid has some safety concerns,” said Dr Hortobagyi, indicating osteonecrosis of the jaw (ONJ), long-bone fractures (ie, atypical femoral fractures), and chronic kidney function impairment.

When compared with more frequent dosing, less frequent dosing in this study was associated with fewer cases of ONJ (0 vs 2, respectively) and lower rates of renal impairment (9.6% vs 7.9%, respectively). No patients experienced long-bone fractures.

Dr Hortobagyi advised that the findings should be “interpreted with caution,” because the study size was, in his terms, “relatively modest,” and there were some “design limitations.” n

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Leukemia

Improvement in PFS, OS, and Response Rate In the RESONATE study, patients with CLL or SLL who received at least 1 previous therapy were randomized to oral ibrutinib or to intravenous ofatumumab.

At 6 months follow-up, PFS rates

“Ibrutinib beat a standard comparator in CLL for the first time. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”

—John C. Byrd, MD

(the study’s primary end point) were 83% in the ibrutinib arm compared with 49% in the ofatumumab arm.

The median PFS was not yet reached in the ibrutinib arm and was 8.1 months with ofatumumab (P <.001), representing a 78% reduction in the risk for progression. The impact on PFS was observed in all patient groups, including the elderly and those with deletions in chromosome 17p (ie, the poor-prognosis subsets).

Furthermore, the OS rates (the secondary end point of the trial) were also

significantly improved with ibrutinib—90% with ibrutinib versus 81% with ofatumumab, representing a 57% reduction in the risk of death (P <.049).

The improvement in survival remained significant despite the crossover of 57 patients who had progressed with ofatumumab.

The ORR was also significantly better with ibrutinib, at 42.6% for ibrutinib compared with only 4.1% for ofatumumab (P <.001). At a median follow-up of 9.4 months, 86% of patients receiving ibrutinib had durable responses and were continuing to receive treatment, with minimal side effects.

“This drug’s efficacy can potentially transform the treatment of CLL, replacing more toxic therapy.”

Photo by © ASCO/Silas Crews 2013

the phase 3 RESONATE study demonstrated. The results were presented at ASCO 2014 and were also published in the New England Journal of Medicine (Byrd JC, et al. 2014;371:213-223).

“Ibrutinib beat a standard comparator in CLL for the first time,” said John C. Byrd, MD, Director, Division of Hematology, the Ohio State University Comprehensive Cancer Center, Columbus, OH. “If I were a patient with CLL, I would want this drug. In the relapsed and refractory setting after 1 prior therapy, there is no good reason not to give this drug outside of a few circumstances.”

Ibrutinib is a first-in-class irreversible inhibitor of Bruton’s tyrosine kinase, and the drug has been given breakthrough therapy designation and was approved for use in patients with CLL earlier in the year by the US Food and Drug Administration.

Photo by © ASCO/Phil McCarten 2014

Ibrutinib Outperforms Ofatumumab in Patients...

—Gregory A. Masters, MD “This is remarkable, especially considering that standard CLL therapies

Continued from page 1

typically produce a 35% to 40% response rate,” Dr Byrd commented.

Both regimens were fairly well tolerated, with similar rates of major hemorrhage and renal toxicities; the rates of atrial fibrillation were higher with ibrutinib, whereas neuropathy was more common with ofatumumab. The risk of diarrhea often observed with ibrutinib was modest and manageable in most patients, Dr Byrd said.

Experts Call to Embrace Ibrutinib “The findings of phase 2 and the confirmatory phase 3 study show ibrutinib should be used for all relapsed refractory CLL,” Dr Byrd maintained.

Gregory A. Masters, MD, Director, Medical Oncology Fellowship, Helen F. Graham Cancer Center, Newark, DE, commented. “It is impressive to see an OS benefit in CLL….This drug’s efficacy can potentially transform the treatment of CLL, replacing more toxic therapy,” Dr Masters said.

Ibrutinib will soon be tested in a phase 3 trial in patients with mantle-cell lymphoma versus the combination of bendamustine plus rituximab. Ibrutinib is also currently being tested in a phase 3 study as first-line therapy for CLL. n

breast cancer

Adjuvant Exemestane More Effective than Tamoxifen in Early-Stage Breast Cancer

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djuvant exemestane is more effective at preventing breast cancer recurrences than ta­ moxifen when given with ovarian function suppression (OFS) in young women with hormone receptor–­ positive early breast cancer, reported Olivia Pagani, MD, Clinical Director, Breast Unit, Oncology Institute of Southern Switzerland, Bellinzona, during ASCO 2014.

In a joint analysis of the Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT), the relative risk of developing a recurrent cancer was reduced by 28%, and the relative risk of a breast cancer recurrence was reduced by 34%, with exemestane plus OFS. “For years, tamoxifen has been the standard hormone therapy for preventing breast cancer recurrences in young women with hormone-sensitive disease. These results confirm that exemestane with ovarian function suppression constitutes a valid alternative,” said Dr Pagani.

The 2 protocols enrolled more than

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5600 premenopausal women (2672 women from TEXT and 3066 from SOFT) who had hormone receptor– positive early breast cancer. They were randomly assigned to exemestane and OFS or to tamoxifen and OFS in the TEXT study or to exemestane plus OFS, tamoxifen plus OFS, or tamoxifen monotherapy in the SOFT study.

The joint analysis included 4690 women (average age, 43 years).

At a median follow-up of 5.7 years, the disease-free survival rates were 91.1% for the exemestane group and 87.3% for the tamoxifen group, corresponding to a hazard ratio (HR) of 0.72 (P = .002).

More than 96% of women were alive at 5 years. Because there were few deaths, no difference was observed in overall survival between adjuvant exemestane and tamoxifen therapy.

She noted that “some premenopausal women may have excellent prognosis with highly effective endocrine therapy alone.” A total of 1996 women in the joint analysis did not

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receive chemotherapy. They tended to be older (aged ≥40 years) and had smaller tumors and no nodal involvement. “More than 97% were free of breast cancer at 5 years when treated with exemestane plus ovarian func-

“Our findings indicate that exemestane is better than tamoxifen when given with ovarian function suppression, but longer follow-up of these young women will be important to assess survival and any long-term side effects and fertility.”

—Olivia Pagani, MD tion suppression,” Dr Pagani said.

This compared with approximately 95% of the tamoxifen plus OFS group, for an HR of 0.41 to 0.53.

Exemestane plus OFS was also more effective than tamoxifen plus OFS for women who received chemotherapy.

Musculoskeletal complaints, osteoporosis, and fractures were more common in the exemestane group, and thrombotic or embolic events were more common in the tamoxifen group. The frequency of severe side effects and the self-reported quality of life did not differ between the groups.

Only 14% of the patients overall completely stopped the protocol-­ assigned treatments before 5 years— an adherence rate that exceeds that in everyday practice, said Dr Pagani.

The early cessation of assigned treatment was more frequent in the exemestane group (16%) compared with the tamoxifen group (11%).

“Our findings indicate that exemestane is better than tamoxifen when given with ovarian function suppression, but longer follow-up of these young women will be important to assess survival and any longterm side effects and fertility,” Dr Pagani concluded.—WK n

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Myeloma

Novel Drug Classes Make News in Multiple Myeloma

By Caroline Helwick

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he results of studies presented at ASCO 2014 highlight 2 novel drug classes that showed strong activity in multiple myeloma (MM), representing potential advances in relapsed or refractory disease.

Panobinostat Extends Survival In the phase 3 PANORAMA-1 trial, the addition of the oral pan-histone deacetylase (HDAC) inhibitor pano­ binostat to a bortezomib regimen led to a significant increase in median progression-free survival (PFS).

“The primary end point was met (P <.001), with a clinically relevant increase in median progression-free survival of approximately 4 months,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston.

PANORAMA-1 was an international, randomized, double-blind, placebo-controlled, phase 3 trial of 768 patients with MM who had received 1 to 3 previous lines of treatment but who were not bortezomib-refractory. The patients were randomized to panobin­ ostat or to placebo, each in combination with intravenous bortezomib and dexamethasone. After 8 cycles of therapy, responders continued to receive fewer doses of bortezomib plus dexamethasone.

The overall response rate (ORR) was similar between the arms, but

Key Points ➤ Adding panobinostat to a bortezomib-containing regimen led to a significant increase in median PFS ➤ The combination almost doubled the rate of complete and near-complete responses ➤ New monoclonal antibodies show impressive results in the treatment of patients with myeloma ➤ SAR650984 and daratumumab showed strong antitumor activity and good tolerability ➤ Overall response rate was 58% with SAR650984, and that rose to 63% among patients receiving the highest dose (10 mg/kg given every other week) ➤ Patients who achieved a partial response or better with 16 mg/kg of daratumumab and had bone marrow involvement showed clear bone marrow progenitor cells after treatment

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the combination almost doubled the rate of complete and near-complete responses (27.6% vs 15.7%, respectively; P = .006).

The median PFS improved significantly, from 8.1 months with placebo

containing combinations and additional HDAC inhibitors are currently in clinical trials.

Anti-CD38 Monoclonal Antibodies Impressive data from small, early-­

“These results confirm the efficacy of panobinostat, bortezomib, and dexamethasone that was previously observed in the PANORAMA-2 trial with patients who were heavily pretreated and bortezomibrefractory.”

—Paul G. Richardson, MD

to 12 months with panobinostat, a 37% reduction in risk (P <.001). After 28 months of follow-up, the median overall survival remained comparable—33.6 months with panobinostat and 30.4 months with placebo.

“These results confirm the efficacy of panobinostat, bortezomib, and dexamethasone that was previously observed in the PANORAMA-2 trial with patients who were heavily pretreated and bortezomib-refractory,” Dr Richardson noted.

Treatment with panobinostat led to more thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia or fatigue, but <5% of patients discontinued treatment as a result of adverse events.

Based on these data, the manufacturer has submitted a New Drug Application to the US Food and Drug Administration (FDA). In May, the FDA granted a priority review status to panobinostat. Other panobino­stat-

phase studies were presented for 2 monoclonal antibodies that target the CD38 protein—SAR650984 and daratumumab.

SAR650984 a New Antibody A phase 1b study evaluated the combination of SAR650984 and lenalidomide plus dexamethasone in 31 patients with highly refractory MM who had received 6 previous treatments, showing strong antitumor activity and good tolerability, according to Thomas G. Martin III, MD, of the University of San Francisco.

“SAR650984 in combination with lenalidomide and dexamethasone showed encouraging signs of activity in this heavily pretreated population,” Dr Martin reported.

The trial explored 3 different dose levels of SAR650984. The ORR was 58%, but this rose to 63% among patients receiving the highest dose (10 mg/kg given every other week), with

Table Patients’ Response Rates with SAR650984, by Previous Anticancer Treatment Very good Partial Minimal Overall partial response, response, response Disease subset response, % % % rate, % Lenalidomide refractory

20

28

8

48

Lenalidomide nonrefractory

33

67

—

100

Pomalidomide refractory

11

22

11

33

Pomalidomide nonrefractory

27

41

5

68

Bortezomib refractory

25

19

13

44

Bortezomib nonrefractory

20

53

—

73

Carfilzomib refractory

7

33

13

40

Carfilzomib nonrefractory

38

38

—

76

25% of patients achieving a very good partial response. The response rates by previous treatments are shown in the Table.

“Upwards of one third of patients had more than a 90% reduction in M protein value,” Dr Martin added. “In patients achieving a very good partial response, very few patients have come off therapy. This is still early in therapy…so I am hoping over time that these responses continue to improve and to deepen.”

Daratumumab as a Single Agent Antitumor activity for daratumu­ mab, used as a single agent, was shown in a phase 2 study of 50 heavily pretreated patients with relapsed or refractory disease. A total of 30 patients received 8 mg/kg and 20 patients received 16 mg/kg for 8 weekly doses, followed by 8 doses twice monthly and then monthly dosing for up to 24 months.

The ORR with daratumumab was 35% with the 16-mg/kg dose and 10% with the lower dose, reported Henk M. Lokhorst, MD, of University Medical Center Utrecht, the Netherlands.

“SAR650984 in combination with lenalidomide and dexamethasone showed encouraging signs of activity in this heavily pretreated population.”

—Thomas G. Martin III, MD “All patients who achieved a partial response or better at 16 mg/kg and who had bone marrow involvement cleared bone marrow progenitor cells after daratumumab treatment,” Dr Lokhorst noted.

Median PFS was 23 weeks in the 16-mg/kg group and 15 weeks in the 8-mg/kg cohort, at a median follow-up of <15 weeks.

“The median PFS estimate in the 16-mg/kg group is rather immature,” Dr Lokhorst said. “The current median PFS in this group is 23 weeks, which is also the longest follow-up of any patient in this cohort.”

The drug was well tolerated, and no severe infusion-related reactions were seen. Daratumumab is being evaluated in combination with lenalidomide plus dexamethasone in phase 3 trials. n

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Payers’ Perspective

Stakeholder Integration Needed to Address a Flawed Reimbursement System

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

A

s usual, ample information pertaining to payers was available at this year’s American Society of Clinical Oncology (ASCO) meeting. The oncology space continues to be an area of challenge, and the appropriate management of patients with cancer has become a moving target.

This year’s meeting provided information on and analysis of many pertinent topics, such as patient affordability, measures of quality in cancer care, changing models of reimbursement, and relevant pharmaceuticals in the pipeline, all of which are issues discussed within the payer community.

Affordability Considering the large number of new and upcoming cancer drugs, including those carrying a 6-figure annual cost, affordability is an obvious issue in oncology for all stakeholders, including patients, providers, and payers.

The cost of cancer care is currently a great concern and is expected to remain a major contributor to the issue of affordability of treatments for cancer, as well as to the affordability of insurance coverage itself. Without health insurance or subsidized coverage through another vendor, few patients would be able to pay out of pocket (OOP) to cover all of the required expenses.

According to a study presented at ASCO 2014 by Lena Van Nimwegen from Duke University and discussed in this issue (see article on page 13), nearly 40% of 300 patients with cancer experienced higher financial burden than they had expected, and 16% experienced “high or overwhelming” financial distress. These data are collected from patients with an annual median household income of $60,000, and the majority (97%) of these patients had prescription drug coverage. The median monthly OOP cost was $591, for a median of 4.6 months.

On the positive side, however, within this study, the amount of subjective financial distress had no correlation with the amount of time a patient received treatment. One can imagine the potential financial burden on someone with this type of income having the maximum high- deductible level.

Outside of the individual insurance

30

market, copay/coinsurance and deductible levels, maximum per-pre-

Affordability is an obvious issue in oncology for all stakeholders. It is hard to measure the value of healthcare without the ability to measure its quality.

scription levels, and OOP maximums are popular discussions with insurance agents and human resource executives within small and large employer companies.

Value in Cancer Care It is hard to measure the value of healthcare without the ability to measure its quality. For the past several years, ASCO has addressed this through its Quality Oncology Practice Initiative (QOPI) program.

The goal of the QOPI is to promote excellence in cancer care, by helping hematology/oncology practices create a culture of self-examination and improvement through the use of prespecified measures, feedback, and improvement tools. ASCO has continued to be progressive within the measure and methodology of this program.

American health & drug benefits

I

The QOPI certification for practices is similar to the National Committee for Quality Assurance accreditation for health plans.

Lowell E. Schnipper, MD, Chair of ASCO’s Value in Cancer Care Task Force, noted at the meeting that the task force is focusing on “patient-centeredness” (see article on page 21).

A goal of ASCO’s value initiative is to give oncology providers the skills and tools to assess the relative value of therapies and to use these in discussing treatment options with their patients. The thought is that a transparent, clinically driven, and methodologically sound method for defining and assessing the relative value of treatment options would drive change among various stakeholders to encourage the promotion of high-value care.

The Value in Cancer Care Task Force is hoping to outline a way of quantifying a score to incorporate efficacy, toxicity, and the cost of treatment to proportionate the degree of a drug’s benefit. ASCO is in a great position to implement this type of approach. This may be analogous to the quality-adjusted life-year measures or to incremental cost-effectiveness ratios that are often assessed by countries outside the United States to determine coverage and utilization policies.

US payers and other healthcare stakeholders have been waiting for a sound, responsible way to determine the coverage of highly valuable drugs, including cancer drugs, in the most appropriate way.

Payment Reform Many healthcare stakeholders will likely agree that the fee-for-service (FFS) reimbursement model is an an-

small, are piloting different strategies in oncology to replace or to supplement, with or without financial risk, the traditional FFS model with a new reimbursement model. One example is UnitedHealthcare’s payment pilot, which has replaced FFS payments with practice-specific episode payments at select oncology groups, with the intent to continue rolling out the program (www.hfma.org/Content. aspx?=17126).

Several presentations at ASCO 2014 centered on payment reform and focused on paying for the value of care, not just the quantity of care. One example was given by Jeffrey Ward, MD, who presented a new ASCO workgroup proposal to reform the payment system in oncology.

Dr Ward discussed the ideal path for reimbursement if the current system is not only tweaked but actually being rebuilt from scratch (see article on page 8). According to Dr Ward, the committee consensus involved a core monthly bundled payment that would be adjusted for quality, pathway utilization, resource utilization, and clinical trial utilization.

This new model would also include the use of pharmaceuticals. Dr Ward believes that the monthly payments could be phased in over time, and although Current Procedural Terminology® codes do not track these utilization aspects directly, 9 codes could replace 63 codes and ultimately align incentives.

Active Involvement The extent of topics presented at the meeting this year on the value of cancer care was impressive. There is a need for all stakeholders to be actively involved in creating solutions to a currently flawed system of traditional FFS reimbursement.

Across the country, great new payment models are under way. As these models are being modified to optimally reward quality and patient-centered care, their expansion is inevitable. tiquated system with perverse incentives that lacks the ability by itself to reward high-quality healthcare, and oncology is no exception.

Various payers, both large and

Across the country, great new payment models are under way. As these models are being modified to optimally reward quality and patient-centered care, their expansion is inevitable. n

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FDA Update Ibrutinib Approved... Continued from page 26 clinical trial of 391 previously treated patients with CLL; of these, 127 patients had CLL with 17p deletion. Participants were randomized to ibrutinib or to ofatumumab until disease progression or until side effects became intolerable.

The trial was stopped early after an interim analysis showed that patients receiving ibrutinib had a 78% improvement in PFS and a 57% OS benefit.

Among the 127 patients with CLL plus 17p deletion, those receiving ibrutinib had a 75% improvement in PFS. Ibrutinib was previously approved for the treatment of patients with mantle-­cell lymphoma.

Ofatumumab Approved for Patients with CLL On April 17, 2014, the FDA approved ofatumumab (Arzerra Injection; Glaxo­ SmithKline), in combination with chlorambucil, for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.

The approval was based on the results of a multicenter, randomized, open-label trial comparing ofatumumab in combination with chlorambucil versus chlorambucil alone. A total of 447 patients were included in the study and fludarabine-based therapy was deemed inappropriate for them because of advanced age or comorbidities. Overall, 72% of patients had ≥2 comorbidities, and 48% had a creatinine clearance of <70 mL/min.

The primary end point of the trial was PFS as assessed by a blinded independent review committee. The median PFS was 22.4 months (95% confidence interval [CI], 19-25.2) in patients receiving ofatumumab plus chlorambucil compared with 13.1 months (95% CI, 10.6-13.8) in patients receiving chlorambucil alone (hazard ratio, 0.57; 95% CI, 0.45-0.72; P <.001).

The most common adverse reactions (≥5%) reported with ofatumu­mab plus chlorambucil were infusion reactions, neutropenia, asthenia, headache, leukopenia, herpes simplex, lower respiratory tract infection, arthralgia, and upper abdominal pain. Overall, 67% of the patients who received ofatumumab had ≥1 symptoms of infusion reaction.

In addition, 10% of patients had a grade ≥3 infusion reaction.

The recommended regimen for ofatumumab in patients with previously untreated CLL is 300 mg on day 1, followed by 1000 mg on day 8 (cycle 1), followed by 1000 mg on day 1 of the subsequent 28-day cycles, for a minimum of 3 cycles and a maximum of 12 cycles.

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Ramucirumab First Drug for Advanced Stomach Cancer On April 21, 2014, the FDA approved ramucirumab (Cyramza; Eli Lilly) for the treatment of patients with advanced stomach cancer or gastro­ esophageal junction adenocarcinoma.

Ramuciru­ mab is an angiogenesis inhibitor that is intended to be used in patients with unresectable cancer or with metastatic stomach cancer after receiving chemotherapy with a fluoropyrimidine- or a platinum-containing agent. This is the first FDA-approved therapy for patients with stomach cancer who have received chemotherapy.

Ramucirumab was approved under the FDA’s priority review program, and was also granted an orphan drug status, because it is intended to treat rare conditions.

The safety and efficacy of ramucirumab were demonstrated in a clinical trial of 355 patients with unresectable or metastatic stomach or gastroesophageal junction cancer. Patients were randomized to ramuciru­ mab (66%) or to placebo (34%). The main end point was OS. The median OS was 5.2 months with ramucirumab compared with 3.8 months with placebo (P <.001). Ramucirumab also improved patients’ PFS compared with placebo.

Results from a second clinical trial of ramucirumab plus paclitaxel versus paclitaxel alone also showed an OS improvement with the addition of ramucirumab.

Common adverse events reported with ramucirumab include diarrhea and high blood pressure. The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes until disease progression or unacceptable toxicity.

Zykadia for Metastatic, ALK-Positive Lung Cancer On April 29, 2014, the FDA approved ceritinib (Zykadia; Novartis) for the treatment of patients with metastatic, anaplastic lymphoma kinase (ALK)-positive non–small-cell lung cancer (NSCLC). Ceritinib is an ALK tyrosine kinase inhibitor that blocks proteins that promote cancer cell growth. The drug is approved for the treatment of patients with late-stage NSCLC who were previously treated with crizotinib, the first and only other ALK tyrosine kinase inhibitor approved by the FDA. The FDA approved ceritinib under its accelerated approval process, 4 months ahead of its scheduled final review date, to expedite access to this drug for a patient population with a

life-threatening condition and very few treatment options.

The safety and efficacy of ceritinib were established in a clinical trial with 163 patients with metastatic, ALK-positive NSCLC. All patients received ceritinib: approximately 50% of the patients had their tumor shrink with this therapy, and this result lasted an average of approximately 7 months.

The reported side effects were mainly gastrointestinal, such as diarrhea, nausea, vomiting, and abdominal pain. Laboratory abnormalities included increased liver enzymes and pancreatic enzymes, as well as increased glucose levels.

Palonosetron Indicated for CINV Prevention in Pediatric Patients On May 28, 2014, the FDA approved a new indication for palonosetron HCl (Aloxi; Eisai) injection for the prevention of acute chemotherapy-induced nausea and vomiting (CINV) associated with initial or repeated courses of emetogenic chemotherapy in children aged 1 month to <17 years. This is the first FDA approval of a therapy for the prevention of acute CINV in patients aged 1 month to 6 months.

The FDA approval was based on 1 randomized, double-blind, noninferiority pivotal trial comparing palonosetron with ondansetron in pediatric patients. The primary end point was complete response (CR), defined as no vomiting, retching, or antiemesis rescue medication required within the first 24 hours after chemotherapy.

CR was achieved in 59.4% of the patients using palonosetron compared with 58.6% of patients receiving ondansetron.

The trial also showed that pediatric patients required a higher dose of palonosetron based on weight than that required by adults. The most frequently reported adverse event with palonosetron was headache.

Palonosetron HCl is already approved for the prevention of CINV in adults aged ≥17 years.

Belinostat Approved for Peripheral T-Cell Lymphoma On July 3, 2014, the FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) for the treatment of patients with peripheral T-cell lymphoma (PTCL), a rare and fast-growing type of non-Hodgkin lymphoma (NHL). The approval was done under the agency’s accelerated approval program. PTCL comprises a diverse group of rare diseases in which lymph nodes become cancerous. PTCL represents approximately 10% to 15% of NHL cases in North America.

Belinostat works by preventing the development of T-cells from becoming cancerous. The drug is approved for use in patients with relapsed or refractory PTCL. According to the FDA, this is the third drug approved since 2009 for this indication.

The safety and effectiveness of bel­ inostat were evaluated in a clinical trial involving 129 patients with relapsed or refractory PTCL. All patients received belinostat until disease progression or until their side effects became unacceptable. The results showed that 25.8% of patients had complete or partial response after treatment.

The most common side effects seen with belinostat were nausea, fatigue, fever, anemia, and vomiting.

Belinostat also received orphan drug designation by the FDA, because it is intended for the treatment of patients with PTCL, which is a rare disease.

Idelalisib Approved for 3 Types of Hematologic Cancers On July 23, 2014, the FDA approved idelalisib (Zydelig; Gilead Sciences) for the treatment of patients with relapsed CLL to be used in combination with rituximab. Idelalisib is recommended for use in this patient population in those for whom rituximab alone would be considered inappropriate therapy because of potential comorbidities.

Also on July 23, the FDA granted idelalisib an accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL), as well as relapsed small lymphocytic lymphoma (SLL). Idela­ lisib is intended to be used in patients who have received at least 2 previous systemic therapies.

Idelalisib’s safety and effectiveness for relapsed CLL were established in a clinical trial of 220 patients with this condition who were randomized to receive idelalisib plus rituximab or placebo plus rituximab. The trial was stopped after the first prespecified interim analysis point, which showed that the active combination resulted in 10.7 months PFS compared with approximately 5.5 months with rituximab plus placebo.

The safety and effectiveness of idela­ lisib in the treatment of FL and relapsed SLL were established in a clinical trial with 123 patients with indolent non-Hodgkin lymphomas. Results showed a 54% objective response rate (ORR) in patients with relapsed FL and 58% ORR for patients with SLL. Idelalisib carries a Boxed Warning regarding the risk of fatal and serious toxicities. The drug was also approved with a REMS (Risk Evaluation and Mitigation Strategy) program. n

august 2014

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31

Kyprolis® (carfilzomib) for Injection

Now Has a Permanent J Code: J9047

Takes Flight

For more information Visit KYPROLIS.com/HCP

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. ©2013 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1112-CARF-436R1

December 2013