VBCC Oct 2014 | Vol 5 | No 8 by Value-Based Cancer Care

OCTOBER 2014 VOL 5 NO 8

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

Reimbursement Reform in Oncology Must Reward for Quality of Care

Cancer Center profile

New Mexico Oncology Medical Home Interview with Barbara L. McAneny, MD

ASCO proposes a new payment model By Dana Butler

Jeffery Ward, MD

he current fee-for-service reimbursement model used in oncology has jeopardized value-based cancer care, according to Jeffery Ward, MD, a member of the American Society of Clinical Oncology (ASCO) Workgroup on Payment Reform. He dis-

ancer care has been undergoing transformation in recent years. The oncology medical home is one model that has shown improved outcomes and patient satisfaction. What are the characteristics of the oncology medical home and how is it different from other cancer centers in the United States? Value-Based Cancer Care (VBCC) discussed these questions with Barbara L. McAneny, MD, CEO, New Mexico Oncology Hematology Consultants, who established the New Mexico Cancer Center’s Oncology Medical Home as part of the COME HOME award from the Center for Medicare and Medicaid Innovation. VBCC: What are the characteristics of an oncology medical home? Barbara L. McAneny, MD: The oncology medical home concept is centered around the idea of “home.” Home is where you go when you need help. The goal of the oncology medical home is to provide all the services that patients Continued on page 25

Fourth Conference

Patient-Centered Oncology Medical Home Improves Health Outcomes at Lower Costs to Patients and Payers By Wayne Kuznar Los Angeles, CA—Oncology practices are evolving in an era of cost containment and a renewed focus on quality. At the Fourth Annual Conference of the Association for Value-Based Cancer Care, John D. Sprandio, MD, Chief of Medical Oncology and Hematology at Oncology Management Services, Ltd, a single-specialty practice trans-

formation company, discussed how his Pennsylvania-based integrated care delivery model has evolved to meet the parallel needs of oncology payers and patients with cancer. Cancer care is undergoing transition. Community-based oncologists have gone from providing approximately 85% of the cancer care in the United

Continued on page 42

cussed the group’s novel proposal for consolidated cancer care at the Community Oncology Town Hall during the 2014 annual meeting of ASCO. “Working toward a better payment system for oncology care, instead of just complaining about the one that we have, Continued on page 8

ESMO 2014 Highlights

CLEOPATRA: Record-Breaking Survival in HER2 Metastatic Breast Cancer by Adding Pertuzumab Dual HER2 blockade a new standard of care By Phoebe Starr Madrid, Spain—Final results from the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) trial show that dual HER2 blockade with the combination of pertuzumab and trastuzumab plus chemotherapy ex-

tended overall survival (OS) by almost 16 months compared with trastuzumab plus chemotherapy alone in patients with HER2-positive metastatic breast cancer. This should become the new standard of care for Continued on page 12

inside VALUE PROPOSITIONS . . . . . . . . . . . . . . . . 7 Medicare covers noninvasive CRC test NCI launches new study of exceptional responders to cancer therapy ECONOMICS OF CANCER CARE . . . . Cost-benefit of robotics in head and neck cancers Medicaid reimbursement impacts cancer screening rates

ESMO 2014 Highlights . . . . . . . . . . . . 12 PD-1 blocker nivolumab impressive in melanoma BRAF-MEK combo inhibitor improves survival VBCC PERSPECTIVE . . . . . . . . . . . . . . . . . . 28 Logistic toxicity: Obstacles to efficient cancer care delivery

PROSTATE CANCER . . . . . . . . . . . . . . . . . . 30 New guideline for systemic therapy IN THE LITERATURE . . . . . . . . . . . . . . . . . . 31 Novel mutations help in overcoming lung cancer treatment resistance END-OF-LIFE CARE . . . . . . . . . . . . . . . . . . . 36 IOM on US end-of-life care FDA UPDATE . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 New combination agent for CINV prevention 4TH CONFERENCE . . . . . 42 Oncology medical home improves outcomes Does CER have value in oncology? DRUG UPDATE . . . . . . . . . . . . . . . . . . . . . . . . . 48 Beleodaq for relapsed/refractory peripheral T-cell lymphoma

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

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

VALUE PROPOSITIONS

BREAST CANCER

Medicare begins coverage for noninvasive CRC test NCI launches study of exceptional responders to drug therapy More…

HER2-derived vaccine cuts disease recurrences More…

VBCC PERSPECTIVE

ECONOMICS OF CANCER CARE

Logistic toxicity: Obstacles to efficient cancer care delivery

Medicaid reimbursement impacts cancer screening rates More…

PROSTATE CANCER Multigene test stratifies prostate cancer risk

ESMO 2014 HIGHLIGHTS

IN THE LITERATURE

Unprecedented survival with pertuzumab BRAF + MEK inhibitor improves survival More…

New mutations identified can cut resistance to lung cancer treatment More…

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno

Medicare coverage not aligned with patients with cancer preferences More…

Does CER have value in oncology? Managing cancer at work enhances value More…

CANCER CENTER PROFILE

DRUG UPDATE

New Mexico Oncology Medical Home

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 Managers Alyson Bruni 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.

4TH CONFERENCE

HEALTH POLICY

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP City of Hope 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

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance 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

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

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com

Value-Based Cancer Care

Beleodaq for peripheral T-cell lymphoma

October 2014

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD President W-Squared Group Longboat Key, FL Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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.

Vol. 5

No. 8

VALUE PROPOSITIONS

Advance Care Planning

Medicare Begins Coverage of Only FDA-Approved Noninvasive Stool DNA Test for Colorectal Cancer

New Collaboration on Novel Immunotherapy Vaccine May Revolutionize Lung Cancer Treatment

Medicare now provides coverage for the only FDA-approved noninvasive stool DNA screening test for colorectal cancer (CRC), after the Centers for Medicare & Medicaid Services (CMS) issued its final National Coverage Determination in October. Cologuard is an easy-to-use test that can be self-administered at home. This test has demonstrated a 92% accuracy rate for detecting CRC in people at an average risk, with 87% specificity. Exact Sciences, the maker of the test, announced that the coverage will go into effect immediately, although the company does not have information about the exact dollar amount that Medicare will cover for the test. This decision by CMS constitutes the first final coverage determination by the agency for a medical device that was approved by the FDA and is a part of the FDA and CMS parallel. Cologuard is the first noninvasive test for CRC that analyzes stool-based DNA as well as blood biomarkers to detect cancer. “Colorectal cancer is often considered the most preventable, yet least prevented cancer due to the lack of patient compliance with screening. CMS’s decision to cover Cologuard will provide Medicare’s 50 million patients with access to this accurate screening option,” said Kevin Conroy, Exact Sciences President, CEO, and Chairman. CRC is treatable when detected early, but it is often diagnosed at a late stage, when a cure is no longer feasible. CRC remains the second-leading cause of cancer-related death in the United States. Exact Sciences Corp Press Release; October 9, 2014

The drugmaker Boehringer Ingelheim (BI) and CureVac, a leader in mRNA (messenger ribonucleic acid)-based drug development, announce an exclusive collaboration for the continuing development of CureVac’s CV9202 vaccine, an immunotherapy vaccine that has shown promising results in early development for the treatment of lung cancer. BI is launching clinical trials for the vaccine in at least 2 settings—(1) in combination with afatinib (Gilotrif) in patients with advanced or metastatic EGFRmutated non–small-cell lung cancer (NSCLC) and (2) in combination with radiotherapy in patients with unresectable stage III NSCLC. This investigational vaccine represents a novel approach to cancer treatment by optimizing the mRNA to mobilize the patient’s own immune system to fight the tumor with a specific immune response. CV9202 is a combination of mRNA molecules coding for 6 antigens overexpressed in lung cancer, and is designed to induce an immune response against the tumor. According to BI, this new agreement reflects the company’s focus on novel treatments with high therapeutic value for patients. “In our collaboration with CureVac, we will investigate combining existing treatments with the approach of sustained activation of the immune system,” said Professor Klaus Dugi, Chief Medical Officer at BI. Ingmar Hoerr, Co-founder and CEO of CureVac GmbH, noted, “Cancer immunotherapy represents one of the biggest innovations in cancer treatment of recent times, and we are delighted to now be working with Boehringer Ingelheim.” PRNewswire, September 18, 2014

NCI Launches Study of Exceptional Responders to Cancer Therapies: A New Phase in Precision Medicine?

Mechanism of Action of Low-Dose Aspirin in Reducing Cancer Mortality Identified

The National Cancer Institute (NCI), a part of the National Institutes of Health, has launched the Exceptional Responders Initiative, a study that will investigate the molecular factors in patients with cancer whose tumors demonstrate exceptional responses to drug therapies. Investigators will examine tumor specimens from patients in clinical trials whose tumor demonstrated an exceptional response compared with other patients in that trial, or other patients who achieved an exceptional and unexpected response to a noninvestigational therapy. The reasons why certain patients with cancer demonstrate unexpected and prolonged remissions after standard therapy remain unclear. The goal is to identify potential molecular markers that will predict positive responses to certain therapies, which will then allow oncologists to better select the most appropriate treatment regimens for individual patients. Tumor tissue and clinical data will be collected from NCI-based and other clinical trials for patients with exceptional responses. Other samples will be collected from standard cancer care settings, such as community practice, and from clinical trials funded by pharmaceutical companies or other sources. Letters are being sent to cancer centers and other oncology practice settings nationwide, asking them to assist in this effort and provide appropriate information for patients demonstrating exceptional responses. “The feasibility of this approach is supported by reports in the literature of relevant mutations in tumor specimens from patients who experienced an exceptional response to a drug in a clinical trial, even though that drug failed to meet the trial’s endpoint for clinical benefit,” said Louis Staudt, MD, PhD, Director of NCI’s Center for Cancer Genomics, and a co-leader of this study. “The ability to identify molecular markers that are able to predict a clinical response in these subsets of patients will provide us with the tools to further advance our ability to conduct studies consistent with the principles of precision medicine,” noted Barbara A. Conley, MD, Division of Cancer Treatment and Diagnosis, NCI, and a co-leader of the study. The ultimate goal is for oncologists to be able to identify patients who may respond to agents with the same or similar mechanism of action, and to build on the data generated by this study that will provide clinicians access to the full genomic data of 100 cases of exceptional responders to identify patterns in drug response. NCI Press Release; September 24, 2014

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New data presented at the 13th Annual AACR International Conference on Frontiers in Cancer Prevention Research identified the mechanism of action by which low-dose aspirin reduces the risk for cancer metastasis. That mechanism is believed to be the inhibition of COX-1 and COX-2 pathways. The realization that the COX-2 pathway is involved in aspirin’s cancer prevention activity is new; previous studies have only found a link to the COX-1 pathway. “Our findings may explain how even a very low dose of aspirin taken daily can produce such a substantial reduction in cancer deaths and metastasis,” said Pierre Massion, MD, Professor of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN. “We found that the potency of low-dose aspirin in inhibiting COX-2 in the tumor cells is as great as or greater than its potency as an inhibitor of COX-1 in the platelet,” Dr Massion said. “This indicates that at a cellular level, aspirin is not selective for the platelet, but could also block COX-2 in cancers.” Dr Massion and colleagues found that in addition to blocking platelet function by inhibiting the COX-1 pathway, low-dose aspirin also reduced levels of the prometastatic molecule prostaglandin E2 (PGE2) through inhibition of the COX-2 pathway. “Thus, the finding that it [aspirin] blocked PGE2 production is likely surprising to most investigators in the field,” Dr Massion said. Previous studies have shown that taking aspirin for ≥5 years reduces the incidence of all cancers by 38%. “This benefit is seen even at the low doses of aspirin required to inhibit platelet aggregation via inhibiting the COX-1 pathway, a finding consistent with the known participation of platelets in the metastatic process,” he noted. The investigators found that (1) the doses of aspirin required to inhibit COX-2–dependent PGE2 production were the same or lower than those needed to inhibit COX-1–dependent platelet aggregation; (2) aspirin inhibited PGE2 production by 45% and reduced the levels of a metabolite of PGE2, prostacyclin, by 37%; and (3) by blocking platelet COX-1, aspirin inhibits platelet adherence to the cancer cells to prevent metastasis, suggesting that these 2 mechanisms work together to reduce cancer mortality risk. American Association for Cancer Research; September 29, 2014

October 2014

www.ValueBasedCancerCare.com

Economics of Cancer Care

Reimbursement Reform in Oncology Must Reward for... has been liberating and exhilarating,” said Jeffery Ward, MD, the immediate past chair of ASCO’s Clinical Practice Committee and an oncologist at the Swedish Cancer Institute in Seattle, WA. The workgroup working on the payment reform at ASCO had as its premise the need to hear voices from across the clinical oncology spectrum, with the goal of reaching “a uniform re-formation of oncology care that can be applied to all cancer care settings.” Fee-for-Service Medicine Has Failed The focus is on transforming reimbursement in oncology away from the fee-for-service model of paying for each service. “Fee-for-service medicine is a barrier to personalized care. It’s an antiquated reimbursement system that only pays for care when it involves physician ‘touches’ and the infusion of drugs,” Dr Ward said. Fee-for-service “only pays for some services, failing to reimburse at all for other essential services provided in oncology offices and clinics. It fails to reward decision-making that brings greater quality, efficacy, or value to the care equation, and conversely it incentivizes inefficiency and the overuse of the most expensive services to maximize reimbursed service,” he continued. Furthermore, fee-for-service medicine takes the focus off the patient and centers on the physician, failing to achieve the personalized care that is the general aim in oncology today. “It’s time to open the current model to scrutiny, recognize how incongruent it is to the future of cancer care, and replace it,” Dr Ward maintained. Quality-Based Payment Model The group explored different concepts for payment reform and ulti-

Fee-for-service in oncology fails to reward decisionmaking that brings greater quality, efficacy, or value to the care equation, and conversely it incentivizes inefficiency and the overuse of the most expensive services.

‘‘

”

—Jeffery Ward, MD

mately came up with a consolidated payment, patient-centered model that will reward for quality of care. “We asked our committee members, if you could throw out all you know and start over—and not just tweak a broken system—how would you like to be paid for what you do?” he said. “What we developed has at its core monthly bundled payments that are adjusted for (ie, rewarded for) quality, pathway utilization, resource utilization and clinical trial participation.” The model does not ignore the importance of drug purchasing, but contains a vehicle for integrating the current ASP (average sales price) + 6% margin into the reimbursement mix, “which will remove the stigma of drug margins from our profession.” At the model’s core are monthly payments that vary according to the treatment of the patient. These payments are developed by taking the gross revenue for typical clinical services and combining them into a lump sum. “It’s forgetting where the revenue came from, and rearranging it into these payments,” Dr Ward explained.

“We believe ASP + 6% could be folded into this bucket and added to ‘treatment month’ payments once an alternative to buy-and-bill is developed and sufficiently tested,” he said. The new payments would not track directly with existing Current Procedural Terminology® (CPT®) codes; the new payment system is intended to cover services that are not compensated

“”

It’s time to open the current [reimbursement] model to scrutiny, recognize how incongruent it is to the future of cancer care, and replace it. —Jeffery Ward, MD

today. New aggregate revenue would be no less than the aggregate amount of current revenue for typical oncology practices. The relative sizes of payments

Medicaid Reimbursement Rate Has Direct Impact on Cancer Screening Rates By Rosemary Frei, MSc

lthough increasing the reimbursement rate for cancer screening tests does not consistently improve the likelihood of Medicaid beneficiaries being screened for cancer, raising the rate of reimbursement for office visits does consistently increase the likelihood that they will be screened for cancer, including breast or prostate cancer, according to results of a new analysis of Medicaid claims and enrollment data

(Halpern MT, et al. Cancer. 2014 Aug 25. Epub ahead of print). In this analysis, a 20% increase in office visit reimbursement was associated with increases in the likelihood of Medicaid beneficiaries being screened for cancer, ranging from a 2.2% increase for mammography to an 8.7% increase for fecal occult blood testing (FOBT). “Our study confirmed what other studies have shown in other areas of medicine: that the office visit is really

Value-Based Cancer Care

October 2014

the key step for Medicaid enrollees, especially, I believe…the primary care provider office visit, because this is the gatekeeper for other services,” lead investigator Michael T. Halpern, MD, PhD, MPH, Health Services Research, RTI International, Washington, DC, told Value-Based Cancer Care. “By increasing reimbursement, that presumably would lead to either more physicians participating in the program, or physicians who are already Continued on page 10

Continued from the cover

at a glance ➤ The current fee-for-service payment model has jeopardized value-based cancer care ➤ It incentivizes inefficiency and overuse of the most expensive services to maximize reward for providers ➤ It is time to recognize its failure and begin to reimburse for quality of care ➤ The new model must focus on patient outcomes, not on the provider ➤ This new model should lead to cost-savings through reductions in hospital use, unnecessary testing, and supportive services ➤ Oncologists should be rewarded for providing patient care that facilitates these savings would reflect the relative amount of time and cost incurred for the activities in the payment period. These distinct periods include: • New patient payments • Treatment month payments • Active monitoring month payments • Transition-of-treatment payments. These monthly payments would be phased in over time, and some components of fee for service would be continued, such as laboratory tests, imaging, bone marrow biopsy, and transplantation. Innovation and Flexibility The adoption of this model should give oncology practices flexibility to build innovative processes of care that will allow them to assume accountability for quality and value of the care they give. Ultimately, the model would also remove the current financial penalty for using lower-cost drugs or for treating with oral drugs. It would also simplify billing by replacing 63 CPT® codes with 9 codes. The end result should be cost-savings through reductions in the use of the hospital and the emergency department, in testing and surveillance, and in the administration of oncolytics and supportive drugs. Oncologists should be rewarded for participating in care that facilitates these savings. Dr Ward noted that ASCO is open to changes in this plan. But change in the current system, he reiterated, is needed. n

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No. 8

Take a bite out of G-CSF acquisition costs* GRANIX is another option in short-acting G-CSF therapy TM

GRANIX™ is an option for hospitals and payers to consider when determining health system budgets » FDA approved through the rigorous BLA† process » Teva’s short-acting G-CSF was first introduced in Europe in 2008 and is available in 42 countries‡1 » GRANIX J Code: J 1446-Injection, tbo-filgrastim, 5 micrograms, effective January 1, 2014 †Biologics License Application. ‡As of February 2014. *Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication

» GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colonystimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. Data on file. Teva Pharmaceuticals: Filgrastim MA Approvals Worldwide. February 2014.

Economics of Cancer Care

Medicaid Reimbursement Rate Has Direct Impact... participating being able to accept more Medicaid beneficiaries, and through that improve access to care and overall health outcomes for this underserved population,” Dr Halpern said. Study Details The investigators used 2007 Medic-

aid data for individuals (aged 21-64 years) who had been enrolled in a feefor-service Medicaid plan for at least 4 months. People who lived in Arizona, New Mexico, Nevada, and Maine were excluded from the analysis because of lack of availability or access to complete data.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Value-Based Cancer Care

In 2007, within the age- and sex-appropriate samples, only 26% of patients received a Pap test; 20% received film or digital mammography; 6% received a colonoscopy; and only 4% received an FOBT. The national Medicaid median screening test reimbursement rate was lowest

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

October 2014

Continued from page 8

“

By increasing reimbursement, that presumably would lead to either more physicians participating in the program, or physicians who are already participating being able to accept more Medicaid beneficiaries, and through that improve access to care and overall health outcomes for this underserved population.

”

—Michael T. Halpern, MD, PhD, MPH for a Pap test ($24); the others ranged from $30.51 for a facility film mammography to $270.94 for a colonoscopy. When the Medicaid reimbursement rate was increased by 20% of the national median reimbursement for that screening test/office visit, the odds ratios for receiving a colonoscopy increased by 1.6%, and the likelihood of receiving a Pap smear was reduced by 0.8%. The odds of receiving mammography increased under all reimbursement arrangements, except for film mammography at facilities, which showed a 5.4% decrease in the odds of receiving a mammography. Not having financial asset tests for Medicaid eligibility was generally associated with an increased likelihood of receiving cancer screening tests, whereas requiring office visit copayments was generally associated with a decreased likelihood. Increased reimbursement for office visits was consistently associated with an increased likelihood of screening for all the tests examined. A 20% increase in office visit reimbursement was associated with increased likelihood of receiving all 4 screening modalities—8.7% for FOBT, 6.9% for colonoscopy, 2.3% for Pap test, and 2.2% for mammography. n

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No. 8

Economics of Cancer Care

Experts Debate Cost-Benefit of Robotic Technology in Head and Neck Cancers By Rosemary Frei, MSc

New York, NY—Four head and neck surgeons, 3 of whom use robots in their practice, squared off in a friendly debate on the pros and cons of advanced technology use, focusing on the examples of thyroidectomy and advanced oropharyngeal cancer, at the 2014 American Head and Neck Society annual meeting.

cost. Dr Schuller also echoed a call he made in a 2012 editorial, in which he wrote that it is time “for our journal leaders to consider mandating some type of discussion of cost-effectiveness in every publication proposing a new diagnostic, therapeutic, or preventive innovation” (Arch Otolaryngol Head Neck Surg. 2012;138:539-540).

It’s Not about the Money First at bat was David J. Terris, MD, Porubsky Distinguished Professor and Chairman, Department of Otolaryngology-Head and Neck Surgery, Georgia Regents University, Augusta. Dr Terris advocated for remote-access thyroidectomy, saying, “This is not about the robot…and it’s not about money. It’s more about patient choice and about enabling innovation. Ultimately, the question is, ‘Should we offer innovative approaches for selected patients, or must we insist that everyone have their surgery done the same way?’” Dr Terris told Value-Based Cancer Care (VBCC) that “if you look at the demographic of surgeons across the country, it’s dominated by middle-aged men, and those individuals bring their own biases to bear. They often say, ‘I don’t care about a neck scar so I’m not concerned about a neck scar in my patients,’ but we shouldn’t substitute our own biases for our patients’ biases.” Dr Terris described a study of patient preferences for surgical approach to thyroid surgery, in which 82% of respondents said they preferred remote access thyroidectomy to cervical thyroidectomy, all costs being equal (Coorough NE, et al. World J Surg. 2014;38:696-703). Furthermore, 89% indicated that the scar from surgery was at least “a little” important.

TORS in Pharyngeal Cancer Less Costly than Radiotherapy Gregory S. Weinstein, MD, Professor, and Director, Division of Head and Neck Surgery, Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, sparred civilly about the use of robots for the surgical treatment of oropharyngeal cancer with C. René Leemans, MD, PhD, Chair, Department of Otolaryngology-Head and Neck Surgery, VU University Medical Center, Amsterdam, The Netherlands. “I think the robotic system would have to become considerably less expensive to be cost-effective,” Dr Leemans told VBCC. “When the market opens up—there is only 1 company now, and that drives cost—that may happen.” Dr Weinstein said that data generated by his team, as well as by researchers at the Mayo Clinic and Johns Hopkins University, indicate that length of hospital stay and the related costs are lower for transoral robotic surgery (TORS) resection of pharyngeal cancer than the combination of chemotherapy and radiation (eg, Richmon JD, et al. Laryngoscope. 2014;124:165-171). “The assumption that the other alternatives are cheaper than robotic surgery is fallacious,” Dr Weinstein told VBCC. “I’d label those who demand that journals require all ‘new’ procedures to provide cost justification as being ‘therapeutic nihilists’ and anti-innovation. I’m in favor of requiring such scrutiny of all existing approaches, not just the new ones. The alternative standard to TORS with the da Vinci Surgical System is chemoradiation therapy, and this is extremely expensive too.” Dr Leemans and Dr Weinstein agreed that an ongoing TORS deintensification trial funded by the National Cancer Institute, ECOG 3311, as well as 2 European trials in preparation, should help clarify the cost-benefit equation. n

It Is about the Money David E. Schuller, MD, Vice President, Medical Center Expansion and Outreach, and Chief Executive Officer Emeritus, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Ohio State University, Columbus, countered that if the patients in the study were simply asked whether they would want a scar, “that’s a flawed survey. You need to ask that question, and also inform the patient that to do a procedure that doesn’t leave a noticeable scar, that will mean cost to the patient Vol. 5

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“

This is not about the robot…and it’s not about money. It’s more about patient choice and about enabling innovation.

”

—David J. Terris, MD

“

You need to…inform the patient that to do a procedure that doesn’t leave a noticeable scar, that will mean cost to the patient and the risk of complications that don’t even exist with the standard approach.

”

“”

I think the robotic system would have to become considerably less expensive to be costeffective. —C. René Leemans, MD, PhD

“

The assumption that the other alternatives are cheaper than robotic surgery is fallacious.

”

—Gregory S. Weinstein, MD

—David E. Schuller, MD

and the risk of complications that don’t even exist with the standard approach,” he told VBCC. Dr Schuller said that he performed thyroid surgery for 40 years, and “I don’t recall any patient expressing a concern over the possibility of a scar in that region. It also was rare to produce a scar that required scar revision.”

Dr Schuller said that experts in the field should agree on a set of parameters to be used to define the ‘best’ approach to thyroid surgery. He proposed a set of 13 such metrics, including operative time, length of hospital stay, morbidity, mortality, functional benefit, cosmetic benefit, magnitude of societal impact, and total October 2014

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ESMO 2014 Highlights

patients with metastatic HER2 disease, according to the study investigators, who presented their results at the 2014 European Society for Medical Oncology (ESMO) Congress. “The final results of CLEOPATRA show that the addition of pertuzumab to standard therapy [trastuzumab plus docetaxel] significantly improved overall survival by 15.7 months. I am so pleased to present these results. The 56.5-month median overall survival is unprecedented for this indication,” stated lead investigator Sandra M. Swain, MD, Medical Director, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, and former president of the American Society of Clinical Oncology. These findings confirm interim results reported 2 years ago, Dr Swain said. “Two monoclonal antibodies that bind at different sites of the HER2 receptor, used together, not sequentially, extended survival,” she told listeners at the meeting. Study Details CLEOPATRA enrolled 808 patients with centrally confirmed HER2-positive metastatic breast cancer from 204 centers in 25 countries. Patients were randomized to treatment with placebo plus trastuzumab and docetaxel versus pertuzumab plus trastuzumab and docetaxel. Docetaxel was given for at least 6 cycles (median, 8 cycles), and both monoclonal antibodies were given until disease progression. The final OS analysis was presented after a median follow-up of 50 months.

Photo © esmo.org

CLEOPATRA: Record-Breaking Survival in HER2...

“

The 56.5-month median overall survival is unprecedented for this indication. This study confirms the pertuzumab/trastuzumab regimen as standard of care for first-line therapy in patients with HER2-positive metastatic breast cancer.

”

—Sandra M. Swain, MD “This is 20 months longer than the last interim analysis,” Dr Swain noted. Median OS was 56.5 months for the dual HER2 blockade arm versus 40.8 months for patients who received trastuzumab plus docetaxel, representing a significant 32% increase in the risk of survival (P = .002). “This change of 15.7 months has changed things for HER2-positive pa-

“

This is one of the biggest steps toward making this disease a chronic condition….I can see no reason to justify the use of trastuzumab without pertuzumab.

”

—Javier Cortés, MD, PhD tients. I have never seen a survival benefit of this magnitude in metastatic HER2-positive breast cancer,” Dr Swain said. The OS improvement was in the context of a 6.3-month improvement in progression-free survival (PFS) reported in the updated final analysis. “PFS was significantly improved in the interim analyses [6.1 improvement] and in the final analysis. This shows that in this blinded study, PFS was a good surrogate for OS,” she continued. There was concern that the combi-

Continued from the cover

nation of 2 monoclonal antibodies would lead to additional toxicities. In this study, rash, mucositis, and diarrhea were increased in the pertuzu mab-containing arm compared with trastuzumab plus docetaxel. There was no increase in cardiac toxicities with dual HER2 blockade. Asymptomatic declines in left-ventricular (LV) ejection fraction were actually less with the combination (6.1% vs 7.4%), and symptomatic LV dysfunction was reported in 1.5% and 1.8% of patients, respectively. These decreases in heart function were reversible in 88% of patients in the combination arm, Dr Swain said. A New Standard of Care “This study confirms the pertuzu mab/trastuzumab regimen as standard of care for first-line therapy in patients with HER2-positive metastatic breast cancer,” Dr Swain said. “The median overall survival data presented by Dr Sandra Swain here, at ESMO 2014, with pertuzumab and trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer are remarkable. This is one of the biggest steps toward making this disease a chronic condition in the near future,” said Javier Cortés, MD, PhD, Head, Breast Cancer Program, Vall d’Hebron University Hospital, Barcelona, Spain, and coinvestigator of CLEOPATRA. “We should consider this combination as the standard of care for our patients. I can see no reason to justify the use of trastuzumab without pertuzumab,” Dr Cortés added. n

PD-1–Blocking Nivolumab Shows Impressive Responses in Melanoma Immunotherapy the death knell of chemotherapy in this setting? By Phoebe Starr

“

Nivolumab had impressive responses and duration of response, and these data suggest that the drug can prolong progression-free survival and overall survival, but the data are not yet mature.

Photo © esmo.org

Madrid, Spain—Immunotherapy marches on, showing continued progress in treating advanced melanoma. At the 2014 European Society for Medical Oncology (ESMO) Congress, first reports from a phase 3 clinical trial showed that the monoclonal anti– PD-1 antibody nivolumab achieved superior responses and longer progression-free survival (PFS) and overall survival (OS) compared with standard chemotherapy in the second- or third-line treatment of patients whose melanoma progressed with ipilimumab therapy.

Value-Based Cancer Care

”

—Jeffrey S. Weber, MD, PhD

“Patients who progress on previous treatment have limited options. In this study, nivolumab had impressive responses and duration of response, and these data suggest that the drug can prolong progression-free survival and overall survival, but the data are not yet mature,” said lead investigator Jeffrey S. Weber, MD, PhD, Director, Donald A. Adam Comprehensive Melanoma Research Center of Excellence, Moffitt Cancer Center, Tampa, FL. Ipilimumab was the first immunotherapy to be approved for the treatContinued on page 13

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ESMO 2014 Highlights

PD-1–Blocking Nivolumab Shows Impressive Responses... Continued from page 12 ment of advanced melanoma. Nivolu mab is a PD-1–blocking antibody, referred to as a “checkpoint inhibitor” because it releases a brake placed on the immune system by the tumor itself. Once the brake is released, the immune system goes into action mounting an antitumor response and shrinking the tumor. Study Details This is the first phase 3 clinical trial of nivolumab in patients with melanoma with progressive disease despite treatment with ipilimumab. The study randomized 405 patients with unresectable melanoma in a 2:1 ratio to intravenous nivolumab 3 mg/kg versus investigator’s choice of chemotherapy (ICC). Patients were treated until disease progression or unacceptable toxicity.

“

This appears to be the death knell of chemotherapy, at least in second and third line.

”

—Jeffrey S. Weber, MD, PHD

Dr Weber explained that the control arm was designed to accommodate differences in preferred chemotherapy regimens between North America and Europe, namely, carboplatin/paclitaxel or dacarbazine, respectively. The patients were stratified prospectively according to PD-1 ligand 1 (PD-

L1) expression, a potential biomarker for response, BRAF status, and best overall response to previous anti– CTLA-4 therapy (ie, ipilimumab). Overall, 30% of patients had BRAF mutations and had also previously received a BRAF inhibitor. Overall response rate (ORR) was 32% for nivolumab versus 11% with ICC by RECIST criteria. Among the responses, 95% were ongoing in the nivolumab arm at the time of the analysis, and the median duration of response in that arm had not yet been reached by the time of presentation at ESMO 2014. The median duration of response in the ICC arm was 3.6 months. No deaths were attributed to drug toxicity. One patient in the nivolumab group experienced grade 5 hypoxia, possibly pneumonitis, and this cause of death was classified as “other” rather than “study drug toxicity,” Dr Weber said. PFS and OS results will be reported when the data are more mature. A New Drug Application for ni volumab has been submitted to the FDA, which has designated it as breakthrough therapy. A similar drug, pembrolizumab, received FDA approval for melanoma based on less robust response data than in the nivolumab trial (ie, 22% ORR), Dr Weber said. A course of treatment with ipilimumab is estimated to cost $120,000. If nivolumab receives FDA approval, its cost is estimated to be at least as high. “This appears to be the death knell of chemotherapy, at least in second and third line. I hate using chemotherapy in

melanoma, and I hope this study puts to rest that it should be used as a comparator arm in clinical trials. In the US, you won’t be able to do this anymore,” Dr Weber said in a separate interview.

“

I believe that melanoma treatment with anti–PD-1 will be the tip of the iceberg. Many other indications for this treatment are emerging, including lung cancer, head and neck cancer, and bladder cancer.

”

—Ignacio Melero, MD, PhD

Expert Discussion Formal discussant of this trial, Ignacio Melero, MD, PhD, of the Uni-

versity of Navarra, Pamplona, Spain, called this “very exciting clinical data with impressive responses.” “I am disappointed that the sur vival data are not available yet,” Dr Melero said. He said that the study included patients with brain metastases, and he is looking forward to hearing the specific outcome in that subgroup, as well as in the 50% of patients with PD-L1 disease. As for potential biomarkers, “We will learn a lot when we get correlative data from this trial,” Dr Melero said. He mentioned that pembroliz umab is also showing good responses in melanoma. “The treatment of melanoma is changing,” Dr Melero said. “If a patient is BRAF wild-type, treatment is with chemotherapy or ipilimumab or the reverse, or a clinical trial. With BRAF-mutated melanoma, it is more entangled. Patients have the option of targeted therapy or immunotherapy. The trend is to move anti–PD-1 agents upfront and get rid of chemotherapy. It is important to study immunotherapy combinations, but we need good biomarkers,” he stated. “I believe that melanoma treatment with anti–PD-1 will be the tip of the iceberg. Many other indications for this treatment are emerging, including lung cancer, head and neck cancer, and bladder cancer,” Dr Melero said. “My main conclusion is that immunotherapy in cancer is no longer a quixotic task,” he concluded. n

Combination of BRAF and MEK Inhibitors Improves Survival in Patients with Advanced Melanoma By Phoebe Starr

Madrid, Spain—Combination therapy with a BRAF inhibitor and a MEK inhibitor improves survival outcomes in patients with advanced BRAF-mutated melanoma, based on results of 2 phase 3 clinical trials presented at the 2014 European Society for Medical Oncology Congress. These studies support the hypothesis that inhibition of BRAF and MEK will improve survival in melanoma by overcoming the mechanism of acquired resistance to vemurafenib, which is thought to be caused by reactivation of cell growth through MEK. In the coBRIM trial, first-line treatment of advanced melanoma with the combination of vemurafenib and cobimetinib (approved in Europe) imVol. 5

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“This study is very important as it shows that using drugs together to turn off two individual proteins (BRAF and MEK) that interact and bind to each other in the cell, gives much improved results for patients. This is a fundamental concept that could have far-reaching consequences for how we treat many cancers,” said lead investigator Grant McArthur, MBBS, BMedThe CoBRIM Study CoBRIM was a phase 3, double- Sc, PhD, Head, Cancer Therapeutics blind, placebo-controlled clinical trial Program, Peter MacCallum Cancer of vemurafenib plus cobimetinib ver- Centre, Melbourne, Australia. Median investigator-assessed PFS sus vemurafenib alone in previously untreated patients with BRAF V600 was 6.2 months for the vemurafenib arm versus 9.9 months for the combimutation metastatic melanoma. A total of 495 patients were random- nation arm, a significant difference (P ized to either arm in a 1:1 ratio. The <.001) representing a 49% reduction in risk for progression or death with the primary end point was PFS. proved progression-free survival (PFS) and overall response rate (ORR) versus vemurafenib alone. In the COMBI-v study, the FDA- approved combination of dabrafenib and trametinib improved overall survival (OS) compared with vemuraf enib alone.

October 2014

combination therapy arm. ORRs were significantly better with the combination therapy compared with monotherapy, at 68% versus 45%; complete response rates were 10% versus 4%, respectively. An interim OS analysis suggested that the risk of death would be reduced by 35% in patients who received both drugs versus those who received vemurafenib plus placebo (P <.05). The combination was tolerable, Dr McArthur said, with a manageable adverse event profile consistent with previous reports. Gastrointestinal events were more common with the combination, and these were mostly grade 1 and manageable with medication and dose reduction. PhotosensiContinued on page 14

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ESMO 2014 Highlights

Combination of BRAF and MEK Inhibitors Improves Survival... Continued from page 13

The COMBI-v Study COMBI-v is an ongoing open-label phase 3 clinical trial of 704 treatment-naïve patients with BRAF V600– mutated advanced melanoma and good performance status who are randomized to the combination of the MEK inhibitor dabrafenib and the BRAF inhibitor vemurafenib. Patients with brain metastases were included, but only if these were treated and stable for at least 12 weeks. An interim analysis showed that the

“

stopped early and patients originally randomized to the vemurafenib arm were allowed to cross over to combi-

Photo © esmo.org

combination therapy reduced the risk of death by 31%, based on a preplanned interim OS analysis presented

Photo © esmo.org

tivity was also more common with the combination therapy. Hyperkeratosis was significantly lower with the combination, because MEK inhibition reduces this side effect of vemurafenib, Dr McArthur said. Creatinine phosphokinase level was increased with the combination, but other adverse events were similar in the 2 arms. “This study provides clear definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and increased overall response rates. The preliminary overall survival is promising, and the combination was tolerable, consistent with previous trials of this combination,” Dr McArthur stated. “We anticipate that the combination of a BRAF and a MEK inhibitor will become a new standard treatment for advanced BRAF-mutated melanoma,” he concluded.

We anticipate that the combination of a BRAF and a MEK inhibitor will become a new standard treatment for advanced BRAF-mutated melanoma.

”

—Grant McArthur, MBBS, BMedSc, PhD at the meeting. Median OS is not yet reached in the combination arm and was 17.2 months in the vemurafenibalone arm (P = .005). Because of the excellent results at the interim analysis, the study was

“

These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for the patients.

”

—Caroline Robert, MD, PHD

nation treatment. Lead investigator Caroline Robert, MD, PhD, Head, Dermatology, Institut Gustave Roussy, Villejuif Cedex, France, presented the results of the interim analysis. She

said that this analysis is now considered the final analysis. “These results further corroborate the early preclinical data that more complete blockade of the MAP kinase pathway delays the emergence of resistance, translating into longer survival for the patients,” said Dr Robert. The combination also reduced the risk of disease progression by 44% versus vemurafenib monotherapy. The median PFS was 11.4 months for the combination versus 7.3 months for vemurafenib alone (P <.001). The ORR was 64% versus 51%, respectively, a significant 13% difference (P <.001). The complete response rate was 13% versus 8%, respectively, and the partial response rate was 51% versus 44%, respectively. The duration of response was almost twice as long with the combination arm compared with monotherapy, 13.8 months versus 7.5 months, respectively. The rate of adverse events was similar in the 2 arms. The combination was associated with increased incidence of pyrexia and a decrease in left-ventricular ejection fraction compared with vemurafenib alone, and the incidence of cutaneous malignancies, hyperproliferative cutaneous events, and photosensitivity was much lower in the combination arm. “Both of these trials of combination therapy go in the same direction,” Dr Robert commented. n

New Data Show PFS, Survival Benefits with Bevacizumab in Breast Cancer By Charles Bankhead

Madrid, Spain—The positive results from 2 studies raised speculation about a possible resurrection of the breast cancer indication for bevacizumab, as reported at the 2014 European Society for Medical Oncology Congress. In one study, adding capecitabine to bevacizumab maintenance therapy led to significant improvements in progression-free survival (PFS) and overall survival (OS) compared with bevacizumab alone in patients with HER2-negative metastatic breast cancer (mBC). The second trial demonstrated a significant improvement in PFS when bevacizumab was added to first- or second-line chemotherapy for locally advanced breast cancer or mBC.

After both presentations, breast cancer specialists seemed divided about whether the data might push beva cizumab back into the breast cancer picture in the United States. Hope Rugo, MD, Director of Breast Oncology at the University of California, San Francisco, commented that the results of the studies did not clarify bevacizumab’s role in breast cancer. In addition, both studies showed higher rates of grade 3 toxicity with beva cizumab. The data are now unlikely to sway the FDA to revisit a breast cancer indication for bevacizumab, she said. Edith Perez, MD, Deputy Director of the Mayo Clinic Cancer Center, Jacksonville, FL, found the results impres-

Value-Based Cancer Care

October 2014

“

Adding capecitabine to maintenance bevacizumab provided statistically significant and clinically meaningful improvements in progression-free survival and overall survival at study closure.

”

—Joseph Gligorov, MD

sive, particularly those from the IMELDA trial involving capecitabine, but was unsure whether the results might resuscitate bevacizumab’s role in breast cancer in the United States. IMELDA involved 54 international sites, where investigators enrolled patients with previously untreated HER2-negative mBC. All patients began treatment with docetaxel and bevacizumab. Patients who did not have disease progression were randomized to maintenance therapy with capecitabine and bevacizumab or to bevacizumab alone, reported Joseph Gligorov, MD, a medical oncologist at Tenon University Hospital in Paris. The primary end point was PFS. The

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ESMO 2014 Highlights

Mixed Results with Postprogression EGFR Inhibition in Advanced Non–Small-Cell Lung Cancer By Charles Bankhead

Madrid, Spain—Continuing an EGFR inhibitor after acquired resistance does not slow the progression of advanced non–small-cell lung cancer (NSCLC) in patients receiving chemotherapy, according to a report presented at the 2014 European Society for Medical Oncology (ESMO) Congress. However, extending anti-EGFR therapy with erlotinib beyond disease progression may be beneficial, according to a second report presented at the meeting. Adding Gefitinib to Chemotherapy Patients who continued gefitinib during initial chemotherapy had a median progression-free survival (PFS) of 5.4 months, which was identical to patients who received placebo at the start of cisplatin-pemetrexed chemotherapy. “This is the first and only randomized, phase 3 study to confirm that continuation of gefitinib in addition to cisplatin-pemetrexed chemotherapy would be of no clinical benefit for patients with acquired resistance to gefitinib,” said Tony Mok, MD, Professor of Clinical Oncology, Chinese University of Hong Kong. “Thus, the standard of care should remain doublet chemotherapy alone.” During a late-breaking presentation at the Presidential Symposium, Dr Mok noted that most patients with advanced NSCLC respond to an EGFR inhibitor, but inevitably, virtually all develop acquired resistance and the disease progresses, at which point most begin chemotherapy. Some evidence has suggested that

continuing an EGFR inhibitor with chemotherapy at least partly overcomes acquired resistance, resulting in an additional progression-free interval that extends beyond what is expected with chemotherapy alone.

“

This is the first and only randomized, phase 3 study to confirm that continuation of gefitinib in addition to cisplatin-pemetrexed chemotherapy would be of no clinical benefit for patients with acquired resistance to gefitinib. Thus, the standard of care should remain doublet chemotherapy alone.

”

—Tony Mok, MD

To test this hypothesis, investigators at 71 centers in Europe and Asia Pacific enrolled and treated 265 Asian patients with advanced/metastatic NSCLC with documented activating EGFR mutations. All patients had initially received gefitinib, and the disease had met the Response Evaluation Criteria in Solid Tumors (RECIST) for progression. Patients were randomized to either continue gefitinib with chemotherapy or to receive a

placebo plus chemotherapy. The primary end point was PFS, and the secondary end points included OS, objective response rate, disease control rate, and safety/tolerability. The results showed an identical duration of PFS in the 2 treatment groups; OS remained immature at the analysis. Nonetheless, the available data showed a significant increase in the survival hazard in the gefitinib group versus the placebo group (hazard ratio, 1.62; P = .029). Extending Erlotinib Therapy beyond Disease Progression In a related presentation at ESMO, investigators reported that extending the EGFR inhibitor erlotinib beyond progression resulted in a second PFS (PFS2; time from progression to discontinuation of treatment or death) with a longer duration than the first PFS (PFS1; start of treatment to progression). This study of extending anti-EGFR therapy beyond disease progression involved 207 Asian patients with stage IV EGFR-positive NSCLC. All patients had disease progression by RECIST criteria, reported Keunchil Park, MD, PhD, Professor of Medical Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. The phase 2, open-label trial had a primary end point of first PFS. Secondary end points included PFS2, objective response rate, best objective response, OS, and PFS1 in the subgroup of patients with the exon 19 deletion. Subsequently, disease progression

occurred in 150 patients, of which 81 continued erlotinib and 69 did not. Patients continuing erlotinib had a median PFS1 of 9.3 months versus 7.2 months among patients who did not. In the patients who continued erlotinib, the median PFS2 exceeded the PFS1 by 3.7 months. The objective response rate was 65.2%, and the disease control rate was 82.5%. Among patients who had centrally confirmed exon 19/L858R mutations, the median PFS1 was 11 months (N = 144), and the median PFS2 was 13.1 months (N = 54).

“

The data show that continuing erlotinib beyond RECIST progression is feasible….However, validation of the optimal patient subset to benefit from postprogression erlotinib needs further research.

”

—Keunchil Park, MD, PhD

“The data show that continuing erlotinib beyond RECIST progression is feasible, with a difference between PFS1 and PFS2 of 3.7 months in postprogression erlotinib-treated patients,” said Dr Park. “However, validation of the optimal patient subset to benefit from postprogression erlotinib needs further research.” n

New Data Show PFS, Survival Benefits with Bevacizumab in... Continued from page 14 trial ended early after an interim analysis showed a significant advantage in favor of maintenance therapy with the combination. When the trial ended, 284 patients had been enrolled and received first-line therapy, and 185 patients entered the randomized stage of the trial. The addition of capecitabine to bevacizumab maintenance therapy more than doubled PFS compared with bevacizumab alone (11.9 vs 4.3 months). In addition, OS was significantly prolonged with combination maintenance therapy (39 vs 23.3 months), but Dr Gligorov emphasized that survival Vol. 5

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data are immature for drawing definitive conclusions. In the bevacizumab-alone arm, grade ≥3 adverse events (AEs) included hypertension, proteinuria, and gastroenteritis. Overall, 52% of the combination group and 30% of the bevacizumab- only group had grade ≥3 AEs. “Adding capecitabine to maintenance bevacizumab provided statistically significant and clinically meaningful improvements in progression-free survival and overall survival at study closure, despite the smaller-thanplanned sample size, because of early

termination of accrual, with a manageable increase in adverse events,” Dr Gligorov concluded. The second study, TANIA, evaluated chemotherapy with or without bevacizumab in patients with locally recurrent breast cancer or mBC that had progressed during or after first-line bevacizumab and chemotherapy. Investigators randomized 494 patients to receive the physician’s choice of chemotherapy alone or in combination with bevacizumab. Data analysis showed a median second PFS of 4.2 months with chemoOctober 2014

therapy alone and 6.3 months when bevacizumab was added. The difference exceeded the predefined 25% improvement in PFS with the addition of bevacizumab. However, the median second PFS fell short of expectations, because the trial had the statistical power to detect an improvement from 7 months with chemotherapy alone to 9.3 months with chemotherapy plus bevacizumab. Grade ≥3 AEs included hypertension, proteinuria, venous thromboembolic events, febrile neutropenia, and congestive heart failure. n

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Health Policy

Medicare Coverage Not Aligned with Preferences of Patients with Cancer, Caregivers at a glance By Rosemary Frei, MSc

survey of patients with cancer and caregivers about the benefits they would like Medicare to cover in their last 6 months of life uncovered large gaps with the benefits that Medicare currently offers (Taylor DH Jr, et al. J Clin Oncol. 2014;32:31633168). Addressing issues related to quality of life and the costs burden of cancer therapy were among the main priorities for patients. The investigators see these results as a basis for a larger discussion of the difficult trade-offs and choices that come with increasing cost and resource constraints. “We found that those most directly facing cancer, patients and caregivers, were able to talk about difficult things in a reasoned manner. We have to come up with a way to have similar discussions nationally. It will be hard, but it is important,” lead investigator Donald H. Taylor, Jr, PhD, MPA, Associate Professor of Public Policy, Duke University, Durham, NC, told Value-Based Cancer Care. “Flexibility of the type we note could be a place where ‘strange bedfellows’ could imagine a political deal on Medicare reform—for example, libertarians who value choice and flexibility, and long-term care advo-

cates who understand the lack of long-term care coverage to be the most consequential ‘hole’ in Medi-

“

The first step in reform is to demonstrate gaps in what is covered by Medicare and some of what is identified as important by patients and family members.

”

—Donald H. Taylor, Jr, PhD, MPA care’s benefit package since the creation of Medicare Part D prescription drug coverage,” Dr Taylor said. A total of 246 patients and 194 caregivers from North Carolina participated in the study between August 2010 and March 2013. The participants had a wide range of education and income, and 50% said that they had spent

≥$2000 out of pocket on medical care in the previous year. The researchers probed the participants’ choices for which benefits Medicare should cover for patients with cancer near the end of life. All except 1 participant chose some level of cancer treatment, with 6.4% choosing the basic level of cancer treatment, 39.5% the intermediate level, 42.3% the high benefit level, and 11.6% the advanced level. In addition, at least 80% chose some level of coverage of 5 other benefit types, the most popular, in descending order, being prescription drugs (not including cancer drugs), primary care, home-based long-term care services designed to address disability, concurrent palliative care beyond the current Medicare hospice benefit, and nursing home care. Unrestricted cash was another popular option among benefits not currently covered by Medicare. Home care and palliative care also fell into this category. “The gap between covered benefits and preferences points toward a subset of patients and caregivers valuing quality of life broadly defined over medical care only,” Dr Taylor and colleagues wrote. Approximately 50% of the respon-

➤ Almost 50% of participants want coverage for nonmedical care benefits ➤ The survey highlights the gaps between what is covered by Medicare and what is important to patients dents wished for coverage of 1 of the following 3 benefits currently not covered by Medicare: • Unrestricted cash • Concurrent palliative care • Home-based long-term care. These choices all meant less medical care, such as the most sophisticated and expensive cancer treatment. African Americans were significantly more likely than whites to choose all 3 of these uncovered benefits. “We view this study as having a primary purpose of agenda setting. We are under no illusions that the type of preferences stated by a substantial minority of participants would be easy to bring about, either politically or technically. However, the first step in reform is to demonstrate gaps in what is covered by Medicare and some of what is identified as important by patients and family members,” concluded Dr Taylor. n

HHS Relaxes Electronic Health Record Certification Criteria

he US Department of Health and Human Services (HHS) has responded to the chorus of voices calling for less complex rules governing electronic health records (EHRs) by not adopting the Voluntary 2015 Edition Electronic Health Record Certification Criteria. In its final rule, released in September 2014, the Office of the National Coordinator for Health Information Technology has instead included 10 optional and 2 revised certification criteria. “The 2014 Edition Release 2 incorporates stakeholder feedback on particular 2014 Edition issues identified as impacting innovation and causing undue burden,” according to the HHS. “The 2014 Edition Release 2 also seeks to continue to improve EHR technol ogy’s interoperability and electronic health information exchange.” Value-Based Cancer Care asked Anna E. Schorer, MD, a Minnesota-based oncologist and a member of the American Society of Clinical Oncology’s Health Information Technology Work

Group, to comment on these new regulations. She noted that the key certification criteria: • Focus on the encryption of health information if it is stored on end-user devices; that is, increase protection of patient data that are stored on devices, such as laptops, that can be lost or stolen • Require EHR technology to be able to support corrections and amendments to a patient record—this should help reduce errors from incomplete or misentered clinical notes • Improve the exchange of laboratory test results between hospitals and ambulatory providers • Focus on the receipt of laboratory test results, which references a common interface that is standard for ambulatory EHR technology • Enable secure messaging between providers and patients • Permit a patient to securely view and download, as well as electronically transmit his or her health information, including the ability to track

Value-Based Cancer Care

October 2014

“

Note that physicians cannot bill for e-mail, but they also cannot bill for phone calls, filling out forms, etc, no matter how many hours a week they chew up.

”

—Anna E. Schorer, MD the use of these patient capabilities. The last 2 items are key to patient– clinician communications being asynchronous rather than relying on a telephone conversation or an office visit, said Dr Schorer. “Note that physicians cannot bill for e-mail, but they also cannot bill for

phone calls, filling out forms, etc, no matter how many hours a week they chew up,” she said. Therefore, increasing the feasibility of secure e-mail/Internet-based communications will make this end of the practice more efficient, Dr Schorer noted. The HHS is also hoping that the revisions will allow providers to choose and customize the EHR technology according to their individual practices’ needs. In addition, the criteria focus on increased interoperability, which means smoother EHR data exchange. For example, the HHS is attempting to have all EHR systems use the same format for dates to standardize the configuration of data for computers. “Information exchange will be a great help to clinical personnel; pretty much everyone would agree on that,” Dr Schorer said. “The trick is,…in a world in which the vendors will prioritize resources to meeting the standard for information exchange, the other pieces are likely to be put in the waiting queue.”—RF n

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The first and only FDA-approved combination therapy Indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma.

2 AGENTS. 1 THERAPY.

DEMONSTRATED DURABLE RESPONSE RATE IN A PHASE II STUDY 1,2

Investigator-assessed analysis

TAFINLAR + MEKINIST

150 mg twice daily

2 mg once daily

in combination TAFINLAR

as a single agent

overall response rate1 overall response rate1

76 54%

% (95% CI: 62, 87)

median duration of response1

(95% CI: 40, 67)

median duration of response1

10.5 5.6

months

(95% CI: 7, 15)

months

(95% CI: 5, 7)

Important Safety Information for TAFINLAR and MEKINIST when used in combination New Primary Malignancies. New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma, including keratoacanthoma, (cuSCC) occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of

TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-positive colorectal carcinoma (n=1), head and neck carcinoma (n=1), and glioblastoma (n=1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Melanoma. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR in combination with MEKINIST. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

TAFINLAR + MEKINIST demonstrated a 76% overall response rate1 Major efficacy outcome: Investigator-assessed response rate1 Overall Response

54%

(95% CI: 40, 67)

Overall Response

76%

(95% CI: 62, 87)

67%

80 70

50%

Response Rates

Study Design: Trial 2 was a multicenter, open-label, randomized (1:1:1) dose-ranging trial designed to evaluate the clinical activity and safety of TAFINLAR in combination with MEKINIST (at 2 different doses) and to compare the safety with TAFINLAR as a single agent in 162 patients with BRAF V600E or V600K mutationpositive, unresectable or metastatic melanoma. Patients were permitted to have had one prior chemotherapy regimen and prior aldesleukin; patients with prior exposure to BRAF or MEK inhibitors were ineligible. Patients were randomized to receive TAFINLAR 150 mg orally twice daily with MEKINIST 2 mg orally once daily (N=54), TAFINLAR 150 mg orally twice daily with MEKINIST 1 mg orally once daily (N=54), or TAFINLAR 150 mg orally twice daily (N=54). Treatment continued until disease progression or unacceptable toxicity.1

50 40 30 20 10 0

Complete Response

Partial Response

TAFINLAR as a single agent (N=54)

Complete Response

TAFINLAR

150 mg twice daily

Partial Response

MEKINIST

2 mg once daily

(N=54)

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Hemorrhage. Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. Venous Thromboembolism. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. Cardiomyopathy. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST

and in none of the patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in 2 of 5 patients. Development of cardiomyopathy resolved in all 5 patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), 2% demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of â&#x2030;Ľ20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. Ocular Toxicities. Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify dose of TAFINLAR. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent. Retinal detachments resulting from MEKINIST are often

TAFINLAR + MEKINIST achieved a median duration of response of 10.5 months1 Efficacy outcome: Investigator-assessed median duration of response1

TAFINLAR

+ MEKINIST

150 mg twice daily 2 mg once daily (N=54)

10.5

months

(95% CI: 7, 15)

Months Months TAFINLAR as a single agent (N=54)

5.6

months

(95% CI: 5, 7)

Independent Radiology Review Committee (IRRC) analyses were supportive of investigator-assessed results1 • 57% overall response rate (ORR) (95% CI: 43, 71) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; 46% ORR (95% CI: 33, 60) with TAFINLAR as a single agent1 – Complete response (CR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 9%; CR with TAFINLAR as a single agent: 7% – Partial response (PR) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily: 48%; PR with TAFINLAR as a single agent: 39% • Median duration of response of 7.6 months (95% CI: 7, not reported) with TAFINLAR 150 mg twice daily + MEKINIST 2 mg once daily; median duration of response of 7.6 months (95% CI: 6, not reported) with TAFINLAR as a single agent1

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (eg, change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. Interstitial Lung Disease. In clinical trials of MEKINIST (N=329) as a single agent, ILD or pneumonitis occurred in 2% of patients. Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. Serious Febrile Drug Reactions. The incidence and severity of pyrexia are increased when TAFINLAR is used in combination

with MEKINIST compared with TAFINLAR as a single agent. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors, or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. To learn more, visit TAFINLARMEKINISTHCP.com Please see additional Important Safety Information for TAFINLAR and MEKINIST when used in combination on the following pages. Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages.

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

Important Safety Information for TAFINLAR and MEKINIST when used in combination (cont'd) Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3ºF or higher. Withhold MEKINIST for any fever higher than 104ºF. Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure, and evaluate for signs and symptoms of infection. Refer to Table 2 of the Prescribing Information for TAFINLAR for recommended dose modifications. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. Serious Skin Toxicity. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N=202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. Hyperglycemia. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia, such as excessive thirst or any increase in the volume or frequency of urination. Glucose-6-Phosphate Dehydrogenase Deficiency. TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. Embryofetal Toxicity. TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST. Most Common Adverse Reactions. The most common (≥20%) adverse reactions in Trial 2 (all grades) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg

twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: pyrexia (fever) (71%, 69%, 26%), chills (58%, 50%, 17%), fatigue (53%, 57%, 40%), rash (45%, 43%, 53%), nausea (44%, 46%, 21%), vomiting (40%, 43%, 15%), diarrhea (36%, 26%, 28%), abdominal pain (33%, 24%, 21%), peripheral edema (31%, 28%, 17%), cough (29%, 11%, 21%), headache (29%, 37%, 28%), arthralgia (27%, 44%, 34%), night sweats (24%, 15%, 6%), decreased appetite (22%, 30%, 19%), constipation (22%, 17%, 11%) and myalgia (22%, 24%, 23%). The most common (≥5%) serious adverse reactions in Trial 2 (grades 3 or 4) for TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily, TAFINLAR 150 mg twice daily and MEKINIST 1 mg once daily, and TAFINLAR as a single agent, respectively, included: renal failure (7%, 0%, 0%), pyrexia (5%, 9%, 0%), back pain (5%, 0%, 2%), and hemorrhage (5%, 0%, 0%). Drug Interactions Effects of Other Drugs on Dabrafenib. Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers. Effects of Dabrafenib on Other Drugs. Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate). Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. Effects of the Combination of Dabrafenib with Trametinib. Coadministration of TAFINLAR 150 mg twice daily and MEKINIST 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions. To learn more, visit TAFINLARMEKINISTHCP.com Please see Brief Summary of Prescribing Information for TAFINLAR and MEKINIST on the following pages. Please see full Prescribing Information and Medication Guide for TAFINLAR and full Prescribing Information and Patient Information Leaflet for MEKINIST.

References: 1. TAFINLAR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 2. Flaherty KT, Infante JR, Daud A, et al. N Engl J Med. 2012;367:1694-1703. TAFINLARMEKINISTHCP.com TAFINLAR and MEKINIST are registered trademarks of the GSK group of companies. ©2014 GSK group of companies. All rights reserved. Printed in USA. MEL156R0 July 2014

(dabrafenib) 50 mg, 75 mg capsules

(trametinib) 0.5 mg, 1 mg, 2 mg tablets

BRIEF SUMMARY TAFINLAR® (dabrafenib) capsules, for oral use MEKINIST® (trametinib) tablets, for oral use The following is a brief summary only; see Full Prescribing Information for each product to view the complete product information 1 INDICATIONS AND USAGE TAFINLAR, in combination with MEKINIST, is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with MEKINIST. Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Cutaneous Malignancies: In Trial 2, the incidence of basal cell carcinoma was increased in patients receiving TAFINLAR in combination with MEKINIST: 9% (5/55) of patients receiving TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of basal cell carcinoma was 28 to 249 days in patients receiving TAFINLAR in combination with MEKINIST and was 197 days for the patient receiving TAFINLAR as a single agent. Cutaneous squamous cell carcinoma (SCC), including keratoacanthoma, occurred in 7% of patients receiving TAFINLAR in combination with MEKINIST and 19% of patients receiving TAFINLAR as a single agent. The range of time to diagnosis of cuSCC was 136 to 197 days in the combination arm and was 9 to 197 days in the arm receiving TAFINLAR as a single agent. New primary melanoma occurred in 2% (1/53) of patients receiving TAFINLAR as a single agent and in none of the 55 patients receiving TAFINLAR in combination with MEKINIST. Perform dermatologic evaluations prior to initiation of TAFINLAR as a single agent or in combination with MEKINIST, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. No dose modifications of TAFINLAR or MEKINIST are required in patients who develop new primary cutaneous malignancies. Non-cutaneous Malignancies: Based on its mechanism of action, TAFINLAR may promote the growth and development of malignancies with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. In patients receiving TAFINLAR in combination with MEKINIST four cases of non-cutaneous malignancies were identified: KRAS mutation-positive pancreatic adenocarcinoma (n = 1), recurrent NRAS mutation-positive colorectal carcinoma (n = 1), head and neck carcinoma (n = 1), and glioblastoma (n = 1). Monitor patients receiving the combination closely for signs or symptoms of non-cutaneous malignancies. Permanently discontinue TAFINLAR for RAS mutation-positive non-cutaneous malignancies. If used in combination with MEKINIST, no dose modification of MEKINIST is required for patients who develop non-cutaneous malignancies. 5.2 Tumor Promotion in BRAF Wild-Type Melanoma In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation status prior to initiation of TAFINLAR [see Indications and Usage (1)]. 5.3 Hemorrhage Hemorrhages, including major hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence and severity of any hemorrhagic event: 16% (9/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. The major hemorrhagic events of intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Intracranial hemorrhage was fatal in 4% (2/55) of patients receiving TAFINLAR in combination with MEKINIST. Permanently discontinue TAFINLAR and MEKINIST for all Grade 4 hemorrhagic events and for any Grade 3 hemorrhagic events that do not improve. Withhold TAFINLAR for Grade 3 hemorrhagic events; if improved resume at a lower dose level. Withhold MEKINIST for up to 3 weeks for Grade 3 hemorrhagic events; if improved, resume at a lower dose level. 5.4 Venous Thromboembolism Venous thromboembolism can occur when TAFINLAR is used in combination with MEKINIST. In Trial 2, treatment with TAFINLAR in combination with MEKINIST resulted in an increased incidence of deep venous thrombosis (DVT) and pulmonary embolism (PE): 7% (4/55) of patients treated with TAFINLAR in combination with MEKINIST compared with none of the 53 patients treated with TAFINLAR as a single agent. Pulmonary embolism was fatal in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Advise patients to immediately seek medical care if they develop symptoms of DVT or PE, such as shortness of breath, chest pain, or arm or leg swelling. Permanently discontinue TAFINLAR and MEKINIST for life-threatening PE. Withhold MEKINIST and continue TAFINLAR at the same dose for uncomplicated DVT or PE; if improved within 3 weeks, MEKINIST may be resumed at a lower dose level. 5.5 Cardiomyopathy Cardiomyopathy can occur when TAFINLAR is used in combination with MEKINIST and with

MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, cardiomyopathy occurred in 9% (5/55) of patients treated with TAFINLAR in combination with MEKINIST and in none of patients treated with TAFINLAR as a single agent. The median time to onset of cardiomyopathy in patients treated with TAFINLAR in combination with MEKINIST was 86 days (range: 27 to 253 days). Cardiomyopathy was identified within the first month of treatment with TAFINLAR in combination with MEKINIST in two of five patients. Development of cardiomyopathy resolved in all five patients following dose reduction (4/55) and/or dose interruption (1/55). Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), 8% of patients developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF ≥10% below baseline). Two percent demonstrated a decrease in LVEF below institutional lower limits of normal with an absolute decrease in LVEF of ≥20% below baseline. Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of TAFINLAR in combination with MEKINIST, one month after initiation, and then at 2- to 3-month intervals while on treatment with the combination. Withhold treatment with MEKINIST and continue TAFINLAR at the same dose if absolute LVEF value decreases by 10% from pretreatment values and is less than the lower limit of normal. For symptomatic cardiomyopathy or persistent, asymptomatic LV dysfunction that does not resolve within 4 weeks, permanently discontinue MEKINIST and withhold TAFINLAR. Resume TAFINLAR at the same dose level upon recovery of cardiac function. 5.6 Ocular Toxicities Retinal Vein Occlusion (RVO): Across all clinical trials of MEKINIST, the incidence of RVO was 0.2% (4/1,749). RVO may lead to macular edema, decreased visual function, neovascularization, and glaucoma. Urgently (within 24 hours) perform ophthalmological evaluation for patient-reported loss of vision or other visual disturbances. Permanently discontinue MEKINIST in patients with documented RVO. If MEKINIST is used in combination with TAFINLAR, do not modify TAFINLAR dose. Retinal Pigment Epithelial Detachment (RPED): Retinal pigment epithelial detachments (RPED) can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. Retinal detachments resulting from MEKINIST are often bilateral and multifocal, occurring in the macular region of the retina. In Trial 2, ophthalmologic examinations including retinal evaluation were performed pretreatment and at regular intervals during treatment. RPED occurred in 2% (1/55) of patients receiving TAFINLAR in combination with MEKINIST. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of RPED was 1% (2/202). Perform ophthalmological evaluation at any time a patient reports visual disturbances and compare with baseline, if available. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of TAFINLAR. Withhold MEKINIST if RPED is diagnosed. If resolution of the RPED is documented on repeat ophthalmological evaluation within 3 weeks, resume MEKINIST at a lower dose level. Discontinue MEKINIST if no improvement after 3 weeks. Uveitis and Iritis: Uveitis and iritis can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR as a single agent and uveitis occurred in 1% (2/202) of patients treated with TAFINLAR in combination with MEKINIST. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, eye pain). If diagnosed, withhold TAFINLAR for up to 6 weeks until uveitis/iritis resolves to Grade 0-1. If TAFINLAR is used in combination with MEKINIST, do not modify the dose of MEKINIST. 5.6 Interstitial Lung Disease In clinical trials of MEKINIST (N = 329) as a single agent, ILD or pneumonitis occurred in 2% of patients. In Trial 1, 2% (5/211) of patients treated with MEKINIST developed ILD or pneumonitis; all five patients required hospitalization. The median time to first presentation of ILD or pneumonitis was 160 days (range: 60 to 172 days). Withhold MEKINIST in patients presenting with new or progressive pulmonary symptoms and findings including cough, dyspnea, hypoxia, pleural effusion, or infiltrates, pending clinical investigations. Permanently discontinue MEKINIST for patients diagnosed with treatment-related ILD or pneumonitis. If MEKINIST is used in combination with TAFINLAR, do not modify the dose of TAFINLAR. 5.7 Serious Febrile Reactions The incidence and severity of pyrexia are increased when TAFINLAR is used in combination with MEKINIST compared with TAFINLAR as a single agent [see Adverse Reactions (6.1)]. In Trial 2, the incidence of fever (serious and non-serious) was 71% (39/55) in patients treated with TAFINLAR in combination with MEKINIST and 26% (14/53) in patients treated with TAFINLAR as a single agent. Serious febrile reactions and fever of any severity complicated by hypotension, rigors or chills occurred in 25% (14/55) of patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) of patients treated with TAFINLAR as a single agent. Fever was complicated with chills/rigors in 51% (28/55), dehydration in 9% (5/55), renal failure in 4% (2/55), and syncope in 4% (2/55) of patients in Trial 2. In patients treated with TAFINLAR in combination with MEKINIST, the median time to initial onset of fever was 30 days compared with 19 days in patients treated with TAFINLAR as a single agent; the median duration of fever was 6 days with the combination compared with 4 days with TAFINLAR as a single agent. Across clinical trials of TAFINLAR administered in combination with MEKINIST (N = 202), the incidence of pyrexia was 57% (116/202). Withhold TAFINLAR for fever of 101.3°F or higher. Withhold MEKINIST for any fever higher than 104°F.

Withhold TAFINLAR, and MEKINIST if used in combination, for any serious febrile reaction or fever complicated by hypotension, rigors or chills, dehydration, or renal failure and evaluate for signs and symptoms of infection. Refer to Table 2 for recommended dose modifications for adverse reactions. Prophylaxis with antipyretics may be required when resuming TAFINLAR or MEKINIST. 5.8 Serious Skin Toxicity Serious skin toxicity can occur when TAFINLAR is used in combination with MEKINIST and with MEKINIST as a single agent [refer to Full Prescribing Information for MEKINIST]. In Trial 2, the incidence of any skin toxicity was similar for patients receiving TAFINLAR in combination with MEKINIST (65% [36/55]) compared with patients receiving TAFINLAR as a single agent (68% [36/53]). The median time to onset of skin toxicity in patients treated with TAFINLAR in combination with MEKINIST was 37 days (range: 1 to 225 days) and median time to resolution of skin toxicity was 33 days (range: 3 to 421 days). No patient required dose reduction or permanent discontinuation of TAFINLAR or MEKINIST for skin toxicity. Across clinical trials of TAFINLAR in combination with MEKINIST (N = 202), severe skin toxicity and secondary infections of the skin requiring hospitalization occurred in 2.5% (5/202) of patients treated with TAFINLAR in combination with MEKINIST. Withhold TAFINLAR, and MEKINIST if used in combination, for intolerable or severe skin toxicity. TAFINLAR and MEKINIST may be resumed at lower dose levels in patients with improvement or recovery from skin toxicity within 3 weeks. 5.9 Hyperglycemia Hyperglycemia can occur when TAFINLAR is administered as a single agent or when used in combination with MEKINIST. In Trial 2, the incidence of Grade 3 hyperglycemia based on laboratory values was 5% (3/55) in patients treated with TAFINLAR in combination with MEKINIST compared with 2% (1/53) in patients treated with TAFINLAR as a single agent. Monitor serum glucose levels as clinically appropriate when TAFINLAR is administered as a single agent or when used in combination with MEKINIST in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination. 5.10 Glucose-6-Phosphate Dehydrogenase Deficiency TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia. 5.11 Embryofetal Toxicity TAFINLAR and MEKINIST both can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use a highly effective non-hormonal contraception during treatment with TAFINLAR and MEKINIST in combination and for 4 months after treatment, since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR or MEKINIST. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in another section of the label: • New Primary Malignancies [see Warnings and Precautions (5.1)] • Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)] • Hemorrhage [see Warnings and Precautions (5.3)] • Venous Thromboembolism [see Warnings and Precautions (5.4)] • Cardiomyopathy [see Warnings and Precautions (5.5)] • Ocular Toxicities [see Warnings and Precautions (5.6)] • Interstitial Lung Disease [see Warnings and Precautions (5.6)] • Serious Febrile Reactions [see Warnings and Precautions (5.7)] • Serious Skin Toxicity [see Warnings and Precautions (5.8)] • Hyperglycemia [see Warnings and Precautions (5.9)] • Glucose-6-Phosphate Dehydrogenase Deficiency [see Warnings and Precautions (5.10)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in the Warnings and Precautions section and below reflect exposure to TAFINLAR as a single agent and in combination with MEKINIST. BRAF V600E or V600K Unresectable or Metastatic Melanoma: The safety of TAFINLAR in combination with MEKINIST was evaluated in Trial 2 and other trials consisting of a total of 202 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received TAFINLAR 150 mg orally twice daily in combination with MEKINIST 2 mg orally once daily until disease progression or unacceptable toxicity. Among these 202 patients, 66 (33%) were exposed to TAFINLAR and 68 (34%) were exposed to MEKINIST for greater than 6 to 12 months while 40 (20%) were exposed to TAFINLAR and 36 (18%) were exposed to MEKINIST for greater than one year. The median age was 54 years, 57% were male, and >99% were white. Table 5 presents adverse reactions from Trial 2, a multicenter, open-label, randomized trial of 162 patients with BRAF V600E or V600K mutation-positive melanoma receiving TAFINLAR 150 mg

twice daily in combination with MEKINIST 2 mg orally once daily (n = 55), TAFINLAR 150 mg orally twice daily in combination with MEKINIST 1 mg once daily (n = 54), and TAFINLAR as a single agent 150 mg orally twice daily (n = 53) [see Clinical Studies (14.2)]. Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, current evidence of Class II or greater congestive heart failure (New York Heart Association), history RVO or RPED, QTc interval ≥480 msec, treatment refractory hypertension, uncontrolled arrhythmias, history of pneumonitis or interstitial lung disease, or a known history of G6PD deficiency were excluded. The median duration of treatment was 10.9 months for both TAFINLAR and MEKINIST (2-mg orally once-daily treatment group) when used in combination, 10.6 months for both TAFINLAR and MEKINIST (1-mg orally once-daily treatment group) when used in combination, and 6.1 months for TAFINLAR as a single agent. In Trial 2, 13% of patients receiving TAFINLAR in combination with MEKINIST experienced adverse reactions resulting in permanent discontinuation of trial medication(s). The most common adverse reaction resulting in permanent discontinuation was pyrexia (4%). Adverse reactions led to dose reductions in 49% and dose interruptions in 67% of patients treated with TAFINLAR in combination with MEKINIST. Pyrexia, chills, and nausea were the most common reasons cited for dose reductions and pyrexia, chills, and decreased ejection fraction were the most common reasons cited for dose interruptions of TAFINLAR and MEKINIST when used in combination. Table 5. Common Adverse Drug Reactions Occurring in ≥10% at (All Grades) or ≥5% (Grades 3 or 4) of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 All All Grades a a 3 and 4 Grades Grades Adverse Reactions General disorders and administrative site conditions Pyrexia 71 5 69 Chills 58 2 50 Fatigue 53 4 57 b 31 0 28 Edema peripheral Skin and subcutaneous tissue disorders 45 0 43 Rashc Night Sweats 24 0 15 Dry skin 18 0 9 Dermatitis acneiform 16 0 11 Actinic keratosis 15 0 7 Erythema 15 0 6 Pruritus 11 0 11 Gastrointestinal disorders Nausea 44 2 46 Vomiting 40 2 43 Diarrhea 36 2 26 33 2 24 Abdominal paind Constipation 22 0 17 Dry mouth 11 0 11 Nervous system disorders Headache 29 0 37 Dizziness 16 0 13 Respiratory, thoracic, and mediastinal disorders Cough 29 0 11 Oropharyngeal pain 13 0 7 Musculoskeletal, connective tissue, and bone disorders Arthralgia 27 0 44 Myalgia 22 2 24 Back pain 18 5 11 Muscle spasms 16 0 2 Pain in extremity 16 0 11 Metabolism and nutritional disorders Decreased appetite 22 0 30 Dehydration 11 0 6 Psychiatric Disorders Insomnia 18 0 11 Vascular disorders 16 5 11 Hemorrhagee Infections and infestations Urinary tract infection 13 2 6 Renal and urinary disorders 7 7 2 Renal failuref

Grades 3 and 4

All Gradesa

Grades 3 and 4

9 2 2 0

26 17 40 17

0 0 6 0

2 0 0 0 0 0 0

53 6 6 4 9 2 13

0 0 0 0 0 0 0

6 4 0 2 2 0

21 15 28 21 11 6

0 0 0 2 0 0

2 0

28 9

0 0

21 0

0 0

0 0 0 0 2

34 23 11 4 19

0 2 2 0 0

0 2

19 2

0 0

National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. Includes the following terms: peripheral edema, edema, and lymphedema. c Includes the following terms: rash, rash generalized, rash pruritic, rash erythematous, rash papular, rash vesicular, rash macular, and rash maculo-papular. d Includes the following terms: abdominal pain, abdominal pain upper, abdominal pain lower, and abdominal discomfort. e Includes the following terms: brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, and vitreous hemorrhage. f Includes the following terms: renal failure and renal failure acute. Other clinically important adverse reactions (N = 202) observed in <10% of patients treated with TAFINLAR in combination with MEKINIST were: Eye Disorders: Vision blurred, transient blindness. Gastrointestinal Disorders: Stomatitis, pancreatitis. General Disorders and Administration Site Conditions: Asthenia. Infections and Infestations: Cellulitis, folliculitis, paronychia, rash pustular. Neoplasms Benign, Malignant, and Unspecified (including cysts and polyps): Skin papilloma. Skin and Subcutaneous Tissue Disorders: Palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, hyperhidrosis. Vascular Disorders: Hypertension. Table 6. Treatment-Emergent Laboratory Abnormalities Occurring at ≥10% (All Grades) or ≥2% (Grades 3 or 4)] of Patients Treated With TAFINLAR in Combination With MEKINIST in Trial 2 TAFINLAR plus TAFINLAR plus MEKINIST 2 mg MEKINIST 1 mg TAFINLAR N = 55 N = 54 N = 53 a

All All All Grades Grades Grades Grades 3 and 4 Grades 3 and 4 Grades 3 and 4a Tests Hematology Leukopenia 62 5 46 4 21 0 Lymphopenia 55 22 59 19 40 6 Neutropenia 55 13 37 2 9 2 Anemia 55 4 46 7 28 0 Thrombocytopenia 31 4 31 2 8 0 Liver Function Tests Increased AST 60 5 54 0 15 0 Increased alkaline 60 2 67 6 26 2 phosphatase Increased ALT 42 4 35 4 11 0 Hyperbilirubinemia 15 0 7 4 0 0 Chemistry Hyperglycemia 58 5 67 6 49 2 Increased GGT 56 11 54 17 38 2 Hyponatremia 55 11 48 15 36 2 Hypoalbuminemia 53 0 43 2 23 0 Hypophosphatemia 47 5 41 11 40 0 Hypokalemia 29 2 15 2 23 6 Increased creatinine 24 5 20 2 9 0 Hypomagnesemia 18 2 2 0 6 0 Hyperkalemia 18 0 22 0 15 4 Hypercalcemia 15 0 19 2 4 0 Hypocalcemia 13 0 20 0 9 0 a No Grade 4 events were reported in patients receiving TAFINLAR as a single agent. ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; GGT = Gamma glutamyltransferase. QT Prolongation: In Trial 2, QTcF prolongation to >500 msec occurred in 4% (2/55) of patients treated with TAFINLAR in combination with MEKINIST and in 2% (1/53) of patients treated with TAFINLAR as a single agent. The QTcF was increased more than 60 msec from baseline in 13% (7/55) of patients treated with TAFINLAR in combination with MEKINIST and 2% (1/53) of patients treated with TAFINLAR as a single agent. 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Dabrafenib Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 or CYP2C8 may increase concentrations of dabrafenib and strong inducers of CYP3A4 or CYP2C8 may decrease concentrations of dabrafenib [see Clinical Pharmacology (12.3)]. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with TAFINLAR. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.

7.2 Effects of Dabrafenib on Other Drugs Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a CYP3A4/CYP1A2 substrate) [see Clinical Pharmacology (12.3)]. Monitor international normalized ratio (INR) levels more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. Coadministration of TAFINLAR with other substrates of these enzymes, including dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of efficacy [see Use in Specific Populations (8.1, 8.6)]. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable. 7.3 Trametinib Coadministration of TAFINLAR 150 mg twice daily and trametinib 2 mg once daily resulted in no clinically relevant pharmacokinetic drug interactions [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy TAFINLAR Pregnancy Category D Risk Summary: Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose of 150 mg twice daily based on AUC. 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 Warnings and Precautions (5.11)]. Animal Data: In a combined female fertility and embryofetal development study in rats, developmental toxicity consisted of embryo-lethality, ventricular septal defects, and variation in thymic shape at a dabrafenib dose of 300 mg/kg/day (approximately three times the human exposure at the recommended dose based on AUC). At doses of 20 mg/kg/day or greater (equivalent to the human exposure at the recommended dose based on AUC), rats demonstrated delays in skeletal development and reduced fetal body weight. MEKINIST Pregnancy Category D Risk Summary: MEKINIST can cause fetal harm when administered to a pregnant woman. Trametinib was embryotoxic and abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 times the human exposure at the recommended clinical dose. 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 the fetus [see Warnings and Precautions (5.10)]. Animal Data: In reproductive toxicity studies, administration of trametinib to rats during the period of organogenesis resulted in decreased fetal weights at doses greater than or equal to 0.031 mg/kg/day (approximately 0.3 times the human exposure based on AUC at the recommended dose). In rats, at a dose resulting in exposures 1.8-fold higher than the human exposure at the recommended dose, there was maternal toxicity and an increase in post-implantation loss. In pregnant rabbits, administration of trametinib during the period of organogenesis resulted in decreased fetal body weight and increased incidence of variations in ossification at doses greater than or equal to 0.039 mg/kg/day (approximately 0.08 times the human exposure at the recommended dose based on AUC). In rabbits administered trametinib at 0.15 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose based on AUC) there was an increase in postimplantation loss, including total loss of pregnancy, compared with control animals. 8.3 Nursing Mothers It is not known whether this drug is present in human milk. Because many drugs are present in human milk and because of the potential for serious adverse reactions from TAFINLAR and MEKINIST in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of TAFINLAR and MEKINIST have not been established in pediatric patients. In a repeat-dose toxicity study of dabrafenib in juvenile rats, an increased incidence of kidney cysts and tubular deposits were noted at doses as low as 0.2 times the human exposure at the recommended adult dose based on AUC. Additionally, forestomach hyperplasia, decreased bone length, and early vaginal opening were noted at doses as low as 0.8 times the human exposure at the recommended adult dose based on AUC. 8.5 Geriatric Use One hundred and twenty-six (22%) of 586 patients in clinical trials of TAFINLAR administered as a single agent and 40 (21%) of the 187 patients receiving TAFINLAR in Trial 1 were ≥65 years of age. No overall differences in the effectiveness or safety of TAFINLAR were observed in the elderly in Trial 1. Across all clinical trials of TAFINLAR administered in combination with MEKINIST, there was an insufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. In Trial 2, 11 patients (20%) were 65 years of age and older, and 2 patients (4%) were 75 years of age and older. 8.6 Females and Males of Reproductive Potential TAFINLAR Contraception: Females: Advise female patients of reproductive potential to use highly effective contraception during treatment and for at least 2 weeks after the last dose of TAFINLAR or at least 4 months after the last dose of TAFINLAR taken in combination with MEKINIST. Counsel patients to use a non-hormonal method of contraception since TAFINLAR can render hormonal contraceptives

ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Warnings and Precautions (5.11), Drug Interactions (7.1), Use in Specific Populations (8.1)]. Infertility: Females: Increased follicular cysts and decreased corpora lutea were observed in female rats treated with trametinib. Advise female patients of reproductive potential that TAFINLAR taken in combination with MEKINIST may impair fertility in female patients. Males: Effects on spermatogenesis have been observed in animals. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with TAFINLAR [see Nonclinical Toxicology (13.1)]. MEKINIST Contraception: Females: MEKINIST can cause fetal harm when administered during pregnancy. Advise female patients of reproductive potential to use highly effective contraception during treatment and for 4 months after the last dose of MEKINIST. When MEKINIST is used in combination with TAFINLAR, counsel patients to use a non-hormonal method of contraception since dabrafenib can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking MEKINIST [see Use in Specific Populations (8.1)]. Infertility: Females: MEKINIST may impair fertility in female patients [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals treated with dabrafenib. Advise male patients of the potential risk for impaired spermatogenesis, and to seek counseling on fertility and family planning options prior to starting treatment with MEKINIST in combination with TAFINLAR. 8.7 Hepatic Impairment TAFINLAR No formal pharmacokinetic trial in patients with hepatic impairment has been conducted. Dose adjustment is not recommended for patients with mild hepatic impairment based on the results of the population pharmacokinetic analysis. As hepatic metabolism and biliary secretion are the primary routes of elimination of dabrafenib and its metabolites, patients with moderate to severe hepatic impairment may have increased exposure. An appropriate dose has not been established for patients with moderate to severe hepatic impairment [see Clinical Pharmacology (12.3)]. MEKINIST No formal clinical trial has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of trametinib. No dose adjustment is recommended in patients with mild hepatic impairment based on a population pharmacokinetic analysis [see Clinical Pharmacology (12.3)]. The appropriate dose of MEKINIST has not been established in patients with moderate or severe hepatic impairment. 8.8 Renal Impairment No formal pharmacokinetic trial for TAFINLAR or MEKINIST has been conducted in patients with renal impairment. Dose adjustment is not recommended for patients with mild or moderate renal impairment based on the results of the population pharmacokinetic analysis. An appropriate dose has not been established for patients with severe renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage of TAFINLAR. Since dabrafenib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with TAFINLAR. There were no reported cases of overdosage with MEKINIST. The highest doses of MEKINIST evaluated in clinical trials were 4 mg orally once daily and 10 mg administered orally once daily on 2 consecutive days followed by 3 mg once daily. In seven patients treated on one of these two schedules, there were two cases of retinal pigment epithelial detachments for an incidence of 28%. Since trametinib is highly bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKINIST. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) for TAFINLAR. See FDA-approved patient labeling (Patient Information) for MEKINIST. Inform patients of the following: • Evidence of BRAF V600E mutation in the tumor specimen is necessary to identify patients for whom treatment with TAFINLAR as a single agent is indicated and evidence of BRAF V600E or V600K mutation in tumor specimens is necessary to identify patients for whom treatment with TAFINLAR in combination with MEKINIST is indicated. • TAFINLAR administered in combination with MEKINIST can result in the development of new primary cutaneous and non-cutaneous malignancies. Advise patients to contact their doctor immediately for any new lesions, changes to existing lesions on their skin, or other signs and symptoms of malignancies [see Warnings and Precautions (5.1)]. • TAFINLAR administered in combination with MEKINIST increases the risk of intracranial and gastrointestinal hemorrhage. Advise patients to contact their healthcare provider to seek immediate medical attention for signs or symptoms of unusual bleeding or hemorrhage [see Warnings and Precautions (5.3)]. • TAFINLAR administered in combination with MEKINIST increases the risks of pulmonary embolism and deep venous thrombosis. Advise patients to seek immediate medical attention for sudden onset of difficulty breathing, leg pain, or swelling [see Warnings and Precautions (5.4)]. • TAFINLAR administered in combination with MEKINIST can cause cardiomyopathy. Advise patients to immediately report any signs or symptoms of heart failure to their healthcare provider [see Warnings and Precautions (5.5)]. • TAFINLAR and MEKINIST can cause visual disturbances that can lead to blindness. Advise patients to

contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.6)]. • MEKINIST can cause interstitial lung disease (or pneumonitis). Advise patients to contact their healthcare provider as soon as possible if they experience signs such as cough or dyspnea [see Warnings and Precautions (5.6)]. • TAFINLAR administered as a single agent and in combination with MEKINIST can cause pyrexia including serious febrile reactions. Inform patients that the incidence and severity of pyrexia are increased when TAFINLAR is given in combination with MEKINIST. Instruct patients to contact their doctor if they develop fever while taking TAFINLAR [see Warnings and Precautions (5.7)]. • TAFINLAR in combination with MEKINIST can cause serious skin toxicities which may require hospitalization. Advise patients to contact their healthcare provider for progressive or intolerable rash [see Warnings and Precautions (5.8)]. • TAFINLAR can impair glucose control in diabetic patients resulting in the need for more intensive hypoglycemic treatment. Advise patients to contact their doctor to report symptoms of severe hyperglycemia [see Warnings and Precautions (5.9)]. • TAFINLAR may cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Advise patients with known G6PD deficiency to contact their doctor to report signs or symptoms of anemia or hemolysis [see Warnings and Precautions (5.10)]. • MEKINIST causes hypertension. Advise patients that they need to undergo blood pressure monitoring and to contact their healthcare provider if they develop symptoms of hypertension such as severe headache, blurry vision, or dizziness. • MEKINIST often causes diarrhea which may be severe in some cases. Inform patients of the need to contact their healthcare provider if severe diarrhea occurs during treatment. • TAFINLAR and MEKINIST can cause fetal harm if taken during pregnancy. Instruct female patients to use non-hormonal, highly effective contraception during treatment and for 4 months after discontinuation of treatment with TAFINLAR in combination with MEKINIST. Advise patients to contact their doctor if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR and MEKINIST [see Warnings and Precautions (5.11), Use in Specific Populations (8.1)]. • Nursing infants may experience serious adverse reactions if the mother is taking TAFINLAR or MEKINIST during breastfeeding. Advise breastfeeding mothers to discontinue nursing while taking TAFINLAR or MEKINIST [see Use in Specific Populations (8.3)]. • Male patients are at an increased risk for impaired spermatogenesis [see Use in Specific Populations (8.6)]. • TAFINLAR and MEKINIST should be taken either at least 1 hour before or at least 2 hours after a meal. TAFINLAR is a registered trademark of GlaxoSmithKline. MEKINIST is a registered trademark of GlaxoSmithKline.

GlaxoSmithKline Research Triangle Park, NC 27709

Cancer Center Profile

New Mexico Oncology Medical Home with cancer need to treat the cancer and manage the complications associated with cancer and its treatment, in the same place, and as quickly and as efficiently as possible. A patient with cancer does not have the energy to confront an inefficient system. It was crucial for us to establish an efficient system that will provide everything a patient with cancer needs right at our facility and avoid the need to use services at emergency departments or hospitals. I thought about all the problems that confront a cancer patient and established policies and procedures to provide as many solutions to those problems as we could. Cancer treatment is done by a multitude of specialists, and patients are overwhelmed by the process of navigating the dysfunctional system. Part of what we do is to coordinate that care, when we cannot deliver it ourselves. However, as an oncology medical home, we need to be available when the patient needs us. For example, when patients call for help, they don’t need to hear, “If this is a medical emergency, hang up and dial 911.” When a patient has cancer, everything feels like an emergency. So if patients call the center and no one answers, they will indeed call 911 and will end up in the emergency department, where they may get unneeded care, such as an extra computed tomography (CT) scan or laboratory work that was already done at the cancer center. This leads to wasteful care that is also very expensive. Emergency physicians do a great job of handling medical emergencies, but they cannot be expected to know what happens with patients who have cancer, and how to manage chemotherapy complications. VBCC: How is your medical home different from cancer centers that are not medical homes? Dr McAneny: The most important thing we did was to change the triage system. A nurse who answers the phone and talks to the patient, I would contend, is not triage. Triage is when you actually figure out what the patient’s problem is, and then you provide the necessary treatment or service, immediately. Instead of trying to keep the patients out of the practice, because the practice was full that day, we changed our schedules and systems to allow the triage nurses to schedule service at the center the same day. So first we rearranged our triage nursing culture and the mindset of every employee in the practice. Everyone had to say, “My job is to figure out what this patient needs, and how I’m Vol. 5

No. 8

going to get it for them.” That is crucial. We then made sure that our systems are set up to meet the patient’s needs at that time, so that if the nurse who is talking to the patient realizes that, for example, the patient had a fever or needed antibiotics, the nurse would invite the patient to come in to the center right then and there. Not tomorrow, not the day after. That makes a huge difference. And it requires that the center stays open late, and is open every day, including on the weekend. We have implemented the COME HOME computerized triage system so that the nurse has the decision support to manage the symptom at the appropriate site of care. We do not want patients with heart attacks or with broken bones coming to the center, for patient safety and for medical liability reasons. The triage pathways are designed to avoid sending the patient to an inappropriate site of care. If the center is not open when the patient gets sick, the patient will end up going to the emergency department and having an avoidable, expensive workup, when possibly all that patient needs is a liter of saline. This is why we provide urgent care levels of service on weekends, on holidays, and on weekday evenings. So the most crucial aspect of an oncology medical home is the mindset that says, “My job is to get you what you need.” The second thing is the notion that we must have the infrastructure in place in the office to manage those complications directly. This is different from a primary care medical home, which must coordinate care given elsewhere but cannot simply provide it. It is also important to have at the practice a physician, a nurse practitioner, or a physician assistant who could see the patient immediately, and get laboratory work back quickly, so that they can efficiently diagnose and treat the patient’s problem. At our medical home we can get laboratory work, x-rays, or CTs immediately, hydrate patients, give intravenous antibiotics, and provide many other services. That has also led us to be able to manage well patients who had fairly serious conditions, such as pulmonary embolism or neutropenic fevers, right at the practice rather than send them to the hospital for prolonged stay, where they could catch resistant bacteria, develop blood clots, or become debilitated from lying in a hospital bed. Our patients are very grateful, because they do not have to spend time away from their home. For a patient with cancer who has a

Continued from the cover

limited time remaining to live, the last place that person wants to spend it is in a hospital.

Barbara L. McAneny, MD

The goal of the oncology medical home is to provide all the services that patients with cancer need, in the same place, and as quickly and as efficiently as possible. VBCC: How many physicians are in your oncology medical home, and who is there after hours? Dr McAneny: My practice has 17 physicians, including medical oncologists, radiation oncologists, radiologists, and a few internists. After hours we become a symptom management facility. If a patient has a fever, nausea, diarrhea, or pain—all the things that bring patients with cancer to ask for care— we provide that care, but we do not provide oncology care, such as chemotherapy infusion or radiation. Our internists or our midlevel oncology providers are in the office after hours. Our oncologists are not working extended hours. We match the staff to our peak time, and we hired very few additional staff when we extended the hours. We have 2 nurses, a person to manage the phones and draw blood, a radiology technician, and a physician. VBCC: The current economics force many oncology practices to join hospitals. Do you have any suggestions on how to reverse this trend? Dr McAneny: The key here is to connect with payers. This is ironic. We have always spent our time arguing and negotiating with payers, trying to avoid reductions in payment. Now, payers are recognizing that as oncology practices move to the hospital, if it is a Medicare patient, the prices go up 50%. If it is a patient in a commercial plan, the prices can increase between October 2014

200% and 300% over the price they were paying for the exact same service in the physician’s office: the same quality, same service, and sometimes the same physician. It is a question of what fee schedule the physicians are being paid under. Payers are beginning to realize this with the increasing trend of hospitals acquiring oncology practices. Hospitals love it, because they can often get 340B drug pricing, and it becomes a big “cash cow” to the hospital. The hospital can bill the insurance company more for the same service. The economics are driving practices into the hospital. The way to stop this is a payment reform that will pay the same amount across different sites of service, and to return the 340B drug program to Congress’ original intention of providing care to uninsured people. A 15-minute office visit or a 1-hour infusion of a drug should cost the same whether the practice is organized under a hospital and is therefore paid under the hospital outpatient’s payment system, or whether the practice is organized as an independent physician office that is paid under the physician fee schedule. That would stop the trend of oncology practices joining hospitals in a heartbeat, because hospitals are not very good at running outpatient practices. Rather, they were designed to manage complicated inpatient visits that need multiple specialties working together for sick patients. VBCC: Do you recommend to other practices to adopt the oncology medical home model? Dr McAneny: Absolutely, for 3 reasons. First, the oncology medical home provides better care for patients. Patients are thrilled to not be in the hospital. They want as good quality of life as they can get. Being home, and having their problems managed aggressively add to that quality. The second reason is that it saves costs for the entire US healthcare system. We cannot afford to spend more healthcare dollars. If we can deliver better care at a lower price, we must do so. Third, we are soon going to move away from the fee-for-service model (I believe within the next 2 years), at which point we will be moving to bundled payments. A practice that cannot manage the expensive parts of patient care will not be able to succeed under a bundled payment system. The oncology medical home model can better deal with this payment system. n

www.ValueBasedCancerCare.com

Breast Cancer

HER2-Derived Vaccine Cuts Recurrences in Patients with High-Risk Breast Cancer By Wayne Kuznar

positive, restricted immunogenic peptide designed to stimulate CD8+ cytotoxic T lymphocytes to recognize

“

Peptide vaccines have the benefit of being easy to construct and manufacture on a large scale, they’re inexpensive, and, very importantly, they are ‘off-the-shelf’ therapy.

Photo by © ASCO/Todd Buchanan 2014

San Francisco, CA—A new GP2 peptide vaccine was safe and reduced the rate of breast cancer recurrence in women with high-risk breast cancer in a phase 2 clinical trial. The vaccine was particularly effective in reducing recurrence in women with HER2 overexpression, reported Elizabeth A. Mittendorf, MD, PhD, Assistant Professor of Surgical Oncology, M.D. Anderson Cancer Center, Houston, at the 2014 Breast Cancer Symposium. The vaccine is delivered in the adjuvant setting, after the completion of standard-of-care therapy, including trastuzumab (Herceptin) where appropriate, along with the immuno adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF) to help stimulate an immune response. “Peptide vaccines have the benefit of being easy to construct and manufacture on a large scale, they’re inexpensive, and, very importantly, they are ‘off-the-shelf’ therapy,” said Dr Mittendorf. GP2 is a HER2-derived HLA-A2–

”

—Elizabeth A. Mittendorf, MD, PhD breast cancer cells with HER2 expression, said Erika J. Schneble, DO, coinvestigator of the study and a general

surgery resident at San Antonio Military Medical Center, TX. In the multicenter phase 2 trial, 180 women with HLA-A2–positive, node-positive or high-risk node-negative breast cancer with any level of HER2 expression who were rendered disease-free with standard-of-care therapy were randomized to receive GP2 plus GM-CSF or GM-CSF alone. HER2 overexpression was present in 57% of patients who received the vaccine and in 55% of patients in the control group. Only 1 grade 3 local and systemic toxicity was reported in the vaccine group. “The toxicities are mostly grade 1 local and systemic toxicities that match the control arm, suggesting that these toxicities are due to just the immunoadjuvant GM-CSF,” said Dr Schneble. Approximately 70% of patients in each arm had grade 1 local toxicities. In all, 70% of patients in the GM-CSF–alone arm and 60% of patients in the vaccine plus GM-CSF arm had grade 1 systemic toxicity.

After a median follow-up of 34 months, the disease-free survival (DFS) rate was 88% with the GP2 vaccine and 81% in the control group (P = .428). Excluding the patients who had a recurrence during their primary vaccination series or who had a second malignancy, the DFS rate was 94% with the vaccine versus 85% in the control group (P = .168). “After completion of the primary vaccine series, there have been no recurrences in the HER2 3+ population,” said Dr Schneble. “This suggests a possible synergy with trastuzumab. All [HER] 3+ patients received trastuzu mab as their standard-of-care therapy.” The concurrent use of trastuzumab and the GP2 vaccine may address the early recurrences, Dr Mittendorf said. A phase 1 clinical trial of concurrent use showed the combination to be safe, with no increases in toxicities. A phase 2 trial examining combination immunotherapy with trastuzumab and a CD8–positive T-cell–eliciting vaccine is expected to begin enrolling patients. n

Most Preoperative Breast MRIs Requested by Nononcologists By Charles Bankhead

San Francisco, CA—Preoperative breast magnetic resonance imaging (MRI) failed to influence clinical management in any subgroup of 257 patients with breast cancer, according to the results of a retrospective review that led one cancer center to discontinue the practice. Preoperative MRI slightly increased the rate of total mastectomy, but it led to additional imaging studies and biopsies in more than 60% of cases. Although the MRI-prompted biopsies identified additional cancers, most of the lesions were low risk, reported Sarah P. Cate, MD, a breast surgeon at Mount Sinai Beth Israel Hospital, New York, at the 2014 Breast Cancer Symposium. “Given these results, we are no longer using preoperative MRI routinely at our institution,” Dr Cate and colleagues concluded in a poster presentation. “Additional studies will be needed to determine strict indications for the use of MRI in the preoperative setting.” Another report at the meeting showed that physicians other than oncologists requested most of the preoperative MRI studies of patients with breast cancer. Despite their frequency, the use of

preoperative breast MRIs remains controversial. In an effort to help clarify the imaging modality’s role in breast cancer, investigators retrospectively reviewed the records of 257 patients who underwent preoperative breast MRI during 2010-2012. The records showed that 155 of the patients subsequently had breast-conserving surgery, and that MRI led to upstaging and subsequent total mastectomy in 8 (3%) patients. Breast density was scattered fibroglandular dense in 117 cases, heterogeneously dense in 95 cases, extremely dense in 19 cases, and predominantly fatty in 8 cases. The preoperative MRI was followed by additional imaging in 158 cases, and 78 patients had additional biopsies as a result of their MRI findings. The biopsies revealed cancer in 32 cases. However, given the low rate of upgrading to total mastectomy, the clinical significance of the cancers remained open to question, said Dr Cate. “We did not find any statistically significant differences in patients who were upgraded to TM [total mastectomy] by clinical factors,…though there was a trend towards upgrade to TM in those who required additional imag-

Value-Based Cancer Care

October 2014

ing,” the investigators noted in their presentation. “We found no clinical factors associated with the need for additional biopsies.”

“

Given these results, we are no longer using preoperative MRI routinely at our institution.

”

—Sarah P. Cate, MD, and colleagues

A study from the Dubin Breast Center at Mount Sinai Hospital in New York showed that 75% of preoperative breast MRI requests came from physicians other than the operating surgeon. The analysis included 964 patients with newly diagnosed breast cancer during 2011-2013. Of 423 breast MRI studies requested for the patients, 241 (57%) occurred before the patients were seen by their breast cancer surgeons. Medical records showed that 181 (75%) of the preoperative MRIs were requested by physicians who were not specialists in breast disease or surgery.

Socioeconomic factors significantly influenced requests for preoperative MRI. Anya M. Romanoff, MD, a research general surgery resident at the Icahn School of Medicine at Mount Sinai, New York, and colleagues, found that 65% of white patients and 66% of Hispanic patients had preoperative MRI compared with 42% of black patients (P = .001) and 26% of Asian patients (P <.001). Preoperative MRI was requested for 62% of patients who had private insurance coverage, 64% of patients with Medicare coverage, and 55% of patients who paid for their care versus 37% of patients with Medicaid coverage (P = .002). An analysis of factors associated with orders for preoperative MRI showed that only race (P = .001) and insurance (P = .018) were significant predictors. The factors that were not associated with preoperative breast MRI included age, history of breast disease, family history of breast cancer, genetic mutation, breast density, mode of breast cancer diagnosis, and biopsy pathology. “Further research is needed to develop guidelines for breast MRI use in newly diagnosed cancer patients,” Dr Romanoff and colleagues concluded. n

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Breast Cancer

Adding Luteinizing Hormone-Releasing Hormone Agonist to Chemotherapy Preserves Fertility in Women with Breast Cancer By Wayne Kuznar

San Francisco, CA—A second study adds to the body of evidence that including a luteinizing hormone-releasing hormone (LHRH) agonist with chemotherapy as treatment for breast cancer increases a younger woman’s likelihood of becoming pregnant. The new data, which were presented at the 2014 Breast Cancer Symposium, come from a long-term follow-up of the phase 3 clinical trial known as PROMISE-GIM6. These data come on the heels of the POEMS trial, in which the rate of premature ovarian failure was reduced by 70% at 2 years with the addition of an LHRH agonist to chemotherapy for the treatment of breast cancer. The current guidelines from the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) consider the use of LHRH analogs to preserve fertility in women with breast cancer as experimental. “With the POEMS trial and this updated analysis of PROMISE-GIM6, both ASCO and ESMO should consider updating their recommendations, and consider LHRH agonists as a strategy to preserve ovarian function and fertility,” said Matteo

Lambertini, MD, an oncology fellow, IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy, who presented the long-term follow-up of PROMISE-GIM6 at the meeting.

“

Both ASCO and ESMO should consider updating their recommendations, and consider LHRH agonists as a strategy to preserve ovarian function and fertility.

”

—Matteo Lambertini, MD The open-label, multicenter, parallel study included 281 premenopausal women with early-stage breast cancer who were candidates for neoadjuvant or adjuvant chemotherapy. They were

randomized to chemotherapy alone or to chemotherapy plus triptorelin 3.75 mg intramuscularly every 4 weeks starting at least 1 week before chemotherapy and continued for the duration of the chemotherapy. Approximately 80% of the patients in each arm had hormone receptor–positive disease. More than 90% of patients received anthracycline-based or anthracycline- and taxane-based chemotherapy. Premature ovarian failure was defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the end of chemotherapy. Over a median follow-up of 7.3 years, 8 pregnancies and 5 live births were reported in the chemotherapy/ triptorelin arm compared with 3 pregnancies and 3 live births in the chemotherapy-alone arm. The 5-year cumulative incidence estimate of menstrual resumption at any time was 72.6% in the chemotherapy/triptorelin arm compared with 64% in the chemotherapy-alone arm (P = .071). Although the difference was not significant, the trend toward an improvement in the resumption of menses is consistent

with the findings in the POEMS study, said Dr Lambertini. Disease control and survival were not adversely affected by triptorelin. The 5-year disease-free survival (DFS) rate was 80.5% in the chemotherapy/ triptorelin arm and 83.7% in the chemotherapy-alone arm (P = .519), a nonsignificant difference. An exploratory multivariate analysis adjusted for baseline disease stage and hormone receptor status “importantly showed no difference in disease-free survival between the 2 treatment arms,” Dr Lambertini said. An exploratory subgroup analysis showed no significant interaction between hormone receptor status and DFS. An LHRH agonist during chemotherapy can be considered to preserve fertility in women with estrogen receptor–negative disease, given the lack of apparent risk, said Hope S. Rugo, MD, Clinical Professor, Department of Medicine (Hematology/Oncology), University of California, San Francisco. However, it is not a substitute for established methods of fertility preservation, such as ovarian stimulation and cryopreservation of embryos and oocytes. n

Study Identifies Important Benefits of Cancer Survivorship Programs By Charles Bankhead

San Francisco, CA—Patients with breast cancer who attended survivorship clinics demonstrated improved compliance with follow-up visits, increased use of supportive services, and felt their concerns were better addressed, according to the results of a cancer center’s patient survey reported by Leah L. Dietrich, MD, an oncologist at Gundersen Health System, La Crosse, WI, at the 2014 Breast Cancer Symposium. The survivorship clinic attendees were significantly more likely to have a medical history and physical examination every 3 to 6 months (P = .004) and regular gynecologic evaluations among users of tamoxifen (P = .003), as recommended by the National Comprehensive Cancer Network (NCCN). Overall, the quality-of-life scores did not differ significantly between the 65 attendees and 52 nonattendees. “Significant differences in quality of life may be found in larger sample sizes, but not in our current study,” Dr Dietrich and colleagues concluded in a poster presentation. “We are doing well with many aspects of survivor care, reVol. 5

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gardless of whether patients are attending survivorship clinics.” They added, “We can improve on some core aspects of our survivorship clinic, such as improving our patients’ recollection and understanding of their treatment summaries and care plans.” The landmark Institute of Medicine report, “From Cancer Patient to Cancer Survivor: Lost in Transition,” provided the impetus for the development of survivorship programs at many hospitals and clinics. However, few studies have examined the impact of these programs on cancer survivorship. The Gundersen Center for Cancer and Blood Disorders implemented a survivorship clinic in 2011. Dr Dietrich and colleagues conducted an evaluation of the program and the patients served by it. The investigators identified 192 women with newly diagnosed stage I to III breast cancer between January 2010 and December 2012 who received all their cancer care at Gundersen Health System. After matching patients who attended the survivorship clinic

with those who did not, the evaluation included 117 patients. The clinic attendees and nonattendees differed only with respect to the frequency of lymph node involvement (24% among attendees and 11% among nonattendees; P = .01).

“

Many of these measures can be used to help us improve our care of cancer survivors and for other institutions to measure quality and effectiveness of their programs.

”

—Leah L. Dietrich, MD The attendees were 50% more likely than nonattendees to recall having received a written treatment summary (63% vs 42%, respectively), but a similar proportion of both groups said they knew who to call with questions (96%100%) and said their primary care proOctober 2014

viders were well informed by cancer care providers (76%-83%). All 65 of the clinic attendees adhered to the NCCN recommendations regarding follow-up history and physical examinations, whereas 46 (88%) followed the recommendations. In addition, 11 of the 12 (92%) clinical attendees underwent the recommended evaluations of tamoxifen and gynecologic status compared with 4 of the 16 (25%) nonattendees. The clinic attendees felt that their concerns were more adequately addressed across all of the domains that were assessed (physical, emotional, practical, spiritual, risk of recurrence, fear of recurrence, and long-term side effects). The only differences that attained statistical significance (P <.05) were practical concerns (work, finances, household activities, etc) and long-term side effects. Dr Dietrich concluded that “many of these measures can be used to help us improve our care of cancer survivors and for other institutions to measure quality and effectiveness of their programs.” n

www.ValueBasedCancerCare.com

VBCC Perspective

Logistic Toxicity: Obstacles to the Efficient Delivery of Cancer Care Barry D. Brooks, MD Chair, US Oncology P&T Committee, McKesson Specialty Health, Texas Oncology

he Merriam-Webster dictionary defines “logistics” as the things that must be done to plan and organize a complicated activity that involves many people. The modern delivery of cancer care precisely parallels this definition. “Bilateral mastectomy?” I repeat incredulously. “Yes. My surgeon told me radiation would be best for me, but I can’t do that.” She is a vigorous woman aged 68 years who recently had a 1.6cm receptor-positive breast cancer excised, but the tumor was anatomically unsuitable for the short-course radiation (MammoSite) we had planned to give her. Standard radiation would involve 6 weeks of Monday through Friday visits to the outpatient radiation department. She continues, “We live in Cayuga, Texas, and it is an hour and a half each way to either Dallas or Waco. My husband has had a stroke, and I just can’t leave him alone for 3 or 4 hours a day. The surgeon says my breasts are so large that removing 1 would leave me lopsided, so we are going to remove them both.” Although her rural stoicism is endearing, the need to amputate both her breasts because of a small cancer is a frustrating example of what I call “logistic toxicity.” In 2014, diagnosing and treating cancer is unavoidably complicated, involving innumerable people, but with all the technology and healthcare delivery sophistication, why does it seem that it continues to get harder, not easier, to deliver routine cancer care? Why do the logistics of payment assistance programs, drug shortages, and clinical trial execution make it almost impossible to practice medicine as one would wish? The exploding revolution in the development of new oral oncolytics may soon free many patients with cancer from frequent visits to outpatient cancer centers for prolonged infusions, allowing patients and their caregivers more freedom to go to work or stay at home, although those same oral medications, with their $10,000 monthly price tag, bring their own challenges (see my “financial toxicity” article in the September issue, page 1). To potentially overcome the daunting coinsurance burdens these costly new oral cancer medications bear, most pharmaceutical and biotechnology companies have financial assistance programs to help patients with the large

Barry D. Brooks, MD cost burdens that their medical insurance plans do not cover. Many of these programs are surprisingly generous, but every company has its own forms, requiring different financial metrics and demographic details that elderly, ill, and not so well-educated patients often need help with how to fill them out properly. Our financial counselors frequently provide this needed assistance, but even they find the variation and complexity of the forms daunting and are often unsuccessful in obtaining the requested funding. Several follow-up phone calls and significant delays are usual before patients can be enrolled in these programs, and many companies candidly acknowledge that less than 25% of eligible patients ever receive the financial aid to which they are entitled. In other words, logistic toxicity frustrates everyone in this circle. Shortages of generic oncology drugs are caused by a special brand of logistic toxicity—governmental price controls. The Medicare Modernization Act of 2003 was intended to reduce excess profitability of the “buy-and-bill” model of Medicare Part B oncology drug delivery by applying the well-known Medicare average sales price (ASP) + 6% formula to them. Although drug spending has indeed been moderated by this legislation, as market competition has ground the price of generic oncology drugs down to a few dollars per dose, the 6% margin can no longer absorb any substantial price increases to adapt to inevitable changes in supply and demand. Whether it is the availability of beef in the former Soviet Union or the availability of life-saving generic oncology drugs in the United States, the cause of the shortages is always the same—government price controls.

Value-Based Cancer Care

October 2014

Trials that could be written up, approved by an Institutional Review Board in a few months, and executed at a cost of less than $5000 per patient in the early 1990s now take more than 2 years to begin enrolling patients and cost more than $100,000 per patient to complete. Anyone who enrolls patients in clinical trials in 2014 can certainly understand the term “logistic toxicity” in reference to our current regulatory burden. In their elegant editorial on this topic recently published in the Journal of Clinical Oncology, Steensma and Kantarjian describe the cancer-like growth of 25 years of bureaucratically generated regulations that have been implemented without any testing or proof that safety is enhanced.1 For-profit commercial contract research organizations now harry researchers through a process riddled with ridiculous queries and clinically insignificant detail. Trials that could be written up, approved by an Institutional Review Board in a few months, and executed at a cost of less than $5000 per patient in the early 1990s now take more than 2 years to begin enrolling patients and cost more than $100,000 per patient to complete. No data that safety is enhanced by this increase in logistic toxicity have ever been provided or sought, but there is no doubt that drug development has been made much more costly and patient access to potentially lifesaving new drugs has been delayed or prevented (ie, they die before having access to a game-changing drug such as ibrutinib in chronic lymphocytic leukemia). Everyone could probably conjure a different example of logistic toxicity in oncology; for example, why isn’t one aspect of “meaningful use” to ensure that electronic health record (EHR) systems are able to communicate with one another? Unlike de Tocqueville,2 I do not believe that we are inevitably destined to have our innovations and energies compressed by a web of complexity and regulation. I think we need to

forcefully advocate for solutions to these problems for ourselves and for our patients. Possible solutions include: 1. My patient with the small breast cancer could have been managed with intraoperative radiation. The technology is available and has been shown to have acceptable comparability to standard approaches. Although it is possible there is a modest increased chance of local recurrence with the novel approach, subsequent mastectomy will still be curable in the vast majority of such patients. Why does better have to be the enemy of good? 2. Financial aid for expensive oral oncolytics could be simplified by all pharmaceutical and biotechnology companies using the same standard form, as is done for college admissions, requesting the minimal required data. Just as some colleges ask for an additional essay, companies could still ask for 1 or 2 unique items as an addendum to the basic form. Financial counselors would become facile with this uniform approach, and more patients would get the financial assistance they need to pay for these critical medications 3. We could pay for generic drugs by one of the several successful formulas used in European countries or we could pay ASP + 50% for mature generic oncology drugs. This latter approach would provide a strong economic incentive for companies to continue manufacturing the drugs and would provide a similar incentive for oncologists to prescribe these lower- cost drugs in lieu of more costly branded agents 4. Clinical trials should be standardized, streamlined, and automated with the help of experienced clinical researchers and modern computer technology to staunch the avalanche of paper and irrelevant minutiae that are smothering clinical trial execution (and hopefully rid us of the parasitic contract research organizations at the same time). Only things that are needed to ensure patient safety and iden tify meaningful efficacy and toxicity would be included in the protocols 5. One last thing…EHR systems should talk to each other. n References

1. Steensma DP, Kantarjian HM. Impact of cancer research bureaucracy on innovation, costs, and patient care. J Clin Oncol. 2014;32:376-378. 2. de Tocqueville A. “Soft Despotism.” In: Democracy in America. Vol II. Book 4;1840.

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Prostate Cancer

New Practice Guideline for Systemic Therapy in Men with Metastatic Prostate Cancer By Rosemary Frei, MSc

new guideline for systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC) is based on a literature review of recent publications and outlines the survival and quality-of-life benefits/toxicity effects of each recommendation (Basch E, et al. J Clin Oncol. 2014 Sept 8. Epub ahead of print). Jointly issued by the American Society of Clinical Oncology (ASCO) and Cancer Care Ontario (CCO), the new guideline considers new systemic therapies for mCRPC, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), and radium-223 (Xofigo). “Something different about this guideline is that quality of life and toxicity have been elevated in the recommendations themselves—the patient experience is prioritized,” lead investigator Ethan Basch, MD, MSc, Co-Chair of the ASCO/CCO Expert Panel that developed the guideline, and Associate Professor of Medicine and Public Health, University of North Carolina at Chapel Hill, told Value-Based Cancer Care. “In addition, the strength of the evidence and the strength of the recommendations are transparent.” The new document builds on previ-

ous guidelines and a review of 25 new randomized, controlled trials. According to the new recommendations:

“

Something different about this guideline is that quality of life and toxicity have been elevated in the recommendations themselves—the patient experience is prioritized.

”

—Ethan Basch, MD, MSc • Continuous androgen-deprivation therapy (ADT) via medication or surgery should be continued indefinitely, even if other therapies are added (benefit: moderate; harm: moderate; evidence: weak; recommendation: moderate) • Abiraterone acetate + prednisone, ra-

dium-223 in men with primarily bone metastases, or enzalutamide should be used in addition to ADT (all—benefit: moderate; harm: low; evidence: strong; recommendation: strong) • Docetaxel (Taxotere) + prednisone also should be used in addition to ADT (benefit: moderate; harm: moderate; evidence: strong; recommendation: moderate) • Other therapies to consider: – Sipuleucel-T (Provenge) in asymp tomatic or in minimally symptomatic men – Cabazitaxel (Jevtana) and prednisone in men whose disease has progressed with docetaxel – Mitoxantrone (Novantrone) + prednisone – Antiandrogens, such as bicalu tamide (Casodex), flutamide (Eulexin), or nilutamide (Nilandron) – Ketoconazole – Low-dose corticosteroid monotherapy • Bevacizumab (Avastin), estramustine (Emcyt), and sunitinib (Sutent) should not be used, because they do not increase survival or improve quality of life • Palliative care should be offered to

all patients receiving any treatment, particularly those with symptoms or quality-of-life reduction. “Our recommendation of early initiation of palliative care—which is distinct from end-of-life care—is an important part of the guideline,” Dr Basch said. “Palliative care is now looked at as beneficial and appropriate across this population, including for patients who may have a long time to live with metastatic cancer. Survival time with metastatic prostate cancer has increased with the availability of new drugs, and now it is recognized that we have to focus on support of the patients and their families and caregivers.” He noted that cost and cost-effectiveness were not taken into consideration in the recommendations, although cost was included in a table in the guideline and in the discussion. Dr Basch said it is important to have more postmarketing data to continue to ascertain the rate of serious adverse events in clinical practice. The team also did not recommend particular sequences or drug combinations, because of an insufficient evidence base for that, he said. n

Multigene Test Stratifies Prostate Cancer Aggressiveness Chicago, IL—The commercially available cell-cycle progression test known as Prolaris is helpful for stratifying risk for men with clinically localized prostate cancer and can help to modify treatment decisions for men with prostate cancer based on the aggressive nature of their tumor, according to a poster presented at the 2014 College of American Pathologists annual meeting by Michael K. Brawer, MD, Vice President of Medical Affairs, Urology, Myriad Genetic Laboratories, Inc, Salt Lake City, UT, and colleagues. The Prolaris prognostic test, made and marketed by Myriad Genetics, Inc, involves a multigene panel that is calculated to reach the cell-cycle progression score. Previous studies funded by Myriad indicate that Prolaris scores strongly correlate with prostate cancer outcomes, such as disease-specific mortality, biochemical recurrence, and metastasis, whether the tissue samples are derived by prostatectomy or by needle biopsy (eg, Bishoff JT, et al. J Urol. 2014;192:409-414). Dr Brawer and colleagues analyzed

data from Myriad’s laboratory database for patients whose prostate biopsies underwent the multigene test and for whom clinicopathologic data were available. The score was calculated by “measuring the RNA expression of 31 cell-cycle progression genes normalized to 15 housekeeping genes,” Dr Brawer and colleagues noted. The test was ordered by 787 physicians. The study set involved 3502 biopsy samples that yielded RNA of sufficiently high quality to undergo the multigene analysis. The test scores ranged from –2.9 to 3.4. Based on the test score, 38.7% of the men had a tumor that was less aggressive than was indicated by the clinicopathologic analysis, and 19.8% had cancer that was more aggressive than was indicated by the clinicopathologic analysis. The highest proportion of cancer cases that were less aggressive or considerably less aggressive, according to the multigene test result, than clinicopathology (39.8%) were in the low-risk category of the American Urological Association (AUA) risk

Value-Based Cancer Care

October 2014

classification. The highest proportion of cases that were more aggressive or considerably more aggressive (29.7%) than indicated by the clinicopathology analysis were in the AUA highrisk category.

“

Our studies have shown that for every 1-unit increase in Prolaris score, you double the risk of dying or failing treatment. Prolaris adds dramatically to the prognostic information.

”

—Michael K. Brawer, MD “Our studies have shown that for every 1-unit increase in Prolaris score, you double the risk of dying or failing treatment,” Dr Brawer told Value-Based Cancer Care. “Prolaris adds dramatically to the prognostic information.”

The investigators also analyzed surveys that had been completed by clinicians. In 198 (64.9%) of the 305 cases, the physicians reported changing the therapy based on the prognostic test results. This included 122 (40%) cases in which the clinicians decided to reduce the therapeutic burden and 76 (24.9%) cases in which they increased the burden. Furthermore, for 103 (32.7%) of 315 cases, the physicians thought that the prognostic score was moderately influential in their therapeutic recommendation. They reported that it was highly influential in 136 (43.2%) of 315 cases and very highly influential in 37 (11.8%) of 315 cases. These results suggest that the multigene prognostic test can improve the risk stratification of patients with prostate cancer and may help to guide treatment decisions based on a more accurate risk score compared with other risk assessment tools, such as the Gleason score, the prostate-specific antigen level, or the clinicopathologic features alone.—RF n

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In the Literature PIK3CA Mutations Associated with Favorable Prognostic Factors in Breast Cancer

Vol. 5

independent predictor of risk of the recurrence of early ER-positive breast cancer treated with adjuvant endocrine therapy, concluded the researchers.

Coexistence of BRAF and TERT Mutations Identified in Papillary Thyroid B:7.625 in Cancer

Among all thyroid T:7.375 in cancers, papil-

lary thyroid cancer (PTC) accounts for 80% to 85% of thyroid malignancies. Studies have shown that the BRAF V600E mutation is found in PTC and conventional PTC. Recently, researchers identified telomerase reverse transcriptase (TERT) promoter mutation chr5:1,295,288C>T (C228T) in thyroid cancers. In a new study, researchers Continued on page 32

In mCRPC therapy…

Is there more to the story?

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

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

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Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT–signaling network may contribute to endocrine resistance in patients with breast cancer. PIK3CA is the most frequently mutated gene in luminal breast cancer. Studies have shown that therapeutic agents targeting the PI3K/AKT pathway are effective for the treatment of luminal cancers, whereas coordinate PIK3CA/RAS mutations may be linked with relapse during endocrine therapy and may predict response to mTOR inhibitors. However, controversy remains over the clinical effect of PIK3CA mutations in the helical versus kinase domains. In a new study, researchers analyzed mutations in the PI3K/AKT and RAS/RAF pathways to determine if improved outcomes occur in patients with estrogen receptor (ER)-positive breast cancer and PIK3CA mutations who are receiving endocrine therapy (Sabine VS, et al. J Clin Oncol. 2014;32:2951-2958). The study included 4540 postmenopausal women with ER-positive breast cancer who were receiving endocrine therapy and participating in the TEAM (Tamoxifen Exemestane Adjuvant Multinational) trial. TEAM is a multinational, randomized, open-label, phase 3 clinical trial of 9776 postmenopausal women with hormone receptor–positive luminal early breast cancer comparing exemestane (Aromasin) 25 mg once daily or tamoxifen (Nolvadex) 20 mg once daily, followed by exemestane for a total of 5 years of adjuvant treatment. For this study, researchers used DNA extracted from formalin-fixed paraffin-embedded breast cancer samples of 4294 patients who had complete mutational data available. Mutational analyses were performed for 26 mutations across 6 genes. PIK3CA mutations were found in 39.8% of the samples; the majority (89.8%) of mutations were on the helical or kinase domains, of which 79.7% were in 3 known hotspots. RAS/RAF mutations, however, were rare (0.6%). The researchers did not see significant differences in patient outcomes associated with PIK3CA mutations (helical or kinase) or the endocrine therapy used. In univariable analyses, PIK3CA mutations were associated with a 24% reduction in the risk of distant metastasis at 5 years. Despite this risk reduction, a multivariable analysis correcting for known clinical and biological prognostic factors failed to demonstrate that PIK3CA mutation is an independent prognostic marker for distant relapse-free survival (hazard ratio, 0.92; 95% confidence interval, 0.75-1.12). The researchers found that the pres-

ence of PIK3CA mutations was associated with favorable prognostic factors, including progesterone receptor positivity, low tumor grade, and less lymph node involvement. Although approximately 40% PIK3CA mutations were exhibited within luminal breast cancer samples, PIK3CA mutations were not shown to act as an

In the Literature Coexistence of BRAF and TERT Mutations Identified in... Continued from page 31

investigated the prognostic value of the BRAF V600E and TERT C228T mutations, individually and cooperatively, in a large cohort of patients with PTC (Xing M, et al. J Clin Oncol. 2014;32:2718-2726).

The retrospective study examined the relationship of BRAF and TERT C228T in 507 patients aged 45.9 ± 14 years who were treated for PTC over a 12-year period (1990-2012) at Johns Hopkins Hospital. The median follow-up was 24 months (interquartile range, 8-78 months) after the initial treatments. Researchers found the coexistence

of the BRAF V600E and TERT C228T mutations in 6.9% of all subtypes of PTC and 7.3% of conventional PTC. Both mutations were more frequently associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence per 1000 perB:7.625rates in son-years were T:7.375 25.8%in versus 9.6%, re-

spectively, in BRAF mutation-positive patients compared with BRAF mutation-negative patients (hazard ratio [HR], 3.22; 95% confidence interval [CI], 2.05-5.07) and 47.5% and 11.4% in TERT C228T mutation-positive patients and TERT C228T mutation-negative patients (HR, 3.46; 95% CI, 2.195.45). The recurrence rate per 1000

For men with mCRPC who progressed on ADT

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

More than 1,000 days. And every day tells a story. MEDIAN OVERALL SURVIVAL FOR ZYTIGA plus prednisone† 35.3 vsMONTHS 30.1 MONTHS with placebo plus prednisone (active compound).‡ IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone. ®

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

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

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In the Literature person-years for patients with PTC harboring both mutations was also significantly higher compared with patients with neither mutation (68.6% vs 8.7%, respectively; HR, 8.51; 95% CI, 4.8414.97), suggesting a synergistic effect of the coexisting 2 mutations. These results were found in the overall analyses of both PTCs and of

the conventional PTC variant. Furthermore, an analysis of disease-free survival rates demonstrated a moderate decline with BRAF V600E or TERT C228T independently, but a sharp decline with 2 coexisting mutations. Similar results were found in the analyses of conventional PTCs. B:7.625 in The coexistence T:7.375of in BRAF V600E

and TERT C228T identifies a unique genetic background for the most aggressive subgroup of patients with PTC, whereas the 2 mutations individually have less impact on the aggressiveness of PTC. These genetic patterns have important prognostic and therapeutic implications in the management of PTC.

Novel Mutations Identified Can Help to Overcome Treatment Resistance in Lung Cancer

Crizotinib (Xalkori), a first-generation ALK tyrosine kinase inhibitor (TKI), is a standard therapy for patients with ALK-rearranged non– small-cell lung cancer (NSCLC). How-

Continued on page 34

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

Learn more today at

www.zytigahcp.com.

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No. 8

Date: 7/28/14

October 2014

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In the Literature Novel Mutations Identified Can Help to Overcome Treatment Resistance... Continued from page 33

ever, most patients will develop resistance to crizotinib within 1 to 2 years, and this has led to the development of next-generation ALK-TKI agents, including alectinib (not yet ap-

proved by the FDA) and the recently approved ceritinib (Zykadia). Because patients still relapse during therapy with these next-generation ALK-TKIs, which limits their clinical benefits, a new study examined the mechanisms of resistance to alectinib and looked for potential strategies to overcome this resistance. Alectinib was chosen

for this as one of the most advanced next-generation ALK inhibitors (Katayama R, et al. Clin Cancer Res. 2014 Sep 16. Epub ahead of print). To determine why ALK-positive lung cancers become resistant to alectinib, the researchers examined 2 different methods. They established a cell-line model of acquired resistance

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

October 2014

to alectinib in the laboratory and analyzed a primary tumor sample from a patient with alectinib-refractory disease. They engineered Ba/F3 models harboring alectinib-resistant ALK mutations and assessed the potency of other next-generation ALK-TKIs in these models. They then tested the antitumor activity of ceritinib in pa-

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 Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

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In the Literature tients with advanced ALK-positive NSCLC whose disease had relapsed while receiving alectinib. The researchers identified 2 novel secondary ALK mutations—a V1180L gatekeeper mutation from the cellline model and an I1171T mutation from the patient who developed resistance to alectinib, both of which were

still sensitive to ceritinib in vitro. The 2 mutations confer resistance to crizotinib as well as to alectinib, and thus add to the growing list of secondary ALK mutations that can mediate re sistance to crizotinib. Furthermore, treatment of the patients with ceritinib led to significant tumor regression, which lasted for 7

months. Thermodynamic simulation suggests that V1180L and I1171T mutations cause resistance by decreasing the binding affinity with alectinib. The ability of ceritinib to overcome ALK mutations in patients who develop resistance to alectinib suggests a potential role for multiple, sequential therapy with various ALK inhibitors,

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 discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 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

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depending on the underlying resistance mechanism. Overall, these findings underscore the importance of serial biopsies to follow the evolution of drug resistance and to identify the best therapeutic strategies that will most likely provide clinical benefit for patients based on the underlying molecular alterations. n

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End-of-Life Care

IOM’s Call to Action on End-of-Life Care in the United States By Laura Morgan

he initiative to improve end-oflife care in the United States is taking center stage, and it is about time. The US population is aging, and the number of older Americans with comorbidities is growing. In addition,

the US population is becoming more culturally diverse, so there is an increased need for more responsive, patient-centered care. Furthermore, the current healthcare system is disjointed, and contains elements that obstruct the

delivery of high-quality end-of-life care, according to a new report. In September 2014, the Institute of Medicine (IOM) released a consensus report, Dying in America: Improving Quality and Honoring Individual Prefer-

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

Value-Based Cancer Care

October 2014

ences Near the End of Life. The report, which comes nearly 17 years after the original end-of-life report, Approaching Death: Improving Care at the End of Life, discusses the current state of end-oflife care and makes recommendations for its improvement. The following are key findings and recommendations of the IOM committee (Table). Call to Action The IOM committee emphasized that individuals nearing the end of life often experience high rates of preventable hospitalizations, which can fragment the delivery of care and create burdens for patients and families. “We have a fragmented, disjointed approach that results in people not getting what they want,” said David M. Walker, Cochair of the panel and former US Comptroller General, at a September 14, 2014, press briefing on the IOM initiative, which was held in Washington, DC. In addition, although palliative care is associated with a higher quality of life, and may even prolong life in some patients, timely referral to palliative care is low. In an effort to improve the delivery of care near the end of life, the IOM committee recommends that public health insurers, care delivery programs, and private health insurers cover the provision of comprehensive care for patients with an advanced illness, including cancer. According to the IOM committee, comprehensive care should be patient-centered, family-oriented, and consistently accessible; encompass coordinated, efficient transfer of information across providers and settings; and align with individuals’ values and goals. Clinician–Patient Communication and Advance Care Planning Patients should have the right to decide how their health is handled, especially as they approach the end of life. However, most people at that stage are physically, cognitively, and/ or mentally impaired, and may not be able to adequately express their wishes. Consequently, these individuals often receive acute care by default, even if they prefer to receive palliative care. Clinician–patient communication and advance care planning are essential for protecting patients from receiving unwanted treatment. The IOM report emphasizes the importance of developing standards for clinician–patient communication. In

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End-of-Life Care

addition, payers and healthcare delivery systems should adopt these standards and should integrate them into assessments, care plans, and the reporting of healthcare quality. Furthermore, clinician–patient discussions about advance care planning should be revisited through the continuum of patients’ care, because preferences may change over time. “Right now, there is too much fear

and apprehension, and the discussions don’t happen,” said Philip A. Pizzo, MD, the other cochair of the panel and a former dean of Stanford University School of Medicine, at the press briefing. “What we call for is that there be an opportunity for discussions with clinicians throughout the life cycle and not just one time,” Dr Pizzo said. “It’s part of the process of living.”

Table Core Components of Quality End-of-Life Care Component Rationale Frequent assessment of the patient’s physical, emotional, social, and spiritual well-being

Interventions and assistance must be based on accurately identified needs

Management of emotional distress

All clinicians should be able to identify distress and direct its initial and basic management; this is part of the definition of palliative care, a basic component of hospice, and clearly of fundamental importance

Offer referral to expert-level palliative care

Patients with palliative needs beyond those that can be provided by nonspecialist-level clinicians deserve access to appropriate expert-level care

Offer referral to hospice if the patient has a prognosis of ≤6 months

People who meet the hospice eligibility criteria deserve access to services designed to meet their end-of-life needs

Management of care and direct contact with patient and family for complex situations by a specialist-level palliative care physician

Care of people with serious illnesses may require specialist-level palliative care physician management, and effective physician management requires direct examination, contact, and communication

Around-the-clock access to coordinated care and services

Patients in advanced stages of serious illness often require assistance, such as with activities of daily living, medication management, wound care, physical comfort, and psychosocial needs; around-the-clock access to a consistent point of contact that can coordinate care obviates the need to dial 911 and engage emergency medical services

Management of pain and other symptoms

All clinicians should be able to identify and direct the initial and basic management of pain and other symptoms; this is part of the definition of palliative care, a basic component of hospice, and clearly of fundamental importance

Counseling of patients/family Even patients who are not emotionally distressed face problems in areas such as loss of functioning, prognosis, coping with diverse symptoms, finances, and family dynamics, and family members experience these problems as well, both directly and indirectly Family caregiver support

A focus on the family is part of the definition of palliative care; family members and caregivers both participate in the patient’s care and require assistance themselves

Attention to the patient’s social and cultural context and social needs

Person-centered care requires awareness of patients’ perspectives on their social environment and of their needs for social support, including at the time of death; companionship at the bedside at the time of death may be an important part of the psychologic, social, and spiritual aspects of end-of-life care for some individuals

Attention to the patient’s spiritual and religious needs

The final phase of life often has a spiritual and religious component, and research shows that spiritual assistance is associated with quality of care

Regular personalized revision of the care plan and access to services based on the changing needs of the patient and family

Care must be person-centered and fit the current circumstances, which may mean that not all of the above components will be important or desirable in all cases

Source: Institute of Medicine. Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life. Washington, DC: National Academies Press; 2014.

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“”

We have a fragmented, disjointed approach that results in people not getting what they want. —David M. Walker

Professional Development With regard to professional education and development, the report identifies 3 areas that leave room for improvement, including (1) insufficient attention to palliative care in medical and nursing school curricula, (2) educational silos that impede the development of interprofessional teams, and (3) deficits in equipping physicians with sufficient communication skills. The importance of educating clinicians and other stakeholders about palliative care cannot be overstated. To stay abreast of trends in palliative care and to deliver optimal palliative care to patients, the IOM committee recommends that educational institutions, credentialing bodies, accrediting boards, state regulatory agencies, and healthcare delivery organizations establish training, certification, and/or licensure requirements for all clinicians who care for patients with advanced serious illnesses. Policies and Payment Systems An untimely referral to hospice care may increase healthcare costs. For example, the current Medicare fee-forservice payment model incentivizes physicians for the quantity of services they provide to patients. In turn, this often results in an increase in the use of acute services, more transitions among care settings, and late enrollment in hospice care, all of which may reduce the quality of end-of-life care and increase its costs; in its report, the IOM committee stresses that palliative care can lower healthcare costs by reducing the use of acute care services. October 2014

“

Right now, there is too much fear and apprehension, and the discussions don’t happen. What we call for is that there be an opportunity for discussions with clinicians throughout the life cycle and not just one time. It’s part of the process of living.

”

—Philip A. Pizzo, MD

To help reduce the avoidable use of acute services and to better honor individuals’ wishes, the IOM committee recommends that payment and healthcare delivery systems provide financial incentives for (1) medical and social support services that decrease the need for emergency department and acute care services, (2) the coordination of care across settings and providers, and (3) advance care planning. In addition, the IOM committee emphasizes the importance of electronic health records for communicating advance care plans across time, settings, and providers. Public Education and Engagement Most Americans are not cognizant of advance care planning, and health community leaders are not doing enough to spread the knowledge. To raise awareness and to educate the public about end-of-life care, the IOM committee recommends that public health and governmental agencies, community-based organizations, healthcare delivery organizations, and payers, among others, encourage the use of advance care planning by utilizing media, prepared educational material, evidence-based information about care options, and dialogue among individuals, their families, and their physicians. n

www.ValueBasedCancerCare.com

Lung Cancer

Comparing the Safety and Efficacy of Stereotactic Radiotherapy versus Surgery in Lung Cancer By Laura Morgan

San Francisco, CA—The use of stereotactic body radiotherapy (SBRT), also called stereotactic radiotherapy or radiosurgery, is an effective option for elderly patients with cancer who are inoperable or who decline surgery, but its safety and efficacy compared with surgery have not been investigated. James B. Yu, MD, MHS, Assistant Professor of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, and colleagues compared the survival and toxicity rates for patients with stage I non–smallcell lung cancer (NSCLC) who received SBRT with patients with NSCLC who underwent surgery.

verall Mortality: Surgery versus Table 1 O Stereotactic Radiosurgery Overall mortality Surgery, Radiosurgery, Month % %

They presented their results at the 2014 American Society for Radiation Oncology meeting. Using Medicare information from the Surveillance, Epidemiology, and End Results database, Yu and colleagues identified patients aged >67 years who had undergone SBRT or surgery for stage I NSCLC between 2007 and 2009. Poisson regression was used to compare the rates of overall mortality, lung cancer–specific mortality, and trends in toxicity. Overall, 367 patients received SBRT and were matched to 711 patients who underwent surgery. The overall mortality rate was higher during months 1, 3, and 6 for patients in the surgery group compared with the SBRT group. Conversely, at 12 and 24 months, the overall mortality rate was

Table 2 P osttreatment Toxicity: Surgery versus Stereotactic Radiosurgery Toxicity Month Surgery, Radiosurgery, after % % treatment

2.9

1.4

5.8

2.2

8.9

7.3

13.7

17.6

0-3

55.8

7.9

21.0

38.4

79.6

69.7

NOTE: The incidence rate ratio for stereotactic radiotherapy versus surgery was 0.7 (95% confidence interval, 0.6-0.82).

NOTE: The incidence rate ratio for stereotactic radiotherapy versus surgery was 1.72 (95% confidence interval, 1.37-2.15).

“

Patients who are healthy enough to get surgery should get surgery, and patients for whom complications would be difficult to overcome should get radiosurgery.

”

—James B. Yu, MD, MHS higher with SBRT compared with surgery (Table 1). Furthermore, after controlling for clinical and sociodemographic factors, overall mortality and lung cancer–specific mortality were higher with SBRT than with surgery. “The mortality data should be taken with a grain of salt. Patients who had surgery were healthier; they underwent surgical staging and were truly stage I, whereas it is likely that some of the patients who were clinically stage I and treated with radiosurgery actually had more dis-

seminated disease,” Dr Yu told Value- Based Cancer Care. “What we found was basically that patients who have undergone surgery are likely to live longer compared with patients who have undergone radiosurgery for a variety of reasons, including differences in staging.” Patients in the surgery group had significantly higher rates of toxicity (P <.001) compared with patients in the SBRT group at 0 to 3 months (Table 2). Dr Yu and colleagues suggest that this may be attributed to the increased rate of surgery-related short-term infections and respiratory complications. However, at 24 months after treatment, the difference in toxicity between the 2 groups was significantly smaller. Commenting on these results, Dr Yu said, “If you have a patient for whom you think having pneumonia, a respiratory complication, or a wound infection would be very dangerous, then those patients should get radiosurgery rather than surgery.” He added, “Our findings support clinical practice in that patients who are healthy enough to get surgery should get surgery, and patients for whom complications would be difficult to overcome should get radiosurgery.” n

Postresection Routine Surveillance with CT Instead of Chest X-Ray Does Not Improve Survival in Early-Stage Lung Cancer But CT cuts the time to diagnosis of successive malignancy By Rosemary Frei, MSc Toronto, Canada—Survival is not improved with routine surveillance using computed tomography (CT) versus chest x-ray in patients who have undergone resection for stage I non– small-cell lung cancer (NSCLC), according to the results of a new analysis presented at the 2014 American Association for Thoracic Surgery meeting. Lead investigator Traves D. Crabtree, MD, Associate Professor of Surgery, Division of Cardiothoracic Surgery, Washington University, St Louis, MO, and colleagues, reviewed the records of 554 patients who had undergone resection for stage I NSCLC between January 2000 and April 2013 at their institution. A total of 232 patients underwent routine postoperative CT surveillance, and 322 patients had routine chest x-ray surveillance. Of these, 149 patients

were excluded from the analysis, because they had not been followed up with only CT or chest x-ray. The median follow-up was 2.5 years (range, 0.3-9.9 years) for the CT group and 3.5 years (range, 0.1-13.1 years) for the chest x-ray group. The 5-year postoperative overall survival (OS) rates were 67.8% in the CT group and 74.8% in the chest x-ray group. Overall, 22% of patients who had chest x-rays were found to have lung malignancy versus 27% of patients in the CT group. The mean time from original lung resection to the diagnosis of the successive malignancy was 1.93 years for the patients receiving CT and 2.56 years for patients in the chest x-ray group. A Cox proportional hazard survival analysis showed that the type of imaging was not a significant predictor of survival. Rather, the significant predic-

Value-Based Cancer Care

October 2014

A significant difference between the 2 groups was found in the mean time from surgery to the diagnosis of a successive malignancy: 2 years for patients in the CT group versus 3.5 years for patients in the chest x-ray group. tors of survival included increasing age, higher Charlson Comorbidity Index, and sublobar versus lobar resection. A propensity score-matching analysis also revealed no differences in survival between the patients followed with CT versus chest x-ray.

The 5-year OS rates from surgery among patients who were diagnosed with a successive malignancy were 33.5% for the CT group and 40.2% for the chest x-ray group. Among 63 patients having a CT with a successive malignancy, 29 (46%) were treated with curative intent; for the 72 patients having chest x-ray, 31 (43%) were treated with curative intent. However, a significant difference between the 2 groups was found in the mean time from surgery to the diagnosis of a successive malignancy: 2 years for patients in the CT group versus 3.5 years for patients in the chest x-ray group. “A randomized, controlled trial would help determine the impact of postoperative surveillance strategies on survival,” concluded Dr Crabtree and his colleagues in their write-up of the results. n

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NCCN Congress Highlights

Experts Debate the Role of Maintenance Rituximab in Follicular Lymphoma By Alice Goodman

New York, NY—In a debate on the role of rituximab (Rituxan) maintenance therapy in patients with follicular lymphoma at the 2014 National Comprehensive Cancer Network Congress, the protagonist and antagonist were not that far apart. Taking the position of protagonist, Richard I. Fisher, MD, Cancer Center Director, Fox Chase Cancer Center, Philadelphia, PA, stated that maintenance therapy is indicated in all patients who are sensitive to rituximab. Taking the side of antagonist in the debate, Andrew D. Zelenetz, MD, PhD, Vice Chair, Medical Informatics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, said that he considers maintenance an option, but that it is not mandatory. Two separate studies by the Swiss Group for Clinical Cancer Research showed that maintenance therapy with rituximab improved progression-free survival (PFS) compared with observation alone, and compared with short-term maintenance therapy, respectively, in patients who responded to initial rituximab. Neither trial showed an improvement in overall survival (OS) with maintenance therapy.

Pro

“These and other studies show that the use of maintenance therapy after chemotherapy prolongs the time patients are in remission,” Dr Fisher stated. More recently, the PRIMA study looked at 1010 patients with follicular lymphoma and a high tumor burden who responded to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy and were then randomized to maintenance therapy or to observation. Rituximab maintenance was superior to observation at the planned interim analysis—the 2-year PFS rates were 82% versus 66%, respectively (P <.001). Maintenance therapy achieved superior PFS compared with observation in all subgroups. Maintenance therapy delayed time to the next antilymphoma treatment and to the next chemotherapy treatment. Maintenance therapy has some risks, Dr Fisher noted, and probably should not be given longer than 2 years. “The real question is not whether to give rituximab again, but whether to give it as maintenance or retreatment when patients relapse,” he stated. Studies to date suggest that either Vol. 5

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“

Studies show that the use of maintenance therapy after chemotherapy prolongs the time patients are in remission.

”

—Richard I. Fisher, MD

strategy will delay the time to chemotherapy, Dr Fisher added. Remaining questions include the optimal duration of maintenance therapy, characterizing long-term complications, and whether newer agents will be an improvement over rituximab for maintenance therapy. Other issues include the cost per life saved, and rituximab meets the current paradigm of <$100,000, Dr Fisher said. “This is cheaper than some targeted therapies,” he added. “There are many questions, but you need to individualize the decision. A lymphoma expert should discuss maintenance therapy with a very well educated patient,” Dr Fisher concluded.

“

One of the big questions in follicular lymphoma is whether PFS should be the goal of treatment. Although OS is the preferred end point, it is a difficult end point in follicular lymphoma trials.

”

—Andrew D. Zelenetz, MD, PhD

Con

“My position is that maintenance therapy is not the standard of care. That doesn’t mean that it shouldn’t be used,” Dr Zelenetz told listeners. “My longest consultation is with a new patient with follicular lymphoma at diagnosis when we discuss treatment. My second longest consultation is whether the patient should get maintenance therapy or whether observation is a good option.” Factors to consider include age, symptoms, short-term and long-term goals, and tumor characteristics.

“One of the big questions in follicular lymphoma is whether PFS should be the goal of treatment. Although OS is the preferred end point, it is a difficult end point in follicular lymphoma trials,” he noted. “The conundrum is that OS improvements are unlikely in the absence of PFS, but PFS does not necessarily predict for OS in follicular lymphoma,” Dr Zelenetz explained. “We would like to see a good relationship between OS and PFS. We see this in aggressive lymphoma, but not in follicular lymphoma. You can change PFS in a major way and not impact on OS,” he added. Given the fact that maintenance therapy does not improve OS in any study to date, and that maintenance and retreatment at relapse have similar outcomes, Dr Zelenetz’s preferred strategy is the latter. “The fact that maintenance rituximab gives you a durable benefit but no OS benefit makes the decision a discussion but not a requirement,” he stated. “Living with the disease is like being in remission. These patients don’t have symptoms, but then they need retreatment. Clinical experience suggests that quality of life in remission is similar to that of low tumor burden. The major concern is risk of transformation,” Dr Zelenetz continued. Patients may fall into 1 of 2 categories. The first is, “I can’t live with knowing I have active lymphoma.” They are the patients who get maintenance therapy (approximately 30% of Dr Zelenetz’s practice). The second group says, “I feel fine and don’t want treatment” (approximately 70% of his practice). n

Updated Management of Chronic Lymphocytic Leukemia New York, NY—The FDA approvals of obinutuzumab (Gazyva), ofatumumab (Arzerra), ibrutinib (Imbruvica), and idelalisib (Zydelig) have changed the treatment paradigm of patients with chronic lymphocytic leukemia (CLL). William G. Wierda, MD, PhD, Medical Director, Department of Leukemia, M.D. Anderson Cancer Center, Houston, discussed where these new drugs fit into the treatment algorithm at the 2014 National Comprehensive

Cancer Network Congress. The first-line treatment of asymptomatic early-stage CLL remains watch and wait. For symptomatic patients with CLL, important considerations in selecting first-line treatment include age, comorbidities, and cytogenetics. The standard of care for younger patients with good performance status includes fludarabine, cyclophosphamide, and rituximab; bendamustine and rituximab; and fludarabine plus rituximab. October 2014

For elderly frail patients, the current standard of care for front-line therapy includes chlorambucil plus obinutuzumab or chlorambucil plus ofatumumab; ibrutinib is a good choice for patients with 17p deletions. “Patients with deletions in 17p were previously untreatable. I’m happy to have this option,” Dr Wierda said. Elderly Patients In a recent study (Goede V, et al. N Engl J Med. 2014;370:1101-1110), obinuContinued on page 40

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NCCN Congress Highlights

Updated Management of Chronic Lymphocytic... Continued from page 39 tuzumab plus chlorambucil achieved significantly improved progression-free survival (PFS) compared with rituximab plus chlorambucil (26.7 months vs 16.3 months, respectively; P <.001), establishing this combination as a standard of care in elderly patients. Currently, there is no significant overall survival benefit.

patients with lymphocytosis convert to complete response, Dr Wierda said. Ibrutinib is very safe, he emphasized, with a low frequency of grade ≥3 adverse events. The 30-month PFS rates are 96.3% in treatment-naïve patients and 68.4% in patients with relapsed/refractory disease.

“PFS of 90% at 3 years is unheard of,” Dr Wierda noted. The PFS rates with ibrutinib at 30 months in patients with relapsed/refractory disease stratified by cytogenetics were 45.9% in patients with 17p deletions, 74.2% in those with 11q deletions, and 89% in patients with

neither abnormality. “There is no question that ibrutinib is the treatment of choice for relapsed patients with no 17p or 11q deletions,” Dr Wierda said. “Even with this new agent, the risk is high in those with 17p deletions. Consider these high-risk patients for transplant,” he said.—AG n

“

There is no question that ibrutinib is the treatment of choice for relapsed patients with no 17p or 11q deletions. Even with this new agent, the risk is high in those with 17p deletions. Consider these high-risk patients for transplant.

”

—William G. Wierda, MD, PhD “Beware of infusion-related reactions and some myelosuppression” with obinutuzumab, Dr Wierda said. A separate study, COMPLEMENT-1, which was presented at the 2013 American Society of Hematology meeting by Hillmen and colleagues, showed that ofatumumab plus chlorambucil was significantly superior to chlorambucil for PFS as up-front therapy in older patients with comorbidities, establishing this combination as a standard as well. Ibrutinib Much has been written about ibrutinib, an oral Bruton’s tyrosine kinase inhibitor, and studies in CLL have shown improved outcomes with this agent. After treatment with ibrutinib is initiated, there is a transient elevation in lymphocyte count (lymphocytosis), but with continued treatment, a dramatic reduction in lymph node size is observed. The majority of patients treated with ibrutinib respond, including treatment-naïve patients and patients with relapsed/refractory disease. Over time, 25712_sundav_fa1_dino_vbcc.indd All Pages

Value-Based Cancer Care

October 2014

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FDA Update FDA Approves New Combination Therapy, Akynzeo, for the Prevention of Nausea and Vomiting Associated with Chemotherapy

The FDA approved a new fixeddose combination of netupitant and palonosetron (Akynzeo; Eisai/Helsinn Healthcare) for the treatment of

patients with cancer who experience chemotherapy-induced nausea and vomiting (CINV). This new oral capsule combines the oral 5-HT3 receptor antagonist palonosetron, which is already approved by the FDA for the prevention of CINV, and the new drug netupitant, a selective antagonist of human substance P/ neurokinin 1/(NK1). Activation of the

NK1 family has been associated with delayed emesis. The FDA approved the new combination for the prevention of CINV at the acute phase (ie, during the first 24 hours) after the start of chemotherapy administration. The combination of netupitant plus palonosetron has been shown to prevent nausea and vomiting during the acute and the delayed

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.

phases after the start of chemotherapy. “Supportive care products, such as Akynzeo, help ease the nausea and vomiting patients may experience as a side effect of cancer chemotherapy,” said Julie Beitz, MD, Director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research. The FDA established the efficacy of the new combination based on 2 clinical trials that included a total of 1720 patients with cancer who were receiving chemotherapy. The patients were randomized to the combination of netupitant plus palonosetron or to palonosetron alone. The efficacy end points in the first trial were complete response (CR)—defined as no emetic episodes (ie, no vomiting or nausea events) and no rescue medication use—rates during the acute (0-24 hours) phase and the delayed (25-120) phase, as well as the CR rates within the overall phase (120 hours) after the start of the chemotherapy administration. The results of the first trial showed CR rates of 98.5%, 90.4%, and 89.6% during the acute, delayed, and overall phases, respectively, after the start of chemotherapy. By comparison, the CR rates in patients receiving oral palonosetron alone were significantly lower, at 89.7%, 80.1%, and 76.5%, respectively. The primary efficacy end point of the second trial was the CR rates in the delayed phase. The CR rates were significantly higher, 76.9%, with the combination therapy agent compared with 69.5% with palonosetron alone (P = .001). Common side effects with the combination drug reported in the clinical trials included asthenia, dyspepsia, constipation, erythema, fatigue, and headache. (October 10, 2014)

FDA Grants Priority Review for Palbociclib, a Novel Breast Cancer Drug

The FDA has granted a priority review status to the CDK 4/6 inhibitor palbociclib (Pfizer) for the treatment of women with advanced or metastatic estrogen receptor–positive, HER2-positive breast cancer. Palbociclib is already designated as a breakthrough therapy by the FDA. The PDUFA date for palbociclib is April 13, 2015, but the new priority review status may push that date forward by as much as 4 months. “If approved as a first-line therapy in combination with letrozole, palbociclib will be an important new option for the thousands of women in the United States who are living with metastatic breast cancer,” noted Garry Nicholson, President, Pfizer Oncology. “We look forward to continuing to work closely with the FDA through the review process.” (October 13, 2014) n

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.

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No. 8

October 2014

www.ValueBasedCancerCare.com

4th Conference

Patient-Centered Oncology Medical Home Improves... States to probably less than 60%. “It is happening because payers are now beginning to allow us to make a business case for quality, and changing the way that we deliver care and allowing us to provide a new value proposition,” said Dr Sprandio. Oncology Management Services was recognized (in 2010) as an oncol ogy patient-centered medical home (PCMH) through the Physician Practice Connections program. The model enables the medical oncology practice to serve as the focus of coordination and accountability. The oncology PCMH is integrating surgical, radiation oncology, inpatient, social, and hospice services. The value proposition of PCMH is better cancer care and better health, at a lower cost. “There’s payer recognition,” Dr Sprandio said. Payer interest in this model is still climbing. Many quality and value drivers characterize the oncology PCMH

The oncology medical home provides prompt palliation of symptoms. Keeping people healthier, treating them in a more timely fashion when they have symptoms to reduce potentially avoidable resource utilization, consistent survivorship care, and rational care at the end of life.

“

”

—John D. Sprandio, MD (Figure 1). The primary drivers are the services provided by the oncology physician-led team. Secondary drivers in-

Figure 1 Oncology PCMH Quality and Value Driver Diagram Triple Aim

Primary Driver

Secondary Drivers

Multidisciplinary guideline concordance

Engagement and orientation

National Committee for Quality Assurance

Patient and family experience of care

Patient responsibilities Practice responsibilities Goals, insurance issues

PCSP recognition PCORI-funded NCQA pilot PCOC standards

Palliation

Patient navigation

American College of Physicians PCMH-Neighbor

Patient-, payer-, and provider-centered Outcomes

Symptom management Focus on performance status

Avoidable resource utilization

Emergency department/ hospitalizations Imaging and lab

Survivorship care Standardized Primary PCMH

End-of-life care

Physician-led care team delivery standards Services

Multidisciplinary input Scheduling and tracking

Staging/guideline adherence Standardized processes/data Care coordination Communication

Symptom management

On-demand access/visits Performance data collection Track success of palliation

Survivorship care

Total cost of care

Goals of therapy

Medical, surgical, lab, radiation, imaging

National Coalition for Cancer Survivorship

Execution of care

Hospice enrollment Place at time of death Resource utilization

Process-of-care standards, care integration Evidence base

American College of Surgeons Commission on Cancer Data collection Treatment and patientcentered standards

National Comprehensive Cancer Network

Standardized care plans Coordination agreements

Documented performance status Driven discussions Shared decision-making

Figure 2 Outcomes of Clinical Nurse Triage Phone Calls in 2013 5106 clinical phone calls; 7.43% of patients were seen in the office within 24 hours of call

Manage symptom(s) at home 84.21%

American Society of Clinical Oncology QOPI standards Survivorship guidelines

Institute of Medicine

National Quality Forum National Cancer Policy Forum

NCQA indicates National Committee for Quality Assurance; PCMH, patient-centered medical home; PCOC, patient-centered oncology care; PCORI, Patient-Centered Outcomes Research Institute; PCSP, patient-centered specialty practice; QOPI, Quality Oncology Practice Initiative. Copyright © 2014 Oncology Management Services, Ltd. Used with permission.

Value-Based Cancer Care

group’s oncology nurse triage phone line demonstrate financial and patient care benefits. “One of the keys in making this work was to engage patients and their families to become excellent, very vocal, very frequent reporters of symptoms,” Dr Sprandio said. In 2013, our oncology PCMH, Dr Sprandio said, had approximately 5106 symptom-related phone calls, 84.21% of which were managed at home by the nurse (or the nurse in conjunction with the doctor) who was trained by following Oncology Management Services’ algorithms (Figure 2). Approximately 7.5% of patients were seen within 24 hours. In the first quarter of 2014, 78% of all symptom-related patient calls occurred from 8:00 am to 6:00 pm during the week; the other 22% came on the weekend and in the evening. The busiest day for unscheduled visits was Friday. “Patients are told that if they’re going into Thursday night, and they might need a “tuneup” to get through the weekend, they come in Friday,” Dr Sprandio said. “We have patients who we see on Monday and Tuesday who are fragile. We give them a tentative appointment for Friday to potentially get them through the weekend.” Emergency department utilization for patients receiving chemotherapy was reduced significantly, from an average of 2.6 annually in 2004 to 0.765 in 2012. “We think that is because our processes are so standardized with each visit that they’re more complete,” Dr Sprandio said. “There are things that are…less often overlooked.” Dr Sprandio noted that physician

Treatment guidelines Survivorship guidelines

Data-driven improvement

clude process-of-care standards, such as the patient-centered oncology care standards and the American College of Physicians’ PCMH Neighbor concept. “The desired outcomes are truly payer- and patient-centric outcomes,” said Dr Sprandio. “It’s one of the unique times when payers’ and patients’ desires and goals are really overlapped….It’s not completely overlapping sometimes, but it’s pretty close. The right drugs, the right care, the right surgery, and so on. Prompt palliation of symptoms. Keeping people healthier, treating them in a more timely fashion when they have symptoms to reduce potentially avoidable resource utilization, consistent survivorship care, and rational care at the end of life.” As an example, metrics regarding the

Continued from the cover

October 2014

Patient sent for radiographic study Go to nearest 0.41% Referred to emergency department primary/specialist Office visit Office visit Chemotherapy 2.39% tomorrow 5.35% today suite intervention 3.47% 0.22% 3.96% Copyright © 2014 Oncology Management Services, Ltd. Used with permission.

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Does Comparative Effectiveness Research Have Value in Oncology? By Wayne Kuznar

Los Angeles, CA—Can comparative effectiveness research (CER) be used for determining value in cancer care? At the Fourth Annual Conference of the Association for Value-Based Cancer Care, C. Daniel Mullins, PhD, Chairman, Department of Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, discussed this topic (see also article in the September issue of this journal) on the challenges of applying CER into value-based oncology therapy. CER and Value in Oncology “We’re all trying to figure out what is this thing called value. We’re trying to figure out which drugs to pay for,

at a glance ➤ How do we define value, and how does CER add value in oncology? ➤ Stopping therapy when it’s no longer effective is especially important for oncologists ➤ Effective use of CER in oncology can shape clinical guidelines, determine sequencing of drug treatments, and help define meaningful improvement in outcomes

“

We’re all trying to figure out what is this thing called value. We’re trying to figure out which drugs to pay for, and how long to pay for them.

”

—C. Daniel Mullins, PHD

and how long to pay for them. What does this mean in terms of CER?” Dr Mullins asked. He noted that healthcare payers are becoming more comfortable with CER methods and are gaining a better understanding of how CER can be used to make informed healthcare decisions. “Most of the payers who talk to me off the record admit they don’t have a problem paying for value-based medicine,” Dr Mullins stated. “In the future, I think this greater comfort with CER is going to have an impact on the way decisions are made,” Dr Mullins stated. Real-World Evidence There is an increasing demand for real-world evidence in research, Dr Mullins said, while admitting that the

aspects of “real world” also need to be defined. Better guidelines on how to obtain a broader patient population in trials are necessary. “We will get to the way medicine is practiced in the real world, but we will preserve the integrity of the clinical trial,” he predicted. “I think that’s near term.” Dr Mullins believes that there will be increasing demands for more appropriate comparators for studies using CER. Healthcare decision makers want to have a say in what the comparators will be. And testing of comparators needs to be done more fairly. Instead of testing comparators as they are labeled for use by the FDA, Dr Mullins said that decision makers want them tested as they are actually

used in the medical community. The use of add-on drugs versus replacement drugs is a newer trend in oncology. Concerns about the value of additional medications can be addressed with CER. One of the more difficult issues facing oncologists is stopping a treatment when it is being used beyond its benefit. “This is an issue we have to deal with, where we recognize that the patient is a decision maker, that there is a joint decision-making process, and how we can get to value by stopping treatment when it no longer has value,” Dr Mullins reasoned.

“

Most of the payers who talk to me off the record admit they don’t have a problem paying for value-based medicine.

”

—C. Daniel Mullins, PHD

He asserted, “If we can handle these issues in the near run, I think CER has a place in really giving us value-based medicine.” Dr Mullins foresees that the effective use of CER in oncology can shape clinical guidelines, determine sequencing of drug treatments, and help define meaningful improvement in outcomes. n

Patient-Centered Oncology Medical Home Improves... Continued from page 42 and practice efficiency have also improved through conversion to an oncology PCMH model. The practice

“

One of the keys in making this work was to engage patients and their families to become excellent, very vocal, very frequent reporters of symptoms.

”

—John D. Sprandio, MD

went from 8.3 full-time employees per physician in 2007 to 5.6 in 2013. Oncology Management Services Vol. 5

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now has 3 alternate payment methodology payer contracts that cover 54% of the practice patient base. “We have an enhancement of fee for service in some of the contracts, a per-member per-month payment for the sickest subpopulation. We have a shared-savings equation in all 3 of the contracts. Then we have some precertification relief, which is helpful too,” he said. Revenue enhancement has also been realized from improved documentation and coding, improved physician efficiency, and new referral patterns. The transition from fee for service to the PCMH occurs in 3 phases. Phase 1 involves reengineering the delivery of care, during which policies and processes of care delivery are standardized and the telephone triage algorithms are implemented. This phase

took up to 6 months. Data submission for recognition constitutes phase 2, with a timeline for completion of 4 to 8 months. Phase 3 consists of quality improvement, including continuous

October 2014

improvement (compared with regional peers) in guideline adherence, utilization of diagnostic and laboratory services, end-of-life care, and hospice, among others. n

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Oncology Medical Home Pilot Improves Outcomes By Wayne Kuznar

“

Los Angeles, CA—Wilshire Oncology Medical Group President Linda D. Bosserman, MD, discussed the group practice’s oncology medical home pilot of value-based innovation at the Fourth Annual Conference of the Association for Value-Based Cancer Care. The Wilshire Oncology Medical Group, Inc, is a collaborative independent oncology practice in California that currently consists of 5 private clinics. The group serves a large patient population, including the indigent, who comprise 25% of the population in the counties covered. The group has 8 medical oncologists, 2 radiation oncologists, and 10 midlevel providers. “We have pioneered…the partnership with the midlevel provider with the clinicians, so patients know they have a team wrapped around them to meet their needs at every possible

We have pioneered… the partnership with the midlevel provider with the clinicians, so patients know they have a team wrapped around them to meet their needs at every possible time point.

”

—Linda D. Bosserman, MD time point,” said Dr Bosserman. Each full-time physician works at approximately 1.7 times the national average. The turning point for Wilshire Oncology came in 2005 when the capitated independent practice association (IPA) that served them terminated its contract. It forced Wilshire Oncology

ilshire Oncology Medical Home Pilot: Emergency Department Visits, Figure 1 W 2010-2012 Emergency department visits PPPY for patients receiving chemotherapy

n=15

0.9

n=33

n=39

0.8

n=14

0.7 0.6

n=14

n=40

1.0

n=39a

0.5

n=35

0.4

n=25

0.3 0.2 0.1 0.0

Prepilot Breast cancer California benchmark

Year 1 Other solid tumors California benchmark

Year 2 Hematologic malignancies California benchmark

Number of patients treated with chemotherapy. PPPY indicates per patient per year.

ilshire Oncology Medical Home Pilot: Hospital Admissions by Tumor Figure 2 W Type, 2010-2012 Admission PPPY for patients receiving chemotherapy

1.0

n=39a n=33

n=35

0.5

n=39

0.0

n=15

n=14

Prepilot Breast cancer California benchmark

n=40

Year 1 Other solid tumors California benchmark

n=25 n=14

Year 2 Hematologic malignancies California benchmark

Number of patients treated with chemotherapy. PPPY indicates per patient per year.

Value-Based Cancer Care

October 2014

to figure out how to take care of patients for the budget offered by another large IPA, leading to the oncology medical home pilot. Implementing Patient-Centered Care Along with implementing electronic health records, Wilshire Oncology sought to improve efficiency and quality by examining National Comprehensive Cancer Network (NCCN) guidelines, leading to the development of patient-centered, value-based cancer care. The goal was to provide evidence-based, validated, outcomes-driven quality patient care. This type of quality care also has to meet national quality standards that follow cost-effective pathways to provide access and affordability to patients. The delivery system has been optimized to follow efficient pathways. “We developed structured things for patients and then payers….Every chemotherapy visit has a structured education, so we can actually ask about fertility,” Dr Bosserman said. “In case the doctor forgot, the nurse asks every patient about fertility. It’s in the intake form, but it’s also in the chemotherapy education and the chemotherapy consent form.” Practice changes targeted prevention. “We’ve always done 3-generational family histories,” she said. “We do integrated genetic evaluation and risk management at the time of making a consultation. I don’t see how you see a breast cancer patient that’s 30 with 3 family members with breast cancer and 2 with ovarian, and not talk about her risk as part of the comprehensive treatment planning.” Care management and coordination is focused on interval care management when a patient is receiving therapy, and also on tertiary, emergency department, hospitalist, and subspecialty cancer care. “We have case care management and coordination, so when you’re on a treatment plan, we educate you about it,” Dr Bosserman said.

Improved Outcomes After the introduction of the medical home pilot, the percentage of patients with metastatic solid tumors who received colony-stimulating factors was reduced markedly, consistent with recommendation from the American Society of Clinical Oncology. Pathway adherence topped 90% among patients receiving chemotherapy- biotherapy or hormone therapy only; if there was an NCCN pathway, 99% of patients were managed according to the pathway, and if there was a level 1 pathway, 92% were managed according to it. Wilshire Oncology directs cancer care from the outset, with an emphasis on patient engagement, including asking patients about medications, new diagnoses, pain, and symptoms via a 39-point questionnaire. Patients are encouraged to rate their symptoms using National Cancer Institute common toxicity criteria. Symptom care is proactive and reactive, and the site of care is optimized to minimize emergency department visits and hospitalizations. By year 2 of the medical home pilot, emergency department visits for patients with breast cancer and other solid tumors who were receiving chemotherapy were reduced to approximately 25% of the rate before the pilot (Figure 1). Hospital admission by tumor type was reduced by more than 50% in years 1 and 2 of the pilot compared with prepilot (Figure 2). Supportive care and end-of-life care are also part of the oncology medical home. Some 94% of the patients have had a discussion of advanced directives, Dr Bosserman said. Palliative and hospice care are integrated into the medical home to minimize intensive care unit and hospital end-of-life care. Payer Engagement Payer engagement is essential for value and is possible by aligning incentives to staff for patient-centered care. Payers must be made aware that care planning, management, and coordination, along with cost-effective drug regimens, a tailored information technology infrastructure, and data analytics, are crucial. Wilshire Oncology was successful in getting Anthem Blue Cross and Blue Shield to turn its focus from medication costs to care planning and management. “They are going to nationally start paying for care planning and care management with their ‘S’ codes using guidelines,” said Dr Bosserman. n

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No. 8

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

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Value-Based Care IN Myeloma

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Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

4th Conference

Managing Cancer at the Workplace Enhances Productivity, Has Value for Employers Investing in cancer management is good business By Wayne Kuznar Los Angeles, CA—It is a good business decision to invest in better cancer management for employees with cancer, according to Lillie D. Shockney, RN, MAS, University Distinguished Service Associate Professor of Breast Cancer, Johns Hopkins Breast Center. This type of effort can maximize the productivity of employees with cancer or cancer survivors and reduce the work-related impact on coworkers, said Ms Shockney at the Fourth Annual Conference of the Association for Value-Based Cancer Care. Of the 13.7 million cancer survivors in the United States, 40% are of working age, and the vast majority of them wish to work during their treatment. To achieve this goal, a discussion with the oncology team about the timing of the treatment plan is imperative, said Ms Shockney. Accommodating Employees with Cancer Ms Shockney requests that the oncology team consider Friday as a day to administer chemotherapy for patients who continue to work, given that most patients will experience side effects in the ensuing 24 hours. “I also want to make sure that if she’s going to be receiving radiation, she may want the 7:00 am appointment, or the 5:30 pm appointment, rather than the 2:00 pm appointment,” Ms Shockney said. Getting patients into cancer rehabilitation before acute treatment to avoid deconditioning is also helpful, as is preparing patients for treatment-related side effects up front. In researching work-related issues in cancer survivors, Ms Shockney discovered that 63.5% of cancer survivors continue to work while receiving treatment

“

Our employees can get their screening mammogram on work hours. If they have a lump or bump or something that’s of concern, they can come over today. It doesn’t matter what the hour; we will work them in today to have a diagnostic evaluation done.

”

—Lillie D. Shockney, RN, MAS or return to work during and after their treatment. More than 70% of persons aged ≥65 years in the United States do not plan to retire, meaning that more people in the future will be diagnosed with cancer while they are working. “We need to get our arms around that with some degree of speed,” she said. Several factors lead to a greater likelihood that an employee with cancer will continue to work and maintain productivity. These factors include: • Flexible working arrangements • Counseling and supportive services for the employee and coworkers • Training and rehabilitation services • A longer duration of sick leave • Ensuring continuity of care. Employees who could work during cancer treatment often do not, because of a lack of workplace support. Caregivers and coworkers of patients with cancer also feel the impact: caregivers and survivors use significant sick time, vacation time, and shortand long-term disability. Work absence is costly, said Ms

Figure Managing Cancer at Work Key Features

Designed for workplace: tools and information specific to managers and employees

Help mitigate escalating costs and enhance productivity by identifying viable work options for employees with cancer

Personalized nurse navigation and follow-up at each stage of the cancer journey

Link with other workplace/ vendor resources to personalize employee experience, enhance outcomes

Integrated application of bestof-class educational content and visual tools: video and interactive graphics to improve engagement, understanding

Collect data and report on platform utilization, navigator utilization, user satisfaction

Value-Based Cancer Care

October 2014

Shockney. The cost of lost productivity among US employees with cancer is equal to 30% of the nation’s healthcare spending. Return to work success depends on a supportive work environment, which includes time off for appointments, discretion regarding hours and workload, and preparation for workplace reentry. Older people and those who do manual labor are less likely to return to work, regardless of the work environment.

The program directs employees to get the right treatment at the right time and place at each stage of cancer, optimizing care and avoiding waste. —Lillie D. Shockney, RN, MAS

Managing Cancer at Work Program Two years ago, Ms Shockney assumed the role of Director of the Johns Hopkins Cancer Survivorship Programs, at which time she set the goal of first developing a program to manage cancer in employees. The program became known as Managing Cancer at Work. Managing Cancer at Work is a unique approach to managing cancer care–related benefits (Figure). Specifically designed for the workplace, it combines personalized nurse navigation with a web-based educational portal. These portals are customized for employees, managers, caregivers, and oncology nurse navigators.

at a glance ➤ Of the 13.7 million cancer survivors in the United States, 40% are of working age and many wish to work during their cancer treatment ➤ 63.5% of cancer survivors continue to work while receiving treatment, or return to work after treatment ➤ The cost of lost productivity among employees with cancer is equal to 30% of the total US healthcare spending ➤ Investing in better cancer management is good business “Our employees can get their screening mammogram on work hours,” Ms Shockney said. “If they have a lump or bump or something that’s of concern, they can come over today. It doesn’t matter what the hour; we will work them in today to have a diagnostic evaluation done.” The program directs employees to get the right treatment at the right time and place at each stage of cancer, optimizing care and avoiding waste, said Ms Shockney. Navigators help direct patients to the most appropriate care. Nurse Navigators Education about advance directives, wills, and social services is also offered as part of Managing Cancer at Work, as well as specialized support for employees with advanced cancer and general screening and prevention education for all employees. Adding new life goals and preserving older goals can be accomplished through the one-on-one nurse navigation. “That does mean doing things in a proactive way, so whether that be fertility preservation or some other referral that they would benefit from,” Ms Shockney said. “The navigator can customize specific information that would be of particular importance for an employee, and she also has navigation tracking software that we’ve built into it for the purpose of keeping track of what intervention she has done…and then the specific process and outcomes measures. That employee can also offer 5 people in their family or friends who are supporting them the ability to also access this information.” n

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4th Conference

Cancer Support Community: Empowering Patients through Knowledge and Psychosocial Care By Wayne Kuznar

Los Angeles, CA—The advocacy community’s goal of patient-centered cancer care has evolved substantially over the past decade, said Kim Thiboldeaux, President and Chief Executive Officer of the Cancer Support Community (CSC), Washington, DC. At the Fourth Annual Conference of the Association for Value-Based Cancer Care, Ms Thiboldeaux outlined a variety of important services and capabilities of the CSC, a global nonprofit advocacy group dedicated to providing support, education, and hope to people affected by cancer. Psychosocial Care In 2009, the headquarters office of The Wellness Community and Gilda’s Club joined forces to become the CSC, one of the largest providers of social and emotional support worldwide. The union was prompted by the Institute of Medicine report, “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs.” “I think that we have made, over the past decade or so, very significant progress in this idea of patient-centered care.” As examples, she cited psychosocial care and distress screening now included in national cancer quality initiatives, and the establishment of cancer support communities inside hospitals at the behest of the hospitals, Ms Thiboldeaux said. “Cancer Support Community is leading a movement to ensure that psychosocial care is integrated into the medical standard of care for people with cancer, that it is embraced, that it is mandated, and that it is reimbursed,” Ms Thiboldeaux said. One tool the research institute at the CSC developed is a distress screening tool called “CancerSupportSource,” which is an electronic web-based tool with 2 validated versions, available in English and Spanish.

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“

Cancer Support Community is leading a movement to ensure that psychosocial care is integrated into the medical standard of care for people with cancer, that it is embraced, that it is mandated, and that it is reimbursed.

”

“It is not just a screening tool,” said Ms Thiboldeaux, but rather a comprehensive screening program “where we get at the heart of some of the psychosocial issues that patients are concerned about, and ask them how they would like to help, and how we can help to create a care plan for them.” The CSC is working with the Community Oncology Alliance and other centers to ensure the integration of distress screening and psychosocial care into oncology medical homes. “We have several hundred trained licensed mental health professionals who work with our centers around the country, work on the helpline, and run the online community and online support groups,” Ms Thiboldeaux said. “Last year, we opened a full Cancer Support Community inside of Greenville Hospital in Greenville, South Carolina,” she said, in addition to centers inside the University of Florida and the Orlando Cancer Center. Hospitals are attracted not only to the distress screening program, but also to the entire evidence-based turnkey model of support. “We have worked very closely with the American College of Surgeons on the development and implementation of their patient-centered standards; now there are 1400 plus hospitals

—Kim Thiboldeaux

around the US who are accredited by the commission who must start doing distress screening, doing navigation, doing survivor care planning,” said Ms Thiboldeaux. Each year, more than $45 million in free support services are provided to patients and families through this service. The helpline offers “on-the-spot” counseling. Online support groups, chat boards, and bulletin boards are part of a vibrant online community.

“

At the Cancer Support Community, our mission is to ensure that all people impacted by cancer are empowered by knowledge, strengthened by action, and sustained by community.

”

—Kim Thiboldeaux Its second line of service is behavioral and psychosocial research. As a third line of service, “we’re also fighting on the policy side to do more to make sure that psychosocial services are reimbursed for the hospitals and practices,” Ms Thiboldeaux said. In 2013, the Community launched the Cancer Policy Institute. “We hired a very skilled policy and advocacy team in Washington, and we’re really uniting our patient voice along with the data from our research institute to create system change in Washington,” she said. In addition to studying the quality-of-life benefit of distress screening, the program’s ability to save money is also being evaluated. The CSC works with small practices that refer patients to its helpline to October 2014

at a glance ➤ CSC is leading a movement to ensure that psychosocial care is integrated into the medical standard of care for patients with cancer ➤ The mission of the CSC is to ensure that all people impacted by cancer are empowered by knowledge and strengthened by action ➤ An electronic web-based tool, “CancerSupportSource,” is a distress screening tool to help patients get information and ask for support connect patients with social workers in the network. Empowering Patients through Knowledge “At the Cancer Support Community, our mission is to ensure that all people impacted by cancer are empowered by knowledge, strengthened by action, and sustained by community,” said Ms Thiboldeaux. The screening program is compliant with the regulations of the Health Insurance Portability and Accountability Act and provides customized reports to patients and providers. It provides real-time reports for the patient and the oncology team, and empowers patients to report their concerns and the type of support they need. Another program initiated by CSC is Open to Options, which helps patients with cancer in their decision-making. “We really help patients insert their own values, their own priorities, take their own realities into consideration when developing their questions around what decision to go with. We’ve had patients call about mastectomy versus lumpectomy—a whole list of issues,” Ms Thiboldeaux said. Open to Options also informs patients about clinical trials and seeks to clear up any misconceptions patients may have about participating in a trial. A cancer experience registry has also been developed, and now includes 7000 patients across a multitude of cancer diagnoses. The metastatic breast cancer registry contains data from 450 patients, who have expressed concern about finding childcare and the burden that copays create, for example. n

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drug update

Beleodaq (Belinostat) Receives FDA Approval for the Treatment of Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma By Lisa A. Raedler, PhD, RPh, Medical Writer

eripheral T-cell lymphoma (PTCL) is a broad term that encompasses several rare and often aggressive types of non-Hodgkin lymphoma.1 The Leukemia & Lymphoma Society estimates that between 10% and 15% of patients with non-Hodgkin lymphoma have a T-cell lymphoma subtype.1 According to data from the Surveillance, Epidemiology, and End Results registry, the incidence of PTCL is less than 1 case per 100,000 individuals in the United States.2 PTCL is most often identified in patients aged ≥60 years.1 PTCL comprises multiple subtypes, each with unique clinical features.3 The most common PTCL subtypes include PTCL not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL); these subtypes account for approximately 70% of all PTCL cases in the United States.3 PTCL is typically characterized by enlarged lymph nodes in the neck, armpit, or groin.1 PTCL also affects the bone marrow, liver, spleen, stomach, and skin.1 Other symptoms of PTCL may include night sweats, fever, weight loss, and rash.1 Compared with patients with aggressive B-cell lymphomas, patients with PTCL have very poor outcomes.4 According to the International T-Cell Lymphoma Study, the overall survival at 10 to 15 years was 10% for patients with PTCL-NOS.5 Traditionally, treatment advances for patients with PTCL have been slower than treatment advances in other types of lymphoma.4 Patients with newly diagnosed PTCL are often treated with single-agent drugs and drug combinations that are used in B-cell lymphomas, including the CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and the EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) regimens.3,4 Because virtually all patients with PTCL will experience disease relapse, high-dose chemotherapy followed by autologous stem-cell transplantation is considered a treatment option for eligible patients.3

For relapsed or refractory PTCL, the relatively new treatment options include pralatrexate and romidepsin, both of which were approved by the US Food and Drug Administration (FDA) in 2009; older cytotoxic drugs and drug combinations include gemcitabine-based combinations, DHAP (dexamethasone, cytarabine, and cisplatin), and ICE (ifosfamide, carboplatin, and etoposide).3

Belinostat was approved under the FDA’s accelerated approval program based on 2 surrogate end points—tumor response rate and duration of response. In 2011, the FDA approved brentuximab vedotin, an antibody-drug conjugate, for the treatment of patients with relapsed or refractory systemic ALCL.6 Clinical trials are under way to assess the activity of this monoclonal antibody in other subtypes of PTCL.3 The cost burden associated with PTCL is significant. A recent retrospective cost analysis evaluated claims data for commercially insured patients with Medicare supplemental benefits to identify patients with PTCL.7 A total of 1000 patients with PTCL were included in the analysis. Results showed that patients with PTCL were hospitalized more often and experienced longer lengths of hospital stays compared with the matched controls without PTCL.7 In addition, patients with PTCL utilized more physician office visits, pharmacy services, emergency department visits, and hospice care compared with the matched control group.7 The mean annual healthcare costs were $75,934 for patients with PTCL compared with $4661 for the matched controls.7 The medical costs for patients with PTCL were primarily driven by hospitalizations (ie, 32% of the overall costs) and pharmacy services (ie, 20% of the overall costs).7 Overall, 11% of patients with PTCL underwent stem-cell transplantation compared with none of the patients in the control group. The average cost of

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stem-cell transplantation exceeded $126,000 per patient.7 Belinostat: A New Treatment Option for PTCL On July 3, 2014, the FDA approved belinostat (Beleodaq; Spectrum Pharmaceuticals) for the treatment of patients with relapsed or refractory PTCL.8 This approval was based on an open-label, single-arm, nonrandomized, international clinical trial conducted at 62 centers and included 129 patients with relapsed or refractory PTCL.8-10 The primary end point was overall response rate, including complete response and partial response, as assessed by an Independent Review Committee using the International Workshop Criteria.8-10 Belinostat, which is administered via intravenous infusion, was approved under the FDA’s accelerated approval program based on 2 surrogate end points—tumor response rate and duration of response.8,9 An improvement in survival or disease- related symptoms has not yet been established.9 Mechanism of Action Belinostat is a histone deacetylase inhibitor.9 Histone deacetylases are enzymes that facilitate the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins.9 In vitro, belinostat causes the accumulation of acetylated histones and other proteins, which results in cell apoptosis and/or cell-cycle arrest of some transformed cells. Belinostat demonstrates preferential cytotoxicity toward tumor cells relative to normal cells.9 Dosing and Administration In patients with relapsed or refractory PTCL, the recommended dosage and schedule of belinostat is 1000 mg/ m2 administered intravenously on day 1 to day 5 of a 21-day cycle. Treatment with belinostat should be repeated every 21 days until disease progression or until unacceptable toxicity.9 Belinostat should be infused over 30 minutes. The infusion time may be extended to 45 minutes if infusion-site pain or other symptoms attributable to the infusion occur. In patients known to be homozygous for the UGT1A1*28 allele, the dose of belinostat should be reduced

to 750 mg/m2.9 Belinostat is primarily metabolized by the liver. The data are insufficient to recommend a specific dose of belino stat in patients with moderate or severe hepatic impairment or in patients with creatinine clearance ≤39 mL/min.9 BELIEF: A Pivotal Phase 2 Clinical Trial The safety and efficacy of belinostat in patients with relapsed or refracto ry PTCL were demonstrated in the BELIEF clinical trial, a single-arm, open- label, nonrandomized, international study.10 In this clinical trial, 129 patients with relapsed or refractory PTCL received belinostat 1000 mg/m2 administered intravenously over 30 minutes once daily on days 1 to 5 of a 21-day cycle.10 Patients received belinostat every 3 weeks until disease progression or until unacceptable toxicity.9,10 The primary efficacy end point was overall response rate, including complete response and partial response. Responses were assessed by an Independent Review Committee using the Cheson 2007 International Workshop Criteria.9,10 The duration of response was a secondary end point. Response assessments were performed every 6 weeks for the first 12 months of the trial, followed by every 12 weeks until 2 years from the initiation of the study treatment.9 The duration of response was measured from the first day of the documented response until disease progression or death. Disease progression was evaluated by the Independent Review Committee.9 The median duration of treatment with belinostat was 2 cycles (range, 1-33 cycles).9,10 Patient population The median age of the 120 patients evaluable for efficacy in the BELIEF trial was 64 years, with 62 patients (52%) aged ≥65 years.9,10 The majority (52%) of the patients enrolled were male; 88% were white, and 77% had an Eastern Cooperative Oncology Group performance status of 0 or 1.9,10 Furthermore, 64% of the patients had confirmed PTCL-NOS, 18% had AITL, and 11% had anaplastic lymphoma kinase-1 negative ALCL.9 Overall, 17% of the patients had platelet counts <100,000/μL.9,10

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drug update

The median time from the initial PTCL diagnosis was 12 months (range, 2.6-266.4 months). The median number of previous systemic treatments for PTCL was 2 (range, 1-8).9,10 Efficacy Among patients receiving belino stat, the overall response rate was 25.8% (Table 1). The response rate was 23.4% among patients with PTCL-NOS and 45.5% for patients with AITL.9,10

Among patients whose disease responded to belinostat, the median duration of response was 8.4 months (95% confidence interval, 4.5-29.4).9,10 The median time to response was 5.6 weeks (range, 4.3-50.4 weeks).10 Overall, 9 of the 120 patients proceeded to stem-cell transplantation after receiving belinostat.9,10 Adverse Reactions The safety of belinostat was assessed

esponse Rates Associated with Belinostat in Patients with Relapsed Table 1 R or Refractory PTCL Patients receiving belinostat (N = 120), Response N (%) Overall response

31 (25.8) (95% CI, 18.3-34.6)

Complete response

13 (10.8) (95% CI, 5.9-17.8)

Partial response

18 (15.0) (95% CI, 9.1-22.7)

CI indicates confidence interval; PTCL, peripheral T-cell lymphoma. Source: Beleodaq (belinostat) injection prescribing information; July 2014.

ll-Grade Adverse Events in ≥10% of Patients with Relapsed or Table 2 A Refractory PTCL Receiving Belinostat Patients receiving belinostat (N = 129) Adverse reactions All grades, % Grade 3 or 4, % Nausea

Fatigue

Pyrexia

Anemia

Vomiting

Constipation

Diarrhea

Dyspnea

Rash

Peripheral edema

Cough

Thrombocytopenia

Pruritus

Chills

Increased blood lactate dehydrogenase

Decreased appetite

Headache

Infusion-site pain

Hypokalemia

Prolonged QT interval

Abdominal pain

Hypotension

Phlebitis

Dizziness

PTCL indicates peripheral T-cell lymphoma. Source: Beleodaq (belinostat) injection prescribing information; July 2014.

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in 129 patients with relapsed or refractory PTCL in the BELIEF clinical trial. Adverse reactions of any severity level were observed in 97% of the patients.9,10 Table 2 summarizes the adverse reactions associated with belinostat in patients with relapsed or refractory PTCL, regardless of causality.9 A total of 61 patients (47%) experienced serious adverse reactions while receiving belinostat or within 30 days after their last dose of belinostat. The most common (>2%) serious adverse reactions included pneumonia, pyrexia, infection, anemia, increased creatinine clearance, thrombocytopenia, and multiorgan failure.9 Overall, 25 (19%) of patients discontinued belinostat treatment as a result of adverse reactions, which included anemia, febrile neutropenia, fatigue, and multiorgan failure. In addition, 12% of patients receiving belinostat had to have dosage adjustments because of adverse reactions.9,10 Overall, 1 treatment-related death from hepatic failure was reported in the BELIEF trial.9,10 In addition, 1 treatment-related death from ventricular fibrillation was reported in another clinical trial with belinostat monotherapy. Echocardiogram analysis did not identify a QT interval prolongation.9 Warnings and Precautions Hematologic toxicity. Belinostat can cause thrombocytopenia, neutropenia, lymphopenia, and/or anemia. During treatment with belinostat, blood counts should be monitored weekly, and dosage modifications should be made as needed for hematologic toxicity.9 Infections. Pneumonia, sepsis, and other serious infections, including fatalities, have occurred with belinostat. Belinostat should not be administered to patients with an active infection.9 Hepatotoxicity. Fatal hepatotoxicity and liver function test abnormalities have occurred with belinostat. Liver function tests should be assessed before initiating treatment and before the start of each cycle. Dose interruptions or adjustments are recommended until recovery. Belinostat should be permanently discontinued if the hepatic toxicity is severe.9 Tumor lysis syndrome. Tumor lysis syndrome has been associated with belinostat in patients with relapsed or refractory PTCL. Patients with advanced-stage disease and/or high tumor burden should be monitored carefully for this syndrome.9 October 2014

Gastrointestinal toxicity. Nausea, vomiting, and diarrhea have been observed with the use of belinostat. Antiemetic and antidiarrheal medications may be required.9 Embryofetal toxicity. Belinostat can cause fetal harm when administered to a pregnant woman; teratogenicity and/or embryofetal lethality can occur. If belinostat is used during pregnancy, or if the patient becomes pregnant while taking belinostat, she should be counseled about the potential hazard to the fetus.9 Use in Specific Populations Pregnancy. Belinostat has been assigned pregnancy category D. Because it is a genotoxic drug and targets actively dividing cells, belinostat may cause teratogenicity and/or embryofetal lethality. Women should avoid becoming pregnant while receiving belinostat.9 Nursing mothers. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from belinostat, either nursing or belinostat should be discontinued based on the importance of the drug to the mother.9 Pediatric use. The safety of belino stat in pediatric patients has not been established.9 Geriatric use. In the BELIEF clinical trial, approximately 50% of the patients were aged ≥65 years; these patients had a higher response rate to belinostat compared with patients aged <65 years (36% vs 16%, respectively). No meaningful differences in response rates were observed in patients aged ≥75 years compared with patients aged <75 years. No clinically meaningful differences in serious adverse reactions were observed based on patients’ age.9,10 Conclusion Belinostat is an effective and safe treatment option for patients with relapsed or refractory PTCL. Belinostat joins pralatrexate and romidepsin as active single agents that are FDA approved for use in this rare and aggressive type of lymphoma. Similar to these previously approved agents, belinostat was approved under the FDA’s accelerated approval program based on surrogate end points. An improvement in survival or in disease-free survival has not yet been established for belinostat. Ongoing clinical trials may provide further survival outcomes. The relatively low incidence of myelosuppression that was observed with

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Beleodaq (Belinostat) Receives FDA Approval... belinostat in patients with relapsed or refractory PTCL warrants further investigation of this drug in combination with other therapies. The safety and efficacy of belinostat in combination with the CHOP regimen and with other agents are being explored for the treatment of patients with newly diagnosed PTCL and B-cell hematologic malignancies.11 The activity of belinostat is also being evaluated

in solid tumors, including small-cell lung cancer.11 n References

1. The Leukemia & Lymphoma Society. Peripheral T-cell lymphoma facts. Revised July 2014. www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/ lymphoma/pdf/peripheraltcelllymphomafacts.pdf. Accessed August 13, 2014. 2. Morton LM, Wang SS, Devesa SS, et al. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265-276. 3. Lymphoma Research Foundation. Peripheral T-cell lymphoma (PTCL). 2012. www.lymphoma.org/site/pp. asp?c=bkLTKaOQLmK8E&b=6300159. Accessed Au-

gust 13, 2014. 4. Foss FM, Zinzani PL, Vose JM, et al. Peripheral T-cell lymphoma. Blood. 2011;117:6756-6767. 5. Vose JM, Armitage J, Weisenburger D; for the International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124-4130. 6. US Food and Drug Administration. FDA approves Adcetris to treat two types of lymphoma. Press release. August 19, 2011. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm268781.htm. Accessed August 14, 2014. 7. Potashman MH, Burudpakdee C, Wang W, et al. Clinical and economic burden of peripheral T-cell lymphoma in the United States. Blood. 2013;122. Abstract 2963.

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8. US Food and Drug Administration. FDA approves Beleodaq to treat rare, aggressive form of non-Hodgkin lymphoma. Press release. July 3, 2014. www.fda.gov/ newsevents/newsroom/pressannouncements/ucm 403929.htm. Accessed August 14, 2014. 9. Beleodaq (belinostat) for injection [prescribing information]. Irvine, CA: Spectrum Pharmaceuticals, Inc; July 2014. 10. O’Connor OA, Masszi T, Savage KJ, et al. Belinostat, a novel pan-histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. J Clin Oncol (Meeting Abstracts). 2013;31(15 suppl). Abstract 8507. 11. ClinicalTrials.gov. Belinostat. Search results. http:// clinicaltrials.gov/ct2/results?term=belinostat&Search= Search. Accessed August 15, 2014.

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

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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