VBCC September 2014, VOL 5, NO 7 by Value-Based Cancer Care

SEPTEMBER 2014 VOL 5 NO 7

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

Oncologists Can Become Value- Financial Toxicity: Based Providers Using Evidence The Elephant in the to Guide Patient Care (Side Effect) Room By Wayne Kuznar

Chicago, IL—Oncologists 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, Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia, at the 2014 American Society of Clinical Oncology meeting, during a session Ezekiel J. Emanuel, MD, PhD on defining value from different stakeholder perspectives. “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.” Costs of Care a Key Concern The $3 trillion that the United States spent on healthcare in 2013 is more Continued on page 10

PD-1 Monoclonal Antibodies Usher in the Era of Immunotherapy in Oncology Oncologists’ enthusiasm echoed by FDA approval of pembrolizumab By Dana Butler

ncologists’ excitement about the promise of immunotherapy is about to be tested in clinical practice, with the recent FDA approval of pembrolizumab (Kytruda; Merck), the first anti–programmed death receptor-1 (PD-1) monoclonal antibody (see article, page 16). New data were presented for the monoclonal PD-1 antibodies, especial-

ly for nivolumab and pembrolizumab, at the 2014 American Society of Clinical Oncology (ASCO) meeting and in subsequent publications. Early Pembrolizumab Data Used by FDA Data presented at ASCO 2014 for pembrolizumab came from the phase 1b KEYNOTE-001 dose-finding study Continued on page 27

Barry D. Brooks, MD Chair, US Oncology P&T Committee McKesson Specialty Health, Texas Oncology

e have all had that patient— the patient who is prescribed a new targeted therapy and cannot comply with it because it is just too expensive. When asked directly about the reasoning for the noncompliance, the patient suggests that taking the treatment is just

too expensive and, in fact, it is cheaper to die. Financial Toxicity Is a Medical Side Effect In 2013, Zafar, Ubel, and their Duke colleagues, introduced a new term for an important, frequently undisclosed

Continued on page 8

FOURTH CONFERENCE

Next-Generation Sequencing Provides Value to Multiple Stakeholders By Wayne Kuznar

Los Angeles, CA—An understanding of the genomic drivers of cancer and linking therapy to these genetic alterations provides value to all stakeholders, including oncologists,

payers, researchers, and patients, said Gary Palmer, MD, JD, MBA, MPH, Senior Vice President of Medical Affairs at Foundation Medicine. Nextgeneration sequencing is the best way Continued on page 30

INSIDE VALUE PROPOSITIONS . . . . . . . . . . 2 new mutations causing lung cancer resistance identified Kaiser implements value-based care

DEFINING VALUE IN ONCOLOGY . . Should oncologists weigh society’s interests in patient care? Involving patients in value discussions

FDA DRUG APPROVALS . . . . . . . . . 16 Pembrolizumab first anti–PD-1 approved ECONOMICS OF CANCER CARE . . 19 Cost burden follows patients into survivorship

IN THE LITERATURE . . . . . . . . . . . . . . . . . . 21 Enzalutamide extends survival in mCRPC PERSONALIZED MEDICINE . . . . . . 28 Oncologists show low confidence in genomic testing 4TH CONFERENCE . . . 30 Predictive versus prognostic testing CER helps define value in cancer care MELANOMA . . . . . . . . . . . . . . . . . . . 37 BRAF protein marker for mortality risk? DRUG UPDATE . . . . . . . . . . . . . . . . 40 Arzerra receives FDA approval for CLL

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

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

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

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*

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

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

Advance Care Planning

VALUE PROPOSITIONS Study Identifies 2 Novel Mutations Responsible for Lung Cancer Resistance and How to Overcome It

The discovery of 2 new mutations in patients with non–small-cell lung cancer (NSCLC) that are the cause of resistance in some patients whose disease does not respond to current targeted therapies has charted the way for overcoming resistance in this patient population. This discovery comes from a new study (funded by the National Cancer Institute and the Japan Society for the Promotion of Science) that investigated the reason why ALK-positive lung cancer becomes resistant to alectinib, a new-generation ALK inhibitor that was recently approved in Japan and received a Breakthrough Therapy designation by the FDA. “We discovered two novel mutations that have not been described before in patients with NSCLC, and these mutations conferred high-level resistance to alectinib,” said lead investigator Alice T. Shaw, MD, PhD, thoracic oncologist, Massachusetts General Hospital Cancer Care, Boston. “Another equally important finding from this study is that we were able to find a way to overcome this type of resistance…using another next-generation ALK inhibitor, ceritinib.” Dr Shaw added, “There are eight next-generation ALK inhibitors that have entered the clinic, and our results show that ALK-positive lung cancer patients may benefit from multiple, sequential ALK-inhibitor therapies depending on the underlying resistance mechanism.” The discovery of these 2 novel mutations, and how to overcome the resistance they cause, reinforce the value of genomic testing and personalized medicine in the clinical practice setting. American Association for Cancer Research press release; September 16, 2014

Kaiser Permanente Implements Value-Based Care/Payment Model

In an exclusive interview with FierceHealthPayer, Jack Cochran, MD, Executive Director of the Permanente Federation, discussed the benefits in implementing value-based care and a payment model at Kaiser Permanente, which represents a partnership between a healthcare delivery entity, hospitals, and the Kaiser health plan. “For our care to be value-based, we think of how many people we have to take care of, and then we figure how much it’ll cost….We think in terms of the entire package, the physicians and their staff, and decide how much we will need to expense them,” Dr Cochran said. The move toward value-based payment required an enhanced focus on data measurement across the entire health plan. Establishing tools to measure data and care transparency is crucial for improving outcomes, which, in turn, can reduce costs. “Doing the right thing will also be the best thing to make sure care is affordable,” he said. Kaiser has moved away from the fee-for-service model, in which providers are paid for each service rendered, and is moving to value-based payment (VBP). “At Kaiser Permanente, under a VBP model, we look at the process of care, which may not entail classically codeable events. We pay them [providers] for their intellect, not for what is just codeable,” Dr Cochran elaborated. He noted that avoiding misuse and errors will help to generate the savings in healthcare that everyone is concerned about. The quality of care must be the focus of healthcare for all, he said. “The entire industry needs to shift its focus on quality at a reasonable cost for families.” Dori Zweig, FierceHealthPayer; August 1, 2014

UK National Health Services Increases Funds for Cancer Drugs Research

At a time when the US government has downsized its financial support for cancer research, the UK’s National Health Services (NHS) announced it was increasing the annual funding it provides to the Cancer Drugs Fund from £200 million to £280 million. “We welcome the moves the Government is taking to increase access to innovative cancer medicines. It is critical that our systems for making new

VALUE-BASED CANCER CARE

SEPTEMBER 2014

drugs available on the NHS take into account how innovative a drug is, as opposed to simply giving the green light to ‘me too’ drugs that replicate the functions of others already available,” said Paul Workman, Interim Chief Executive of the Institute of Cancer Research, London. “Making more money available to the Cancer Drugs Fund and using it in a more targeted way could significantly improve access to important new treatments like abiraterone, which was discovered at The Institute of Cancer Research, and was recently turned down by NICE [National Institute for Health and Care Excellence] for use in patients pre chemotherapy.” The Institute of Cancer Research press release; August 28, 2014

NIH Launches Second Personalized Medicine Clinical Trial in Lung Cancer

The National Institutes of Health (NIH) announced the launch of the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) to investigate the value of targeted therapies in patients with early-stage lung cancer associated with genetic mutations. ALCHEMIST is the second personalized medicine clinical trial launched as part of the new National Clinical Trials Network (NCTN), which is supported by the National Cancer Institute (NCI). The first NCTN trial was launched in June 2014 and targets patients with advanced squamous-cell lung cancer. ALCHEMIST includes 3 complementary component trials that together will provide important information for patients with few treatment options. The 3 components are (1) a screening trial, (2) a treatment trial for patients with EGFR mutations, and (3) a treatment trial for patients with rearrangements in the ALK gene. Each trial is listed as an independent trial at cancer. gov/clinical trials (ie, NCT02194738, NCT02193282, and NCT02201992, respectively). “We believe that the findings from ALCHEMIST will not only help answer an important question about the addition of targeted therapies in earlier-stage disease, but will also help us in understanding the prevalence and natural history of these genomic changes in earlier-stage lung cancer. We also hope to gain a better understanding as well regarding the genetic changes in the tumor at the time of recurrence,” said Shakun Malik, MD, Head of Thoracic Cancer Therapeutics in the Clinical Investigations Branch of the NCI. “The findings will help to define clinical, biologic and molecular behaviors of this type of lung cancer.” All patients enrolled in the ALCHEMIST component trials will have to undergo surgical removal of their tumors. Eligibility criteria include having been diagnosed with lung adenocarcinoma or similar types of lung cancer, and receiving standard therapy after the surgical removal of the tumor that consists of chemotherapy with or without radiation therapy, as prescribed by the patient’s physician. In the ALCHEMIST screening trial, the surgically removed tissue will be tested for changes in the ALK and the EGFR genes. Patients with EGFR mutations or rearrangements of the ALK gene will be enrolled in 1 of the 2 randomized, placebo-controlled treatment component trials according to their specific genetic alterations. The 2 treatment trials will evaluate the value of using a therapy that has been approved by the FDA for patients with lung cancer and a genetic alteration. The specific therapies to be investigated are erlotinib (Tarceva), which is FDA approved for patients with EGFR genetic mutations, or crizotinib (Xalkori), which is FDA approved for patients with rearrangements in the ALK gene. Although these 2 agents are indicated for the treatment of patients with advanced lung cancer and the respective genetic alterations, it is not known whether they can prevent cancer recurrence in individuals who are free of disease (in this case, after their tumor was surgically removed). The goal is to determine whether erlotinib or crizotinib will prevent lung cancer recurrence, as well as prolong survival. The trials also involve other clinical aspects that will address survival, DNA sequencing, and genomic analysis. The intent is to enroll 800 patients who fit the eligibility criteria. Patients will be followed up for 5 years. National Institutes of Health press release; August 18, 2014

VOL. 5

NO. 7

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

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Melissa Lawlor THE LYNX GROUP

THE PATIENT PERSPECTIVE

IN THE LITERATURE

Financial toxicity: the elephant in the (side effect) room

Enzalutamide extends survival in mCRPC Lenalidomide plus R-CHOP improves outcomes in lymphoma More…

VALUE PROPOSITIONS NIH launches second personalized medicine lung cancer trial More…

PERSONALIZED MEDICINE Oncologists unsure about genetic testing

DEFINING VALUE IN ONCOLOGY Determining when a treatment is clinically meaningful Oncologists must begin to address value More…

4TH CONFERENCE The value of next-generation sequencing Establishing standards and access to quality care More…

MELANOMA

FDA UPDATE Pembrolizumab approved for advanced melanoma Bortezomib indicated for retreatment of myeloma

Noninvasive imaging distinguishes between benign/malignant skin lesions More…

Human Resources Jennine Leale

ECONOMICS OF CANCER CARE

Associate Director, Content Strategy & Development John Welz

Cost burden follows patients into survivorship More…

DRUG UPDATE

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly

Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

VBCC Editorial Board

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Manager Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 10 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

NO. 7

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care  San Francisco, CA

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

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD President W-Squared Group Longboat Key, FL

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

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

VOL. 5

Arzerra receives FDA approval for previously untreated CLL

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

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com • Telephone: 732-992-1891 • Fax: 732-992-1881. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

SEPTEMBER 2014

www.ValueBasedCancerCare.com

The Patient Perspective

Financial Toxicity: The Elephant in the (Side Effect)...

See article on page 12

Continued from the cover

side effect of modern cancer therapy: financial toxicity.1-3 They persuasively argued that financial toxicity should be treated like any medical side effect, because it is as likely as any physical toxicity to cause noncompliance with a prescribed regimen. I enthusiastically embraced the term and began using it in my everyday lexicon with patients, payers, and my colleagues. Unfortunately, after the 3 publications from the Duke team in 2013, “financial toxicity” has not found its way into publications and essays that focus on the financial burden resulting from increasing copays, coinsurance, and high deductibles introduced in the Affordable Care Act era. A poignant study by Dusetzina and colleagues published this year reported that commercial patients with chronic myelogenous leukemia (CML) and higher copays were 70% more likely to abandon therapy than similar patients with lower copays (17% vs 10%, respectively).4 CML is compatible with a normal life expectancy if a patient takes the close to a miracle drug imatinib (Gleevec), but CML is typically lethal within 5 to 6 years if one does not take it.4 Despite this clear clinical benefit, at 6 months, the patients in the highest quartile copay discontinued therapy 70% more often, even though the mean copay differential was only $36 monthly.4 For a drug that offers patients a functional cure, this level of price sensitivity is truly surprising. Imatinib is generally well tolerated and was abandoned in these patients for its financial toxicity, not for its gastrointestinal or bone marrow toxicities. What is the scale of this problem? In the study by Zafar and colleagues, 42% of the 254 patients reported substantial financial burden.1 To conserve money, “20% took less than the prescribed amount of medication, 19% partially filled prescriptions, and 24% avoided filling prescriptions altogether.”1 Although this study was enriched with patients seeking copay assistance, almost 66% of the patients were not taking their medication as prescribed because of a single, largely unaddressed, side effect: financial toxicity.1 Similarly, a study by Fenn and colleagues concluded that “increased financial burden as a result of cancer care costs is the strongest independent predictor of poor quality of life among cancer survivors.”5

Barry D. Brooks, MD

The patients in the highest quartile copay discontinued therapy 70% more often, even though the mean copay differential was only $36 monthly. Oncologists often avoid talking about the cost of the treatments that they prescribe, because they lack granular knowledge of an individual patient’s financial burden and the skills needed to negotiate this dimly lit part of oncology practice, preferring to say, “That’s not my job.” Addressing a side effect that caused more than 50% of patients to not take

to be covered under the more generous medical part of a patient’s insurance, whereas oral medications are frequently covered under the prescription benefit. Less costly prescriptions at the first and second tiers of benefits usually require a modest copay of $0 to $10 for the first tier and perhaps $20 to $40 for the second tier. Treatments for cancer are frequently in a third tier, in which benefits switch from a copay (a fixed dollar amount) to coinsurance (a percent of total cost). For example, a postmenopausal patient with breast cancer may have no copay for tamoxifen, a $30 copay for anastrozole, and coinsurance payment of $3000 (total cost $9000) for everolimus (Afinitor). Oral oncolytics now make up approximately 25% of our therapies for cancer, but more than 50% of new oncology drug approvals are oral medications. Oral oncolytics are never inexpensive, with new ones typically priced at $7000 to $10,000 monthly. Gone are the days when an oncologist can hand a patient a prescription and then breeze into the next examination room. Instead, oncologists need to wade deeper into the sometimes messy engagement known as the doctor–patient relationship and discuss the financial challenges associated with the treatment being prescribed. If a patient reports that he or she cannot afford a treatment, and if there is no copay assistance available, the oncologist should be willing to discuss less costly alternative therapies. Prescribing less than the best therapy for a patient is extremely uncom-

Addressing a side effect that caused more than 50% of patients to not take a medication as prescribed would certainly be considered part of an oncologist’s job, if that toxicity were other than financial. a medication as prescribed would certainly be considered part of an oncologist’s job, if that toxicity were other than financial. The point is that financial toxicity is a medical toxicity: if patients do not take their medication, they cannot benefit from it. Insurance Coverage and Noncompliance Noncompliance is more common with oral oncolytics than other types, because parenteral medications tend

VALUE-BASED CANCER CARE

SEPTEMBER 2014

fortable for the majority of oncologists, but we should not let the perfect be the enemy of the good. For example, for many years, I have substituted tamoxifen (Nolvadex) for an aromatase inhibitor in financially challenged patients with postmenopausal luminal A-type breast cancer. The benefit of these drugs is very similar, but before the availability of generic options for aromatase inhibitors, the difference in price was approximately 100-fold between the 2

drug classes. In this circumstance, most financially strapped patients have been willing to trade 1% or 2% of clinical benefit for affordability. However, with a disease such as CML, no inexpensive alternative medication is currently available. All an oncologist can do in such a case is to help the patient obtain copay assistance. Payers, including Medicare, should create a new class of drug coverage for critical oral oncolytics that require only a modest copay.

Payers, including Medicare, should create a new class of drug coverage for critical oral oncolytics that require only a modest copay. Although payers acknowledge this decidedly patient-unfriendly aspect of their coverage, no comprehensive programs to address this increasing burden have been put forward. Drug makers are part of this problem as well. Although many companies have good patient-assistance programs, new drugs always cost more than the ones they replace. When oncologists prescribe costly new regimens, they should begin discussing the potential for financial toxicity just as they discuss the potential for any other unavoidable medical side effect. Perhaps this simple act will begin to draw attention to the proverbial elephant in the room that is responsible for more patients’ poor compliance with prescribed cancer regimens than any other medical side effect. Patients with cancer can never be cured by a medication they cannot afford to take. Financial toxicity is everyone’s problem. Having a name for our pain does not remedy the problem, but it is a start. n References

1. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient’s experience. Oncologist. 2013;18:381-390. 2. Ubel PA, Abernethy AP, Zafar SY. Full disclosure—out-of-pocket costs as side effects. N Engl J Med. 2013;369:1484-1486. 3. Bath C. Disclosing medical costs can help avoid ‘financial toxicity.’ ASCO Post. 2013;4. 4. Dusetzina SB, Winn AN, Abel GA, et al. Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol. 2014;32:306-311. 5. Fenn KM, Evans SB, McCorkle R, et al. Impact of financial burden of cancer on survivors’ quality of life. J Oncol Pract. 2014 May 27 [Epub ahead of print].

VOL. 5

NO. 7

Defining Value in Oncology

Should You Consider the Interests of Society at Large When Treating the Individual Patient? Oncologists debate value-based moral questions of patient care By Wayne Kuznar Chicago, IL—With 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 the 2014 American Society of Clinical Oncology (ASCO) meeting. 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 more than $30,000 monthly or per treatment cycle. These ballooning costs in cancer care present an ethical dilemma for oncologists and for society. Oncologists’ Ethical Dilemmas The professional norm that says

at a glance ➤ With the ever-rising costs of cancer care, oncologists are faced with the dilemma of balancing their duties to individual patients and to society at large ➤ Patients trust their doctors to treat them on an individual basis, not for the physician’s own benefit or for the good of society ➤ Patients must trust their oncologists to do the best for them in light of available resources ➤ With finite healthcare resources, the question is not whether to ration resources, but how to ration them ➤ Oncologists owe it to society to ensure that resources are allocated, and to reduce waste to maximize value ➤ Oncologists’ focus should be on reducing healthcare waste, improving efficiency, and developing a strong evidence base to assess value

VOL. 5

NO. 7

“”

Oncology providers are faced with balancing their duties to individual patients and society. —BEVERLY MOY, MD, MPH

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, De partment 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 moral intuitions, as well as to reduce waste to maximize the value of our interventions,” said Dr Jagsi. “Physician stewardship of society’s scarce resources is best accomplished at the societal 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 evidence base for the assessment of value, includ-

ing 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. Patient-Centered Care The professional ethic of medicine is patient-centered, countered Daniel P. Sulmasy, MD, PhD, Associate Director of the McLean Center for Clinical Medical Ethics, University of Chicago, in which the goal of the clinical encounter is to promote the good of the individual patient. Patients must trust that oncologists will do the best for them in light of the available resources. “Questions of justice might arise regarding the

“

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.

”

—DANIEL P. SULMASY, MD, PHD other goods. “The existential situation of sickness demands that patients be able to trust that their doctors are applying this public good for their

“

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

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,” Dr Sulmasy said. Economists suggest that medicine is a public good, he said, given the necessity of health for access to many

SEPTEMBER 2014

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 pointed out. n

www.ValueBasedCancerCare.com

Defining Value in Oncology

Oncologists Can Become Value-Based Providers...

at a glance ➤ Achieving value-based cancer care requires a change in the payment system ➤ Unnecessary testing and use of expensive therapies are encouraged by rewarding oncologists for each service rendered ➤ When a therapeutic equivalent exists at a lower cost, oncologists must use it ➤ Oncologists should want to get out of the fee-for-service system, so they can focus on the patient

“

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

than the entire economy of France, which is the fifth largest economy in the world, said Dr Emanuel. The amount spent on cancer care represents approximately 50% more than what will be spent on expanding insurance coverage under the Affordable Care Act. Yet, the median household income in the United States 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 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. Part of the prob-

”

—EZEKIEL J. EMANUEL, MD, PHD

lem is the large sums of money being spent on cancer drugs for a few additional months of survival. But even drugs that provide cures— such as sofosbuvir (Sovaldi) 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

“

One drug for cancer care can wipe out the median income of a household.

”

—EZEKIEL J. EMANUEL, MD, PHD

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 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 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 (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

Continued from the cover

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 A second obligation is to prescribe the lowest-cost treatment when therapeutically equivalent alternatives exist. “We have lots of places in cancer where we have therapeutic equivalent and wide variation in cost,” Dr Emanuel stressed. “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 lowestcost treatment.”

The $84,000 price tag seems for sofosbuvir, 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.

“

”

—EZEKIEL J. EMANUEL, MD, PHD 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

Determining When a Treatment Is Clinically Meaningful Weighing therapeutic value and cost impact By Dana Butler Chicago, IL—At the 2014 American Society of Clinical Oncology (ASCO) meeting, Jennifer Malin, MD, PhD, Medical Director of Oncology at WellPoint, Inc, discussed what makes certain treatments clinically meaningful and others less so. She discussed studies presented at the meeting that are good examples of value in cancer care and studies that show no value. Dr Malin based her discussion on the criteria that ASCO recently pro-

posed for evaluating clinical trial results with or without “clinically meaningful outcomes” (Ellis LM, et al. J Clin Oncol. 2014;32:1277-1280). These criteria consider the tumor type and the initial treatments used to evaluate whether a new regimen for metastatic cancer demonstrates improvement in median overall survival (OS) from 2.5 months to ≥6 months. “Powering studies to achieve these end points would be worth consider-

VALUE-BASED CANCER CARE

SEPTEMBER 2014

ation. 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,” Dr Malin noted. She discussed 2 studies presented at the meeting that showed clear value, unlike many others that did not. Examples of Value One of the 2 studies showing clini-

cally meaningful outcomes was a phase 2 study of a subset of patients with lymphoma and poor prognosis and 1 study that included patients with early-stage, HER2-positive breast cancer. The 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) Continued on page 12

VOL. 5

NO. 7

Christine Celgene Patient Support® Specialist

Your single source for personal support

Celgene Patient Support® offers you and your patients financial assistance and insurance-related services from a single Specialist assigned to your area. Co-pays for Celgene medications are reduced to $25 or less for eligible patients. Celgene Commercial Co-pay Programa

Financial assistance through third-party organizations

Celgene Free Medication Programa

Help with locating transportation assistance

Call Celgene Patient Support® at 1-800-931-8691 Monday – Friday, 8 AM – 7 PM ET

Online enrollment now available at www.celgenepatientsupport.com Or e-mail us: patientsupport@celgene.com a

Subject to eligibility requirements.

08/14

US-CELG140179a

Defining Value in Oncology

Determining When a Treatment Is Clinically...

Continued from page 10

appeared to reduce the negative prognostic significance of the nongerminal center B-cell (GCB) phenotype (a subset of DLBCL). At 2 years, progression-free survival (PFS) for this subset was 50%, and OS was 75% with the “R2CHOP” regimen, mirroring outcomes in the patients with GCB. This represented a 2-year relative increase in OS of 30%, 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

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.”

“

Trastuzumab clearly provides tremendous value for these patients, at a total drug cost of $81,336 and incremental cost of $76,601. It may have limited value, however, in the group with 0 to 1 positive nodes.

at a glance ➤ A new drug showing a 2-year relative increase in OS of 30%, at an estimated total cost of $73,682, and an incremental cost of $26,540 has value for patients ➤ By contrast, a new drug with limited to no improvement in outcomes, a total cost of $92,410, and an incremental cost of $32,521 has no value for patients ➤ When new drugs today cost $170,000, they should show significant improvements in outcomes to demonstrate value ➤ Oncologists could use such data to have meaningful conversations with patients about treatment options

”

—JENNIFER MALIN, MD, PHD

of 5 randomized trials of adjuvant trastuzumab. The analysis focused on 4220 HER2-positive patients with tumors ≤2 cm (mostly lymph node– positive), a group for whom the benefit of trastuzumab has not clearly been established. Commenting on this study, Ciara C. O’Sullivan, MD, of the National Cancer Institute, Bethesda, MD, said that trastuzumab reduced disease recurrence and mortality by approximately 30% in all groups, except in patients with 1 or no positive lymph nodes: their mortality risk was reduced by only 2%. “Trastuzumab clearly provides tremendous value for these patients, at a

Studies Showing No Value Among the studies that showed no clinically meaningful outcomes, and therefore no value, was a phase 1 study of escalating doses of cabozantinib plus abiraterone in patients with castration-resistant prostate cancer. In this study, a prostate-specific antigen decline of >75% was observed in 63% of the men who received the 20-mg dose and in 13% of the men receiving 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.” However, according to Dr Malin, these 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 trastuzu mab 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 paclitaxel 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,

Involving Patients in the Value Discussion in Oncology

we need to look for significant improvements in outcomes,” she commented. Value Discussions with Patients Oncologists could use such data to have more meaningful conversations with patients about treatment options, Dr Malin suggested.

“

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.

”

—JENNIFER MALIN, MD, PHD

“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 by Weeks and colleagues published in the New England Journal of Medicine in 2012 showed that approximately 25% of patients with advanced lung cancer and approximately 35% of patients with advanced colorectal cancer believed it was “very likely” that their cancer therapies could actually 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

See also VBCC Perspective, page 1

By Robert Osborne

Chicago, IL—Involving patients in the search for value in cancer care requires a better understanding of value and the development of more effective communication and teaching aids, according to a presentation at the 2014 American Society of Clinical Oncology (ASCO) meeting about defining value from different stakeholder perspectives.

The challenge begins with arriving at a definition of value that provides a common ground for all stakeholders, said Diane Blum, MSW, former Editor-in-Chief of Cancer.net and a member of ASCO’s Value in Cancer Care Task Force. Ms Blum’s personal preference is a definition that emphasizes the need to find a common ground

VALUE-BASED CANCER CARE

SEPTEMBER 2014

around value for patients, their families, physicians, and payers. Characteristics unique to cancer care further complicate efforts to define value, Ms Blum continued. In contrast to other health problems, a diagnosis of cancer evokes emotions that center on the life-threatening nature of the disease and a sense of urgency to man-

age the threat. It creates an imperative to bring in more therapies, particularly new therapies, to fight the threat of cancer. Often, a reluctance to stop active treatment influences the clinical decision-making. “Value of treatment, and what it means to the patient, is influenced by this very emotional response to the Continued on page 14

VOL. 5

NO. 7

Metastatic Cancer... If the origin is uncertain or unknown… is it really a diagnosis?

Not for your patient.

An advanced microRNA-based testing service from Rosetta Genomics … enabling a personalized approach to cancer treatment. Introducing the Rosetta Cancer Origin Test™, which may help accurately identify your metastatic patient’s cancer origin using advanced and proven microRNA technology. The Rosetta Cancer Origin Test™ identifies about 95% of all cancer origins with 90% sensitivity1. The Cancer Origin Test has the highest concordance with final clinicopathological diagnosis at world-renowned centers of excellence2.

The Rosetta Cancer Origin Test™ may help: • When you have patients with metastatic cancer of uncertain or unknown origin • When a patient with metastatic cancer fails to respond as expected to treatment • If there is atypical presentation or discordant findings • When a basic IHC panel does not yield a definitive diagnosis • When evaluation costs need to be managed • When family members fear genetic links to certain cancers

To learn more please visit RosettaGenomics.com or call us: 1.888.522.7971 | 1.215.382.9000 REFERENCES 1. Meiri E, Mueller WC, Rosenwald S, et al. A second-generation microRNA-based assay for diagnosing tumor tissue origin. Oncologist. 2012; 17:801-812. 2. Pentheroudakis G, Pavlidis N, Fountzilas G, et al. Novel microRNA-based assay demonstrates 92% agreement with diagnosis based on clinicopathologic and management data in a cohort of patients with carcinoma of unknown primary. Mol Cancer. 2013;12:57. Rosetta Genomics and Rosetta Cancer Origin Test are trademarks of Rosetta Genomics, Ltd. ©2013 Rosetta Genomics, Ltd. All rights reserved. Rosetta Genomics is CAP Accredited and CLIA Certified. RG- 24.0.0.15 Rev2 1/14

Defining Value in Oncology

Involving Patients in the Value Discussion... diagnosis,” said Ms Blum. Value in cancer care is a dynamic process, influenced by hopes and expectations that change throughout the disease continuum and require regular reassessment. Perception of value changes as care transitions from curative to palliative. In many cases, value rests in the effort put forth and not only in clinical response, Ms Blum said. The Patient’s Perspective From the patient’s perspective, the definition of value incorporates multiple considerations that can vary in

at a glance ➤ Involving patients in the value discussion in oncology requires a better understanding of value and effective communication ➤ Medical expenses are the leading cause of personal bankruptcy, and the cost of cancer care tops all others ➤ Financial toxicity is as serious as drug toxicities and can lead to nonadherence ➤ Oncologists must recognize the financial burdens that cancer places on patients and, when appropriate, discuss the use of lower-cost therapies and financial assistance ➤ A treatment plan that is agreeable to the physician and the patient should take into account the patient’s preferences and goals

Photo by © ASCO/Todd Buchanan 2009

Continued from page 12

“

Value of treatment, and what it means to the patient, is influenced by this very emotional response to the diagnosis.

”

—DIANE BLUM, MSW

importance from one patient to another, including clinical benefit, side effects, quality of life, cost, and individual preferences. Cost is the driving factor in the search for value in cancer care. The high cost of cancer care has given rise to the concept of “financial toxicity.” “We’ve all known for years that people have financial burdens from cancer, but they have gotten worse in recent years,” said Ms Blum. “There has been so much more in terms of cost-sharing, through premiums, through copays, through coinsurance and deductibles.” “Financial toxicity, in terms of the

long-term effects on the family, is as serious as other toxicities of cancer,” she added. Medical expenses are the leading cause of personal bankruptcy in the United States, and the cost of cancer care tops all others, Ms Blum said. Financial distress can lead to nonadherence or to the need to compromise on necessities brought about by medical expenses. Providers should recognize the financial burdens imposed by cancer and should discuss with patients the potential for using lower-cost therapies when available, as well as sources of financial assistance. Shared decision-making includes helping patients understand cost at a time when many patients are feeling fearful and overwhelmed, said Ms Blum. Ms Blum cited an article that suggested that a cancer diagnosis for many patients is the “triple whammy”—bad news, having to discuss money with a doctor, and having to make choices that seem to involve choosing between money and survival (Ubel PA. Oncologist. 2010;15[suppl 1]:5-10). The Choosing Wisely program has encouraged physicians and patients to have conversations about value and cost, said Ms Blum. Choosing Wisely in oncology includes avoiding unnecessary therapy—even chemotherapy—that is unlikely to benefit patients with advanced solid tumors, and instead focuses on symptom relief and palliative care. She advised healthcare providers to involve patients in every phase of the care continuum. Shared decision-making includes asking patients about their preferences regarding what is

important to them. To the extent possible, treatment plans should attempt to incorporate the patients’ preferences and goals. “You can get all kinds of answers,” said Ms Blum. “‘My daughter is getting married in 6 months, and I have to be in good shape for that,’ or ‘My husband had a stroke and my treatment has to be determined by how much I can take care of him.’” The results of the discussion should be a treatment plan that is agreeable to the physician and patient, and is based on the application of evidence to the individual patient, Ms Blum added.

“

Financial toxicity, in terms of the longterm effects on the family, is as serious as other toxicities of cancer.

”

—DIANE BLUM, MSW

Much work remains to improve discussions with patients about value in cancer care, she concluded. Better measures of value are needed. Oncologists and patients need more education about value. Oncologists and patients need to have more communication about value, as well as more tools to aid the discussion. “Ideally, we are going to move to a system that has the high-quality, high-value care that we want and…a sustainable system for the patient today and the patient tomorrow,” Ms Blum said. n

Oncologists Must Begin to Address Value in Patient Care By Dana Butler

Chicago, IL—The topic of value in cancer care was addressed at a special session at the 2014 American Society of Clinical Oncology (ASCO) meeting. Lowell E. Schnipper, MD, Harvard Medical School, Boston, and Chair of the ASCO Task Force on Value in Cancer Care noted that value is not about the number of dollars spent but rather about the cost of a treatment to a patient, who may experience financial and physical toxicities. “We need to begin a conversation

VALUE-BASED CANCER CARE

“

We need to begin a conversation about what is the value for the patient—not the dollars expended, but how well we are doing for our patients. What is their physical and financial toxicity?

”

—LOWELL E. SCHNIPPER, MD

about what is the value for the patient—not the dollars expended, but how well we are doing for our patients. What is their physical and financial toxicity?” Dr Schnipper emphasized. Value Affected by Many Aspects of Care Dr Schnipper noted that the concept of value is centered around the patient, and the success of a value-based treatment is determined by the outContinued on page 15

SEPTEMBER 2014

VOL. 5

NO. 7

Defining Value in Oncology

Payment Reform Requires Abandoning the Fee-for-Service Approach Oncologists are urged to lead toward a system change By Robert Osborne Chicago, IL—The oncology community has taken a leadership role in payment reform and must retain that position as the pressure mounts for fee-for-service (FFS) alternatives, according to Mark B. McClellan, MD, PhD, Director, Health Care Innovation and Value Initiative, Brookings In stitution, Washington, DC, and former Commissioner of the FDA. Traditional payment models have focused on responding to higher costs with reductions in payments to physicians. Public and private payers have adopted the practices, which have failed to control costs. “The problem with these strategies is that they don’t work,” said Dr McClellan at an education session during the 2014 American Society of Clinical Oncology meeting. “They are increasingly out of step with many of the things that oncologists do to deliver better health and better quality care to their patients.” Dr McClellan noted that cancer care increasingly involves a team whose members provide a variety of services that are poorly reimbursed, such as care coordination, patient and fami-

ly engagement, communication with and education of patients, and the use of new technologies. These services revolve around the growing emphasis on patient-centered care to provide the most appropriate care for an indivi dual patient. Successful Features of a New Payment Model Feasible alternatives to the FFS payment model share some characteristics that are essential for the success of any future payment system, he said. A payment system must not require payers to assume too much risk, and must result in less growth in costs. The system also must not impose excessive risk on physicians. Risks should be well understood, and uncertainty must be kept to a minimum. A successful payment system must have a high likelihood of improving patient care and must have evidence for redirecting resources to highervalue uses, said Dr McClellan. As an example, he cited care planning to prevent complications and to avoid unnecessary services and services that patients do not want.

Oncologists Must Begin... comes, not by the volume of care. Patient-centered care is the key element in value-based care, and this is true in oncology as in other disciplines. Oncologists should “use all health-related resources in an appropriate manner that is resource-efficient. This implies doing our best for our patients,” he said. The elements that comprise value in patient care include variation in quality and outcomes, harm to the patient, waste, health disparities, and the failure to prevent disease. The Quality Oncology Practice Initiative should help to minimize variation in the quality of care. New models of payment reform are currently being tested by providers and payers to improve value-based care. Oncologists Wrestling with a Value System The goal is to create a transparent, clinically driven, methodological-

VOL. 5

NO. 7

“

Given that nobody trusts anyone in healthcare more than they trust their physicians, physician leadership is absolutely critical to success.

”

—MARK B. MCCLELLAN, MD, PHD

The plan must not be too hard to implement, he continued. The sys-

tem should have a manageable set of payment features and codes, have the support of payers and providers, and should align with other payer and physician activities. An alternative payment system has no chance to succeed without physician support. “Given that nobody trusts anyone in healthcare more than they trust their physicians, physician leadership is absolutely critical to success,” said Dr McClellan. “People aren’t going to trust the government, and they’re not going to trust their health plans when they say these changes are going to reform payment and lead to better results. They are going to believe their physicians.” Several alternatives already in place essentially represent add-on features to FFS payment, he continued. Examples include guideline-based treatment pathways and payments based on adherence to the pathways and guidelines. The patient-centered medical home also provides additional payment for meeting certain quality criteria. “What really matters is not just the payments to physicians, which acContinued on page 18

Continued from page 14

ly sound method for defining and assessing the relative value of care options in oncology, which ultimately would “drive change” among payers and industry and would 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. “And we want patients to have ready access to information that will help them understand the relative value of treatment options that meet their unique needs.” The tool would describe the different clinical scenarios, 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.

“

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

For example, for the first-line treatment of NSCLC, carboplatin (Paraplatin) plus paclitaxel (Taxol) yields a median OS of 8.2 months

SEPTEMBER 2014

and costs $374; cisplatin (Platinol) plus pemetrexed (Alimta) offers 10.3month survival and costs $6183; the combination of paclitaxel, carboplatin, and bevacizumab (Avastin) 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. The value algorithm will also consider the different toxicity profiles and the treatment setting, because similar degrees of drug-induced toxicity will be viewed differently in early disease and in metastatic disease. “Ultimately, we hope to finalize a way of quantifying with a numerical score, which ideally would summate to 100,” he said, and would be proportionate to the degree of benefit. The test will be whether this approach takes hold and develops traction, Dr Schnipper noted. n

www.ValueBasedCancerCare.com

FDA Drug Approvals FDA Approves First Anti–PD-1: Pembrolizumab Indicated for Advanced Melanoma

The FDA approved the first anti– programmed death receptor-1 (PD-1) therapy, pembrolizumab (Keytruda; Merck), for patients with unresectable or metastatic melanoma and disease progression after treatment with other melanoma therapy, such as ipilimu mab, or, for a patient with BRAF V600 mutation, after BRAF inhibitor therapy. The FDA accelerated its approval for pembrolizumab based on early clinical data from the KEYNOTE-001 phase 1b trial showing a high tumor response rate and long durability of response rather than on actual improvements in survival or in disease progression. Ongoing phase 2 and 3 clinical trials are being conducted to provide confirmatory information that is expected to demonstrate clinically meaningful improved outcomes, including potential improvement in survival and/or reduction in disease progression. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is the first-ever anti–PD-1 therapy to receive FDA approval. The FDA also granted pembrolizumab a breakthrough therapy designation for advanced melanoma based on the positive early results from the phase 1b trial in 173 patients with unresectable or metastatic melanoma whose disease progressed after previous therapy, reflecting an unmet medical need for this patient population. “The accelerated FDA approval of Keytruda is a meaningful development for patients with advanced melanoma,” said Omid Hamid, MD, Director of the Melanoma Center at the Angeles Clinic and Research Institute, and a principal investigator for the pembrolizumab melanoma clinical program. “Our new ability to target the PD-1 pathway with Keytruda is a very exciting step in the immunotherapy field.” The FDA approval was based on early results from the ongoing mul ticenter, open-label, randomized, dose-comparative KEYNOTE-001 phase 1b trial. A total of 89 patients received the 2-mg/kg dose every 3 weeks; other patients received different doses, including a 10-mg/kg dose, which was just as effective. Overall, 411 patients were included in this trial. The overall response rate in the 89 patients receiving the 2-mg/kg dose was 24% (95% confidence interval, 1534), including 1 complete response and 20 partial responses. At the time of the analysis, 86% of patients with ob-

jective responses had ongoing responses, with the duration of response ranging between 1.4 and 8.5 months. In addition, 8 of these patients are still showing ongoing responses of ≥6 months. All patients had received previous treatment with ipilimumab or a BRAF inhibitor in patients with a BRAF V600 mutation; the patients had disease pro-

VALUE-BASED CANCER CARE

25712_sundav_fa1_dino_vbcc.indd SEPTEMBER 2014

All Pages

gression within 24 weeks after the last dose of previous therapy. Patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of pembrolizumab every 3 weeks until unacceptable toxicity or until disease progression. The major efficacy outcomes analyzed were confirmed overall response rate and duration of response. The approved dosing schedule for

pembrolizumab is 2 mg/kg every 3 weeks, based on these early results from the KEYNOTE-001 phase 1b trial. Severe immune-mediated adverse events were uncommon. Pembroliz umab was discontinued because of adverse events in 6% of 89 patients receiving the 2-mg/kg dose, and in 9% of the 411 patients across all doses investigated in the phase 1b trial. Serious

VOL. 5

NO. 7

FDA Drug Approvals adverse reactions occurred in 36% of all the patients receiving this new immunotherapy. The most common serious adverse events reported in ≥2% of patients who received pembrolizumab include renal failure, dyspnea, pneumonia, and cellulitis. The most common adverse events (reported in ≥20% of patients) were fatigue, cough, nausea,

pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. (September 4, 2014)

Bortezomib Receives New FDA Indication for Retreatment of Patients with Myeloma

Bortezomib (Velcade; Millennium/ Takeda Oncology), which is already

approved by the FDA as an intravenous (IV) or subcutaneous treatment for patients with multiple myeloma, recently received a supplemental new indication for the retreatment of adults with myeloma whose disease had previously responded to bortezomib therapy and had relapsed (ie, progressed) at least 6 months after the last treatment with bortezomib.

Isn’t it time therapy evolved? Unchanged for decades, standard regimens for relapsed or refractory acute myeloid leukemia (AML) seem almost prehistoric.1-3 And while the wait for an epigenetic breakthrough continues, the question is still what to do for patients with relapsed or refractory disease, whose only real hope for survival is a successful transition to transplant.4-6 Developing novel technological approaches that may enable more patients to pursue the option of

transplant is an exciting prospect. Complete remission (CR) is one thing, but the quality of those CRs is what ultimately matters.3 At Sunesis, we are committed to enabling the broadest constituency of patients to cross the bridge to transplant by striving to evolve better options for induction therapy. Survival data from the largest industrysponsored multinational study on relapsed and refractory AML are expected later this year.

Driving induction forward References: 1. Yates JW, Wallace HJ Jr, Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57(4):485-488. 2. Herzig RH, Lazarus HM, Wolff SN, Phillips GL, Herzig GP. High-dose cytosine arabinoside therapy with and without anthracycline antibiotics for remission reinduction of acute nonlymphoblastic leukemia. J Clin Oncol. 1985;3(7):992-997. 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Acute Myeloid Leukemia (Version 2.2014). © 2014 National Comprehensive Cancer Network, Inc. Available at NCCN.org. 4. Armistead PM, de Lima M, Pierce S, et al. Quantifying the survival benefit for allogeneic hematopoietic stem cell transplantation in relapsed acute myelogenous leukemia. Biol Blood Marrow Transplant. 2009;15(11):1431-1438. 5. Fung HC, Stein A, Slovak MI, et al. A long-term follow-up report on allogeneic stem cell transplantation for patients with primary refractory acute myelogenous leukemia: impact of cytogenetic characteristics on transplantation outcome. Biol Blood Marrow Transplant. 2003;9(12):766-771. 6. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood. 1992;80(4):1090-1093.

VOL. 5

NO. 7

9/3/14 2:35 PM SEPTEMBER 2014

Retreatment with bortezomib can be restarted at the last dose the patient had tolerated previously. The new indication includes a labeling update with dosing guidelines and safety and efficacy data related to the use of bortezomib as a single agent or in combination with dexamethasone. “For the past 11 years, Velcade has played an important role as the only therapy proven to extend overall survival for patients with newly diagnosed and relapsed multiple myeloma,” said Michael Vasconcelles, MD, Global Head, Oncology Therapeutic Area Unit, Takeda. “With these newly approved dosing guidelines, physicians will be able to provide their patients, who have previously received Velcade, with an effective treatment extending Velcade use across the continuum of care of multiple myeloma.” The new supplemental indication was based on the results from a phase 2 clinical trial, RETRIEVE, as well as other supportive data. The single-arm, open-label, international RETRIEVE trial included 130 patients with myeloma (aged ≥18 years) who had previously responded to bortezomib-based therapy and whose disease relapsed at least 6 months after previous therapy. The overall response rate was 38.5%; 1 patient achieved a complete response and 49 patients achieved a partial response. The median duration of response was 6.5 months (range, 0.6-19.3 months). All patients had previously received a treatment regimen with bortezomib, with a median of 2 previous lines of therapy (range, 1-7), and had previously demonstrated a partial response or better. A total of 94 patients received dexamethasone in combination with bortezomib. RETRIEVE met its primary end point of best confirmed response to retreatment. The safety of retreatment with bortezomib was consistent with the known safety profile of IV bortezomib in patients with relapsed myeloma; no cumulative toxicities were reported with retreatment. The most common adverse event was thrombocytopenia, which was reported in 52% of patients. The incidence of grade ≥3 thrombocytopenia was 24%. Peripheral neuropathy was observed in 28% of patients, and the incidence of grade ≥3 peripheral neuropathy was 6%. The incidence of serious adverse reactions was 12.3%. The most common serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Overall, 13% of patients discontinued bortezomib retreatment because of adverse events. (August 8, 2014) n

www.ValueBasedCancerCare.com

Defining Value in Oncology

Payment Reform Requires Abandoning...

Continued from page 15

count for only 16% of overall healthcare costs, and an even smaller share of Medicare spending, but what’s going on with overall costs and overall quality of care for patients,” said Dr McClellan. “Doctors influence $7 of every $8

at a glance ➤ The oncology community must continue to lead in the shift away from the FFS model ➤ A new payment model must not require payers or physicians to assume too much risk ➤ It should have the support of payers and of physicians; the latter is crucial for the success of any new payment model ➤ A new payment system must improve patient care and support redirecting resources to higher-value uses

spent overall on healthcare. The hope is that overall costs will go down, and the fear, which has been shown in some of the mixed results reported so far, is that is not always the case,” he said. Alternatives that incorporate shared risks and shared savings do appear promising. Physicians provide a host of services that lead to better quality healthcare, better patient satisfaction, and lower costs. However, physicians do not get paid for services such as preventive services, setting up care teams, longer phone hours that would help avoid emergency department visits, and better protocol-based approaches to care. Medicare has implemented a shared-savings approach on a pilot basis, noted Dr McClellan. Physicians continue to be reimbursed on a FFS basis, but a separate track related to overall cost of care has been introduced. Whenever the episodic cost of care decreases, physicians share in the cost-savings.

Episode-Based Payment FFS reimbursement would give way to case- or episode-based payment. Rather than payment for volume or services, the payment would incorporate sets of services, such as a set fee

“

The payment would include the overall payment per patient per month of chemotherapy.… This is a shift away from fee for service.

”

—MARK B. MCCLELLAN, MD, PHD

for a month of chemotherapy administration, instead of payment based on average sales price. “The payment would include the overall payment per patient per month of chemotherapy,” said Dr McClellan. “Payment would be based on overall

case or patient cost. This is a shift away from fee for service. That’s easier for health plans to deal with if they have a good understanding of the finances involved.” For an alternative payment system to work, several reforms must occur to ensure that physicians have adequate support within the system, he added. Medicare and other payers must share data with physicians and other providers in a timely and useful manner, including simplified integration with electronic health records. Meaningful performance measures derived from practice must be developed to minimize the burden and maximize the relevance to clinical practice. Physicians need assistance with upfront costs and with the development of new practice capabilities, Dr McClellan continued. Finally, payment reform must be aligned across all payers and other providers and must include bundled payments. n

Maximizing Value and Quality in Gynecologic Cancer Care—Work in Progress By Wayne Kuznar

Chicago, IL—Comparative effectiveness research (CER) and cost-effectiveness analyses have helped to define value as it relates to gynecologic oncology, said speakers during an education session on maximizing value and

“

Targeted therapies may be more costeffective than global treatment with expensive therapeutics. Testing to select individuals likely to benefit from targeted interventions is potentially cost-effective.

”

—LAURA J. HAVRILESKY, MD, MHSC

quality in gynecologic cancer care, at the 2014 American Society of Clinical Oncology meeting. The rising cost of healthcare has

forced an examination of value. Value is defined as desirable health outcomes achieved per monetary unit spent, suggested Laura J. Havrilesky, MD, MHSc, Associate Professor of Obstetrics and Gynecology at Duke University Medical Center, Durham, NC. Although CER is being used to determine value in cancer care, the cost of the therapies being compared in such studies is rarely considered, because of research funding restrictions, Dr Havrilesky said. By contrast, a cost-effectiveness analysis compares the cost and effectiveness of 2 current therapies, adding an essential component to value measurement. Implications of Cost-Effectiveness Analyses for Cancer Care In oncology, the measure of cost-effectiveness is usually related to patient overall survival (OS), which is expressed as a dollar amount per quality-adjusted life-year (QALY) gained. “Drug cost is critical,” said Dr Havrilesky. “Targeted therapies may be more cost-effective than global treat-

VALUE-BASED CANCER CARE

SEPTEMBER 2014

at a glance

“

Most patients don’t receive guideline care. The application of existing best practices is the most cost-effective form of quality improvement.

”

—WILLIAM A. CLIBY, MD ment with expensive therapeutics.” In ovarian cancer, “testing to select individuals likely to benefit from

➤ Targeted therapies may be more cost-effective than global treatment with expensive therapeutics ➤ Predictive testing to determine the effectiveness of targeted therapies could be cost-effective ➤ Following NCCN guidelines in surgical staging and in selecting chemotherapy regimens improves ovarian cancer survival ➤ Guideline-based care is cost effective and is an important driver of survival in ovarian cancer targeted interventions is potentially cost-effective when compared with global treatment,” Dr Havrilesky said. Intraperitoneal chemotherapy for ovarian cancer has risen to the level of standard therapy based on improvement in OS compared with intra venous chemotherapy and an in

VOL. 5

NO. 7

Economics of Cancer Care

Cost of Treatment in Metastatic Breast Cancer Increasing Significantly with End-of-Life Hospitalizations Tampa, FL—Patients with HER2-positive metastatic breast cancer consume 2.5 times more financial resources in their last 6 months of life, according to study results presented at the 2014 Academy of Managed Care Pharmacy meeting. The study focused on realworld healthcare resource utilization and costs of patients with HER2positive metastatic breast cancer who received trastuzumab (Herceptin) near the end of life. This retrospective, observational review gathered claims data from the IMS LifeLink Health Plan Claims Database between January 1, 2002, and June 30, 2012. Patients were excluded if they received lapatinib (Tykerb) for first- or second-line therapy. (IMS LifeLink is a comprehensive database of integrated medical and pharmacy claims from more than 79 US health plans, for approximately 87 million deidentified lives.) The study included 2 cohorts—patients who were alive at the end of the 6-month follow-up (N = 670) and those who were not (N = 196). The costs were based on the allowed amount on the claims (adjusted for inflation to 2012 US dollars). The mean 6-month total healthcare cost was 2.54 times higher in patients who died than in patients who were still alive—$69,426 versus $26,857, respectively (95% confidence interval, 2.063.13; P <.001). The costs were significantly higher

for those who died during the 6-month follow-up in each care component measured, including hospital inpatient, hospice, emergency department, physician office, other outpatient, home health/durable medical equipment, and pharmacy.

“

The main driver of higher costs during those 2 last months is hospitalization.

”

—THOMAS J. BRAMLEY, RPH, PHD

In the cohort of patients who died, there was a 20-fold increase in inpatient costs and a 14-fold increase in hospice costs between the sixth and first months before the end of life. “The main driver of higher costs during those 2 last months is hospital-

ization,” lead investigator of the study Thomas J. Bramley, RPh, PhD, Senior Vice President, Scientific Consulting, Xcenda, told Value-Based Cancer Care. In the cohort of patients who were still alive at 6 months, the monthly costs were similar throughout the study. The researchers cautioned that results cannot be generalized to patients who were not commercially insured or who had HER2-negative breast cancer. Amy P. Abernethy, MD, PhD, Palliative Medical Specialist, Director, Duke Cancer Care Research Program, who was not involved with the study, said that the finding that healthcare, especially inpatient care and hospice costs, is more expensive in the last 6 months of life is consistent with other studies and what is expected. As people get sicker, they need more healthcare, including treatments for cancer and hospitalizations, Dr Abernethy told Value-Based Cancer Care. Hospice care, which helps keep people out of hospitals, increased in the last 6 months, potentially lowering some of the inpatient costs. She pointed out that the study did not provide information on whether the treatments that were provided made “good sense.” “Part of the problem is that it is really hard to figure out who is going to die and who needs a shift to a hospice focus and when. We can’t say whether or not there is any signal [in this study] that these women should not

Photo by © ASCO/Scott Morgan 2014

By Kate O’Rourke

“

The number one take-home message is that we have to get better at figuring out where people are on the curve of prognosis, so that we can help them make good decisions.

”

—AMY P. ABERNETHY, MD, PHD

have been getting therapy, because we don’t actually have a sense of how sick they were at the time of treatment,” Dr Abernethy pointed out. “The number one take-home message is that we have to get better at figuring out where people are on the curve of prognosis, so that we can help them make good decisions.” n

Maximizing Value and Quality in Gynecologic... Continued from page 18 cremental cost-effectiveness ratio of <$40,000 per QALY gained, which is well within the limit that is accepted as cost-effective. Although adding bevacizumab (Avastin) to a standard chemotherapy regimen can improve progression-free survival by several months, the incremental cost-effectiveness ratio exceeds $400,000 per 1 year of progression-free survival, she noted. The cost of beva cizumab would have to decline to 25% of its current reimbursement to be cost-effective in this setting. A predictive test to determine treatment with bevacizumab could possibly improve its cost-effectiveness, with

VOL. 5

NO. 7

an incremental cost-effectiveness ratio of approximately $130,000 per QALY. Until then, high-profile biologic agents do not appear to meet the standard societal willingness-to-pay thresholds. Gynecologic oncologists must consider the possible toxicity level and the inconvenience of added treatments and the potential additional out-ofpocket expenses when considering adding novel therapies to the treatment regimen, deciding for or against maintenance chemotherapy, assigning treatment for recurrent disease, and when making the decision to move a patient to end-of-life care, Dr Havril esky pointed out.

Guideline-Based Care Improves Survival William A. Cliby, MD, Professor of Obstetrics and Gynecology at the Mayo Clinic, Rochester, MN, presented the evidence-based measures of quality in gynecologic surgery, again using ovarian cancer as an example. Overall, the cancer care delivery system in the United States is in crisis, he said, because cancer care is often not as patient-centered, accessible, coordinated, or evidence-based as it could be. Adherence to National Comprehensive Cancer Network (NCCN) guideline care is a reasonable outcome measure. Following NCCN guidelines in

SEPTEMBER 2014

surgical staging and in selecting chemotherapy regimens improves survival in patients with ovarian cancer. However, “most patients don’t receive guideline care,” said Dr Cliby. “The application of existing best practices is the most cost-effective form of quality improvement.” Case volume and guideline care have been shown to be important drivers of survival in this disease, but 25% of patients with ovarian cancer are treated across 65% of centers, all with fewer than 8 cases per center. Similar themes are observed with the care of patients with cervical cancer, he noted. n

www.ValueBasedCancerCare.com

Economics of Cancer Care

Cost Burden Follows Patients with Cancer into Survivorship By Charles Bankhead

he high cost of cancer care follows patients well into survivorship, as annual medical costs and losses in productivity exceed those of people without cancer by 50% to 100%, a study for the Centers for Disease Control and Prevention (CDC) showed (Ekwueme DU, et al. MMWR Morb Mortal Wkly Rep. 2014;63:505-510). The total annual medical and productivity costs (direct and indirect) for cancer survivors averaged $11,800 for men and $12,400 for women, according to this study. By comparison, medical and productivity costs for people without cancer averaged $6100 among men and $7800 among women. Given the growing number of cancer survivors in the United States, the projected averages and total costs will continue to increase as well. “Cancer survivors face physical, emotional, psychosocial, employment, and financial challenges as a result of their cancer diagnosis and treatment,” stated Donatus U. Ekwueme, PhD, Senior Health Economist, Division of Cancer Prevention and Control at the CDC, and lead investigator of this study, in a press release. “With the number of cancer survivors expected to increase by more than 30 per-

at a glance ➤ The annual medical costs and productivity losses for cancer survivors are 50% to 100% higher than for people with no history of cancer ➤ The medical costs for male cancer survivors are $8091 versus $3904 for men without cancer; $8412 for female survivors compared with $5119 for women without cancer ➤ Approximately 75% of productivity losses among cancer survivors of both sexes result from employment disability ➤ Approximately 42% of employed cancer survivors report changes in work status, responsibilities, or behaviors as a result of their cancer ➤ Approximately 32% of cancer survivors say that their disease adversely affects daily activities outside of work

cent in the next decade—to 18 million Americans—medical and public health professionals must be diligent in their efforts to help reduce the burden of cancer on survivors and their families.”

status (12.2% vs 28.1%, respectively). Among employed cancer survivors, approximately 42% reported changes in work status, responsibilities, or behaviors as a result of cancer. Of

“

Cancer survivors face physical, emotional, psychosocial, employment, and financial challenges. With the number of cancer survivors expected to increase by more than 30 percent in the next decade… medical and public health professionals must be diligent in their efforts to help reduce the burden of cancer on survivors.

”

—DONATUS U. EKWUEME, PHD The number of people in the United States living with cancer has more than quadrupled since 1971, from 3 million to 13.4 million. According to the National Cancer Institute (NCI), cancer survivors account for almost 5% of the US population. To obtain current information about medical costs and productivity losses among cancer survivors, the investigators analyzed data from the Medical Expenditure Panel Survey (MEPS) for 2008 to 2011. The survey of cancer survivors includes items related to employment, limitations in physical and mental tasks, work-related productivity, and daily activities outside of work. The sex-stratified total annual medical costs were derived from actual expenditures by cancer survivors and people without cancer. The researchers also evaluated medical costs by source of payment and by service type. Lost productivity was estimated from the combination of employment disability, health-related missed days of work, and illness-related days in bed. The medical costs and productivity losses were adjusted to 2011 dollars. Economic Burden Compared with people without cancer, cancer survivors were more likely to be female (51% vs 57.5%, respectively), to be non-Hispanic whites (66.1% vs 84.8%, respectively), to have ≥3 comorbid conditions (16.6% vs 43.5%, respectively), and to report fair/poor health

VALUE-BASED CANCER CARE

SEPTEMBER 2014

the survivors, approximately 32% said that cancer adversely affected activities outside of work. The medical expenditures and costs associated with lost productivity were substantially higher among cancer survivors than among those without a history of cancer, for both sexes. The medical costs for male cancer survivors averaged $8091 compared with $3904 for men without cancer. The averages for women were $8412 for cancer survivors and $5119 for women without cancer. The productivity losses among cancer survivors averaged $3719 for men and $4033 for women. The corresponding values for people without cancer were $2260 for men and

$2703 for women. Approximately 75% of productivity losses among cancer survivors (men and women) resulted from employment disability. Approximately 10% of the cancer survivors reported being uninsured and might face added barriers to needed healthcare services. The investigators noted that provisions of the Affordable Care Act are expected to address some of the problems faced by uninsured cancer survivors by providing access to health insurance. Survivorship Programs Needed “The economic data presented in this report investigating the economic consequences of surviving cancer highlight the need to develop comprehensive intervention programs to improve the quality of the cancer survivorship experience and decrease the economic burden of cancer survivorship in the United States,” the researchers concluded. This study is based on an ongoing collaborative effort called the Health Economics Research on Cancer Workgroup. Established to promote health economics research related to cancer, the workgroup consists of participants from the CDC, the NCI, the Agency for Healthcare Research and Quality (which sponsors MEPS), the American Cancer Society, the Livestrong Foundation, and Emory University in Atlanta, GA. A primary objective of the collaboration is to address the research needs and gaps in information identified by the Institute of Medicine, including the 2005 landmark report, “From Cancer Patient to Cancer Survivor: Lost in Transition.” n

By the Numbers Cancer Survivorship in the United States 19 million—Approximate number of projected cancer survivors by 2024 14.5 million—Approximate number of cancer survivors alive on 1/1/2014 3,131,440—Female breast cancer survivors in 2014 2,975,970—Prostate cancer survivors in 2014 747,400—Survivors diagnosed ≥30 years ago 430,090—Lung cancer survivors in 2014 60,620—Survivors aged ≤14 years 64%—Survivors diagnosed ≥5 years ago 15%—Survivors diagnosed ≥20 years ago 5%—Survivors aged <40 years Source: American Cancer Society. June 3, 2014. www.cancer.org.

VOL. 5

NO. 7

In the Literature Enzalutamide Extends Survival in Men with Metastatic Prostate Cancer

VOL. 5

Lenalidomide plus R-CHOP Improves Outcomes in Patients with Lymphoma

Although intensive high-dose chemotherapy can be used as salvage therapy for some patients with relapsed or refractory diffuse large B-cell B:7.625 in the majority of lymphoma (DLBCL), them will die from T:7.375this in cancer. There-

fore, the development of a more effective initial therapy is crucial to improving long-term outcomes in this patient population. In a study of patients with newly diagnosed DLBCL, the addition of lenalidomide (Revlimid) to R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and

Continued on page 22

In mCRPC therapy…

Is there more to the story?

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page. Please see brief summary of full Prescribing Information on subsequent pages.

NO. 7

SEPTEMBER 2014

Date: 7/28/14

21 Group 360 Job #: 710241

www.ValueBasedCancerCare.com

Customer Code: 016819-140612

T:9.75 in

Prostate cancer is the sixth leading cause of cancer-related mortality in men. Suppressing androgen receptor overexpression has led to improved outcomes in men in this patient population. Enzalutamide (Xtandi), a new oral androgen receptor inhibitor, has shown promising results for men with metastatic castration-resistant prostate cancer (mCRPC) who had not received chemotherapy (Beer TM, et al. N Engl J Med. 2014;371:424-433). PREVAIL was a multinational, double-blind, randomized, placebo-controlled, phase 3 trial. Between Sep tember 2010 and September 2012, PREVAIL included 1717 chemotherapy-naïve patients with asymptomatic or mildly symptomatic mCRPC who progressed with androgen-deprivation therapy. A total of 1717 patients were randomized to receive 160 mg daily of enzalutamide (N = 872) or placebo (N = 845); 1715 patients received at least 1 dose of enzalutamide. The coprimary end points were radiographic progression-free survival and overall survival (OS). Secondary end points included the time until the initiation of cytotoxic chemotherapy, the time until the first skeletal-related event, the best overall soft-tissue response, the time until prostate-specific antigen (PSA) progression, and a decline in PSA of ≥50% from baseline. The study was stopped early after an interim analysis of OS (which was conducted as planned when 540 deaths had been reported) showed a benefit of the active treatment. The enzalutamide group had an 81% reduction in the risk of radiographic progression or death (hazard ratio [HR], 0.19; P <.001). At the 22-month interim analysis, treatment with enzalutamide compared with placebo resulted in a 29% decrease in the risk of death (HR, 0.71; P <.001). The median OS was an estimated 32.4 months in the enzalutamide group and 30.2 months in the placebo group. Enzalutamide improved all secondary end points. For example, overall response to imaging of soft-tissue disease with enzalutamide succeeded in 59% of patients (20% complete responses and 39% partial responses) versus 5% in the placebo group (P <.001). In addition, enzalutamide delayed the median time to chemotherapy initiation by 17 months. Patients receiving enzalutamide did not need to initiate chemotherapy until a median of 28 months versus 10.8 months in the placebo arm (HR, 0.35; P <.001). Enzalutamide also exhibited a favorable safety profile. Grade ≥3 adverse

event rates were on par between the enzalutamide and placebo arms (43% vs 37%, respectively), although the safety observation period was 3 times longer with enzalutamide than with placebo (17.1 months vs 5.4 months, respectively). The most common adverse events reported with enzalutamide were fatigue and hypertension.

In the Literature Lenalidomide plus R-CHOP Improves...Continued from page 21

prednisone; this new combination is known as R2CHOP) mitigated the negative prognostic significance of the non–germinal center B-cell (GCB) phenotype (Nowakowski GS, et al. J Clin Oncol. 2014 Aug 18. Epub ahead of print). Lenalidomide has previously

shown activity in patients with relapsed or refractory DLBCL, particularly in those with the non-GCB subtype. Researchers from the Mayo Clinic conducted a phase 2, open-label, single-arm study of 64 patients with newly diagnosed, untreated, stage II to stage IV CD20-positive DLBCL. For comparison, 87 patients with DLBCL

who had received treatment with conventional R-CHOP were selected from the Mayo Clinic lymphoma database. This control group was treated during a similar time frame and met the same inclusion criteria as the patients in the active study. The DLBCL molecular subtype was determined by tumor B:7.625 in immunohistochemistry T:7.375 in and was clas-

sified as GCB or non-GCB. Of the 64 patients enrolled, 60 were eligible for response evaluation. The treatment consisted of 25 mg lenalidomide daily on days 1 to 10 with standard R-CHOP every 3 weeks for 6 cycles. The primary end point was event-free survival (EFS), with secondary end points of progression-free sur-

For men with mCRPC who progressed on ADT

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

More than 1,000 days. And every day tells a story. 35.3 IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone.

MONTHS MEDIAN OVERALL SURVIVAL FOR ZYTIGA® plus prednisone† vs 30.1 MONTHS with placebo plus prednisone (active compound).‡

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

T:9.75 in

IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival. ADT=androgen-deprivation therapy.

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

VALUE-BASED CANCER CARE

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

SEPTEMBER 2014

Date: 7/28/14

VOL. 5

Customer Code: 016819-140612

NO. 7

Group 360 Job #: 710241

In the Literature vival (PFS) and overall survival (OS). The overall response rate was 98%, with 80% of patients achieving a complete response. At a median follow-up of 23.5 months, the median duration of response had not yet been reached. In patients receiving R2CHOP, the EFS rate was 59% at 24 months. Because no patients received subsequent treat-

ment for lymphoma before disease progression, the results for EFS and PFS were identical. At 24 months, the OS rate was 78%. In the patients receiving R-CHOP, the 24-month PFS and OS rates were 28% versus 64% and 46% versus 78% in B:7.625 inversus the GCB the non-GCB patients patients, respectively. T:7.375 inSurprisingly, no

differences in PFS or OS were seen with R2CHOP between patients who had the non-GCB phenotype and those who had the GCB phenotype (60% vs 59% and 83% vs 75%, respectively). The R2CHOP regimen was well tolerated. The most common grade ≥3 adverse events were neutropenia (87%), leukopenia (80%), and thrombocytope-

nia (44%). One patient had grade 5 sepsis after the first cycle of therapy. “This study demonstrated that the addition of lenalidomide to conventional R-CHOP resulted in similar PFS rates and OS rates between sub-types,” said lead investigator Grzegorz S. Nowakowski, MD, Assistant Professor of Medicine, Mayo Clinic, Rochester,

Continued on page 24

B:10 in

T:9.75 in

003307-130924

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

VOL. 5

Every day tells a story.

NO. 7

Date: 7/28/14

SEPTEMBER 2014

Customer Code: 016819-140612

www.ValueBasedCancerCare.com

Group 360 Job #: 710241

In the Literature Lenalidomide plus R-CHOP Improves...Continued from page 23

MN, in a press release. “This is intriguing as patients with the non-GCB phenotype have traditionally experienced poorer outcomes. The results of this study support further evaluation of this regimen in this sub-type of DLBCL.”

Medicaid Coverage for Hematopoietic Cell Transplantation Varies among States

Variation in Medicaid policies among states may lead to gaps in Medicaid coverage for complex treatments and procedures in oncology, and, as a result, may affect access to care and

patient outcomes. Researchers used hematopoietic-cell transplantation (HCT) as a case study to highlight variations in Medicaid coverage among states (Preussler JM, et al. J Oncol Pract. 2014;10:e196-e200). HCT, an optional benefit under Medicaid, is an example of a nondrug oncology service for which there is no

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA

VALUE-BASED CANCER CARE

SEPTEMBER 2014

specific coverage guidance. To characterize variation in coverage for HCT among state Medicaid programs, researchers reviewed coverage benefits for 2012 from state Medicaid websites and compared the data with the recommended HCT benefits developed by multiple stakeholders. The coverage was reviewed for transplantation pro-

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders 4 Edema 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

VOL. 5

NO. 7

In the Literature cedure; donor search; prescriptions; clinical trials; and patient food, lodging, and transportation. The data were coded on a 3-point scale for each state; states were ranked according to the number of variables for which they met the recommended benefits criteria. Although all states provide coverage for HCT through their Medicaid

programs, the findings showed substantial variation in coverage by state. Among the 47 states for which data were available, no state provided the recommended benefits in all 5 categories, and only 4 states met at least 4 of the 5 categories. Overall, 39 states provided the recommended prescription coverage and

35 states did not cover clinical trials. The coverage for donor search varied, with 8 states not providing coverage at all, and 20 states meeting the recommended benefits. It is not unusual for patients to relocate to be closer to their transplantation center and to stay nearby for ≥3 months posttransplant. Yet, only 29 states provided the recom-

ZYTIGA® (abiraterone acetate) Tablets

Table 1: Adverse Reactions due to ZYTIGA in Study 1 (continued) ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

VOL. 5

NO. 7

SEPTEMBER 2014

mended coverage for patient lodging and transportation coverage. Among the states that did not fully meet the recommended benefits, the researchers identified 3 examples of coverage restrictions that can serve as barriers to HCT access among Medicaid patients, including (1) lack of coverage for standard indications of trans-

Continued on page 26

www.ValueBasedCancerCare.com

In the Literature Medicaid Coverage for Hematopoietic Cell Transplantation... Continued from page 25

plantation, (2) limitations on the number of inpatient days allowed annually, and (3) the absence of coverage for searching for a donor.

This study shows considerable variation in coverage for HCT through individual state Medicaid programs. The researchers note that these findings can be extrapolated to other areas in oncology. A majority of Medicaid programs clearly define coverage guidelines for common cancers. How-

ever, coverage parameters for other cancers may not be specific, and variation in coverage may increase the disparities in access to cancer care for already medically underserved populations, especially if treatment requires a combination of several specialties and modalities.

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information]. Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

Gemtuzumab Ozogamicin Improves Overall Survival in Patients with AML, Warrants New Considerations

Gemtuzumab ozogamicin (Mylotarg) was granted accelerated approval by the FDA in May 2000 for the treatment of patients aged ≥60 years with recurrent acute myeloid leukemia (AML) who were not considered candidates for other chemotherapy. However, Pfizer voluntarily withdrew its drug from the US market in June 2010, after the disappointing results of the SWOG (Southwest Oncology Group) S0106 study, which was required for postapproval support by the FDA. The study was terminated early when no improvement in clinical benefit was observed and after more deaths occurred with gemtuzumab ozogamicin. Because SWOG S0106 and other randomized trials have shown conflicting results, researchers conducted a new meta-analysis to assess the efficacy of adding gemtuzumab ozogamicin to induction chemotherapy in adults with AML (Hills RK, et al. Lancet Oncol. 2014;15:986-996). The meta-analysis included data on 3325 patients from 5 randomized, open-label trials of gemtuzumab ozogamicin, given to adults in conjunction with the first course of intensive induction chemotherapy for AML compared with chemotherapy alone. Overall survival (OS) was the primary end point for all 5 trials. Secondary end points included risk of relapse, complete remission, and 30-day mortality. In the trials, gemtuzumab ozogamicin was given at 3 mg/m2 on day 1, 6 mg/m2 on day 4, and 3 mg/m2 (up to a maximum of 5 mg per dose) on days 1, 4, and 7. The median follow-up was 60.8 months. The addition of gemtuzumab ozogamicin to induction chemotherapy significantly improved OS at 5 years (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.82-0.98). At 6 years, the absolute survival benefit, defined by cytogenetic characteristics, was observed in patients with low risk (20.7%; OR, 0.47; 95% CI, 0.31-0.73) and intermediate risk (5.7%; OR, 0.84; 95% CI, 0.75-0.95). However, patients with adverse cytogenetic characteristics did not benefit (2.2%; OR, 0.99; 95% CI, 0.83-1.18). Furthermore, gemtuzumab ozogamicin significantly reduced the risk for relapse (OR, 0.81; 95% CI, 0.730.9), despite no improvement in the proportion of patients achieving complete remission with or without peripheral count recovery (OR, 0.91; 95% CI, 0.77-1.07). Although the researchers identified no significant inContinued on page 42

VALUE-BASED CANCER CARE

SEPTEMBER 2014

VOL. 5

NO. 7

Immunotherapy

and were later used by the FDA for its accelerated approval of the first anti– PD-1 for melanoma. A total of 411 patients with advanced melanoma received different doses, from 2 mg/kg to the higher dose of 10 mg/kg. In the phase 1b KEYNOTE-001 trial of 411 patients, all patients had stopped responding to previous melanoma therapy, including ipilimumab. Overall, 34% of patients responded to pembrolizumab therapy. At 1 year, 88% of responders were still responding, with the longest response at the time of the meeting being 76 weeks. The median progression-free survival (PFS) was 5.5 months, and the estimated overall survival (OS) rate at 1 year was 69%. The median OS was not reached at the time of analysis.

“”

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

“

This is one of the most benign therapies I’ve ever used in my clinic.

”

—ANTONI RIBAS, MD, PHD

“These are early data, but they tell us we are on to something really important,” said Antoni Ribas, MD, PhD, Professor of Medicine at the David Geffen School of Medicine, University of California, Los Angeles, at the meeting. 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%. Ongoing confirmatory phase 2 and 3 clinical trials are under way to provide further survival information to the FDA, as confirmation of the accelerated approval and breakthrough therapy designation for pembrolizumab. Nivolumab Shows Durable Results The long-term follow-up of the pivotal phase 1 trial of nivolumab showed ongoing responses in 56% of 107 pa-

VOL. 5

NO. 7

tients with melanoma. At a median follow-up of 22 months, the median 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 nivolu mab, 3 mg/kg, the median PFS was 9.7 months and the median OS was 20.3 months, reported Stephen Hodi, MD, of Dana-Farber Cancer Institute, Boston. Mario Sznol, MD, of Yale School of Medicine, New Haven, CT, discussed the concurrent treatment of nivolumab and the anti–cytotoxic T-lymphocyte antigen 1 antibody ipilimumab, which led to a 2-year OS rate of 79%, and 88% of responders had ongoing responses at the time of analysis. The grade 3/4 toxicity rate was 62%, but this was

Photo by © ASCO/Zach Boyden-Holmes 2014

Photo by © ASCO/Todd Buchanan 2014

—JEFFREY S. WEBER, MD, PHD

“

Continued from the cover

edented 2-year survival.” Dr Sznol reported updated data for the phase 1 CA209-004 trial and for the phase 2/3 trials. All 94 patients had stage III or IV melanoma. In the phase 1 cohort of 53 patients, 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. The most common grade 3/4 toxicities were increased lipase and amylase—reversible laboratory abnormalities. One drug-related death occurred in the latest cohort, which resulted from colitis. “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 met-

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

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 unprec-

”

—MARIO SZNOL, MD

astatic melanoma, it doesn’t get any better than that…I cannot help but be impressed,” said Jeffrey S. Weber, MD, PhD, of H. Lee Moffitt Cancer Center and Research Institute in Tampa, FL, when discussing the results. Enrollment has been completed for

SEPTEMBER 2014

a phase 3 trial comparing nivolumab plus ipilimumab versus nivolumab or ipilimumab alone, as well as a phase 2 trial comparing nivolumab plus ipilim umab versus ipilimumab alone. Anti–PD-1 Antibodies in NSCLC and Renal Carcinoma The phase 1 multicohort CA209012 trial of patients with non–smallcell lung cancer (NSCLC) evaluated nivolumab as a single agent and in combination with ipilimumab, chemotherapy, and erlotinib. Nivolumab monotherapy in the first-line setting produced responses in 30% of patients, but the median duration of response

Photo by © ASCO/Silas Crews 2012

PD-1 Monoclonal Antibodies Usher in...

“

These data are encouraging as we seek to identify new treatments for patients, particularly those who progress following treatment with anti-angiogenic therapy, as they have limited options.

”

—ROBERT MOTZER, MD was not reached. “Responses are ongoing in 4 of 6 (67%) responders,” said Scott N. Gettinger, MD, of Yale. The 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 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%. In the phase 2 CheckMate-010 trial in advanced renal carcinoma, single-agent nivolumab produced responses in 20% to 22% of patients and

Continued on page 28

www.ValueBasedCancerCare.com

Personalized Medicine

Oncologists Show Low Genomic Confidence about the Use of Genetic Testing

See also page 37

By Lilly Ostrovsky

redictive multiplex genomic (or genetic) testing may revolutionize the treatment of cancer by identifying targetable mutations in cancer genes for their individual patients. Although genetic testing is commercially available, its use in clinical practice has not been fully investigated. A team of researchers recently conducted a survey to assess oncologists’ current knowledge and use of genomic testing, their attitudes about multiplex genomic testing, and their genomic confidence (Gray SW, et al. J Clin Oncol. 2014;32:1317-1323). The survey included 160 oncologists at Dana-Farber Cancer Institute/ Brigham and Women’s Hospital, Boston, and was conducted before the institution of the multiplex genomic testing at this major cancer institute, as part of the Profile research study that analyzes DNA from tumor tissues to provide meaningful results to patients. “When we find alterations in patients’ tumors, and when we are able to match those alterations with targeted cancer therapy, the improvement in the quality of patients’ lives, and sometimes the length of their lives, is dramatic,” lead researcher Stacy W. Gray, MD, AM, Department of Medical Oncology, Dana-Farber Cancer Institute, told Value-Based Cancer Care. “I see what a difference these medications can make, and I feel very strongly that we have to try to help as many people as possible who may benefit from genetic testing and targeted therapies,” Dr Gray pointed out. A total of 160 oncologists at the cancer institute completed the survey,

which examined physicians’ genomic confidence and asked them: • To estimate the percentage of patients for whom they would want genomic testing • How often they would disclose the results to patients • How often they would use results to inform treatment recommendations • The terms they would use to describe genomic testing to patients • Where would they seek information to learn more about the test results. Oncologists’ Genomic Confidence The results showed that many oncologists lacked genomic confidence. Specifically: • 22% of the survey participants were not very or not at all confident in their knowledge of genomics • 14% lacked confidence in their ability to explain genomic concepts to patients • 26% lacked confidence in their ability to make treatment recommendations based on genomic data. Based on a conversation with Dr Gray, continuing education in the area of genetics is crucial for oncologists. “I think that one of the major challenges of the delivery of personalized cancer care is the fact that our understanding of cancer genetics, and our understanding of the complex pathways that are in patients’ tumors changes almost on a day-to-day basis,” Dr Gray explained. “Genetics has been a very small part of medical school curricula until very recently, and, even now, it does not play a major role in most med-

ical schools’ curriculum. And so I think that because the field changes so quickly and because a lot of people need to learn on the job, continuing medical education is essential,” she pointed out.

“

When we find alterations in patients’ tumors, and when we are able to match those alterations with targeted cancer therapy, the improvement in the quality of patients’ lives…is dramatic.

”

—STACY W. GRAY, MD, AM

Current and Future Use of Genetic Testing When asked about the future use of multiplex genetic testing, 18% of oncologists anticipated testing patients infrequently (≤10% of patients), and

PD-1 Monoclonal Antibodies Usher in... yielded 1-year survival rates of 63% to 72% in patients with previous antiangiogenic treatment. 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 showed responses in 43% to 48% of patients and 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 anti angiogenic therapy, as they have limited options,” said Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, NY. Safety and Tolerability The toxicities associated with anti–

VALUE-BASED CANCER CARE

SEPTEMBER 2014

25% anticipated testing most patients (≥90%). Some factors involved in oncologists’ decisions on whether to use genomic testing include the stage of the disease, patient characteristics (eg, age), and genetic status. Overall, 73% of participating oncologists reported that genetic testing would increase their patients’ treatment options, prognostic information, and satisfaction; the time required to discuss treatment options; as well as research opportunities. The oncologists’ genomic confidence was one of the strongest predictors of their anticipation of using this type of testing for their patients. Disclosure of Genetic Findings to Patients The findings showed that nearly 23% of oncologists rarely or only sometimes would disclose tier-1 results. This was a surprising finding, because tier-1 results are clinically relevant, and the researchers expected that only a small percentage of oncologists would not disclose tier-1 results to their patients. The researchers attributed the high percentage of nondisclosures to lower genomic confidence among the oncologists and to lower baseline genetic testing. For example, the oncologists with higher genomic confidence were more likely to report tier-1 and tier-2 results. In addition, more than 40% of oncologists believed in the disclosure of uncertain genetic findings, and 39% disagreed with the policy of prohibiting the return of tier-3 results. Again, higher genomic confidence played a role in oncologists’ wishing to disclose tier-3 results to their patients. n

Continued from page 27

PD-1 agents are primarily immunerelated and transient, although some can be concerning. Nivolumab was associated with adverse events (AEs) in 85% of patients, but only 20% were grade 3/4. The combination of nivolumab and ipilim umab resulted in grade 3/4 AEs in 49% of patients across the arms; 6% of patients had grade 3/4 pneumonitis, which was reversible. Approximately

33% of patients discontinued treatment because of AEs, and 3 patients died. With pembrolizumab, almost 66% of patients had at least 1 drug-related AE of any grade, and 10% of patients had grade 3/4 toxicity. Grade 3/4 pneumonitis was reported in 4 patients. It is safe to assume that oncologists will learn to manage the immunerelated toxicities associated with anti–PD-1 agents. n

VOL. 5

NO. 7

Now enrolling: MURANO study Investigating the Selective BCL-2 Inhibitor GDC-0199/ABT-199 in Chronic Lymphocytic Leukemia GDC-0199/ABT-199 is an investigational agent that has not been approved by regulatory agencies.

A Phase III Study of GDC-0199/ABT-199 Plus Rituximab Compared With Bendamustine Plus Rituximab in Patients With Relapsed or Resistant Chronic Lymphocytic Leukemia (CLL)

GDC-0199/ABT-199 + rituximab

Phase III Relapsed or resistant CLL (N=370)

GDC-0199/ABT-199 continued for 2 years or until disease progression

Bendamustine + rituximab Randomize Primary Endpoint

Secondary Endpoints

• Investigator-assessed progression-free survival, defined as time from randomization until disease progression or death from any cause

• Overall response rate • Incidence of adverse events

Key Inclusion Criteria

Key Exclusion Criteria

• Adult patients ≥18 years of age • Diagnosis of CLL per diagnostic criteria and relapsed or refractory CLL per the iwCLL guidelines • Previously treated with 1-3 lines of therapy (eg, completed ≥2 treatment cycles per therapy), including ≥1 standard chemotherapy-containing regimen • Previously treated with bendamustine, only if duration of response was ≥24 months • ECOG performance status of 0-1 • Adequate bone marrow function • Adequate renal and hepatic function

• Transformation of CLL to aggressive non-Hodgkin lymphoma or CNS involvement by CLL • Undergone an allogenic stem-cell transplant • A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease • Hepatitis B, hepatitis C, or known HIV-positive • Receiving warfarin treatment • Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug • Received any anticancer or investigational therapy within 14 days prior to the first dose of study drug or has not recovered from previous therapy • Received CYP3A4 inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamezapine, phenytoin, St John’s Wort) within 7 days prior to the first dose of GDC-0199/ABT-199 • Prior GDC-0199/ABT-199 treatment

To learn more about this study, please visit www.ClinicalTrials.gov (NCT02005471, GO28667) or call the Trial Information Support Line at 1-888-662-6728.

GDC-0199/ABT-199 is being codeveloped by AbbVie and Genentech, a member of the Roche Group.

Reference: ClinicalTrials.gov, as of 5/2014. A2396579

4th Conference

Next-Generation Sequencing Provides Value... to study the cancer genome to identify a patient’s mutations, Dr Palmer said at the Fourth Annual Conference of the Association for Value-Based Cancer Care. Our understanding of cancer is growing. In 2003, no alterations were known in lung adenocarcinoma. By 2012, in addition to KRAS and EGFR, the known genetic mutations were ALK fusions, ERRB2, BRAF, PIK3CA, AKT1, MAP2K1, NRAS, ROS1 fusions, and RET fusions. Next-generation sequencing is becoming a critical component of the diagnosis in many situations. Matching the correct targeted therapy to the correct patient will improve the tumor response and overall outcomes, but it is diagnostically challenging with the growing number of clinically relevant genomic alterations identified. Next-generation sequencing allows for the simultaneous and rapid sequencing of hundreds of millions of DNA molecules. Of the approximately 20,000 genes in the human genome, only a few hundreds are unambiguously associated with cancer. By contrast, whole-genome targeted sequencing only sequences a limited subset of genes. “You’re going to miss a lot of rarer alterations, or even some novel alterations that I think will turn out to be very treatable, if you don’t use a next-generation sequencing type approach,” said Dr Palmer. Next-generation sequencing “lets the tumor in a sense tell you what the drivers are, without looking for any specific ‘hot spots’.” The 5 types of genetic alterations are base substitutions, short insertions and deletions, focal amplification, ho-

Continued from the cover

Table Proposed Indications for Next-Generation Sequencing 1. Patients newly diagnosed with: -Stage IV adenocarcinoma of the lung -Carcinoma of unknown origin: actionable findings (~75%) lead to precise treatment decisions -Stage IV rare or uncommon solid tumors for which no systemic treatment exists -Stage IV solid tumors for which the median overall survival is <2 years 2. Patients diagnosed with solid tumors whose only specimen was obtained via fine-needle aspiration, thoracentesis, paracentesis, or endobronchial ultrasound yielding insufficient tissue to complete requisite molecular testing, thereby placing the patient at risk for new invasive diagnostic procedure(s)

“

You’re going to miss a lot of rarer alterations, or even some novel alterations that I think will turn out to be very treatable, if you don’t use a next-generation sequencing type approach [which] lets the tumor in a sense tell you what the drivers are.

”

—GARY PALMER, MD, JD, MBA, MPH

mozygous deletion, and gene fusion. “All of them can be detected by next-generation sequencing done by world-class computational biologists,” Dr Palmer said. Value to Oncologists Foundation Medicine provides a patient report for the oncologist that details genetic alterations in that individual patient that are identified by next-generation sequencing and

VALUE-BASED CANCER CARE

SEPTEMBER 2014

3. Patients with stage IV solid tumors who have exhausted established guidelinedriven systemic therapy/therapies and requisite molecular testing, but who maintain adequate functional status as deemed by the treating physician the appropriate targeted therapies for those alterations. Of the first 2000 cases in which next-generation sequencing has been used, 82% have had “actionable” findings. Overall, a mean of 3 to 4 reportable genetic alterations and a mean of 1.6 actionable alterations have been found per patient. The typical patient for whom next-generation sequencing is done has exhausted recommended therapies. That patient is “still viable. The doctor still wants to treat the patient; the patient still wants to be treated,” Dr Palmer said. Rather than pick a therapy regimen off the shelf, “it makes sense, at some level, to look for a target and use a targeted therapy,” he said. “Our data suggest now that 6% of our lung cancer cases will have HER2 alterations that are potentially treatable,” he said. “That’s more than the ENO4 ALK. You could make a case that if you’re checking for ENO4 ALK…that you should be checking for HER2 alterations.”

“

Value to Payers Foundation One has come up with a list of proposed indications for the use of next-generation sequencing (Table), which includes patients newly diagnosed with carcinoma of unknown origin. In such patients, the clinical utility lies in the approximately 75% who are found to have actionable alterations leading to precise treatment decision-making. It may, therefore, not be as important to pinpoint the organ of origin to identify a treatment approach, adding even more clinical utility, said Dr Palmer. Next-generation sequencing for the indications listed in the Table can displace other genetic tests that currently cost thousands of dollars, he said. In approximately 10% of patients, either no driver mutation is found or a genomic alteration for which

“It cuts the cost of the trial,” Dr Palmer said. “It cuts the time it takes to get people into the trial, and I think it will lead to an approval process in which drugs will be approved based on their genomic implications, the patients’ indications, rather than the histology of the particular tumor.” Approximately 66% of BRAFmutated tumors have ≥1 additional actionable alteration that may benefit from combination therapy that may be tested in clinical trials. Although these data will not currently help oncologists select treatment when there are multiple driver mutations, these multiple targets would not have been discovered without the use of next-generation sequencing. n

there is no FDA-approved therapy or clinical trial options is found. A finding of no actionable alterations is strong evidence against the use of a targeted agent, adding further value to the testing. Value to Researchers Next-generation sequencing also has value to researchers and to drug developers, said Dr Palmer. First is a shift in the design of clinical trials to multiarm biomarker-driven protocols. These protocols can improve efficiency with homogeneous patient populations and consistent eligibility. Grouping multiple studies reduces screening failures, allowing for a high “hit rate.”

Our data suggest now that 6% of our lung cancer cases will have HER2 alterations that are potentially treatable.

”

—GARY PALMER, MD, JD, MBA, MPH

VOL. 5

NO. 7

4th Conference

Predictive Testing Holds More Value to Oncology Stakeholders than Prognostic Testing Improved outcomes, enhanced patient experience, reduced overall costs By Wayne Kuznar Los Angeles, CA—Predictive testing offers greater value over prognostic testing to most stakeholders in cancer care, because it has a direct impact on disease treatment rather than simply predicting the course of the disease (which is, ironically, the role of prognostic testing), said S. Macey Johnson III, MBA, Vice President, Managed Care and Reimbursement, bioTheranostics, San Diego, CA, at the Fourth Annual Conference of the Association for Value-Based Cancer Care. A prognostic test measures the risk for disease recurrence. It can be used with tumor positive or tumor negative markers. With this type of testing, “we’re not talking about driving a treatment decision or a particular medical intervention,” said Mr Johnson. Examples of prognostic testing include BRCA testing to determine the risk for hereditary breast and ovarian cancers, and the Oncotype DX Colon Cancer Assay, which quantifies recurrence risk in stage II and stage III colon cancer (Table 1). By contrast, predictive markers can be defined as a single trait or a signature of traits (ie, a single gene or a multigene panel) that separates different patient populations with respect to the outcome of interest in response to a particular targeted treatment. “It’s about getting the right drug to the right patient at the right time,” Mr Johnson said. “Therefore, there should be cost-savings and synergies associated with employing this practice in the clinical setting.” Predictive tests include the tests that identify HER2 or KRAS mutations that can predict the clinical benefit of specific targeted therapies, or the CancerTYPE ID test, which identifies primary tumor type in metastatic cancer and predicts response to extended endocrine therapy (Table 1). In the case of CancerTYPE ID, the test is performed at year 5 for women who are estrogen receptor–positive and who want to determine if they should continue to receive endocrine therapy for years 5 through 10. A predictive test may relieve a patient of the burden of receiving a treatment to which he or she will not respond, said Mr Johnson. Triple Value of Predictive Testing The value proposition behind pre-

VOL. 5

NO. 7

dictive testing is the triple aim of improving outcomes, improving the patient experience, and reducing or controlling the overall cost. Health economics models show that predictive testing can indeed control costs, with cost offsets.

Table 1 Examples of Prognostic versus Predictive Testing Prognostic testing

Description

Oncotype DX Colon Cancer Assay

Quantifies recurrence risk in stage II and stage III colon cancer, beyond traditional qualitative measures

BRCA testing

Predicts the risk for hereditary breast or ovarian cancer in women

Predictive testing

Description

HER2

Tumor-cell genetic makeup in invasive/metastatic breast cancer

KRAS

Tests for KRAS mutation to predict clinical benefit of cetuximab and panitumumab

CancerTYPE ID

Identifies primary tumor type in metastatic cancer

Table 2 Impact of Prognostic-Only Testing on Stakeholders

A predictive test may relieve a patient of the burden of receiving a treatment to which he or she will not It’s about getting respond. the right drug to the right patient at the right time.

“

”

—S. MACEY JOHNSON III, MBA

“Patient experience can vary, because in some situations, the patients certainly will have the information and knowledge, but the experience may not be as positive if you are at extremely high risk for a certain disease state and you are a nonresponder to the best-in-class drug,” Mr Johnson noted. In prognostic testing, improving and standardizing outcomes are much more difficult. “Some would argue it doesn’t exist at all,” said Mr Johnson. “The patient experience, though, can often be enhanced.” Patients who know that their risk for a certain disease is low or high, for example, can empower themselves to better make decisions about how and how often to use the healthcare delivery system. Prognostic testing falls short of predictive testing in controlling costs. “There’s typically no direct return on investment, not a direct return, or cost offset with the prognostic test,” Mr

Stakeholder

Value of testing

Patient

Often sees value in prognostic testing thanks to lower anxiety and sense of empowerment

Physician

Varies by disease state May see limited value in prognostic testing and greater value in predictive testing

Payer

Skeptical of prognostic-only testing because of lack of perceived clinical utility or action ability

Regulator

Evolving, but focus may shift to predictive testing

Johnson pointed out. Payers and regulators tend to be skeptical of prognostic-only testing, because of the lack of perceived clinical utility or “actionability” (Table 2). Advanced Diagnostic Tests Diagnostic testing has traditionally failed to capture its fair share of value in the healthcare system. “With the complexities of the data sets that are being developed, I think this is even going to continue to manifest itself, at least until some of the reforms hit in 2016,” Mr Johnson advised. Diagnostic testing is estimated to influence 70% of the decisions made by US physicians, yet only 2% of the $2 trillion spent annually on healthcare flows to diagnostic providers. “The value proposition still has a long way to go in terms of the overall industry,” he said. The future of capturing the value of diagnostic tests may lie in a new bill (H.R. 4302). A key component of this bill is the creation of a new type of testing known as “advanced diagnostic tests” or “laboratory-developed tests” (LDTs). Advanced diagnostic tests include (1) a multianalytic assay with an algorithm, and (2) tests approved by the

SEPTEMBER 2014

FDA. Under the second type, many of these tests will switch from a CLIA (Clinical Laboratory Improvement Amendments) pathway, with a regulatory perspective, to an outright FDA-approval pathway. For the new advanced diagnostic tests, the payment rate for the first 3 quarters will reflect the laboratory’s actual list charge, and, thereafter, payment rates will be based on payer data reported by the laboratory. It will require the Centers for Medicare & Medicaid Services to establish an advisory panel to provide input on payment rates for new tests and the factors used in determining coverage and payment processes for new tests. The BRACAnalysis test is one of the first LDTs submitted for FDA premarketing approval. “I can assure you it’s not going to be the last,” said Mr Johnson. “You’re going to see many LDTs now rethinking their overall business strategy due to the new bill that has recently been passed,” he noted. The goal is to obtain a permanent Current Procedural Terminology® code for the test, instead of continually billing under a miscellaneous code, which would improve efficiencies for payers, manufacturers, and developers. n

www.ValueBasedCancerCare.com

4th Conference

Improving the Value Paradigm in Drug Development Will Require More Efficient Clinical Trials, New Biomarkers

By Wayne Kuznar

Los Angeles, CA—Much remains to be done to usher in the era of personalized healthcare, including better methods of drug development, said presenters at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

“

What payers want is straightforward and consistent across payer types, he claimed. Payers want persuasive evidence (usually peer-reviewed evidence) that a treatment strategy—a drug or a device—leads to clinically meaningful improvements in outcomes.

We expose patients…to technologies that may have little, if any, chance of real benefit. We’re spending a whole lot of money on really big, long trials with tiny effects, and then we argue about the meaning of the results.

”

—LOUIS JACQUES, MD “We’re using an insurance paradigm to incubate developing technologies, and frankly I don’t think that makes an ounce of sense,” said Louis Jacques, MD, Senior Vice President and Chief Clinical Officer at ADVI, Washington, DC. Drug development has focused on small effects for big populations, creating high numbers needed to treat to prevent an adverse outcome but also exposing many patients to potential harm. The best way to do research in this paradigm is unclear, but randomized controlled trials will not necessarily lead to the solution. Instead, the methodological rigor needs to match the risk of making an erroneous conclusion, Dr Jacques said. Clinical Trials Are Inefficient “We expose patients…to technologies that may have little, if any, chance of real benefit,” said Dr Jacques. “We’re spending a whole lot of money on really big, long trials with tiny effects, and then we argue about the meaning of the results.”

Too often drug development revolves around “me too” products, combinations of generics at a premium price point, and new molecular entities that do not improve quality of life, daily patient function, or morbidity and mortality. None of these approaches are of interest to payers, argued Dr Jacques. Health outcomes of interest to payers include longer life and improved function, improvement of symptoms, and a reduction in the need for burdensome tests and treatments (Table). An outcome of lesser interest is an improvement in disease-specific survival without an improvement in overall survival. Finding small effects requires large and long trials that are expensive to conduct, complex statistical analyses, and the use of composite end points, resulting in evidence that may not be clear and consistent. Research and development (R&D) in the cancer arena need to move beyond the status quo, agreed Christiane Langer, MD, Group Medical Director

Table What Are Clinically Meaningful Outcomes? More persuasive • Longer life and improved function/participation • Longer life with arrested decline • Significant symptom improvement allowing better function/participation • Reduced need for burdensome tests and treatments Less persuasive • Improved disease-specific survival without improved overall survival • Surrogate test result better • Procedural success • Image looks better • Doctor feels better

VALUE-BASED CANCER CARE

SEPTEMBER 2014

in Oncology US Medical Affairs at Genentech, South San Francisco, CA. The knowledge of biology should be applied to tailor the design of early clinical studies to increase the success rate of R&D, which stands at <10%. “We need to move from just pure luck and chance to enhanced predictability,” Dr Langer said. The average per-patient cost of oncology clinical trials has jumped from $38,300 in 2007 to $65,300 in 2010 as a result of the increased complexity and longer timelines of the trials. An improved understanding of disease mechanisms through the human genome should improve the efficiency of clinical trials, but simply identifying targets does not mean that the right drugs will be developed or will be applied to optimize outcomes.

“

We need to move from just pure luck and chance to enhanced predictability.

”

—CHRISTIANE LANGER, MD

Companion Diagnostics Key to Improved Outcomes The development and regulation of companion diagnostics are also of interest to payers, because linking a drug to a specific test may narrow the potential market for the drug but improve outcomes. The lack of FDA oversight of companion diagnostics, however, may “scare” payers, said Dr Jacques. “Imagine something that doesn’t even have fundamental analytic or clinical validity data, except what the company is giving us,” he said. The coverage and payment of companion diagnostics are challenges at the moment, because the test and the treatment may cross Medicare program benefit boundaries. For example, Medicare Part B administrative con-

tractors may deal with the test, whereas Part D plans deal with the drug. An increase in the number of molecularly targeted therapies in the oncology R&D pipeline is a driver for the need to develop companion diagnostics, and, in the future, targeted ther apies will be codeveloped with a companion diagnostic, Dr Langer predicted. Overall, 36% of cancer therapies in phase 3 clinical trials currently in the pipeline involve targeted therapies compared with 45% that are in phase 1 trials, reflecting a growing focus on targeted agents. For a biomarker to be useful as part of a companion diagnostic, its predictive value would need to be differentiated from its prognostic implications, she said. One example of a biomarker of response that predicts benefit from a drug is the KRAS mutation status of colorectal cancer, which improves the cost-effectiveness of EGFR monoclonal antibody–based therapy. Patients with KRAS wild-type have a doubling of median overall survival with cetuximab (Erbitux). Another example is vemurafenib (Zelboraf), which shrinks target lesions in patients with BRAF V600E–mutated metastatic melanoma. The codevelopment of vemurafenib and the BRAF V600E mutation test took only 5 years from the New Drug Application to the FDA approval and launch. “This is a really accelerated timeline for getting a very valuable drug in a targeted population on the market and to the patients,” Dr Langer noted. Barriers to Personalized Medicine Identifying an “actionable” target is one of the barriers to personalized medicine. Tumor heterogeneity is a challenge to identifying dominant mutations. The relevance of circulating tumor cells in relation to circulating tumor DNA is also not known, because they appear to be distinct entities. Changes in the molecular characteristics of the tumor after primary treatment may have consequences for second- and third-line therapies. “There’s so much we don’t know and we need to know before we can really move effectively and make personalized medicine a real success,” Dr Langer said. Economic barriers include the lengthy duration of drug development and the high cost of R&D. Several “supertargeted” drugs may be needed for subsets of cancers, adding further cost. n

VOL. 5

NO. 7

4th Conference

Payer Challenges in Oncology: Establishing Standards and Access to Quality Care By Wayne Kuznar

Los Angeles, CA—Payers are scrambling to devise effective strategies to cope with rapidly changing access to quality cancer care as a result of escalating costs. At the Fourth Annual Conference of the Association for Value-Based Cancer Care, John Fox, MD, MHA, Associate Vice President of Medical Affairs at Priority Health, Grand Rapids, MI, tackled changing access and payer challenges in oncology. “For oncologists, access to healthcare is not the same as access to high-quality oncology care,” said Dr Fox. He emphasized that access to oncology care is changing, and where that care is being provided is changing as well.

Between 2006 and 2012, 469 oncology practices in the United States entered into contractual relationships with hospitals for services or were acquired by hospitals, reported Dr Fox. In addition, 288 oncology clinics closed, 407 practices were struggling financially, 131 practices either merged with or were acquired by a corporate entity, and 43 practices were sending patients elsewhere for treatment. Payer–Provider Collaboration Dr Fox believes that collaborating with providers is the key to controlling costs while improving quality in oncology. The collaboration between Priority

Table 1 Priority Health Oncology Medical Home Payment reform • Plan pays acquisition cost for drugs • Care management fee for patients receiving oral/intravenous chemotherapy Payment enhancements • Annual $1500 per physician infrastructure development fee • Payment for treatment planning (S0353 and S0354) and advance care planning (S0257) • Shared savings for reductions in emergency department visits and hospitalizations Care reform • Implementation of preferred therapeutic regimens • Standardized care management programs • Patient engagement programs with a “call me first” policy • Enhanced access to same-day and next-day care

Table 2 Oncology Medical Home Accreditation Standards, Draft Subject to Change Domain

Objective validation

Patient engagement

Percent of patients receiving treatment plan before the initiation of chemotherapy

Expanded access

Number of annual emergency department visits per chemotherapy patient Number of annual hospital admissions per chemotherapy patient Patient satisfaction scores related to expanded access

Evidence-based medicine

Percent of patients treated according to guidelines Percent of patients with: • high risk of emesis receiving antiemetics • >20% risk for neutropenia receiving G-CSF • stage I/II breast cancer with advanced imaging • stage I/II prostate cancer with advanced imaging • staging documented in chart before treatment • performance status documented before treatment

Comprehensive team-based care

Percent of patients with stage IV cancer and documented advanced care plan discussions Average number of days on hospice at time of death Percent of patients receiving • ≥1 psychosocial distress screenings • a survivorship plan within 30 days of completion of treatment

Quality improvement

Survival rates for breast, colon, and non–small-cell lung cancers, by stage Chemotherapy given within 30 days of end of life Percent of patients who die in acute care setting

G-CSF indicates granulocyte colony-stimulating factor.

VOL. 5

NO. 7

Health and providers in Michigan led to the development of the oncology medical home (OMH) initiative in Michigan. The plan included payment reform, payment enhancements, and patient care reform (Table 1). The agreement between the plan and the providers was intended to last 6 months, but is now in its third year, and all participating practices have agreed to continue. This initiative was successful, because it was consistent with the way that healthcare providers want to practice medicine, Dr Fox asserted. The downside, he said, is that Priority Health is regional and is not the predominant payer in all areas of Michigan, including Detroit. “It’s exceptionally difficult for practices to conform to, comply with, or participate in multiple payer strategies,” Dr Fox acknowledged. In 2012, an all-payer meeting was held in Michigan to try to reach an agreement on a single set of quality metrics, quality access, and cost metrics so that oncologists would know how they would be measured. Support from the Michigan Society of Hematology and Oncology and other professional groups was high, but they were unable to convince the providers to agree. Nevertheless, “there’s a lot of enthusiasm among the providers for being able to articulate what access to high-quality oncology care means,” Dr Fox claimed. He talked about a recent collaborative effort by the Commission on Cancer (CoC), the Community Oncology Alliance (COA), the American Society of Clinical Oncology, and the Community Oncology Medical Home project to develop national accreditation standards that would determine an OMH and could be adopted by anyone. When practices apply for inclusion in this OMH initiative, they must agree to comply with the eligibility criteria and the care standards (Table 2), Dr Fox said. The OMH accreditation eligibility criteria for practices include the (1) use of a certified electronic medical record, (2) leadership support for the medical home concept and accreditation, (3) staff orientation on the importance and significance of OMH, (4) willingness to share practice and aggregate patient data, and (5) administration of the COA patient satisfaction survey every 6 months. Standards of Oncology Medical Home The CoC and COA have developed

SEPTEMBER 2014

standards for OMH consisting of 5 domains of patient care, assessments, infrastructure, and process standards. But most important, according to Dr Fox, are the methods to objectively val-

“

The key question is whether or not we can coalesce around these standards and begin to talk more about access not to oncology care but access to high-quality oncology care.

”

—JOHN FOX, MD, MHA

idate care. The ability to verify care is of primary importance to payers. Accreditation standards for OMHs consist of the 5 domains developed by the CoC and COA (Table 2). “We are evaluating this today in Michigan to decide if we can get all payers to agree that this would be the standard by which we would assess oncology practices, whether they be community-based practices or employee practices, to provide comparable information not only for payers, but also for patients,” said Dr Fox. He questioned whether these are the standards that payers in collaboration with providers will agree to use to assess the quality of cancer care and provide incentives for access to high-quality care practices in the state of Michigan. “For me, the key question is whether or not we can coalesce around these standards and begin to talk more about access not to oncology care but access to high-quality oncology care,” Dr Fox concluded. n

www.ValueBasedCancerCare.com

THIRD ANNUAL

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

October 29 – October 31, 2014 • Marriott Marquis • San Francisco, CA A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the ﬁeld of cutaneous malignancies on topics in melanoma, basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, and cutaneous T-cell lymphoma.

CONFERENCE CHAIR

WORLD CUTANEOUS MALIGNANCIES CONGRESS

Sanjiv S. Agarwala, MD Bethlehem, PA

PROGRAM COMMITTEE

Axel Hauschild, MD Kiel, Germany

Paul Nghiem, MD, PhD Seattle, WA

Pierluigi Porcu, MD Columbus, OH

Aleksandar Sekulic, MD, PhD Scottsdale, AZ

™

TARGET AUDIENCE

This educational initiative is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to participate.

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Review the molecular biology and pathogenesis of malignant melanoma, CTCL, BCC, and MCC, including how they relate to targeted therapy • Describe how to tailor therapeutic options and optimal sequencing for individual patients with melanoma, CTCL, BCC, and MCC • Utilize emerging data and recent advances with new molecular targets for the treatment of patients with metastatic melanoma, CTCL, BCC, and MCC into clinical practice • Identify new technologies for the prevention and early detection of cutaneous malignancies

PHYSICIAN CONTINUING MEDICAL EDUCATION

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Postgraduate Institute for Medicine and Center of Excellence Media. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION*

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. *This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

DISCLOSURE OF CONFLICTS OF INTEREST

Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conﬂict of interest (COI) they may have as related to the content of this activity. All identiﬁed COIs are thoroughly vetted and resolved according to PIM policy. The existence or absence of COIs for everyone in a position to control content will be disclosed to participants prior to the start of each activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at 732-992-1520.

This activity is jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

For more information please visit www.CutaneousMalignancies.com

AGENDA*

WEDNESDAY, OCTOBER 29 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception/Exhibits

THURSDAY, OCTOBER 30 6:45 am - 9:15 am

Breakfast Product Theaters

9:15 am - 9:30 am

Break

9:30 am - 9:45 am Welcome to the Third Annual World Cutaneous Malignancies Congress - Setting the Stage for the Meeting – Sanjiv S. Agarwala, MD 9:45 am - 11:45 am General Session I The Molecular Biology of Cutaneous Malignancies Implications for Personalized Therapy • Understanding the molecular biology of malignant melanoma: a clinical perspective – Antoni Ribas, MD • The molecular basis of basal cell carcinoma (BCC) – James MacDonald • Cutaneous T-cell lymphoma (CTCL): molecular aspects of disease development and response to targeted agents – Anjali Mishra, PhD • Immunologic characterization of tumor cells in CTCL: application to clinical practice – Rachel Clark, MD, PhD • Virus-positive and virus-negative Merkel cell carcinoma (MCC): implications for the clinician – Isaac Brownell, MD, PhD Question & Answer Panel Discussion

• Ongoing clinical studies in BCC – Aleksandar Sekulic, MD, PhD • New systemic therapies in CTCL: beyond the old paradigms – Steve Horowitz • Emerging treatment options in MCC: chemotherapy and alternative approaches for metastatic disease – Shailender Bhatia, MD Question & Answer Session 4:35 pm - 5:15 pm Tumor Board Breakout Sessions • Attendee cases in malignant melanoma • Attendee cases in BCC • Attendee cases in CTCL and MCC 5:15 pm - 7:00 pm

FRIDAY, OCTOBER 31

Cocktail Reception/Exhibits

7:00 am - 8:00 am

Breakfast

8:00 am - 8:15 am

Break

8:15 am - 8:30 am Review of Thursday’s Presentations and Preview of Today’s Sessions – Sanjiv S. Agarwala, MD

11:45 am - 12:00 pm Break

8:30 am - 9:30 am General Session IV Prevention and Early Detection • Early detection of primary tumors in melanoma – Susan M. Swetter, MD • A new serologic assay for early detection of recurrent MCC – Paul Nghiem, MD, PhD • An update on the SCREEN trial: skin cancer screening in Germany – Axel Hauschild, MD Question & Answer Session

12:00 pm - 1:00 pm

9:30 am - 9:45 am

Meet the Experts/Lunch in the Exhibit Hall

1:00 pm - 2:15 pm General Session II Current Treatment Algorithms in Cutaneous Malignancies • Current approaches to therapy in malignant melanoma: the US perspective – Antoni Ribas, MD • Current approaches to therapy in malignant melanoma: the EU perspective – Axel Hauschild, MD • Current treatment options for advanced BCC – Karl Lewis, MD • Current treatment options in CTCL – Pierluigi Porcu, MD • Update on NCCN guidelines for the management of MCC – Christopher K. Bichakjian, MD 2:15 pm - 2:30 pm

Break

2:30 pm - 2:50 pm Keynote Debate International Focus on Melanoma: Case Presentation Followed by US vs EU vs Latin America Debate on Therapy – Sanjiv S. Agarwala, MD; Héctor Martínez Saíd, MD; Axel Hauschild, MD 2:50 pm - 4:35 pm General Session III Emerging Therapies, Combos, and Targeted Agents • Changing arena of adjuvant therapy in malignant melanoma – Reinhard Dummer, MD, PhD

Break

9:45 am - 11:10 am General Session V What’s Hot in New Drugs and Clinical Trial Data • Anti–PD-1 antibodies ± ipilimumab in melanoma – Caroline Robert, MD, PhD • Real-world management of BCC: the RegiSONIC study – Jean Tang, MD, PhD • New data on lymphoma biology with applications to CTCL – Leandro Cerchietti, MD • Rationale and status of immune targeted therapies for MCC – Isaac Brownell, MD, PhD Question & Answer Session 11:10 am - 11:25 am Keynote Panel Discussion Is There a Role for “Conventional Therapies” for Cutaneous Malignancies in the Era of Targeted Agents? – Sanjiv S. Agarwala, MD; Axel Hauschild, MD; Paul Nghiem, MD, PhD; Pierluigi Porcu, MD; Aleksandar Sekulic, MD, PhD 11:25 am - 11:30 am

Closing Remarks – Sanjiv S. Agarwala, MD

*Agenda subject to change.

For full faculty information please visit www.CutaneousMalignancies.com

WCMC2014ConfAd Ksize_60914

4th Conference

Comparative Effectiveness Research Helps Define Value in Cancer Care How should we determine cost-effectiveness? By Wayne Kuznar Los Angeles, CA—Comparative effectiveness research (CER) can be beneficial to determining value in cancer therapies, but challenges remain in applying this approach in oncology. Daniel C. Malone, RPh, PhD, Professor of Pharmacy, University of Ari-

“

One of the problems with the federal initiatives for CER is that we can’t talk about costs. But when it comes to CER and using technologies efficiently, we have to bring cost into it.

”

—DANIEL C. MALONE, RPH, PHD zona College of Pharmacy, Tucson, shared his insights and experience related to CER in value-based oncology therapy at the Fourth Annual Conference of the Association for Value-Based Cancer Care. An evidence-based medicine triad— consisting of individual clinical knowledge, the values and expectations of patients, and the best available clinical evidence—is important to improving value in medicine, said Dr

Malone (Figure). He emphasized the need to consider patient values as well as individual provider preferences in addition to clinical evidence. CER provides best scientific evidence in making decisions about patient care. “It is the synthesis of evidence that compares benefits and harms,” said Dr Malone. He cautioned that the positive and negative aspects of therapies must be considered, to help patients and their providers make better decisions and, ultimately, to improve health. Incorporating CER in Oncology “One of the problems with the federal initiatives for CER is that we can’t talk about costs. But when it comes to CER and using technologies efficiently, we have to bring cost into it,” Dr Malone insisted. Using randomized controlled trials to test cancer drugs presents a problem for the CER approach, because it would be unethical to randomize patients with cancer to a placebo or to a knowingly ineffective comparator to assess the relative value of a drug. Pragmatic trials, however, differ from efficacy studies, which measure an intervention’s performance under ideal, controlled circumstances. “Pragmatic trials are really what we call effectiveness trials,” Dr Malone explained. “Does this drug work when we get it out into usual practice?” Pragmatic trials allow cancer drugs to be evaluated in a comparative manner. The strict inclusion and exclusion criteria used in efficacy studies also prevent the treatment from being used in a wide range of patient populations. Sometimes the patient population that can gain the most benefit from a treatment is not able to receive it until much later than other populations.

VALUE-BASED CANCER CARE

SEPTEMBER 2014

Figure What Is Evidence-Based Medicine? EBM triad

Conscientious, judicious use of best evidence in making decisions about the care of the individual patients

Individual clinical expertise

Patient values and expectations

EBM

Best available external clinical evidence

EBM indicates evidence-based medicine. Source: Sackett DL, et al. BMJ. 1996;312:71-72.

“We tend to see these products that are used more in advanced stages of cancer eventually moving into the earlier stages of cancer,” Dr Malone said. Observational studies and systematic reviews are also used in CER to evaluate treatment options.

“

How do we define value in cancer care? Obviously, it’s unmet medical needs. Another component to the value of therapy is its advantages over existing options.

”

—DANIEL C. MALONE, RPH, PHD

Defining Value in Cancer Care Dr Malone asked, “How do we define value in cancer care? Obviously, it’s unmet medical needs. Another component to the value of therapy is its advantages over existing options.”

These include better efficacy and fewer side effects. He acknowledged that evaluating unmet medical needs from a comparative effectiveness standpoint is challenging. “There is a whole host of intangible factors, such as patient quality of life. There are other factors that we may not be able to grasp via some quantitative approach that we need to take into account,” Dr Malone said. He cautions against simply using a measure of central tendency, such as median survival or median progression-free survival, to represent outcomes for a constellation of patients. “Means and medians ignore outliers. They ignore distribution,” Dr Malone warned. He advocates the use of hazard ratios and confidence intervals to better understand the variation of an oncology treatment. “We really haven’t come to grasp what defines cost-effectiveness,” said Dr Malone. “It’s very complicated. Every drug can be cost-effective in the right patient at the right time.” n

VOL. 5

NO. 7

Melanoma

BRAF Protein Expression Potential New Marker for Mortality Risk in Melanoma Toronto, Ontario—BRAF protein expression is correlated with melanoma progression and poor patient survival, according to recent studies that were reviewed at the 2014 Canadian Dermatology Association annual conference. The team of researchers was given the best scientific poster presentation award at the meeting. The first meta-analysis (Safaee Ardekani G, et al. PLoS One. 2012;7:e47054) demonstrated a 1.7 hazard ratio (HR) for mortality from melanoma among patients with a BRAF V600E mutation. A subsequent study indicated that high BRAF protein expression is also a significant prognostic factor in patients with primary melanoma (Safaee Ardekani G, et al. Br J Dermatol. 2013;169:320-328). “We found that high BRAF protein expression is associated with poor prognosis and lower patient survival over 5 years of follow up,” Gholamreza Safaee Ardekani, MD, a PhD candidate, Department of Dermatology and Skin Science, University of British Columbia, Vancouver, told Value-Based Cancer Care. “This means BRAF protein expression could be a cheap and feasible prognostic factor to predict an elevated risk of death in melanoma patients.” Based on the 4 melanoma studies that involved 674 patients, the 2012 meta-analysis revealed a 47.8% preva-

“

This means BRAF protein expression could be a cheap and feasible prognostic factor to predict an elevated risk of death in melanoma patients.

”

—GHOLAMREZA SAFAEE ARDEKANI, MD

lence rate of BRAF mutation in melanoma samples and a 9.6% prevalence rate in colorectal cancer samples. It also showed a 1.7 HR for mortality in patients with the BRAF V600E mutation compared with those without the BRAF mutation.

The team then explored the correlation between BRAF protein expression and melanoma progression, which had not been examined before. The investigators evaluated BRAF protein expression in tissue samples of patients with melanoma in the Vancouver General Hospital’s tissue bank from 232 patients with primary melanoma and in 138 patients with metastatic melanoma. In the 2013 study, the researchers found a significant correlation between high BRAF protein expression and other key prognostic markers, including thicker tumors, a greater likelihood of ulceration, and higher stage of disease. Furthermore, high BRAF protein expression in primary melanoma was associated with a 2.08 HR for worse overall survival and a 2.39 HR for worse disease-specific survival. However, BRAF expression was not correlated with survival in patients with metastatic melanoma. A multivariate Cox regression analysis showed that stage and tumor thickness, but not BRAF expression, were

By Rosemary Frei, MSc

independent prognostic factors for poor overall and disease-specific survival among patients with either form of melanoma. There was also an association between high BRAF protein expression and the presence of the BRAF V600E genetic mutation, but this was not statistically significant. The researchers concluded that BRAF protein expression can be an inexpensive prognostic marker for disease progression and poor survival in melanoma. “This is a very exciting area of research, but the exact molecular mechanism behind these observations needs to be further investigated,” Dr Safaee Ardekani told Value-Based Cancer Care. n

Noninvasive Imaging Technology Distinguishes Between Benign and Malignant Skin Lesions Toronto, Ontario—New laser-based imaging technology differentiates malignant melanoma from other cancerous and benign skin lesions, according to a preliminary study presented at the 2014 Canadian Dermatology Association annual conference. The investigators are now refining the approach to differentiate between malignant melanoma and all types of nevus, a common category of benign skin pigmentation. This new imaging modality may lead to a reduction in the use of skin biopsies and the potential associated scars. “We wanted to come up with a technology with high specificity, high sensitivity, and low cost to help clinicians in

VOL. 5

NO. 7

“

We wanted to come up with a technology with high specificity, high sensitivity, and low cost to help clinicians in their decision of whether to biopsy or not.

”

—BAHMAN SOTOODIAN, MD their decision of whether to biopsy or not,” Bahman Sotoodian, MD, of the University of Alberta, Edmonton, Canada, told Value-Based Cancer Care.

Dr Sotoodian and his team created a device that uses blue and red lasers from 2 “maps” of skin lesions—a copolarized and a cross-polarized image, which correspond to the light reflected from the surface and deeper layers of the skin. The version of the device used in the preliminary study did not contain a lens and, therefore, the maps were of speckle patterns rather than true images. The speckle-image analyses of benign and malignant skin lesions of 214 patients who received treatment at Vancouver General Hospital’s Skin Care Centre between 2008 and 2010 successfully distinguished between malignant melanoma and the benign

SEPTEMBER 2014

lesion known as seborrheic keratosis (P = .001), with a sensitivity of 82% and a specificity of 78%. The technique also accurately differentiated between seborrheic keratosis and nevus (P = .001), as well as between other malignant and benign pigmented skin lesions, but with less accuracy. “We’re making some modifications to our optical apparatus, including adding some lenses,” in the quest to produce differentiations between malignant melanoma and nevus, Dr Sotoodian told Value-Based Cancer Care. The researchers are also adapting the mathematical analyses to a wider range of benign and malignant skin lesions.—RF n

www.ValueBasedCancerCare.com

THIRD ANNUAL CONFERENCE

October 31November 1, 2014 Marriott Marquis San Francisco, CA

CONFERENCE CHAIRS Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Roy S. Herbst, MD, PhD

Ensign Professor of Medicine Professor of Pharmacology Chief of Medical Oncology Director, Thoracic Oncology Research Program Associate Director for Translational Research Yale Cancer Center, New Haven, CT

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker and immunotherapy research in oncology. Guided by the expertise of leaders in this ﬁeld, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This activity has been designed to meet the educational needs of medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology/hematology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid cancers or hematologic malignancies, and interested in the use of molecular biomarkers to help optimize patient care. Research scientists interested in the ﬁeld of molecular biomarkers in oncology are also invited to participate.

DESIGNATION OF CREDIT STATEMENTS ACCREDITATION STATEMENT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Postgraduate Institute for Medicine and Center of Excellence Media, LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION

The Postgraduate Institute for Medicine designates this live activity for a maximum of 9.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

AMERICANS WITH DISABILITIES ACT

Event staff will be glad to assist you with any special needs (ie, physical, dietary, etc). Please contact Linda Sangenito prior to the live event at 732-992-1520.

DISCLOSURE OF CONFLICTS OF INTEREST

The Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conﬂict of interest (COI) they may have as related to the content of this activity. All identiﬁed COI are thoroughly vetted and resolved according to PIM policy. The existence or absence of COI for everyone in a position to control content will be disclosed to participants prior to the start of each activity. Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC

EDUCATIONAL OBJECTIVES

After completing this activity, the participant should be better able to: • Assess emerging data and recent advances in the discovery of molecular biomarkers on the management of patients with solid tumors and hematologic malignancies •

Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors and hematologic malignancies

•

Outline the practical aspects and value-based considerations of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

This activity is supported, in part, by independent educational grants from Lilly USA. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com. This activity is also supported, in part, by an educational grant from Prometheus. Current at time of printing.

SUBMIT AN ABSTRACT BY OCTOBER 3, 2014 Submit an abstract for the Third Annual PMO Live Conference. This is an opportunity to share research, programs, and results with your peers. This session will facilitate communication among the various professionals and programs to advance the knowledge of all our members and those in attendance.

www.pmo-live.com/conference/abstracts

AGENDA*

FRIDAY, OCTOBER 31 7:00 am - 12:00 pm Registration 11:45 am - 2:15 pm Product Theaters 2:15 pm - 2:30 pm

Break

2:30 pm - 2:40 pm

Welcome to the Third Annual PMO Live Conference, a Global Biomarkers Consortium — Opening Remarks – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

2:40 pm - 4:15 pm

General Session I: Cancer Care in the Era of Molecular Biomarkers • Personalized medicine in oncology: therapeutic advances from cytotoxic chemotherapy to molecularly targeted agents – Razelle Kurzrock, MD • Understanding cancer at the molecular level – Caroline Robert, MD, PhD • Standardization of molecular biomarker testing – Mark Sausen, MD • Implications of molecular diagnostics on clinical trial design – John J. Wright, MD, PhD Question & Answer Session

4:15 pm - 4:30 pm

Break

4:30 pm - 5:30 pm

General Session II - Part 1: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Breast cancer – Hope Rugo, MD Question & Answer Session

5:30 pm - 7:00 pm

Welcome Reception and Exhibits

SATURDAY, NOVEMBER 1 7:00 am - 8:00 am

Product Theater

8:00 am - 8:15 am

Break

8:15 am - 8:30 am

Review of Friday’s Presentations and Preview of Today

8:30 am - 9:30 am

General Session II - Part 2: Incorporating Molecular Biomarkers into the Therapy of Solid Tumors — Case Studies on “How I Treat” • Melanoma – Sanjiv S. Agarwala, MD • Colorectal cancer – Axel Grothey, MD Question & Answer Session

9:30 am - 9:45 am

9:45 am - 11:05 am General Session III: Incorporating Molecular Biomarkers into the Therapy of Hematologic Malignancies — Case Studies on “How I Treat” • Myeloid hematologic malignancies – Jorge E. Cortes, MD • Chronic lymphocytic leukemia – William Wierda, MD, PhD • Multiple myeloma – Sagar Lonial, MD • Lymphoma – Anas Younes, MD 11:05 am - 12:00 pm Keynote Lecture: Markers of Resistance to Targeted Therapies – Alberto Bardelli, PhD Question & Answer Session 12:00 pm - 1:00 pm Meet the Experts and Lunch in the Exhibit Hall 1:00 pm - 1:15 pm

Break

1:15 pm - 2:00 pm

Tumor Board Breakout Sessions • Attendee cases in solid tumors • Attendee cases in hematologic malignancies

2:00 pm - 2:15 pm

Break

2:15 pm - 3:30 pm

General Session IV: Molecular Biomarkers for the Early Detection of Cancer: Are They Ready for Prime Time? • Developing and validating biomarkers via the Early Detection Research Network (EDRN-NCI) – Sudhir Srivastava, PhD, MPH • Beyond PSA: novel molecular biomarkers for prostate cancer – Mark Rubin, MD • Airway biomarkers for lung cancer detection in the post-NLST era – Avi Spira, MD, MSc • Early detection biomarkers for breast cancer – Karen Anderson, MD, PhD Question & Answer Session

3:30 pm - 3:45 pm

Break

3:45 pm - 4:00 pm

Keynote Lecture: Actionable Genomic Alterations in Oncology – Phil Stephens, PhD

4:00 pm - 4:50 pm

General Session V: Regulatory and Economic Aspects of Personalized Medicine in Oncology • Understanding the regulatory aspects of personalized medicine in oncology – Andrew Stainthorpe, PhD • A debate on health economics and molecular biomarkers: can we afford personalized medicine in oncology? – Gary Johnson, MD, MS, MBA, and Ken Schaecher, MD, FACP, CPC Question & Answer Session

4:50 pm - 5:00 pm

Closing Remarks – Jorge E. Cortes, MD – Roy S. Herbst, MD, PhD

Break *Agenda subject to change.

GBC2014ConfAd Ksize_91514

Drug Update

Arzerra (Ofatumumab) Receives FDA Approval for Patients with Previously Untreated Chronic Lymphocytic Leukemia for Use in Combination with Chlorambucil By Lisa A. Raedler, PhD, RPh, Medical Writer

hronic lymphocytic leukemia (CLL), the most common type of leukemia in adults, is a cancer that predominantly affects the B-cell lymphocytes.1 Normal B-cell lymphocytes originate in the bone marrow, develop in the lymph nodes, and fight infection by producing an immune response.1 In CLL, excess B-cells accumulate in the bone marrow and blood, where they crowd out healthy blood cells.2 According to the Leukemia & Lymphoma Society, more than 15,600 Americans were diagnosed with CLL in 2013.3 The incidence of CLL increases significantly among people aged ≥50 years; only a small fraction of adults are diagnosed in their 30s and 40s.3 Most patients with CLL are asymp tomatic and learn they have the disease as a result of a routine physical examination or a blood test.4 As CLL advances, patients can experience enlarged lymph nodes and an enlarged spleen, abnormal bleeding, and infections.5 According to the American Society of Clinical Oncology, the prognosis for patients with CLL varies significantly based on disease subtype and risk status, with survival ranging from approximately 1 year to more than 20 years.6 The 5-year overall survival rate for patients with CLL of all stages is approximately 79%.6 The cost burden associated with CLL is significant. A recent cost analysis conducted in Germany using the direct and indirect costs of CLL calculated the total per-patient cost to be approximately $13,500 annually compared with approximately $6600 annually for patients in an age- and sexmatched control group.7 The economic burden of CLL was primarily driven by inpatient and pharmaceutical costs in this study. From a societal perspective, productivity loss was the highest cost associated with a diagnosis of CLL.7 Patients with early-stage CLL are typically not treated, whereas patients with symptomatic intermediate- and high-risk CLL usually receive chemotherapy combined with a monoclonal antibody–targeting CD20.2 Studies comparing chemotherapy, such as Copyright © 2014 American Health & Drug Benefits. All rights reserved.

fludarabine or the combination of fludarabine and cyclophosphamide, with immunotherapy (ie, rituximab in treatment-naïve patients with CLL) have shown that the rituximab-containing combinations significantly improve complete response rates, remission duration, and overall survival in CLL.2 Bendamustine is indicated as a single agent for the treatment of CLL.8 Studies of bendamustine combined with rituximab have demonstrated promising results in untreated and in previously treated patients with CLL.2

The FDA expanded the approved indications for ofatumumab for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabinebased therapy is considered inappropriate. No consensus exists regarding the management of patients with relapsed or refractory CLL. Treatment decisions are based on several factors, including the timing of relapse, patient age, disease extent, overall health, and previous therapies.9 Drugs that are frequently used in the relapsed/ refractory CLL setting (either alone or in combination) include bendamustine, chlorambucil, fludarabine, ofatumumab, and rituximab.9 The development of drugs for the treatment of CLL has been fruitful, with the US Food and Drug Administration (FDA) recently approving 3 new therapies. In November 2013, the FDA approved obinutuzumab in combination with chlorambucil for the treatment of patients with previously untreated CLL.10 Obinutuzumab is a humanized monoclonal antibody that targets CD20 on the surface of CLL cells.11 Ibrutinib was approved by the FDA in February 2014 for patients with CLL who have received at least 1 previous therapy.12 Ibrutinib is the first drug designed to target Bruton’s tyrosine

VALUE-BASED CANCER CARE

SEPTEMBER 2014

kinase, a protein necessary for the growth and survival of malignant B-cells.13 In July 2014, the FDA approved idelalisib in combination with rituximab for patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy, as well as for patients with relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma who have received at least 2 previous systemic therapies.14 Idelalisib inhibits PI3K delta, a protein that is overexpressed in many B-cell cancers. PI3K delta affects the viability, proliferation, and migration of malignant B-cells.12 FDA Approves Expanded Indication for Ofatumumab On April 17, 2014, the FDA expanded the approved indications for ofatumumab (Arzerra; GlaxoSmithKline), an anti-CD20 monoclonal antibody, for use in combination with chlorambucil for the treatment of previously untreated patients with CLL for whom fludarabine-based therapy is considered inappropriate.15 Ofatumumab was initially approved in 2009 for the treatment of patients with CLL that is refractory to fludarabine or to alemtuzumab.16 The FDA approved this new indication for ofatumumab based on a multicenter, randomized, open-label, parallel-arm trial of 447 patients with CLL for whom fludarabine-based therapy was deemed inappropriate based on the patient’s age and/or comorbidities.15 The primary end point of this trial was progression-free survival (PFS) as assessed by a blinded Independent Review Committee (IRC).15 The results of this randomized clinical trial fulfilled the postmarketing requirement by the FDA for the man ufacturer to verify ofatumumab’s clinical benefit in patients with CLL. Consequently, the approval of the new indication for ofatumumab was converted from accelerated approval to regular process approval.17 Mechanism of Action Ofatumumab binds to extracellular loops of the CD20 molecule, which is expressed on normal B lymphocytes and on B-cell CLL cells. After ofatumumab binds to the CD20 molecule, the Fc domain of the antibody medi-

ates immune effector functions that result in cell lysis in vitro. Complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity are possible mechanisms of cell lysis that occurs after ofatumumab binding.16 Dosing and Administration In patients with previously untreated CLL, the recommended dosage and schedule of ofatumumab is 300 mg on day 1, followed by 1000 mg on day 8 of the first 28-day cycle, followed by 1000 mg on day 1 of subsequent 28-day cycles. Treatment should be administered for a minimum of 3 cycles until best response or a maximum of 12 cycles.16 In the phase 3 study of ofatumumab in combination with chlorambucil, the oral agent was given at a dose of 10 mg/m2 on days 1 to 7 of the 28-day cycle.16 Patients receiving ofatumumab should be premedicated with acetaminophen, an antihistamine, and a corticosteroid. Infusion facilities should be adequately equipped to monitor and treat infusion reactions.16 During the first infusion of ofatumumab (cycle 1, day 1, 300-mg dose), the rate of infusion should be initiated at 3.6 mg per hour (12 mL per hour). The cycle 1, day 8, and subsequent infusions (cycles 2-12, 1000-mg dose) can be initiated at a rate of 25 mg per hour.16 If no infusion-related adverse events are observed, the rate of ofatumumab infusion can be increased every 30 minutes (Table 1).16 If a grade ≥3 infusion-related event was experienced during the previous administration of ofatumumab, the initial rate of infusion should decrease to 12 mg per hour (12 mL per hour).16 Pivotal Phase 3 Clinical Trial The safety and efficacy of ofatumumab in patients with previously untreated CLL were demonstrated in a phase 3 open-label, multicenter clinical trial known as COMPLEMENT 1. In this trial, 447 patients with CLL who were deemed unfit for fludarabine-based therapy were randomized to receive chlorambucil alone (N = 226) or ofatumumab combined with chlorambucil (N = 221).18 Chlorambucil was given orally at a dose of 10 mg/m2 on days 1 to 7 every

VOL. 5

NO. 7

Drug Update

28 days in both arms of this study. Ofatumumab was administered as an intravenous infusion every month (first 28-day cycle: 300 mg on day 1 and 1000 mg on day 8; subsequent 28day cycles: 1000 mg on day 1). In this trial, approximately 60% of the patients with CLL received 3 to 6 cycles of ofatumumab and 30% received 7 to 12 treatment cycles.18 The primary end point of this phase 3 study was PFS as assessed by a blinded IRC using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) update of the National Cancer Institute Working Group guidelines. Secondary efficacy end points, which included overall response rate, complete response rate, and duration of response, were also assessed by the IRC using the 2008 IWCLL guidelines.18 Patient Population Patients with previously untreated CLL who enrolled in the phase 3 clinical trial comparing ofatumumab plus chlorambucil with chlorambucil alone were considered by the investigators to be inappropriate for fludarabine- based therapy for reasons that included advanced age and the presence of comorbidities.18 The median age of the population studied was 69 years, with the majority (69%) of patients in both arms aged ≥65 years.16,18 The study enrollees were mostly male (63%) and white (89%) and had 2 or more comorbidities (72%).15,18 A total of 48% of the patients had a creatinine clearance of <70 mL/min.16 Beta-2 microglobulin was elevated (>3500 mcg/L) in 72% of patients at baseline.18

Efficacy and Safety In this phase 3 clinical trial, the combination of ofatumumab and chlorambucil in previously untreated patients with CLL resulted in a statistically significant improvement in IRC-assessed median PFS compared with chlorambucil alone (22.4 months vs 13.1 months, respectively).18 These data and results of secondary end point analyses are summarized in Table 2.16,18 A total of 217 previously untreated CLL patients received ofatumumab combined with chlorambucil and 227 patients received chlorambucil alone.17 Overall, grade ≥3 neutropenia was observed in 26% of patients receiving the combination of ofatumumab plus chlorambucil compared with 14% in patients receiving chlor ambucil alone; grade ≥3 infusion-reVOL. 5

NO. 7

lated events were 10% in the combination group and were not available for the chemotherapy alone; grade ≥3 infections were similar between the 2 groups—15% with the combination versus 14% with chlorambucil alone.17

Table 1 Infusion Rates for Ofatumumab in Previously Untreated Patients with CLL

Adverse Reactions

Infusion Reactions Overall, 67% of the patients who received ofatumumab plus chlorambucil experienced ≥1 infusion reactions, with 10% of patients experiencing reactions of grade ≥3 severity.16 None of these events was fatal.16 In the phase 3 clinical trial, the term “infusion reaction” encompassed events that occurred on the day of or within 24 hours of the end of an ofatumumab infusion and resulted in interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.16 Severe infusion reactions (grade ≥3) or infusion reactions that led to treatment interruption or discontinuation occurred most frequently during the first cycle of ofatumumab (56% on day 1 and 23% on day 8).16 The rates of reactions decreased with subsequent infusions.16 Infusion reactions led to the discontinuation of treatment in 3% of the patients.16 Cytopenia The most common grade 3 or 4 hematologic adverse reactions associated with ofatumumab combined with chlorambucil included neutropenia (29%), lymphopenia (29%), and leukopenia (23%).16 Neutropenia occurring up to 60 days after the last dose of ofatumumab was reported as a serious adverse event in 3% of patients.16 One of these patients died as a result of neutropenic sepsis and agranulocytosis.16 Prolonged neutropenia was observed in 6% of patients receiving ofatumumab plus chlorambucil versus in 4% of patients receiving chlor ambucil alone.16 Late-onset neutropenia occurred in 6% of patients receiving ofatumumab plus chlorambucil versus in 1% of patients receiving chlorambucil alone.16 Warnings and Precautions Ofatumumab has no contraindi cations. Boxed warning. Ofatumumab carries a boxed warning regarding the risk for hepatitis B virus (HBV) infection reactivation.16 High-risk patients

Interval after start of infusion, min

Cycle 1, day 1,a mL/hr

Cycle 1, day 8b and cycles 2 -12,c mL/hr

0-30

31-60

61-90

100

91-120

100

200

121-150

200

400

151-180

300

400

>180

400

Cycle 1, day 1 = 300 mg; median duration of infusion = 5.2 hrs. Cycle 1, day 8 = 1000 mg; median duration of infusion = 4.4 hrs. c Cycles 2 through 12 = 1000 mg; median durations of infusions = 4.2-4.4 hrs. CLL indicates chronic lymphocytic leukemia. Source: Arzerra (ofatumumab) injection prescribing information; April 2014. a

Table 2 Ofatumumab plus Chlorambucil versus Chlorambucil Alone in Previously Untreated CLL Ofatumumab plus chlorambucil Chlorambucil Efficacy end points (N = 221) (N = 226) Progression-free survival, median, mo

22.4 (95% CI, 19-25.2)

Hazard ratio Stratified log rank P value Overall response, % P value

13.1 (95% CI, 10.6-13.8)

0.57 (95% CI, 0.45-0.72) P <.001 82.4 (95% CI, 76.7-87.1) 68.6 (95% CI, 62.1-74.6) P = .001

Complete response, %

Duration of response, median, mo

22.1 (95% CI, 19.1-24.6)

13.2 (95% CI, 10.8-16.4)

CI indicates confidence interval; CLL, chronic lymphocytic leukemia. Source: Arzerra (ofatumumab) injection prescribing information; April 2014. should be screened for HBV infection before initiating ofatumumab therapy. HBV carriers should be monitored for signs of active infection during and after treatment with ofatumumab. In addition, progressive multifocal leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ofatumumab.16 Infusion reactions. Ofatumumab can cause serious, including fatal, infusion reactions that manifest as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (eg, myocardial ischemia or infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid or anaphylactic reactions.16 Patients receiving ofatumumab should be premedicated with acetaminophen, an antihistamine, and a corticosteroid. However, infusion re-

SEPTEMBER 2014

actions can occur despite premedication.16 Treatment interruption or discontinuation may be required.16 The administration of ofatumumab should cease if infusion reactions of any severity are observed.16 Medical management for severe infusion reactions, including angina or other signs and symptoms of myocardial ischemia, should be instituted. If anaphylaxis occurs, ofatumumab should be discontinued immediately and permanently, and appropriate medical treatment should be initiated.16 HBV reactivation. HBV infection reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or the detection of HBV surface antigen (HBsAg) in a person who was previously HBsAg negative and hepatitis B core antibody (anti-HBc) positive. HBV reactivation is often followed by hepatitis B (ie, increased transaminase levels). Severe cases of reactivation can be followed by increased bilirubin levels, liver failure, and death.16

Continued on page 42

www.ValueBasedCancerCare.com

Drug Update

Arzerra (Ofatumumab) Receives FDA Approval for... HBV reactivation has occurred in patients receiving ofatumumab, with some cases resulting in hepatitis, liver failure, or death.16 Cases have been reported in patients who are HBsAg positive, as well as patients who are HBsAg negative but anti-HBc positive. Reactivation also has occurred in patients who appeared to have resolved HBV infection.16 All patients for whom ofatumumab is being considered should be screened for HBV infection before the initiation of treatment.16 Patients with evidence of HBV infection should consult with physicians who have expertise in managing HBV to discuss the monitoring and potential use of HBV antiviral therapy.16 Patients with evidence of current or previous HBV infection should be evaluated for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment with ofatumumab. HBV reactivation has been reported for at least 12 months after the completion of therapy.16 If patients develop HBV reactivation during treatment with ofatumumab, the agent (and any concomitant chemotherapy) should be discontinued. Appropriate treatment should be instituted.16 Data regarding the safety of resuming ofatumumab in patients who develop HBV reactivation are insufficient.16 HBV infection. Fatal HBV infection has been documented with ofatumumab in patients who had not been previously infected.16 Patients with clinical and laboratory signs of hepatitis should be monitored.16 Progressive multifocal leukoencephalopathy. Death resulting from PML has occurred with ofatumu mab.16 PML should be considered in any patient describing the onset of or changes in preexisting neurologic signs or symptoms. If PML is suspected, ofatumumab should be discontinued. Evaluation for PML, including neurology consultation,

should be initiated.16 Tumor lysis syndrome. Patients receiving ofatumumab have experienced tumor lysis syndrome (TLS), which has resulted in hospitalization.16 Patients who are at greater risk of TLS include those with high tumor burden and/or high circulating lymphocyte counts (>25 × 109/L).16 Prophylaxis of TLS using antihyperuricemic agents and hydration beginning 12 hours to 24 hours before the infusion of ofatumumab should be considered.16 The management of TLS includes aggressive intravenous hydration and antihyperuricemic agents, correction of electrolyte abnormalities, and renal function monitoring.16 Cytopenias. Severe cytopenias can occur with ofatumumab, including neutropenia, thrombocytopenia, and anemia. Patients who received ofatumumab combined with chlorambucil have experienced pancytopenia, agranulocytosis, and fatal neutropenic sepsis.16 Patients receiving ofatumumab also experienced grade 3 or 4 late-onset neutropenia, occurring at least 42 days after the last dose, and/or prolonged neutropenia that does not resolve between 24 and 42 days after the last dose.16 Complete blood count (CBC) should be monitored at regular intervals during and after the conclusion of therapy with ofatumumab. The frequency of CBC monitoring should increase in patients who develop severe cytopenias.16 Immunizations. There are no studies evaluating the safety of immunization with live viral vaccines in association with ofatumumab.16 Live viral vaccines should not be administered to patients who have recently received ofatumumab. Specific Populations Ofatumumab has been assigned pregnancy Category C.16 There are no adequate or well-controlled studies of ofatumumab in pregnant women.16

Ofatumumab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.16 Caution should be exercised when administering the drug to a nursing woman.16 The safety and efficacy of ofatumumab in pediatric patients have not been established.16 In the clinical trial of previously untreated patients with CLL, 148 (68%) of the 217 patients receiving ofatumumab plus chlorambucil were aged ≥65 years.16 Patients aged ≥65 years were more likely to experience specific grade ≥3 adverse reactions compared with young patients, especially neutropenia (30% vs 17%, respectively) and pneumonia (5% vs 1%, respectively). In patients aged ≥65 years, 29% experienced serious adverse events compared with 13% of young patients. No significant differences in the effectiveness of the combination of ofatumumab and chlor ambucil were observed between older and younger patients with previously untreated CLL.16

Continued from page 41

1. ASCO Answers fact sheet: chronic lymphocytic leu-

kemia. 2013. www.cancer.net/sites/cancer.net/files/ asco_answers_cll.pdf. Accessed August 8, 2014. 2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. Revised 2011. www.lls.org/content/ nationalcontent/resourcecenter/freeeducationmaterials/leukemia/pdf/cll.pdf. Accessed August 8, 2014. 3. Leukemia & Lymphoma Society. CLL incidence. www.lls.org/#/diseaseinformation/leukemia/ chroniclymphocyticleukemia/incidence/. Accessed August 8, 2014. 4. Leukemia & Lymphoma Society. CLL signs and symptoms. www.lls.org/#/diseaseinformation/ leukemia/chroniclymphocyticleukemia/signssymp toms/. Accessed August 8, 2014. 5. Cancer.net. Leukemia—chronic lymphocytic—CLL: symptoms and signs. June 2013. www.cancer.net/ cancer-types/leukemia-chronic-lymphocytic-cll/ symptoms-and-signs. Accessed August 8, 2014. 6. Cancer.net. Leukemia—chronic lymphocytic—CLL: statistics. Updated February 18, 2014. www.cancer. net/cancer-types/leukemia-chronic-lymphocytic-cll/ statistics. Accessed August 8, 2014. 7. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32. 8. Treanda (bendamustine) for injection [prescribing information]. North Wales, PA: Teva Pharmaceuticals, Inc; August 2013. 9. Veliz M, Pinilla-Ibarz J. Treatment of relapsed and refractory chronic lymphocytic leukemia. Cancer Control. 2012;19:37-53. 10. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Press release. November 1, 2013. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm373209.htm. Accessed August 14, 2014. 11. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech; November 2013. 12. US Food and Drug Administration. Ibrutinib (Imbruvica). Updated February 13, 2014. www.fda. gov/drugs/informationondrugs/approveddrugs/ ucm385878.htm#. Accessed August 14, 2014. 13. Imbruvica (ibrutinib) capsules [prescribing information]. Sunnyvale, CA: Pharmacyclics, Inc; February 2014. 14. Business Wire. U.S. Food and Drug Administration approves Gilead’s Zydelig (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. Press release. July 23, 2014. www.marketwatch.com/story/ us-food-and-drug-administration-approves-gil eads-zydelig-idelalisib-for-relapsed-chronic-lympho cytic-leukemia-follicular-lymphoma-and-small-lym phocytic-lymphoma-2014-07-23. Accessed August 8, 2014. 15. US Food and Drug Administration. Ofatumumab. Updated April 17, 2014. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm393823. htm. Accessed August 8, 2014. 16. Arzerra (ofatumumab) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 2014. 17. Hillmen P, Robak T, Janssens A, et al. Ofatumumab + chlorambucil versus chlorambucil alone in patients with untreated chronic lymphocytic leukemia (CLL): results of the phase III study complement 1 (OMB110911). Abstract 528. Abstract presented at the 55th American Society of Clinical Oncology Annual Meeting and Exposition. New Orleans, LA; December 7-10, 2013. 18. National Cancer Institute. FDA approval for ofatumumab. Updated April 23, 2014. www.cancer.gov/ cancertopics/druginfo/fda-ofatumumab. Accessed August 8, 2014. 19. Clinicaltrials.gov. Ofatumumab in CLL. http:// clinicaltrials.gov/ct2/results?term=Ofatumumab+ in+CLL&Search=Search. Accessed July 23, 2014.

may warrant revision of its regulatory status. In an accompanying editorial (Lancet Oncol. 2014;15:913-914), Kharfan-Dabaja concurred that the data support consideration by regulatory authorities to review their decision with the view of making this therapy

available again. Although the optimal dose and dosing schedule remain elusive, Kharfan-Dabaja said that a single dose of 3 mg/m2 on day 1 or fractionated dosing of 3 mg/m2 on days 1, 4, and 7 are reasonable recommendations for prescribing guidance. n

Conclusion The addition of ofatumumab to chlorambucil represents a clinically meaningful improvement, with manageable side effects, for the treatment of previously untreated patients with CLL who are deemed inappropriate to receive fludarabine therapy. This doublet has demonstrated improved PFS in this patient population with limited therapeutic options. The safety and efficacy of ofatumumab combined with other agents for the treatment of CLL and other hematologic malignancies are being explored.19 Examples include a trial combining ofatumumab and ibrutinib for patients with relapsed or refractory CLL, and a trial combining idelalisib with ofatumumab in patients with previously untreated CLL or small lymphocytic lymphoma.19 n References

In the Literature Gemtuzumab Ozogamicin... Continued from page 26

teraction between different dosing schedules, they noted significant interaction between gemtuzumab ozogamicin (3 mg/m2 vs 6 mg/m2) with respect to 30-day mortality. Fewer early deaths were associated with the

lower dose of gemtuzumab ozogamicin compared with the higher dose of the drug. The investigators noted that these findings demonstrate significant OS benefit in patients with low-risk and intermediate-risk AML without adverse cytogenetic characteristics, and

VALUE-BASED CANCER CARE

SEPTEMBER 2014

VOL. 5

NO. 7

A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to discuss the most recent available data concerning improvements in cost of care, safety profiles, and patient preferences as they pertain to the use of emerging agents used in the treatment of patients with MM. IN MULTIPLE MYELOMA

Value-BasedCare

™

November 2013 u 8th IN A SERIES

Cost-Effective Use of Imaging Modalities for Diagnosis and Monitoring in Multiple Myeloma

Topics include: • Effective Treatment of Newly

Diagnosed and Relapsed/ Refractory Patients with MM: Utilizing Optimal Dosing Regimens • Appropriate Duration of Therapy

for MM in a Value-Based Care Plan • Improving the Standard of Care

in MM: Interpreting Overall Survival Data and Assessing the Cost of a Complete Response • Establishing a Value-Based

Paradigm for the Management of Patients with MM: A Pharmacoeconomic Analysis of Treatment Options

Introduction Identification, characterization, and management of osteolytic bone lesions are key aspects of care in multiple myeloma (MM).1 A comprehensive, chart-based study from the Mayo Clinic, published in 2003, revealed that 84% of patients with myeloma developed skeletal lesions at some time during the course of their disease.2 Based on conventional radiography at the time of diagnosis, 79% of patients presented with at least one type of skeletal abnormality (Figure 1).2 In the decade since the publication of this influential study, these high estimates of skeletal-related events have held constant.1 What has changed, however, are the options available to clinicians for imaging the skeleton. Although radiographic skeletal survey remains the fundamental imaging study at both the initial workup and follow-up of the patient with MM, additional newer technologies can be utilized. These include magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET) scan, which may be combined with CT scan (PET-CT). Bone densitometry is another imaging technology with application in the disease.3 These technologies may provide helpful diagnostic and follow-up information on the patient, but despite evidence-based guidelines on imaging in MM, there is currently no standard for their appropriate clinical use.3-7 Individual providers, institutions, and payers are tasked with the decision to deploy or to forego MRI, CT, and PET on a case-by-case basis. The choice to utilize these sophisticated imaging methods ultimately affects the value of myeloma care: overuse or inappropriate use of such technologies results in unnecessary utilization costs; failure to use the technologies when prudent may result in a lower quality of care. This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients. These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

The most recent of the guidelines, from the National Comprehensive Cancer Network (NCCN), recommends radiographic skeletal survey for all patients at initial workup and for the follow-up of every patient annually or when symptoms are present.3 The NCCN makes provisional recommendations for MRI, CT, and PET scans, which are described as “useful under some circumstances” in initial workup and may be used “as clinically indicated” for follow-up surveillance.3 When is additional testing “useful” and “indicated”? Different organizations and experts have given various answers to this question. According to the NCCN, PET-CT scanning and MRI scans provide greater sensitivity than did conventional radiography.3 Therefore, during an initial workup in a patient who presents with bone pain, weakness, or other symptoms in

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care. Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

STAKEHOLDER’S PERSPECTIVE Assessing the Optimal Use of Imaging Modalities in Patients with Myeloma ...........................5

Imaging Options in MM: Evidence-Based Guidelines and Expert Consensus Since 2007, 5 different sets of clinical practice guidelines have been issued on the use of imaging technologies in MM (Table).3-7 These guidelines provide a good starting point for individual providers, institutions, and payers seeking to evaluate these modalities. This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

James R. Berenson, MD Institute for Myeloma & Bone Cancer Research West Hollywood, CA

An official publication of

11/15/13 9:58 AM

VIEW THE SERIES ONLINE AT: