VBCC Dec 2014 | Vol 5 | No 10

december 2014 VOL 5 NO 10

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

Patient-Focused Multidisciplinary Care at Meridian Cancer Center Interview with Mark J. Krasna, MD

Supportive Care Is Palliative

By Kate O’Rourke

Boston, MA—Palliative care has long been thought of as care only at the very end of life, but oncologists have recently realized the value of providing it earlier in the course of treatment. At the 2014 Palliative Care in Oncology Symposium, Patricia A. Ganz, MD, Director of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, advocated for palliative care being

central to survivorship care.

“Some of Patricia A. Ganz, MD the common palliative care concerns that we see in cancer survivors are very similar to what you see in patients with advanced cancer,” said Dr Ganz. These include fatigue, depression, insomnia, physical limitations, cognitive changes, lymphedema, sexual dysfunction, and menopause-like symptoms.

Continued on page 13

Fourth Conference

Oncology nurse navigators at Meridian Cancer Center.

C

ancer care requires the use of many experts and services, in addition to the care provided by medical oncologists. Access to patient support services is an integral component of cancer care.

Value-Based Cancer Care (VBCC) asked Mark J. Krasna, MD, Corpo-

rate Medical Director of Oncology, Meridian Health, Jersey Shore University Medical Center, Neptune, NJ, to describe key characteristics of a multidisciplinary approach to cancer care and its unique value for patients, providers, and the entire care continuum.

Continued on page 8

ASH 2014 Highlights

Posttransplant Brentuximab: New Standard of Care for Hodgkin Lymphoma?

By Phoebe Starr

San Francisco, CA—Early posttransplant consolidation with brentuximab vedotin (Adcetris) significantly improved progression-free survival (PFS) compared with placebo in patients with Hodgkin lymphoma who are at risk for disease progression in the placebo-controlled phase 3 AETHERA

© 2014 Engage Healthcare Communications, LLC

trial. AETHERA is the first placebo-­ controlled trial to compare brentuximab and placebo in patients with Hodgkin lymphoma after transplant.

The results of the study were presented at the 2014 American Society of Hematology annual meeting.

The median PFS was 43 months for Continued on page 25

Pathways-Based Cancer Care Reduces Hospitalizations, Care Variation, and Costs

By Wayne Kuznar

Bruce Feinberg, DO

Los Angeles, CA—An oncology pathways-based decision-support tool in­ stituted as a collaboration between a payer, oncologists, and other network providers can modify physician behavior that results in cost-savings and reductions in cancer-related inpatient ad-

missions, according to Bruce Feinberg, DO, Vice President and Chief Medical Officer at Cardinal Health Specialty Solutions, Dublin, OH. At his presentation at the Fourth Annual Conference of the Association for Value-Based Cancer Care, Dr Feinberg Continued on page 42

inside 9

VBCC PERSPECTIVE . . . . . . . . . . . . . . . . . . 38 The sixth vital sign in oncology

PALLIATIVE CARE . . . . . . . . . . . . . . . . . . . . . 12 New policy mandates will shape discussions on death and dying

MELANOMA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Nivolumab ups long-term survival

BREAST CANCER . . . . . . . . . . . . . . . . . . . . . . .

Trastuzumab biosimilars are coming

ECONOMICS OF CANCER CARE . . . . 14 Can the US afford personalized medicine?

PERSONALIZED MEDICINE . . . . . . . . . 23 Genetic profiling identifies missed gene mutations ASH 2014 HIGHLIGHTS . . . . . . . . . . . . . . .25 What’s causing high drug costs in the United States?

4TH CONFERENCE . . . . . . 42 Shift to value-based care brings new oncology models INTERVIEW WITH THE INNOVATORS . . . . . . . . . . . . . . . . . . . . . . . . . . . .48 Therapy guidance with the breast cancer index assay DRUG UPDATE . . . . . . . . . . . . . . . . . . . . . . . . . 52 Keytruda: first PD-1 inhibitor for unresectable/metastatic melanoma

NEW PHASE 3 DATA

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

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

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

PFS (%)

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

20 0

0

3

6

183 161

116 83

Number at risk IMBRUVICA® 195 Ofatumumab 196

Months

Ofatumumab 9

12

15

38 15

7 1

0 0

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

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

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

ORAL, ONCE-DAILY DOSING

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage - Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®.

The mechanism for the bleeding events is not well understood.

IMBRUVICA® may increase the risk of hemorrhage in patients receiving anti-platelet or anti-coagulant therapies. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA®. Twenty-six percent of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Cytopenias - Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA®. Monitor complete blood counts monthly.

Atrial Fibrillation - Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA®, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation.

Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (eg, palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA® treatment and dose modification.

Second Primary Malignancies - Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in

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

patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

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

ADVERSE REACTIONS The most common adverse reactions (≥20%) in the clinical trials were thrombocytopenia (56%), neutropenia (51%), diarrhea (51%), anemia (37%), fatigue (28%), musculoskeletal pain (28%), upper respiratory tract infection (28%), rash (26%), nausea (25%), and pyrexia (24%). Approximately 5% of patients receiving IMBRUVICA® discontinued treatment due to adverse events. These included infections, subdural hematomas, and diarrhea. Adverse events leading to dose reduction occurred in approximately 6% of patients.

DRUG INTERACTIONS CYP3A Inhibitors - Avoid concomitant administration with strong or moderate inhibitors of CYP3A. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA® dose.

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

SPECIFIC POPULATIONS Hepatic Impairment - Avoid use in patients with baseline hepatic impairment.

Please review the Brief Summary of full Prescribing Information on the following page.

To learn more, visit us at

www.IMBRUVICA.com

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

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Accelerated approval was granted for this indication based on overall response rate. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials [see Clinical Studies (14.1) in full Prescribing Information].

Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy [see Clinical Studies (14.2) in full Prescribing Information].

Chronic Lymphocytic Leukemia with 17p deletion: IMBRUVICA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion [see Clinical Studies (14.2) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five percent of patients with MCL and 26% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 23 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation.

Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification [see Dosage and Administration (2.3) in full Prescribing Information].

Second Primary Malignancies: Other malignancies (range, 5 to 10%) including carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 8%).

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Atrial Fibrillation [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

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

Infections and infestations

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

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

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

34 14 14 14 13

0 3 7 5 1

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

Preferred Term

General disorders and administrative site conditions

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

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

All Grades (%)

Grade 3 or 4 (%)

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

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

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) 57 17 47 29 41 9

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

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

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in an open label clinical trial (Study 1) that included 48 patients with previously treated CLL and a randomized clinical trial (Study 2) that included 391 randomized patients with previously treated CLL or SLL. The most commonly occurring adverse reactions in Study 1 and Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, upper respiratory tract infection, rash, nausea, and pyrexia.

Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued treatment due to adverse events. These included infections, subdural hematomas and diarrhea.

Adverse events leading to dose reduction occurred in approximately 6% of patients.

Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Tables 3 and 4.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1 System Organ Class Gastrointestinal disorders

Infections and infestations

General disorders and administrative site conditions

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

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

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

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

Grade 3 or 4 (%) 4 2 2 0 2 0 0

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

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

10*

0

10

2

10 10 17

0 0 8

IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1 Percent of Patients (N=48) All Grades Grade 3 or 4 (%) (%) 71 10 54 27 44 0

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

* Based on laboratory measurements per IWCLL criteria and adverse reactions Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in Study 2.

Table 5: Non-Hematologic Adverse Reactions ≥ 10% Reported in Study 2

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

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

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

48 26 17 15 14

4 2 1 0 0

18 18 6 9 6

2 0 1 0 1

28 24

2 2

30 15

2 1

16 15 11 10

1 10 1 4

11 13 6 5

2 9 0 1

24 14 12

3 0 0

13 1 1

0 0 0

28 17

2 1

18 7

1 0

14 11

1 0

6 5

0 0

11

0

3

0

10

0

3

0

Subjects with multiple events for a given ADR term are counted once only for each ADR term.

The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Study 2

Neutrophils Decreased Platelets Decreased Hemoglobin Decreased

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

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

* Based on laboratory measurements per IWCLL criteria DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IMBRUVICA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 391 patients randomized in Study 2, 61% were ≥ 65 years of age. No overall differences in effectiveness were observed between age groups. Grade 3 or higher adverse events occurred more frequently among elderly patients treated with IMBRUVICA (61% of patients age ≥ 65 versus 51% of younger patients) [see Clinical Studies (14.2) in full Prescribing Information].

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions].

• Atrial Fibrillation: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration.

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 PRC-00526 07/14

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 Vice President/Group Publisher Russell Hennessy rhennessy@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

VALUE PROPOSITIONS

ASH 2014 HIGLIGHTS

The new HPV vaccine can cut cancer incidence More…

Immunotherapy the newest breakthrough in Hodgkin lymphoma More…

BREAST CANCER

VBCC PERSPECTIVE

Trastuzumab biosimilars are coming More…

Financial toxicity the sixth vital sign in oncology

PALLIATIVE CARE

MELANOMA Long-term survival with nivolumab More…

Supportive care is palliative More…

A conversation with Franco Carli, MD, MPhil

Pathways-based care reduces hospitalizations, care variation Financial incentives for patients with cancer improve treatment eff iciency More…

Vice President of Finance Andrea Kelly

IN THE LITERATURE

DRUG UPDATE

Human Resources Jennine Leale

Economic impact of targeted therapies More…

Editorial Assistant Cara Guglielmon Senior Production Manager Lynn Hamilton The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris

Associate Director, Content Strategy & Development John Welz

Big jump in spending for oral oncologics More…

CANCER PREHABILITATION

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager 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 Manager Kashif Javaid Administrative Services Team Leader 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 Communica­ tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014

by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

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

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

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

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

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc 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 Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd. Albuquerque, NM Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

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

Keytruda: First PD-1 inhibitor for unresectable or metastatic melanoma

VBCC Editorial Board

Director, Quality Control Barbara Marino

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4TH CONFERENCE

ECONOMICS OF CANCER CARE

I december 2014

Denise K. Pierce DK Pierce & Associates Zionsville, IN 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.

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VALUE PROPOSITIONS

Advance Care Planning

Immunotherapy Vaccine for Patients with Newly Diagnosed Glioblastoma Shows Promising Results

ImmunoCellular Therapeutics, Ltd, a company focused on the development of immune-based therapies for the treatment of a variety of cancers, presented positive results for its leading vaccine, ICT-107, an intradermally administered autologous vaccine made of the patient’s own dendritic cells pulsed with 6 synthetic tumor-associated antigens. The ICT-107 vaccine is targeting patients with glioblastoma multiforme. The updated results from a randomized, placebo-controlled phase 2 clinical trial were presented in November at the annual meeting of the Society for Neuro-Oncology.

The phase 2 ICT-107 trial demonstrates a significant progression-free survival benefit and a numeric overall survival (OS) benefit in patients receiving ICT-107 compared with placebo: the median OS was 23.9 months in the control group but it has not yet been reached in the vaccine group.

At the time of the analysis, 65% of ICT-107–treated patients and 50% of the control group patients were alive. No differences were found in adverse effects. “ICT-107 continues to hold promise for patients with newly diagnosed glioblastoma, as no other immunotherapy has shown statistical benefit for a clinical outcome in a controlled trial in this patient population,” said Patrick Y. Wen, MD, Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute, Professor of Neurology at Harvard Medical School, and principal investigator on the trial. This vaccine will soon move to phase 3 testing. ImmunoCellular Therapeutics, Ltd; November 14, 2014

High Immunologic Response Seen with Oral Vaccine for Pancreatic Cancer in a Phase 1 Extension Trial

A Swiss-German biotech company released new data from an extension of the VXM01-01-DE randomized, placebo-controlled, double-blind phase 1 dose-escalation trial of its investigational oral T-cell vaccine VXM01 that is directed against the tumor vascular EGFR-2 (VEGFR-2) as a target gene.

The new data come from an extension of the trial that enrolled 27 additional patients with inoperable pancreatic cancer. Previously, 45 patients were randomized to 4 doses of VXM01 within 1 week or to placebo plus standard-of-care treatment. In the extension trial, patients in the treatment arm

received monthly boosting vaccinations for up to 6 months in addition to the 4 vaccinations. Overall, 66% of the patients showed a strong T-cell–mediated immune response against the target VEGFR-2 after the initial vaccination with VXM01 or after boosting. The main adverse event was a decrease in platelet count. In an interim analysis, median OS was 10.3 months in the treatment arm, and the effect was higher in patients with a target-specific T-cell response after VXM01 treatment (12.3 months for responders vs 5.4 months for nonresponders). “We are enthusiastic about the high immunological response rate and the improved survival of patients responding to VXM01 treatment,” said Hubertus Schmitz-Winnenthal, MD, a principal investigator. “This is especially exciting given the patients’ life expectancy and the observed safety profile, even under continued treatment.” VAXIMM AG, Basel, Switzerland/Mannheim, Germany; December 4, 2014

M.D. Anderson Cancer Center Launches New Programs After FDA’s Approval of Novel HPV Vaccine

Researchers at M.D. Anderson Cancer Center applauded the FDA for its recent approval of the new vaccine against 5 new strains of the human papillomavirus (HPV) that were not covered by the original Gardasil vaccine.

The new vaccine, Gardasil 9, provides protection against 5 additional strains of HPV that cause the vast majority of cervical, vulvar, vaginal, and anal cancers. “This is an incredible step forward in our fight to end cancer,” said Ronald A. DePinho, MD, President of M.D. Anderson Cancer Center. “Up to 80 percent of the world will be infected with HPV at some point, according to estimates. M.D. Anderson hopes the vaccine approval will change the conversation about HPV vaccination from sex to saving lives,” he said. Researchers and clinicians at this cancer center are launching new programs to address HPV-related cancers in their entire institution and in the whole country. “We are developing a national partnership with peer institutions in 18 states to increase HPV vaccination rates, Dr DePinho said. “One initiative funded for $1.5 million will result in an unparalleled effort to accelerate the conversion of scientific discoveries into clinical advances.” It is believed that this vaccine will cover close to 90% of cervical cancers and will save many lives. M.D. Anderson Cancer Center press release; December 10, 2014 n

FDA Update Jakafi Gets New Indication for Use in Patients with Polycythemia Vera

The FDA approved ruxolitinib (Jakafi; Incyte Corporation) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The FDA approval was based on Protocol CINC424B2301, a multicenter, open-­ label, active-control trial of 222 patients with PV whose disease was resistant to or who were intolerant of hydroxyurea.

The composite end point was durable hematocrit control and spleen volume reduction, and a durable hematocrit control that obviated the need for regular phlebotomy. Patients were randomized to ruxolitinib 10 mg twice daily (N = 110) or to best available care (N = 112).

Ruxolitinib was superior to best available therapy in durable hematocrit control and in spleen volume reduction at week 32 (21% vs 1%; P <.001) and at week 48 (19% vs 1%; P <.001), as well as in a relatively high rate (55%) of durable hematocrit control at week 48.

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through week 32 were thrombocytopenia and anemia. The most common nonhematologic adverse events (incidence >10%) were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms.

Overall, 4% of patients discontinued therapy with ruxolitinib because of adverse events. (December 14, 2014)

Cyramza Approved in Combination with Docetaxel for Metastatic NSCLC

Ramucirumab (Cyramza; Eli Lilly) received a new indication for use in combination with docetaxel for the treatment of patients with metastatic non–small-cell lung cancer (NSCLC) whose disease is progressing with or after platinum-based chemotherapy.

In patients with EGFR or ALK mutations, disease progression should be considered for treatment with an FDA-approved medication for these genetic mutations before administering ramucirumab. Earlier in the year, the FDA approved ramucirumab alone and in combination with paclitaxel for the treatment of patients with ad-

vanced gastric or gastroesophageal junction (GEJ) adenocarcinoma after disease progression while using firstline therapy.

The approval of ramucirumab in combination with docetaxel for patients with NSCLC was based on results of the multicenter, double-blind, placebo-­ controlled study of 1253 patients with previously treated metastatic NSCLC that showed improved overall survival (OS). Patients were randomized to ramucirumab in combination with docetaxel on day 1 of a 21-day cycle (N = 628) or to placebo plus docetaxel (N = 625). The median OS was 10.5 months in the ramucirumab plus docetaxel arm and 9.1 months in the placebo plus docetaxel arm, a significant difference (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.98; P = .024). Progression-free survival (PFS) was also significantly longer with ramucirumab than with placebo (HR, 0.76; 95% CI, 0.68-0.86; P <.001).

Among 1245 patients who received at least 1 dose of ramucirumab plus docetaxel, the most frequent adverse reactions (incidence ≥30%) were neutrodecember 2014

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penia, fatigue/asthenia, and stomatitis/ mucosal inflammation. The most common serious adverse reactions with the active combination were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). (December 12, 2014)

Cyramza plus Paclitaxel for Advanced Gastric Cancer After Chemotherapy

The FDA approved ramucirumab (Cyramza; Eli Lilly) in combination with paclitaxel for patients with advanced or metastatic gastric cancer or with GEJ adenocarcinoma whose cancer has progressed while receiving or after fluoropyrimidine- or platinum-containing chemotherapy. In April, ramucirumab was approved as monotherapy for advanced or metastatic gastric cancer or GEJ adenocarcinoma.

This new approval was based on the RAINBOW study, a phase 3 clinical trial that compared ramucirumab plus paclitaxel versus placebo plus paclitaxel. Ramucirumab plus paclitaxel significantly extended median OS at 9.6 months compared with 7.4 months (P = .017) with placebo plus Continued on page 17

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Cancer Center Profile

Patient-Focused Multidisciplinary Care at Meridian Cancer...

Continued from the cover

VBCC: What are the main characteristics of a multidisciplinary practice?

Dr Krasna: The multidisciplinary cancer program is focused on a geographic identity that allows patients to get all their care at the same place. It also usually involves having nurse navigators and the entire interdisciplinary support team at the same cancer center, including a nurse navigator, a social worker, a genetic counselor, and psychosocial counseling. Often there is also a dietitian and research nurses.

The most important element is to have all the physicians, the medical oncologists, the radiation oncologists, and the surgical oncologists see the patient on the same day, during the same visit. If you can build a program that is truly multidisciplinary from the start, the majority of patients will be seen and their case reviewed by all the necessary experts on the same visit.

That is especially important for patients with locally advanced cancer.

The cornerstone of a successful multidisciplinary program is to have all providers give their opinions at the beginning of the care to ensure we reach the right treatment, and the right sequencing. In a patient-centered care model, the patient should have the opportunity to hear all the specialists and get their consensus before beginning a definitive intervention.

VBCC: It must be difficult to get so many experts in the same place.

Dr Krasna: The biggest challenge for a multidisciplinary care program is how to use the experts efficiently to provide great value for the patient; from the physicians’ perspective, this means not wasting time. We have to be very efficient in utilizing everyone’s time. We therefore have to provide a well-oiled machine for the clinic to function properly, which is why nurse navigators are so important for each disease team.

In addition, we are currently implementing an oncology-specific electronic medical record (EMR) system (using Varian Aria) for the entire Meridian Health System, to enhance the care coordination among all the different experts involved in the care of each patient, including the inpatient and the outpatient care. Although some of our medical oncologists are employed

8

VBCC: Can you briefly describe the structure of Meridian’s cancer center?

Dr Krasna: Meridian Health System is a 6-hospital system in New Jersey along the Jersey shore. We provide cancer services at each of the 6 locations to minimize travel for patients. In that part of the state, having just 1 cancer center for the whole system would not work. Our patients want to get the majority of their care close to home. Our cancer center at Jersey Shore University Medical Center is the so-called academic medical center for the system, which serves the tertiary, or the quaternary cases.

We are implementing the multidisciplinary clinic model in each of our centers. We have just built a sixth freestanding outpatient cancer center in Jackson, NJ. It includes chemotherapy infusion, radiation oncology, and our multidisciplinary clinic, and it serves a community that does not have access to many oncology specialists. Over the next year or two, all our facilities will include at least a multidisciplinary

clinic area adjacent to the medical or the surgical oncologists.

Each center has several nurse navigators, which, in accordance with the American College of Surgeons Commission on Cancer, includes a survivorship navigator. All our physicians will have access to our EMRs, which could link to their own EMR system; this will increase their efficiency and reduce errors. This means that a treatment provided at one of the freestanding cancer centers will now also be a computerized order entry. Each follow-up for that patient, all the notes, will be available to all the providers on the same EMR system.

billing structure. In a multidisciplinary cancer care program, the physical entry to the facilities is considered a part of the hospital, even if it is the outpatient area. This means each patient will receive 2 separate bills—a professional fee bill, and a facilities fee bill. This is not necessarily more expensive, but it is a duplication of paperwork, and we disclose this to patients upfront. We tell every patient, “You’re going to have 2 sets of copays. You may even have 2 sets of coinsurance.” I have found that as long as you explain and disclose it to patients early on, they are very understanding. But it is something that we are doing proactively.

VBCC: How do you address the cost issues with patients?

Dr Krasna: Two main cost areas have come up for us: first, as can be expected, is the use of new and expensive drugs. We ask patients about their coverage, and when relevant, consider if a particular new cancer drug is significantly better than an alternate drug that may be covered by their policy.

On the hospital side, all our pharmacists now do what we call “a financial timeout,” which examines the drug prescribed and the patient’s coverage.

If the financial timeout reveals that there are alternatives that may be covered by the patient’s insurance, but the particular drug that we ordered is not, this will be discussed with the patient and the treating physician. A good example would be giving the patient trastuzumab (Herceptin) rather than a newer drug, such as pertuzumab (Perjeta). That discussion has to happen upfront: as cancer drugs are becoming more expensive, the patient’s out-ofpocket portion of the cost can be too much for that patient.

A second issue regarding costs is our

VBCC: Anything else to add?

Dr Krasna: Meridian Health System has one of the largest accountable care organizations (ACOs) in New Jersey.

Because this is such a large ACO, we are now implementing a clinically integrated network. Over the next couple of years, regardless of what happens in the Affordable Care Act, we should be able to have an episode-of-care model within our clinically integrated network.

Our multidisciplinary care paradigm enables us to be very efficient, and allows us to have all our physicians working together to meet the same quality outcomes from patient to patient. We hope that this will help us negotiate a new reimbursement system with payers where we share the risk and the savings. For example, if we could show payers that we can take care of a patient with stage II lung cancer using the correct workup, the correct safe operation, and the correct and appropriate chemotherapy regimen as adjuvant therapy, it may help us to get the payers to agree to give us more exclusive “bundled payments” for cancer management. This is a way for us and for the payer to share the risk, and the savings.

We will roll this out first through the clinically integrated network; the episode-of-care model for the treatment of patients with cancer, at least in solid organ tumors, is our future model of care. The multidisciplinary program can help to reach that goal. I believe multidisciplinary care is the best model to show payers that our team all has the same goals and the same quality outcomes. And payers are also realizing the value for them in getting quality care rather than just the use of the newest and most expensive therapies. n

Amesse Photography

Mark J. Krasna, MD

directly by us, others are in private practice, but they still want to be engaged with our multidisciplinary program and our facilities.

Our oncology-specific EMR system will help us better coordinate the care in our multidisciplinary clinics. As the cancer center director, my challenge is to have enough administrative support structure, and make it efficient, so that a medical oncologist is not waiting for 1 hour between patients. Another challenge is to make all the resources—a social worker, navigators, and genetic counselors—work for the good of the patient. That is a resource that hospital-based or freestanding cancer centers can do a little more easily than a private practice medical oncologist’s office.

From left: Pierre J. Mendoza, MD; Lani Gernalin, RN, BSN, OCN; Mark A. Perlmutter, MD, FACS; Michael Lasser, MD.

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Breast Cancer

Trastuzumab Biosimilars Are Coming

By Alice Gooodman

New York, NY—The high cost of cancer drugs makes the potential for biosimilar oncology drugs of particular interest to oncologists and to patients. To date, no oncology biosimilar has been approved by the FDA. Global studies of trastuzumab (Herceptin) biosimilars are currently under way. One trastuzumab biosimilar is already approved in South Korea, and the company is in the process of filing for its regulatory approval in Europe. During the next 3 years, this biosimilar will likely be approved in the United States.

“Most patients with HER2-positive breast cancer benefit from trastuzumab, and about 20% of all breast cancer patients are HER2-positive. Now that the patent for trastuzumab will be expiring in the next 2 to 3 years, there is a lot of interest in developing biosimilars,” explained Francisco J. Esteva, MD, PhD, of the Perlmutter Cancer Center, New York University Langone Medical Center. At the 2014 Chemotherapy Foundation Symposium, Dr Esteva updated attendees about trastuzumab biosimilars.

The FDA approval of a trastuzumab biosimilar could have significant ramifications if it is less expensive and equally effective as its original agent. Trastuzumab is one of the most important drugs to be developed in the past few decades and remains the backbone of treatment of patients with HER2-positive breast cancer in the metastatic, neoadjuvant, and early-stage settings.

The FDA has yet to approve any cancer-related indications for any of the monoclonal antibody biosimilars.

The FDA approval of an oncology biosimilar will be held to a different standard from the common generic drugs, according to Dr Esteva.

“Biosimilars are like snowflakes. They look the same, but they are not identical. This is an important concept regarding biosimilars. It is difficult to make the same drug and biological systems identical,” Dr Esteva explained.

The FDA’s requirement for approval of biosimilars is that clinical trials show that the biosimilar and the originator drug are comparable and interchangeable in terms of immunogenicity, safety, and efficacy in the most sensitive and homogeneous population. Response rate—not survival or progression-free survival—is an acceptable primary end point in clinical trials of biosimilars versus the originator drug.

Trastuzumab Biosimilars Under Development

Currently, 4 trastuzumab biosimilars are under development by 4 pharmaceutical companies: • CT-P6 (Celltrion) is farthest in development • ABP-980 (Amgen) • PF-05280014 (Pfizer) • BCD-022 (Biocad).

A randomized phase 1/2b clinical

“

Bio­similars are like snowflakes. They look the same, but they are not identical. This is an important concept regarding biosimilars.

It is difficult to make the same drug and biological systems identical.

”

—Francisco J. Esteva, MD, PhD

trial of CT-P6 showed equivalent pharmacokinetics and safety to trastuzumab in patients with HER2-positive metastatic breast cancer. A randomized phase 3 trial comparing CT-P6 plus paclitaxel with trastuzumab plus paclitaxel (Taxol,

Abraxane) showed similar response rates, safety, and time to disease progression in patients with HER2-positive metastatic breast cancer.

A phase 1 clinical trial showed sim­ ilar pharmacokinetics for the compound PF-05280014 and for trastuzumab in healthy volunteers. “The pharmaco­ kinetics is not identical. The Pfizer compound [PF-05280014] is similar to the trastuzumab compound marketed in the United States, but not the one made in Europe,” Dr Esteva said.

Ongoing phase 3 clinical trials are comparing PF-05280014 and BCD-022 with trastuzumab in the metastatic setting, and other phase 3 trials are comparing ABP-980 and CT-P6 with trastuzumab in patients with early-stage breast cancer.

Earlier in 2014, CT-P6 was approved in South Korea under the name Herzuma, and Celltrion is filing for its approval in Europe, Dr Esteva said. He expects that CT-P6 will be available in the United States within the next 3 years.

In the United States, the first approval of trastuzumab biosimilars will probably be in the neoadjuvant setting, Dr Esteva predicted. “This is the ideal platform for testing trastuzumab biosimilars, because it is the most homogenous population not confounded by prior use of chemotherapy and other factors, and it is the most sensitive population to trastuzumab-based chemotherapy,” he said. n

New York, NY—Investigators at Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, Rockefeller University, and the National Cancer Institute are moving forward in their understanding of the adverse association between obesity and breast cancer. Preliminary studies show associations between adipocytes, aromatase, proinflammatory cytokines, low-grade chronic inflammation, and breast tumors. Improved understanding of these associations will potentially lead to targeted interventions, said Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, and immediate Past President of the American Society of Clinical Oncology, at the 2014 Chemotherapy Foundation Symposium.

Why the focus on obesity and breast cancer? Obesity is projected to affect more than 60% of the US population by the year 2030. This will have wideVol. 5

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Photo courtesy of ASCO

Obesity a Risk Factor for Breast Cancer?

“

We think that obesity may replace cigarette smoking as the nation’s number one risk factor for cancer.

”

—Clifford A. Hudis, MD

spread consequences for many diseases, Dr Hudis said.

“The unprecedented change in rates of obesity has broad public health implications. What does this have to do with cancer? Uterine cancer mortality is higher in obese people, and cancers of the esophagus, pancreas, breast, and liver are associated with obesity,” Dr Hudis explained.

Furthermore, obesity is a risk factor for postmenopausal breast cancer (not for premenopausal breast cancer). “Explanations for this association are both facile and complex,” Dr Hudis continued.

“We all know that adipocytes make estrogen, but the answer as to why this happens is complex and involves insulin and insulin-like growth factor,” he said.

“A new discovery is that adipocytes produce inflammatory macrophages that alter interleukin (IL)-6, IL-1 beta, and tumor necrosis factor (TNF) december 2014

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alpha,” Dr Hudis explained.

“We began to develop the notion that at least part of this was due to increased inflammation. Postmenopausal breast cancer may be a consequence of chronic low-grade inflammation in visceral fat and breast tissue,” he said.

Studies in mice showed the highest aromatase levels in oophorectomized animals in white adipose tissue in the mammary gland and the visceral fat.

Animals on a eucaloric diet added a few pounds during menopause that was induced by oophorectomy.

“An unexpected finding we stumbled on were crownlike structures [CLS] consisting of dead or dying adipocytes in the animals, surrounded by macrophages that secrete proinflammatory mediators. This is a toxic stew of inflammation in the mammary gland of the mouse. Higher amounts of fat in oophorectomized animals contribute to the rates of Continued on page 10

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Breast Cancer

The Future of Immunotherapy in Breast Cancer

By Alice Goodman

New York, NY—The oncology community is abuzz with the promise of immunotherapy, sparked by the success of immunotherapeutic approaches in advanced melanoma. There is major interest in studying immunotherapy in other cancers, including breast and lung cancer.

At the 2014 Chemotherapy Foundation Symposium, Heather L. McArthur, MD, MPH, a medical oncologist in the Breast Medicine Service, Memorial Sloan Kettering Cancer Center (MSKCC), New York, updated listeners on a novel approach being studied at her institution for the treatment of breast cancer using cryoablation in combination with anti–PD-1 and anti– CTLA-4 inhibitors. Thus far, preliminary results suggest that this is a worthy strategy to pursue.

“Immune checkpoint inhibition in breast cancer is an unbelievably exciting topic right now,” Dr McArthur said. But, she cautioned, “Immunology is complicated and intimidating.

I’ve been designing these studies for more than 5 years, and I still come out of meetings saying this is exciting and complex. The future of this field requires a multidisciplinary effort, so we need to create building blocks for the conversations we need to have.”

The CTLA-4 inhibitor ipilimumab and the PD-1 inhibitor nivolumab achieved an unprecedented survival improvement in melanoma, with 1-year survival of 94%, Dr McArthur said.

“We need to have a balance of immune activation and immune sup-

“

Immune checkpoint inhibition in breast cancer is an unbelievably exciting topic right now.

Immunology is complicated and intimidating….The future of this field requires a multidisciplinary effort.

”

—Heather L. McArthur, MD, MPH pression. The ‘gas’ to the system is kept in check with the ‘brakes,’ and the brakes are PD-1. If the brakes are removed by anti–PD-1 agents, then you have immune stimulation to fight the tumor,” she explained.

Studies provide hints that anti–PD-1 checkpoint inhibitors may be worth pursuing in breast cancer, particularly in triple-negative and HER2-positive breast cancers, she said.

Obesity a Risk Factor... Continued from page 9 CLS,” Dr Hudis explained.

The investigators went on to look at this in normal tissue in women’s breasts in patients undergoing surgery. In an initial series of 30 patients, the investigators encountered parallel findings to what they saw in mice, including histologic evidence of CLS of the breast white adipose tissue associated with increasing body mass index.

Dr Hudis pointed out that a small number of obese and overweight patients do not have evidence of lowgrade chronic inflammation, and that a modest number of overweight and even lean patients demonstrate elevated proinflammatory mediators and CLS of the breast.

“We have confirmed the pattern seen in mice in women’s breasts,” he

10

emphasized. “We think this is a systemic phenomenon, and the white adipose tissue of the breast can be a sentinel for generalized inflammation,” Dr Hudis said.

The goal of these studies is to define biomarkers that identify adipocyte inflammation with the potential to modulate and target it.

“We think this axis of obesity–inflammation–aromatase may be useful for reducing the risk of breast cancer or its progression. It may be a biomarker, and we need to scientifically investigate the effect of lifestyle changes and anti-inflammatory agents on these lesions,” Dr Hudis said. “We think that obesity may replace cigarette smoking as the nation’s number one risk factor for cancer.”—AG n

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Tumor-infiltrating lymphocytes (TILs) are prognostic in triple-negative and HER2-positive breast cancer.

The 2013 GeparSixto study showed that TILs predicted response to carboplatin in triple-negative and HER2-­ positive breast cancer. TILs also predict response to trastuzumab, Dr McArthur added.

“The next question is, ‘If modern immune strategies work in melanoma and we have predictive markers [ie, TILs], can we expect immune approaches to work in breast cancer?’” she asked.

In pilot studies at MSKCC, CTLA-4 blockade achieved stable disease in breast cancer, but not the dramatic responses seen in melanoma. “This could be because breast cancer does not have as high a mutational load as melanoma,” Dr McArthur suggested.

The next step was to determine how to optimize the immune response. The investigators hypothesized that cryoablation and anti–CTLA-4 therapy could be a good combination in breast cancer. The thinking was that cryoablation of the tumor would create tumor fragments, optimizing tumor antigen presentation; then, immune modulation could enable an immune response that is specific to an individual’s tumor.

In a pilot study of 18 women with planned mastectomy, 6 women had cryoablation alone, 6 received anti– CTLA-4 treatment with ipilimumab, and 6 received the combination before surgery.

Cryoablation was performed with magnetic resonance imaging guidance, and after a series of freeze and thaw cycles, tumor fragments were seen.

The procedure was well-tolerated. Biopsies were obtained up front, and the mastectomy sample was analyzed.

More absolute numbers of T-cells and more diverse T-cells were present in triple-negative and HER2-positive samples compared with normal tissue. In the tumor bed, the ratios of types of T-cells changed after ipilimumab and cryoablation. In the periphery, serum T-cells were activated by ipilimumab.

“Cryoablation changes the clonal evolution of the T-cells. This is exciting and innovative, and we have much to learn,” Dr McArthur told listeners.

Building on the pilot study, the MSKCC investigators have planned a randomized study of ipilimumab plus nivolumab and cryoablation in early-stage breast cancer. Future strategies could include combining immunotherapy with conventional therapies, radiation, and other ablative strategies, Dr McArthur said.

“Given the success of immunotherapy in melanoma and some solid tumors; and that TILs are predictive and prognostic in breast cancer; and preliminary data that we can alter tumor, stromal, and blood immune elements; there is good reason to be optimistic about immunotherapy approaches in breast cancer,” Dr McArthur stated. n

Hepatitis B Screening Before Chemotherapy in Early-Stage Breast Cancer Is Cost-Effective

By Rosemary Frei, MSc

Miami, FL—The best bet for preventing the reactivation of latent hepatitis B virus (HBV) infection before adjuvant chemotherapy is to screen patients with early-stage breast cancer for the virus, according to data presented at the 2014 Society for Medical Decision Making annual North American meeting. Lead investigator William W. L. Wong, MMath, PhD, Assistant Professor and Decision Modeller, Toronto Health Economics and Technology Assessment Collaborative, University of Toronto, Ontario, Canada, and his colleagues

showed that it is cheaper in the long run to screen everyone than to test only individuals who are most likely to harbor HBV infection.

“There is no consensus on the strategy at the present time,” Dr Wong told Value-Based Cancer Care. “Our data suggest that screening everybody is cost-effective, even if the overall prevalence of hepatitis B virus in the population is only 0.4%.”

Dr Wong pointed out that the results are congruent with a 2012 article published by some of his coinvestigators, which showed that

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Breast Cancer

Hepatitis B Screening Before Chemotherapy in Early-Stage... Continued from page 10 screening all patients with lymphoma for HBV before chemotherapy is cost-effective. Dr Wong also noted that his results mesh with recommendations for routine HBV screening before chemotherapy from the Centers for Disease Control and Prevention and the American Association for the Study of Liver Diseases.

However, the recommendations by Dr Wong and his colleagues are not in line with the American Society of Clinical Oncology provisional clinical opinion, which states that evidence does not support routine screening for HBV in patients receiving treatment for malignancies (Artz AS, et al.

J Clin Oncol. 2010;28:3199-3202).

“

Our data suggest that screening everybody is costeffective, even if the overall prevalence of hepatitis B virus in the population is only 0.4%.

”

—William W. L. Wong, MMath, PhD Dr Wong’s group used Markov computer modeling to test which screening strategy is the most cost-­ effective in women with early-stage breast cancer: not screening any of the patients, screening all patients and treating those who test positive for the HBV surface antigen with either lamiv­ udine (Epivir) plus tenofovir (Viread) or entecavir (Baraclude), or screening only high-risk patients and treating those who test positive for HBV. The results showed that the screenall strategy would be associated with 2 severe reactivations of HBV per 100,000 people screened over the lifetime of the cohort, including none that would lead to mortality. By comparison, there would be 40 severe reactivations and 9 deaths with no screening, and 11 reactivations and 2 deaths with the screening of only high-risk patients. There would also be fewer interruptions of chemotherapy as a result of the treatment of HBV and/or its sequelae and fewer liver-related deaths with screening all patients versus screening only highrisk patients or no screening at all.

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0.0035 quality-adjusted life-years (QALYs) and an additional cost of $164 to $266 (Canadian dollars) per person. The other 2 strategies would be less costly, but would not result in as large an increase in QALYs. Overall, there would be a range of

an incremental cost-effectiveness ratio of $47,808 per QALY gained to $76,527 per QALY gained with the screen-all strategy compared with no screening, depending on whether lamivudine plus tenofovir is used (lamivudine is much less expensive than entecavir).

Moreover, at a willingness-to-pay threshold of $100,000 per QALY, the screen-all approach was associated with a 97% probability of being cost-effective when the combination of lamivudine plus tenofovir is used compared with no screening. n

First- and every-cycle Neulasta achieved: ■

94% relative reduction in febrile neutropenia (17% placebo vs 1% Neulasta; P < .001)1,2

■

93% relative reduction in febrile neutropenia–related hospitalization (14% placebo vs 1% Neulasta; P < .001)1,2

■

80% relative reduction in febrile neutropenia–related IV anti-infective use (10% placebo vs 2% Neulasta; P < .001)1,2

Phase 3 study in patients with breast cancer receiving 100 mg/m2 docetaxel for up to 4 cycles given placebo (n = 465) or Neulasta (n = 463); primary endpoint: incidence of febrile neutropenia.1 Febrile neutropenia = absolute neutrophil count (ANC) < 0.5 × 109/L and temperature ≥ 38.2°C.

Support through every cycle Help reduce the incidence of infection and protect your patients receiving myelosuppressive chemotherapy* from febrile neutropenia.

*Myelosuppressive chemotherapy regimens associated with a clinically significant risk of febrile neutropenia.

Neulasta® (pegfilgrastim) is administered by subcutaneous injection.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta for ARDS. Discontinue Neulasta in patients with ARDS.

Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment.

Permanently discontinue Neulasta in patients with serious allergic reactions.

Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Please see brief summary of Neulasta Prescribing Information on the adjacent page.

References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta (pegfilgrastim) Prescribing Information. Thousand Oaks, CA: Amgen; 2011. © 2012 Amgen Inc. All rights reserved.

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Every appropriate patient.

Every cycle.

www.neulastahcp.com

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Palliative Care

New Policy Mandates Poised to Change Discussions About Death and Dying

By Kate O’Rourke

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

71678-R1-V1

AMGNL10681 New Campaign Journal Ad PI Composite Master -04 Incremental Ad Insertions Colors: K + live/trim_DO NOT PRINT Bleed: NA Trim: 7.63"w x 10.75"h Live: 7"w x 9.625"h Output @ 100% Giant Creative Strategy

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence malignancies receiving myelosuppressive anticancer drugs in Neulasta-treated patients as compared with placebo-treated patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation.

System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim.

Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim.

The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading.

Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta.

• Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] Blood and lymphatic system disorder: Sickle cell crisis • Serious Allergic Reactions [See Warnings and Precautions] [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity.

Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice.

Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

Anthony L. Back, MD, Seattle Cancer Care Alliance, and Professor of Medicine, University of Washington, Seattle, has spent roughly 15 years

LASERS PRINTED AT

dividual Preferences Near the End of Life.” A key recommendation in the report is that clinicians need to initiate conversations about dying.

100%

Boston, MA—In September 2014, the Institute of Medicine (IOM) released a report entitled, “Dying in America: Improving Quality and Honoring In-

“

How do we get from telling patients that we will give them an extra layer of support to talking about the really tough stuff?

”

—Anthony L. Back, MD studying the patient–physician encounter at the end of life. “There is a lot that is new. We have a policy mandate that we have never had before,” said Dr Back at the 2014 Palliative Care in Oncology Symposium.

According to Dr Back, much has changed in the past 2 years regarding end-of-life issues. Commenting on the IOM report, Dr Back said, “It is our responsibility to get the conversation started.”

According to Dr Back, the IOM report is different from other reports that might have broached the same topic, because it is specific. “It gives us a clear roadmap of what to do,” he said. “The fact that the Institute of Medicine is behind this is something that we should be pointing out to our colleagues and our administrators every time we get a chance, because this is the body that sets the tone for policy direction in the United States.”

The second policy mandate comes from the American Society of Clinical Oncology (ASCO). A provisional clinical opinion issued by ASCO in 2012 called for clinicians to sit down with patients and have “a frank discussion” about prognosis, with “a reasonable forecast of survival” and an “explicit discussion of the medically appropriate goals of treatment” (Smith TJ, et al.

J Clin Oncol. 2012;30: 880-887).

Dr Back pointed out that there is a new public dialogue about death that has begun to take place in the United Continued on page 13

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Palliative Care

Supportive Care Is Palliative Survivorship Care Similar to Palliative Care Dr Ganz has been a leader in survivorship research and care for the past 25 years. For conceptualizing the 3 components of survivorship care, she devised what is known as “the three Ps of cancer survivorship care” (Ganz PA. BMC Med. 2011;9:14): • Palliation of ongoing symptoms • Prevention of late effects of cancer treatment or second cancers • Health promotion to maximize future wellness.

Dr Ganz’s interest in providing palliative care to patients with cancer in

at a glance ➤ Some common concerns in cancer survivors are very similar to what you see in patients with advanced cancer ➤ These include fatigue, depression, insomnia, physical limitations, cognitive changes, lymphedema, sexual dysfunction, and menopauselike symptoms ➤ Long-term adverse effects are symptoms that begin during cancer treatment and persist when treatment ends, such as fatigue, cognitive impairment, and pain ➤ Survivorship programs should include consultants who can help patients deal with anxiety and depression

Continued from the cover

“

Some of the common palliative care concerns that we see in cancer survivors are very similar to what you see in patients with advanced cancer….

From the very beginning, at diagnosis and staging, we need to be thinking about palliative care.

”

—Patricia A. Ganz, MD

various stages of their disease was sparked by her work with patients with advanced cancer at the Veterans Affairs Medical Center-Sepulveda in the San Fernando Valley. “I thought, ‘Why don’t we have the nutritionist, the physiatrist, and psychologist, who make the rounds with me on my unit, see patients wherever they are in the cancer care continuum?’” said Dr Ganz.

“Why should we give all these goodies to people only when they are at the end of life? I began to embrace the idea of palliative care along the whole cancer care continuum. From the very beginning, at diagnosis and staging, we need to be thinking about palliative care,” she said.

According to Dr Ganz, palliative care is defined as medical care that concentrates on reducing the severity of symptoms, particularly if there is not a curative treatment; the goal is to prevent pain and to improve quality of

life for patients facing complex illness.

And many cancer survivors suffer from long-term and late effects, where cancer-directed treatment is not the focus. Rather, treatment needs to focus on the survivor’s symptoms.

Dealing with Long-Term Symptoms Long-term adverse effects are defined as symptoms or problems that begin during cancer treatment and persist when treatment ends, such as fatigue, cognitive impairment, and pain.

Late effects are symptoms that occur months to years after treatment ends, such as a second cancer, congestive heart failure, or lymphedema.

Survivorship Programs Survivorship programs may include clinical consults focusing on mental health, pain management, physical medicine, vocational rehabilitation, en-

docrinology, cardiology, gynecology/ fertility, pulmonary, and neurology/ neuropsychology.

“In a survivorship program, you have to line up consultants who are going to be able to help you deal with the anxiety and depression in terms of the mental health services and pain management,” said Dr Ganz. She has worked to cultivate endocrinologists and cardiologists who are willing to learn about survivors and their specific problems. For example, dysauto­nomia occurs in patients who have received radiation for Hodgkin lymphoma, but many clinicians are not familiar with this disease, and may be baffled by patients who present with symptoms such as the inability to remain upright, excessive fatigue, and chest pain.

“”

Survivorship care and palliative care are integrated, integral, attached to each other at the hip.

—Patricia A. Ganz, MD

Palliative care clinicians have a role in caring for survivors because of their focus on symptom management, Dr Ganz said.

“Survivorship care and palliative care are integrated, integral, attached to each other at the hip,” said Dr Ganz.

“All of you who are interested in palliative care need to pay attention to survivors.” n

New Policy Mandates Poised to Change Discussions... Continued from page 12 States. An article in the New York Times, “Fighting to Honor a Father’s Last Wish: To Die at Home,” made a big splash in September 2014. The article went viral and generated more than 1000 comments on the New York Times website. The book, Being Mortal: Medicine and What Matters in the End, is on the best-seller list.

To improve communication skills about end-of-life issues, clinician training is needed. “How do we get from telling patients that we will give them an extra layer of support to talking about the really tough stuff? That is the stuff we need to teach,” said Dr Back. “It has got to be different than the death panel conversation, and we need to distinguish our public converVol. 5

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sation from the private conversations that we have with patients.”

Clinicians have traditionally not been good regarding talking about end-of-life issues. A recent study demonstrated that between 60% and 80% of patients receiving palliative care with radiation or chemotherapy for incurable cancer do not understand that the intent of the treatment is palliative, not cure (Weeks JC, et al. N Engl J Med. 2012;367:1616-1625).

Communication Tools for Oncologists Dr Back has developed various resources and tools that clinicians can use to sharpen their communication with patients at the end of life. Many

of these tools are available at vitaltalk. org, including the following examples of PAUSE and REMAP: PAUSE for End-of-Life Discussions Pause: take a moment to initiate using phrases such as, “There is something I’d like to put on our agenda today” Ask permission: explain why using phrases such as, “Could we take a moment” or “This will help me guide you” Understand: ask about values using phrases such as, “If this got much worse, what would be important?”

Suggest: name a surrogate. Who is the person who knows you the best?

Expect emotion: empathize first by using phrases such as, “This is a tough thing to talk about, for anyone.” december 2014

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REMAP for Late End-ofLife Discussions Reframe: status quo isn’t working Expect emotion: empathize first Map: what is important Align: with deep values Plan: match treatments to values.

According to Dr Back, “Communication is a learned expertise. He emphasizes that communication is “not just about learning more phrases or more knowledge. We need clinicians to develop in a more complicated way, and this is something we need to build into all of our systems for supporting clinicians and educating them, so they can do the work in a way that is effective and sustainable.” n

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Economics of Cancer Care

Payers Debate the Economics of Personalized Medicine in Oncology

By Wayne Kuznar

San Francisco, CA—The rising costs of biomolecular testing and targeted drugs have prompted many to ask whether the United States can afford personalized medicine in oncology.

At the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative, medical directors from 2 health plans tackled this question from the payer perspective.

Ken Schaecher, MD, Medical Director at SelectHealth, answered “it depends” to the key question. Dr Schaecher noted that healthcare costs in the United States now stand at 17.2% of gross domestic product. The United States can afford personalized medicine “until we decide not to,” he said, pointing out that some targeted medicines cost upwards of $100,000 annually, because the United States has no threshold to pay for these medicines.

Most payers have defined sets of rules, Dr Schaecher said, but the problem in the United States is the large number of payers, each with their own set of rules. Sometimes, even within a plan, one set of rules may be

“

Provide payers with evidence that it’s useful, and that it would be no more costly or preferably less costly than the current approach to management, and you win the day. It’s that easy.

“

We can identify disease at an earlier state, and as a general rule, the earlier we treat various cancers, the more effective it is clinically, and, as important, the more costeffective it is….The answer to this question, ‘Can we afford personalized medicine?’ is a resounding ‘yes.’

”

—Gary Johnson, MD, MS, MBA

at a glance ➤ The rising cost of molecular testing and targeted drugs has raised the question whether the United States can afford personalized medicine in oncology ➤ Personalized medicine enables providers to select the right treatment for the right patient, which improves health outcomes, and would be supported by payers, if used appropriately ➤ Establishing a threshold for the annual costs of highpriced targeted medicines may make personalized medicine more cost-effective ➤ Standardized testing and proof that the therapies are useful and not more costly than those already in use will help get payers to cover them ➤ By reducing the use of treatments not likely to work in a given patient, personalized medicine can reduce provider liability

14

”

—Ken Schaecher, MD

applied, but different benefit structures mean that one patient can get a therapy that another cannot.

Is It Cost-Effective?

Gary Johnson, MD, MS, MBA, Regional Medical Director at Humana, said that paying for treatments and tests is always possible, but the real question is, “Should we pay?” As stewards of the premium dollar, insurers can cover anything they want to but they will have to raise premiums to do so.

The targeted approach to care allowed by personalized medicine creates the opportunity for greater cost-effectiveness, as in KRAS testing to select patients with colorectal cancer for targeted therapy. Being able to select the right treatment for the right patient improves health outcomes, said Dr Johnson.

Personalized medicine “shows us where treatments will be effective, and just as important, where treatments will not be effective so we can avoid toxicities and morbidities from treatments that, in essence, cause

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harm,” he said. “All of this is the goal of managed care and of clinical care.”

By reducing unnecessary risks of treatments not likely to work in a given patient, personalized medicine can reduce provider liability, said Dr Johnson.

A well-defined treatment pathway linked with a diagnostic marker provides legal cover denial of a treatment.

“We can identify disease at an earlier state, and as a general rule, the earlier we treat various cancers, the more effective it is clinically, and, as impor­ tant, the more cost-effective it is,” he said. “BRCA testing, which has been around for decades, and Oncotype DX, for breast cancer are additional examples of why the answer to this question, ‘Can we afford personalized medicine?’ is a resounding ‘yes.’ ” The higher price tags of targeted therapies reduce the cost-effectiveness of personalized medicine, said Dr Schae­cher.

“We’ve found that, typically, with more targeted therapies, the price tag goes up, and there’s only so much money in the bank,” he reasoned. “A great example is crizotinib. It has a $96,000 price, because it only works in 4% of the non–small-cell lung cancer [NSCLC] population that has the mutation. That price tag is much above most of the other therapies used in NSCLC.” The Biomarkers Dilemma Biomarker costs are increasing as well, Dr Schaecher said, with some tests exceeding $3000.

The misapplication of information in directing therapy is another potential con to personalized medicine in oncology. Sometimes, tests with low sensitivity or specificity are being used to determine clinical utility. And, in some instances, providers select the same treatment they would have oth-

erwise without the biomarker test.

There is also a risk that information from testing may be applied when evidence is not present, said Dr Schae­ cher. “It’s arguable that there is adequate evidence for whole-genome sequencing in oncology, but for most payers, they don’t believe that the evidence is there yet,” he said. “Using biomarkers in a one-off circumstance can help one patient but, unfortunately, as payers, we have to make broad payer-based decisions and not individual decisions. When there’s a lack of evidence we have to be consistent in our decisions. If I make an exception for one patient, that can bind us to make an exception for every patient going forward.”

Pharmacogenetic testing to identify drug metabolism may also add cost without utility. It is unproven that knowing that a patient may be a rapid metabolizer of an antidepressant medication is going to alter the therapy.

That can occur in the oncology arena also, said Dr Schaecher.

A lack of process standardization across laboratories argues against the wholesale use of biomarker tests. “As much as we would like all of the tests to be FDA-approved, sometimes FDA approval can mean different things,” Dr Schaecher said. “Many [tests] are home-brewed, done in university labs, and when you don’t have that standardization, it’s harder for us to want to approve having a test covered.”

Finally, a patient may still insist on a therapy anyway with a negative biomarker test.

“Provide payers with evidence that it’s useful, and that it would be no more costly or preferably less costly than the current approach to management, and you win the day,” said Dr Schaecher. “It’s that easy.” n

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Economics of Cancer Care

Big Jump in Spending for Oral Oncologics

By Charles Bankhead

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n 2011, approximately $23 billion was spent on anticancer drugs (oncologics) in the United States, of which 77% was for drugs administered by healthcare providers. Increasingly, new oncologic drugs are introduced as oral therapies, and their share in the total expenditures grows. Thus, quarterly expenditures for oral oncologic drugs was $1.4 billion (in 2012 dollars), an increase of 37% over a 5-year period ending in 2011, according to a new analysis by Rena M. Conti, PhD, Assistant Professor of Pediatrics and Public Health Sciences, University of Chicago, and colleagues (Conti RM, et al. Health Aff [Millwood].

2014;33:1721-1727).

Using data from the IMS Health National Sales Perspectives database for 2006-2011, Dr Conti and colleagues found that the spending increased from $940.3 million per quarter in 2006 to $1.4 billion. Most of the increase was a result of the growing expenditures for new brand-name oral drugs. Utilization of oral oncologics also increased, but more modestly compared with the increase in costs, they reported.

“The potential clinical benefits of using the oral oncologics discussed in this article must be weighed against their financial costs for patients,” Dr Conti and colleagues noted. “Many commercial insurers do not require substantial patient cost-sharing for physician-administered drugs. However, insurers may impose high cost-sharing for oral oncologics.”

“

The potential clinical benefits of using the oral oncologics…must be weighed against their financial costs for patients. Many commercial insurers do not require substantial patient cost-sharing for physician-administered drugs. However, insurers may impose high cost-sharing for oral oncologics.

”

—Rena M. Conti, PhD, and colleagues

“Since 2007, 26 states have passed laws requiring insurers to offer patients cost-sharing parity between oral and physician-administered oncologics. Whether and how these policies affect clinical outcomes and spending are important topics for future research,” they added.

Oncologic drugs lead all prescription therapeutic classes in national spending. Sales of specialty drugs, including oncologics, have risen by 9.5% in 2006 and by 8.9% in 2007, outpacing all pharmaceutical sales (1.6% increase in 2007, 1% decrease in 2012) and total medical spending (3% in 2009-2011).

Dr Conti and colleagues cited several potential contributors to the rising utilization of and expenditures for oncologics, including increasing can-

cer incidence in the United States, the introduction of new brand-name agents and the “virtually guaranteed coverage” by insurers after FDA approval, insurance reimbursement policies that encourage the use of brandname oncologics, and postlaunch price increases for some brand-name and generic oncologics.

The analysis encompassed 47 oral oncologic drugs available during the period reviewed. Targeted therapies accounted for 30% of the agents, hormonal therapies for 26%, and alkylating agents for 19%. The data showed that 43% of the oncologics were available as generics throughout the study period.

The average quarterly spending on oral oncologics increased by 37%, or

$20 million; by contrast, the utilization of oral oncologics increased by 10% during the same period.

Overall, the average quarterly spend­ ing increased by 61%, and utilization by 30%, on brand-name oncologics; by contrast, spending on generic oncologics during the study period decreased by 65%, although their use increased by 16%. Spending on generic oral oncologic agents decreased by 56%, and their use decreased by 12%.

“Our results suggest that spending levels and trends are driven by the use of new brand-name oral oncologics,” Dr Conti and colleagues noted.

“Many of these drugs represent significant therapeutic advances over the standard of care for the treatment of specific cancers.”

“”

Many of these drugs represent significant therapeutic advances over the standard of care for the treatment of specific cancers.

—Rena M. Conti, PhD, and colleagues

“However, data limitations prevented us from correlating spending and utilization levels and trends according to guideline-consistent indications, including those that may not be approved by the FDA,” they added. n

Early Adoption of Postlumpectomy Brachytherapy Was a Costly, Premature Oversight

By Rosemary Frei, MSc

Miami, FL—The rise in the popularity of brachytherapy-based accelerated partial-breast radiotherapy before long-term evidence was available to show whether it is effective was an expensive oversight, according to a team of researchers. Heather Taffet Gold, PhD, MA, Associate Professor, Section on Value and Effectiveness, and Assistant Director, Health Disparities and Outcomes Research, New York University Cancer Institute, presented the results of the study at the 2014 Society of Medical Decision Making Annual North American meeting.

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tomy between 2005 and 2007.

The 1-year average unadjusted payment for brachytherapy-based radiotherapy was significantly higher than for whole-breast radiation therapy, at $10,470 versus $6260, respectively.

Furthermore, the 1-year total unadjusted payment was also higher, at $12,180 versus $9460, respectively.

The team’s multivariable analyses showed that the cost of brachytherapy was 1.66 times higher than for wholebreast radiation therapy. In addition, 1-year total payments were 31% higher for brachytherapy and 45% greater when complications were present. The highest payments were for women who had comorbidities, with 54%

“

These funds could have been used instead to develop additional RT treatment registries to gather sufficient evidence of effectiveness and to create appropriate financial payment models to curb use outside of research studies.

”

—Heather Taffet Gold, PhD, MA

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higher payments for women with 2 comorbidities and 135% higher for those with ≥3 comorbidities.

Dr Taffet Gold and colleagues calculated that there was an additional $40 million in treatment costs and $29 million in extra overall costs over each year for every 10,000 women undergoing brachytherapy-based radiotherapy instead of whole-breast radiation therapy.

“These funds could have been used instead to develop additional RT [radiation therapy] treatment registries to gather sufficient evidence of effectiveness and to create appropriate financial payment models to curb use outside of research studies,” Dr Taffet Gold and colleagues concluded. n

www.ValueBasedCancerCare.com

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Cancer Prehabilitation

A Conversation with Dr Franco Carli, a Leader in Cancer Prehabilitation Research

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By Julie K. Silver, MD

n 2013, I coauthored the first review on cancer prehabilitation.1 Since its publication, I have been inundated with requests from various healthcare professionals to learn more about prehabilitation. This is the first of 3 perspectives by a researcher, a physician, and a patient regarding prehabilitation.

Let us begin by defining cancer prehabilitation, which is not as simple as “whatever is done before surgery or other cancer treatments begin.” In a previous review, my colleagues and I defined it as “a process on the cancer continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment and includes physical and psychological assessments that establish a baseline functional level, identify impairments, and provide interventions that promote physical and psychological health to reduce the incidence and/or severity of future impairments.”2 Prehabilitation is time-based and outcomes-focused, with document­ able data that compare a patient’s baseline status to the status at discrete points along the care continuum; ideally there are at least 4 times when patients are assessed, including (1) baseline, (2) after prehabilitation but before the start of cancer treatment, (3) after cancer treatment (eg, surgery) at the rehabilitation evaluation, and (4) at discharge from rehabilitation. This means that handing someone an educational booklet or a printed sheet of exercises or encouraging a better diet before surgery would not be considered prehabilitation.

Franco Carli, MD, MPhil, Professor of Anesthesia, McGill University, Montréal, Québec, Canada, has been studying surgical prehabilitation in patients with colorectal cancer. Recently, Dr Carli and his colleagues published the results of a randomized controlled trial (RCT) with a trimodal prehabilitation approach that included nutritional supplementation, stress reduction, and exercise components; one group had prehabilitation and postoperative rehabilitation and the Editor’s Note: This is a 3-part series on cancer prehabilitation. Part 1 is a cancer prehabilitation researcher’s perspective.

Part 2 is an oncology physician’s perspective, and Part 3 is a patient’s perspective.

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other group only had postoperative rehabilitation.3 Dr Silver: Briefly describe your new study and why it is important.

Dr Carli: This RCT was set up to determine whether multimodal prehab (exercise + nutritional supplement + relaxation), starting 4 weeks before colorectal resection for cancer and con-

tinued for 8 weeks after surgery, would help patients recover faster than a rehab group receiving the same multimodal regimen after surgery.

The results demonstrated that >80% of the prehab patients returned to baseline by 8 weeks compared with 60% of the rehab-only group. This is the first time multimodal prehab and/or rehab was administered in this population.

Although it is clear that the patients who are in the prehab have more chance to return to baseline faster, 60% of the rehab patients can catch up by 8 weeks. Only 30% of patients in the historical control group, where no intervention was done, returned to preoperative baseline by 8 weeks. This could suggest that prehabilitation is the optimal way, but if limited time for prehab is allowed, at least the program can be initiated after surgery.

Dr Silver: How did your earlier studies utilizing a single modality (exercise) influence your multimodal approach?

Dr Carli: In our first RCT, using intense exercise, we found that many of the patients were unable to sustain such efforts. Also, we found almost 20% of patients with high anxiety and depression. Finally, we did not account for nutrition, and we believe this was an important component to control for together with the other 2 components.

Dr Silver: How important is the nutritional component, and why?

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Dr Carli: In our recent study on preoperative nutritional assessment in this population, 62% of patients were considered well-nourished, 26% suspected or nutritionally at risk, and 8% severely undernourished. According to the PGSGA (nutritional assessment questionnaire), 52% of patients scored 4 to 8 or >9, indicating requirement for dietary intervention or symptom management.

Undernutrition, before or after surgery, is associated with higher mortality, morbidity, costs, and delayed recovery after abdominal surgery. This implies that appropriate nutrition ought to be considered in the perioperative period.

Dr Silver: How important is the psychosocial component, and why?

Dr Carli: These patients are under intense psychological stress once they receive the diagnosis of cancer and the need for surgical treatment. They feel lost and with lowered self-esteem. The majority of patients (>75%) wanted to participate in the prehabilitation study. It is clear that 4 weeks are not sufficient to intervene with modification of their behavior; however, the counseling helps them to meditate and improve their breathing. This component of the prehabilitation could help them to allay their anxiety, and make them more willing to be engaged in the prehab program, and be more empowered. We have included the psychosocial component, because there is sufficient evidence in the literature that stress reduction improves wound healing.

Dr Silver: What are the key take-home points for researchers regarding prehabilitation?

Dr Carli: There is a need to determine whether prehab impacts other outcomes besides functional capacity; for example, postoperative complications or hospital readmissions. These represent important outcomes for the institution and society. And, of course, impact on health costs of this program. In addition, there is a need to determine how and what type of exercise influences outcomes (aerobic vs resistance), and what type of nutrition (immune nutrition or regular) should be used.

Dr Silver: What are the key take-home points for oncologists regarding prehabilitation?

Dr Carli: Oncologists should be inter-

ested in joining the team [in addition to surgeons], because at least 30% to 40% of the patients will need some type of adjuvant therapy, and the stress associated with this intervention is not less than that caused by surgery. I could see a concept of tumor board where all care is reviewed, including whether the patient should begin prehabilitation.

Dr Silver: With limited time and/or resources, what are the most impor­ tant tests, and what are the most important interventions?

Dr Carli: I believe that patients want to recover as soon as possible after hospital intervention. Recovery for our patients means the ability to function in society and to be independent. Walking is a measure of functional capacity.

We use the 6-minute walk test, which is easy to be administered and monitored and has been validated in surgical patients. We have reported that with <60% of predicted value (approximately <390 meters), patients with colorectal cancer are at risk for postoperative cardiorespiratory complications. Nutritional questionnaires, such as the PG-SGA or RS-2002, can be used as screening tools in the surgeon’s office or in the preoperative clinic.

Clearly, each patient needs to be assessed for nutritional risk and for physical fitness before starting prehabilitation. Those that we need to pay more attention to are the elderly (age >70 years), malnourished or poorly nourished, those living alone in nursing homes, and those with comorbidities, such as diabetes, cardiorespiratory disease, or body mass index >40 kg/m2.

Dr Silver: What will you be studying next, and why?

Dr Carli: We want to better understand the impact of physical activity and/or nutrition on muscle function and mental behavior, and how to minimize the time for patients to recover from surgery. Of course, the sooner the patient recovers, the better the quality of life and the less cost to society.

Dr Silver: What is the role of nursing in prehabilitation?

Dr Carli: Essential. Nurses are part of the team and can lead in this program by coordinating the various steps patients go through. They are professionals with knowledge and adequate health education to explain the various

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FDA Update Cyramza plus Paclitaxel for Advance... Continued from page 7

paclitaxel. Furthermore, ramucirumab plus paclitaxel significantly delayed disease progression: the PFS was 4.4 months with the active combination versus 2.9 months (P <.001) with placebo plus paclitaxel. Overall, 28% of patients responded to ramucirumab plus paclitaxel versus 16% with placebo plus paclitaxel (P <.001).

The FDA approved this new therapy with a boxed warning regarding the risk for bleeding, including severe and sometimes fatal hemorrhaging.

Ramucirumab injection should be permanently discontinued in patients with severe bleeding.

The most common adverse reactions in the trial with the active combination and ≥2% higher than in the placebo group were fatigue, neutropenia, diarrhea, and epistaxis. The most common serious adverse events with ramucirumab plus paclitaxel were neutro­ penia (3.7%) and febrile neutropenia (2.4%); furthermore, 19% of patients receiving the active combination had to

receive granulocyte colony-stimulating factors. (November 5, 2014)

Blincyto First Immunotherapy Approved for B-Cell Acute Lymphoblastic Leukemia

The FDA approved blinatumomab (Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lympho-

blastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia.

The drug acts as a connector between the CD19 protein (which is found on the surface of B:7.625 mostin B-cell lymphoblasts) and the CD3 protein found on T:7.375 in T-cell lymphocytes, using the body’s

T-cells to destroy the leukemia cells.

The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated approval program to approve the drug 5 months ahead of the scheduled date. Blinatumomab has an orphan drug designation. The FDA is now requiring the manufacturer to conduct a new clinical trial to show a survival benefit with blinatumomab in Continued on page 18

In mCRPC therapy…

Is there more to the story?

components of prehabilitation and provide support.

Dr Silver: What else do you want to share with oncologists about prehabilitation or your work?

Dr Carli: We need to have more institutions that are engaged in this type of work, so that we could exchange information and learn from each other’s experience. We also need government grants and other research and education funding to understand better what we are trying to achieve. The majority of patients involved in prehabilitation are unanimously excited by the program. They feel engaged and not abandoned; they believe they can control their health, and this is a positive objective of prehabilitation. n References

1. Silver JK, Baima J. Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. Am J Phys Med Rehabil. 2013;92:715-727.

2. Silver JK, Baima J, Mayer RS. Impairment-driven cancer rehabilitation: an essential component of quality care and survivorship. CA Cancer J Clin. 2013;63:295-317.

3. Gillis C, Li C, Lee L, et al. Prehabilitation versus rehabilitation: a randomized control trial in patients undergoing colorectal resection for cancer. Anesthesiology. 2014;121:937-947.

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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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Customer Code: 016819-140612

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Dr Silver: Is prehabilitation undervalued and underutilized in oncology?

Why, or why not?

Dr Carli: In my view, it is underutilized, but I am not sure whether it is undervalued. This depends on whether the underutilization is because this intervention is not well-known in many circles or is not considered an option because it does not “cure” cancer. To any patient, this program makes sense. Most of the patients ask, “Why, then, is it not made available?”

FDA Update Blincyto First Immunotherapy Approved... Continued from page 17

patients with relapsed or refractory Ph-negative precursor B-cell ALL. The approval was based on the safety and efficacy of blinatumomab in a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumomab for at least 4 weeks.

The results showed a 32% complete remission rate lasting approximately 6.7 months. The trial was not designed to show improvement in survival.

Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system adverse events.

The most common side effects reported were pyrexia, headache, peripheral

edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor.

Blinatumomab was approved with a (REMS) Risk Evaluation and Mitigation Strategy program to inform healthcare providers about the serious risks associatedB:7.625 withinthis medication.

The product information also carries a T:7.375 in boxed warning to alert providers of

the risks and serious side effects associated with the use of blinatumomab.

(December 3, 2014)

Avastin plus Chemotherapy for Platinum-Resistant Gynecologic Cancers

The FDA approved a new indication for bevacizumab solution (Avastin; Genentech) to be used in combination

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

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FDA Update with paclitaxel, pegylated liposomal doxorubicin, or topotecan for the treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

The approval is based on the results of the AURELIA study, an international, randomized trial with investigator-assessed PFS. AURELIA compared bevacizumab plus chemotherapy ver-

sus chemotherapy alone. Overall, 179 patients were randomized to bevaciz­ umab plus chemotherapy and 182 patients received chemotherapy alone with 1 of the 3 chemotherapies.

Treatment continued until disease progression, unacceptable toxicity, and/or consent B:7.625 withdrawal.

All the in patients had received ≤2 previous T:7.375 in chemotherapy regimens, had ECOG

performance status of 0 to 2, and had disease recurrence within <6 months of the platinum-based therapy.

Bevacizumab plus chemotherapy had a significant PFS improvement compared with chemotherapy alone (HR, 0.38; 95% CI, 0.30-0.49; P <.001), with a median PFS of 6.8 months versus 3.4 months, respectively; however, the OS was not significantly different,

with a median OS of 16.6 months versus 13.3 months, respectively (HR, 0.89; 95% CI, 0.69-1.14).

The most common adverse reactions (≥15%) with bevacizumab plus chemotherapy were neutropenia, peripheral sensory neuropathy, and hypertension.

Gastrointestinal perforations were reported in 1.7% of patients who received bevacizumab. (November 14, 2014) n

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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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In the Literature Vemurafenib/Cobimetinib Combination Improves Outcomes in Advanced Melanoma

Although the BRAF inhibitor vemurafenib (Zelboraf) improves progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma, 25% of patients using it as monotherapy end up with a second

cancer. Combining BRAF and MEK inhibitors has been shown to prevent or delay the onset of resistance with BRAF inhibitors alone. A new study investigated the use of combining vemurafenib with the experimental MEK inhibitor cobimetinib (Larkin J, et al. N Engl J Med. 2014;371:1867-1876).

This international, multicenter, randomized, phase 3 trial included 495

patients with untreated, unresectable locally advanced or metastatic BRAF V600 mutation melanoma. Patients were randomized in a 1:1 ratio to vemurafenib (960 mg twice daily) together with placebo (control group) or to cobimetinib (combination group; 60 mg once daily for 21 days, followed by 7 days off). The median follow-up at the time of reporting was

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

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7.3 months. The primary end point was investigator-assessed PFS. The secondary end points were rates of confirmed objective response and OS. The median PFS was 9.9 months in the combination group compared with 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval, 0.39-0.68; P <.001). The combina-

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) System/Organ Class All Grades1 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 tion group had a significantly higher complete or partial response compared with the control group—68% versus 45%, respectively (P <.001); this included a complete response rate of 10% versus 4%, respectively.

Interim OS analyses showed higher rates of survival at 9 months with the combination compared with control (81% vs 73%, respectively).

Adverse events were reported in ≥20% of the patients in either group (eg, arthralgia, alopecia, diarrhea, and rash); however, combining vemurafenib with cobimetinib decreased the number of secondary cutaneous cancers. No significant difference was observed in grade ≥3 adverse events.

Drug discontinuations were similar (13% and 12%, respectively).

Approximately 50% of patients diagnosed with melanoma carry the BRAF mutation. Combination therapy with vemurafenib and cobimetinib demonstrated improvement in PFS and response rate, reduced second cancers, and early evidence of improved OS among patients with BRAF V600 mutation metastatic melanoma, at the cost of some increase in toxicity.

ZYTIGA® (abiraterone acetate) Tablets

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) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest 7 discomfort 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 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) System/Organ Class All Grades1 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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Assessing the Economic Impact of Targeted Therapies in Advanced NSCLC

Improved understanding of the biology of non–small-cell lung cancer (NSCLC) has led to increasing stratification of treatment based on pathologic and molecular characteristics to obtain the greatest clinical benefit for patients while minimizing the adverse effects.

Continued on page 22

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In the Literature Assessing the Economic Impact of... Continued from page 21

However, these advances have come at a financial cost. In a recent review article, researchers examined the economic impact of screening for molecular abnormalities and new targeted treatments for advanced NSCLC (Graham DM, Leighl NB. Front Oncol. 2014;4:258).

The researchers found that major

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determinants of cost are molecular testing and drug price. For a molecular targeted therapy, adequate tissue sampling and accuracy of testing method are important.

International guidelines recom­ mend routine immunohistochemistry (IHC) staining for NSCLC diagnosis, the use of histologic subtype and molecular testing to detect EGFR muta-

tion, and EML4-ALK fusion for patients with advanced NSCLC. The amount of tissue required and the labor intensiveness depends on the biomarker screening technique used (eg, IHC or fluorescence in situ hybridization [FISH]).

The researchers reviewed testing methods and cost across a range of studies. One study analyzed the cost-ef-

ZYTIGA® (abiraterone acetate) Tablets

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

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fectiveness of testing for using FISH and IHC. The data showed that FISH testing was assessed at $106,707 per quality-adjusted life-year (QALY) gained compared with $57,165 per QALY gained for IHC. A Canadian study explored the cost-effectiveness of 2 treatment approaches for patients with EML4-ALK fusion–positive tumors. One approach consisted of molecular screening (initial IHC and, if positive, confirmatory testing with FISH) and targeted treatment with crizotinib (Xalkori). Molecular testing led to an increase of 0.11 QALYs and a $2725 (Canadian dollars) increase in cost per patient.

Fusion testing accounted for $60 of those costs. For patients who have confirmed EML4-ALK–positive tumors, first-line therapy with crizotinib resulted in an incremental cost-effectiveness ratio (ICER) of $250,632 per QALY gained, which is more than the frequently accepted cost-effectiveness thresholds.

Drug cost is an underlying concern for patients and payers regarding targeted therapies. Studies of EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR-mutated advanced NSCLC have demonstrated improved response rate, quality of life, and PFS compared with chemotherapy.

Given these clinical benefits, analyses have been performed to determine the cost-effectiveness of firstline EGFR TKI therapy. A British study that compared gefitinib (Iressa) with platinum-doublet chemotherapy calculated an estimated ICER of £59,216 to £70,390 per QALY for gefitinib; however, it was not considered cost-effective at standard willingness-to-pay thresholds.

In a separate study, from the perspective of the Chinese healthcare system, researchers compared the cost-effectiveness of erlotinib (Tarceva) monotherapy and platinum-doublet chemotherapy in patients with advanced EGFR mutation NSCLC. Treatment with erlotinib was deemed cost-effective, with an ICER of $85,927.41 per QALY gained.

The cost of lung cancer in the United States is predicted to be $15.19 billion by 2020, without accounting for changes in treatment and the FDA approval of novel agents. As technology advances, molecular testing costs may become lower. The advances in targeted therapies have dramatically changed the diagnosis and treatment of NSCLC for patients with a previously poor prognosis. Collaboration among clinicians, payers, and manufacturers is needed to ensure that treatment cost does not limit patient accessibility to potentially beneficial treatments. n

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Personalized Medicine

Genetic Profiling Can Identify “Actionable” Mutations in Tumors That Are Missed by Traditional Tests

By Wayne Kuznar

San Francisco, CA—Comprehensive genetic profiling can identify clinically meaningful alterations in 85% of patients with cancer, said Juliann Chmielecki, PhD, Senior Scientist of Cancer Genomics at Foundation Medicine, at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.

As more cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies.

The number of clinically relevant genes across solid tumors is high.

Clinically relevant alteration is defined as an alteration for which an FDA-approved targeted therapy is available for that tumor type or for another tumor type.

In 2012, researchers found at least 1 clinically relevant genomic alteration in 59% of colorectal cancer (CRC) and non–small-cell lung cancer (NSCLC) tissue specimens, and revealed 2 gene fusions, C2orf44-ALK in CRC and KIF5B-RET in lung adenocarcinoma.

Further screening of 561 lung adenocarcinomas showed RET fusions in 2% of tissue samples.

The pace of targeted therapy discovery is rapid; by 2014, RET fusion– positive NSCLC was found to respond to the RET inhibitor cabozantinib (Cometriq).

Multiple diagnostic tests for the myriad genetic alterations in cancers may exhaust precious biopsy material, said Dr Chmielecki.

In a study of clinically relevant somatic mutations in NSCLC specimens, the fraction of mutations with an allele frequency under the limit of detection by capillary Sanger sequencing was 55%. “Next-generation sequencing– based tests miss most of the actionable alterations within a given patient,” Dr Chmielecki said.

New Genetic-Profiling Test To address the challenges presented by small biopsies, the multiple classes of genetic alterations, and the tumor samples that may have small tumor content, “we developed a test that has all 4 classes of alterations, with very high sensitivity and positive predictive value,” Dr Chmielecki stated.

The new genetic-profiling test is based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions, copy number alterations, and selected Vol. 5

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Next-generation sequencing–based tests miss most of the actionable alterations within a given patient….We developed a test that has all 4 classes of alterations, with very high sensitivity and positive predictive value.

”

—Juliann Chmielecki, PhD

fusions across 314 cancer-related genes from formalin-fixed paraffin-embedded specimens.

Of more than 13,000 patients who had undergone genetic profiling, 97% had 1 genetic mutation reported and 85% of samples had at least 1 clinically relevant alteration.

“When we look at the 314 cancer-­ related genes, we’re not finding a huge number of alterations per patient,” Dr Chmielecki said. “A higher number is usually cancers that are associated with carcinogens, such as lung cancer and melanoma.” Alterations per sample ranged from 0 to 57, and clinically relevant alterations per sample ranged between 0 and 28.

The solid tumor types that were rep-

resented in the >13,000 specimens included lung (19%), breast (14%), colon (9%), brain (5%), ovarian (5%), pancreatic (4%), soft tissue (4%), and other (32%, mainly rare tumors).

The investigators found a huge number of low-frequency alterations that could be linked to targeted therapies “that may be clinically relevant, even though they’re not occurring in hot spots of high-frequency genes,” Dr Chmielecki said.

Novel Alterations A novel KIF5B-RET fusion was identified and was later discovered to be present in 1% to 2% of patients with NSCLCs; KIF5B-RET–transformed cells are sensitive to RET in-

hibitors, suggesting that RET kinase inhibitors should be tested in prospective trials of patients with NSCLC with RET fusions. Multiple patients with KIF5B-RET fusion are known to have responded to a RET inhibitor, she indicated.

HER2/ERBB2 alterations were observed across 27 tumor types. “This phenomenon may extend well beyond the gastric and breast cancer field, and into areas that have not been looked at,” said Dr Chmielecki.

“There are clinical case reports showing sensitivity of HER2 amplification outside of breast and gastric cancers, as well as some of these newer mutations being discovered.” Nearly 50% of all HER2/ERBB2 alterations are missed by current tests, she noted.

EGFR alterations were identified in 151 cases (6.8% of total cases) across 13 different tumor types, including breast cancer. An EGFR mutation is not usually tested for in a person with breast cancer. By site of organ, EGFR alterations occurred in glial, lung, brain, head and neck, bladder, kidney, uterine, breast, bone, colorectal, esophageal, skin, and stomach tumors.

Fusions were identified in 13 kinases across multiple tumor types. Of the 248 kinase fusions that were identified, many with novel 5’ fusion partners were identified (2.2% of total cases). n

Researchers Call for More Focus on the Economic Impact of Personalized Treatment in Metastatic NSCLC

By Rosemary Frei, MSc

T

wo clinician-researchers are suggesting that more emphasis should be placed on maximizing the cost-benefit assessment of a precision medicine approach to testing and treating metastatic non– small-cell lung cancer (NSCLC), particularly with patient survival and the duration of treatment increasing appreciably (Graham DM, Leighl NB. Front Oncol. 2014;4:258).

Donna M. Graham, MD, a clinical research fellow, Centre for Cancer Research and Cell Biology, Queen’s University, Belfast, United Kingdom, and Natasha B. Leighl, MD, MMSc, of the Princess Margaret Cancer Centre,

Toronto, Ontario, Canada, focused on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and crizotinib (Xalkori); the latter targets the EML4-ALK fusion gene.

They acknowledge that “these targeted therapies have dramatically changed the diagnosis and treatment of NSCLC.” However, they also note that the monthly cost (in Canadian dollars) for the EGFR TKI erlotinib (Tarceva) is $2847, and for crizotinib it is $10,400, plus additional expenses associated with these treatments.

“These medications have made a great difference for many of our patients. But it’s critical that we try and december 2014

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do better with respect to negotiating lower prices of the drugs for our patients,” Dr Graham told Value-Based Cancer Care in a telephone interview.

Dr Graham and Dr Leighl showed that the cost-effectiveness of EGFR mutation testing and EGFR TKI treatment for patients with EGFR-mutated advanced NSCLC vary greatly, depending on the determination of costs. For example, lower cost-effectiveness figures were found in studies using the low-end negotiated costs (Brown T, et al. Health Technol Assess.

2013;17:1-278) or when some medications were donated (Zhou C, et al.

Lancet Oncol. 2011;12:735-742).

Continued on page 24

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Personalized Medicine

New Approaches to Treatment in the Era of Molecular Biomarkers

By Wayne Kuznar

San Francisco, CA—Transformative changes in cancer therapy will require new models for clinical research and practice. Retrofitting current knowledge into traditional paradigms is suboptimal and will slow the progress in discovering effective targeted agents, said Razelle Kurzrock, MD, Director, Center for Personalized Cancer Therapy and Clinical Trials Office, Moores Cancer Center, University of California, San Diego, at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.

Common cancers are difficult to treat, especially in the metastatic setting.

Metastatic tumors are complicated, Dr Kurzrock said, and it is unlikely that monotherapy will produce prolonged responses or complete remission.

“While it is often claimed that we need new drugs to treat cancer, a more fundamental problem may be the way we classify cancer,” she said.

Although excellent anticancer drugs exist, they often work poorly, because patients with the wrong cancers are being treated with them. In unselected populations, the survival gain with targeted agents is minimal, with an average gain of only 2 months, according to Dr Kurzrock. These agents work only in patients with a sensitizing mutation or aberration.

More rational patient selection will identify patients with the best chance to respond, and this is already occurring. The Profile-Related Evidence Determining Individualized Cancer Therapy (PREDICT) protocol uses a

tion brings the dimerization domains closer together.”

“

While it is often claimed that we need new drugs to treat cancer, a more fundamental problem may be the way we classify cancer.

histology-independent targeted approach in which multiple molecular aberrations were identified and used to match patients with targeted agents.

Patients with 1 genetic mutation had a 27% complete/partial response rate when a matched therapy was available compared with only 5% in patients with a cancer that did not have a matching therapy (P <.001).

“Molecular aberrations do not segregate well by organ of origin,” said Dr Kurzrock.

For example, in PREDICT, a PIK3CA mutation was evident in 10% of advanced cancers originating in various organs, including 29% of endometrial cancers, 24% of breast cancers, and 13% of lung cancers.

Even when initiated in a phase 1 clinical trials program, personalized medicine improves clinical outcomes.

At M.D. Anderson Cancer Center, failure-free survival improved with phase 1 matched therapy, but not with unmatched therapy compared with pre-

”

—Razelle Kurzrock, MD

vious conventional therapy.

In using next-generation sequencing of 75 patients with cancer, no 2 patients had the same molecular portfolio, “which speaks to the need to customize therapy for each patient,” Dr Kurzrock said. “This is going to get even more complicated, because, so far, we’ve only done targeted next-generation sequencing in the genomics, not having touched on transcriptomics, proteomics, or epigenetic changes.”

Three-dimensional in silico modeling is being used to predict response to treatment, and is showing that tumors in patients with the same genetic abnormality may behave differently, depending on where the precise mutation is located. For example, patients with exon 20 insertion mutations are classically resistant to EGFR inhibitors, but 2 patients with non–small-cell lung cancer with exon 20 insertion mutations have responded to cetuximab (Erbitux), which was predicted by in silico modeling, “because that muta-

Transformation in Chronic Myelogenous Leukemia The revolution in improved outcomes—more than 90% response rates, median survival of ≥20 years—in patients with chronic myelogenous leukemia (CML) may be a model for solid tumors, Dr Kurzrock said. This revolution has been driven by a known target, the BCR-ABL fusion, and the subsequent development of the targeted agent imatinib (Gleevec), and a move to treat newly diagnosed patients. The use of the BCR-ABL target then continued with the development of new targeted tyrosine kinase inhibitors for patients with CML. However, when patients reach the blast crisis phase of CML, the response rate drops to <10%, and the median survival is only approximately 12 months, much like outcomes with solid-tumor metastatic disease.

Strategies to transform outcomes in solid tumors may lie in treating newly diagnosed disease and using combination treatments for advanced disease.

Supercomputers are being used to identify convergence pathways in patients with several genetic alterations to reduce the number of drug combinations that may be necessary.

Liquid biopsies—sequencing DNA taken from the bloodstream—are also being tried, and “may obviate the problem that each metastasis may be a little different,” Dr Kurzrock said. n

Researchers Call for More Focus on the Economic Impact... Continued from page 23 One study found that drug cost was the biggest driver of increased cost associated with EGFR mutation testing and treating EGFR-positive patients with erlotinib, despite the higher costs associated with the molecular testing required to stratify patients to these therapies (Bajaj PS, et al. J Med Econ. 2014;12:1-9). The cost of testing for mutation did not exceed $0.019 per member per month; however, that was offset by the reduced treatment of chemotherapy-related adverse events. Conversely, the overall treatment expenditures accounted for $0.013 per member per month, with long-term treatment making the greatest contribution to cost.

24

“

These medi­cations have made a great difference for many of our patients. But it’s critical that we try and do better with respect to negotiating lower prices of the drugs for our patients.

”

—Donna M. Graham, MD

“So these cost-effectiveness studies may be more complex to interpret, with longer survival and treatment duration,” Dr Graham said.

The researchers also examined the

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overall cost-effectiveness of crizotinib therapy, including testing with immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH).

The main Canadian study on this topic,

which Dr Leighl helped conduct (Djalalov S, et al. J Clin Oncol. 2014;32: 1012-1019), showed that the incremental cost-effectiveness ratio for using crizotinib first line in EML4-ALK fusion–positive tumors was $255,970 (Canadian dollars) per quality-adjusted life-year gained. This is “in excess of commonly accepted cost-effectiveness thresholds,” the pair noted.

Dr Graham and Dr Leighl concluded that these expensive medications must be used judiciously, stating that “collaboration with payers and manufacturers is a key to ensure that cost of treatment is not prohibitive for patients and permitting further advances in lung cancer therapy.” n

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ASH 2014 Highlights

the group receiving brentuximab versus 24 months for the group receiving placebo (P = .001), representing a 43% reduction in the risk for disease progression. The 2-year PFS rates were 65% and 45%, respectively, for the cohorts.

“In my opinion, once this study is published, brentuximab should be the standard of care for patients with risk factors for disease progression,” namely, with remission duration <1 year, extranodal disease, B symptoms, 2 or more previous salvage therapies, and primary refractory disease,” stated lead investigator Craig H. Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York.

Dr Moskowitz called the 20% difference in 2-year PFS “unprecedented” in any lymphoma.

Autologous stem-cell transplant (ASCT) cures approximately 50% of patients with relapsed or refractory Hodgkin lymphoma. The other 50% will relapse after transplant. Before this

© American Society of Hematology. All rights reserved.

Posttransplant Brentuximab: New Standard...

“

Continued from the cover

Once this study is published, brentuximab should be the standard of care for patients with risk factors for The disease progression.

20% difference in 2-year PFS is “unprecedented” in any lymphoma.

study, no investigational regimen had improved posttransplant outcomes.

Brentuximab is an antibody-drug conjugate directed to CD30, which is typically expressed in classic Hodg­ kin lymphoma cells. Although brentuximab has been approved by the FDA for the treatment of relapsed or refractory Hodgkin lymphoma and for systemic anaplastic large-cell lymphoma, it is not approved for post-

”

—Craig H. Moskowitz, MD

transplant consolidation.

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

See also pages 26, 35, 36

or placebo. Of patients in the placebo group who progressed, 85% were crossed over to brentuximab.

Brentuximab achieved superior PFS in all prespecified subgroups, including primary refractory patients who relapsed within 12 months of frontline therapy and patients who relapsed after 12 months with extranodal disease.

The overall survival (OS) was no different between the 2 treatment arms in the interim analysis at 2 years, which could be attributed to the high percentage of patients receiving placebo who crossed over to the active treatment arm. The final OS analysis will be presented in 2016.

The most common adverse events in the brentuximab arm included peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%).

Dose reductions of brentuximab effectively alleviated peripheral neuropathy in the majority of patients. n

Stem-Cell Transplant Safe in HIV-Related Lymphoma

By Phoebe Starr

at a glance ➤ For chemotherapy-sensitive patients with relapsed/ refractory HIV-related lymphoma, AHCT should now be the standard of care ➤ Excluding patients from clinical trials on the basis of HIV infection alone is no longer justified ➤ AHCT resulted in an estimated 1-year OS rate of 86.6% and PFS of 82.3% in these patients ➤ The 1-year disease progression was estimated at 12.5%, with a 5% mortality rate

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with HIV infection, are at greater risk for serious infections. Thus, they are typically not considered candidates for AHCT, which is a curative therapy for lymphoma. Despite effective antiretroviral therapy, HIV infection (AIDS) persists as a risk factor for lymphoma.

“Chemotherapy-sensitive patients with relapsed/refractory HIV-related lymphoma may successfully undergo AHCT with favorable outcomes. Our study shows that exclusion from clinical trials on the basis of HIV infection alone is no longer justified. In fact, in clinical practice, patients with controlled HIV infection—with emphasis on the word ‘controlled’—should be receiving transplants as standard of care,” said lead study investigator Joseph Alvarnas, MD, Director of Medical Quality at City of Hope, Duarte, CA. “These results are an important advancement for patients and their physicians seeking access to effective treatments. Payers should also recognize that this treatment should now be the standard of care for these patients,” Dr Alvarnas stated.

Single-Arm Clinical Trial The single-arm, multi-institutional trial was conducted jointly by the

Blood and Marrow Transplant Clinical Trials Network and the AIDS Malig© American Society of Hematology. All rights reserved.

San Francisco, CA—Patients with HIV-­ related lymphoma should not be excluded from clinical trials of autologous hematopoietic-cell transplant (AHCT). Moreover, they should be offered AHCT as a standard treatment option, according to the results of a phase 2 trial reported at the 2014 American Society of Hematology meeting.

The concern has been that immunocompromised patients, such as those

“

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

”

—Joseph Alvarnas, MD nancy Clinical Trials Consortium. The results should be generalizable to a broader spectrum of centers, because december 2014

I

the 16 transplant centers included in the study do not specialize in the treatment of HIV and AIDS. The single-arm study showed that AHCT achieved an estimated 1-year overall survival rate of 86.6% and a progression-free survival rate of 82.3% in patients with HIV-related lymphoma. The estimated rate of disease progression at 1 year was 12.5% and the estimated mortality rate was 5%.

The study included 40 HIV-infected patients with lymphoma who had at least 1 risk factor for disease progression; approximately 50% had ≥3 risk factors for disease progression. Patients underwent AHCT with a modified BEAM (carmustine, etoposide [Toposar], cytarabine [Depocyt], melphalan [Alkeran]) regimen.

Patients did not receive antiretro­ viral therapy during the preparative regimen; that therapy was resumed after the resolution of gastrointestinal toxicities. All patients received standard institutional supportive care after transplant.

At a press conference, Dr Alvarnas noted that a case-control study of 151 matched patients with lymphoma who did not have HIV infection showed similar mortality outcomes to the patients in the present study. n

www.ValueBasedCancerCare.com

25

ASH 2014 Highlights

Cancer Drug Pricing in the United States: What Is Driving the High Costs?

See also pages 35, 36

By Wayne Kuznar

San Francisco, CA—The cost of medical innovation, in particular, a fair price for new cancer medicines, is a complex topic that requires urgent attention, said speakers at a special symposium at the 2014 American Society of Hematology meeting. The financial burden imposed by cancer treatments, and how best to reduce this burden without compromising patient outcomes, generated heated exchanges.

Some charged that the price tag of new cancer drugs does not match the clinical benefit. Others emphasized the impact on patients as reducing outcomes.

US Market Shoulders Bigger Cost Burden Three new drugs approved by the FDA for the treatment of chronic myeloid leukemia (CML) cost approximately $100,000 annually, or almost 5 times the cost of imatinib (Gleevec) in 2001. Before 2000, the average cancer drug price was from $5000 to $10,000 annually. By 2005, the increase was between $30,000 and $50,000 annually, and then ≥$100,000 by 2012, observed Hagop M. Kantarjian, MD, Professor of Medicine and Chairman, Department of Leukemia, M.D. Anderson Cancer Center, Houston.

The US taxpayers subsidize most of the research and development in cancer.

Ironically, when drugs are approved, US patients and the healthcare system pay 50% to 200% more than the rest of the world on comparable drugs.

‘‘

”

—Hagop M. Kantarjian, MD

Of the 13 drugs approved by the FDA in 2012 for cancer indications, 13 were priced at ≥$100,000 annually.

Even older drugs are increasing in

26

price at a rate of 10% to 20% annually.

The price for imatinib increased from $28,000 in 2001 to $92,000 in 2012.

added, “is what our patients can afford.” When it comes to cancer drugs, out-of-pocket (OOP) costs are not af-

“

In one study, equipping patients with understandable information on the burden of costs of cancer care reduced OOP costs in 57% of cases, without requiring a change in the treatment regimen.

”

—S. Yousuf Zafar, MD, MHS

“The explanation is that the industry can charge what the market bears,” said Dr Kantarjian. In addition, the US taxpayers subsidize most of the research and development in cancer, he noted. “Ironically, when drugs are approved, US patients and the healthcare system pay 50% to 200% more than the rest of the world on comparable drugs,” Dr Kantarjian said.

In addition, the pharmaceutical companies claim that it now costs $1 billion to research, develop, and bring to market a cancer drug. Dr Kantarjian suggested that this is not the case, saying that the revised estimate is that the actual cost is 5% to 20% of that cost estimate, which amounts to $60 million to $170 million.

High Costs Affect Patient Outcomes The end result, Dr Kantarjian noted, is the financial harm to patients—high rate of personal bankruptcies, and emotional and socioeconomic adverse effects on patients and their families.

Overall, 10% of patients with cancer do not take their medications, and 20% are poorly adherent. This adversely affects survival rates, he said.

In CML, for example, the 10-year relative survival rate in Sweden is 80% compared with a 5-year survival rate of only 60% in patients with CML in the United States, based on SEER data.

Despite this disparity in survival, patients in the United States have a 30% higher cost of treatment.

Patients have “skin in the game,” Dr Kantarjian said. The key question, he

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fordable for many patients.

In part, the reason that US patients pay more is the vast number of lobbyists for the pharmaceutical industry, said Dr Kantarjian. The lack of patient advocates keeps drug prices high in the United States, he argued. “Even elected officials appear to represent interest groups,” he said. “Only patients are patient advocates.” It will take a patient-based grassroots movement to reverse the tide.

“

What is the US getting for these higher prices? Broader access to new medicines than other countries have….The market may fix itself; it always has.

”

—Alex W. Bastian, MBA

Market Forces Drive Drug Costs Alex W. Bastian, MBA, of GfK Market Access, San Francisco, argued that practical market forces drive drug cost, as with other commodities. The high cost is an “unintended consequence” of continued investment in drug research by the private market.

“What is the US getting for these higher prices? Broader access to new medicines than other countries have,” Mr Bastian said.

He noted that spending on cancer treatment accounts for approximately

6% of all healthcare spending, which is lower in the United States than in Europe. Rising costs are a global phenomenon, and rising healthcare spending is not an isolated US phenomenon.

Between 1998 and 2014, a total of 249 hematologic cancer drugs were unsuccessful, which creates a huge burden on pharmaceutical companies.

“The market may fix itself; it always has….Natural mechanisms provide balance to the system, and one of these is loss of exclusivity” (ie, patent expirations), he added.

Dr Kantarjian countered that a drug purchase by a patient is not a business transaction. “We are talking about a population who did everything right, including buying insurance, and now they are dying and are humiliated,” he said.

According to Mr Bastian, drug pricing reflects American-style capitalism.

“Alternative pricing models are very difficult to implement.”

Greater Transparency Can Improve Outcomes The cost of paying for cancer impacts the efficacy of treatment, agreed S. Yousuf Zafar, MD, MHS, Assistant Professor, Division of Medical Oncology, Duke Cancer Institute, Durham, NC. High patient cost burden is associated with a 70% higher likelihood of nonadherence to treatment.

Improving transparency may be one way to empower patients and improve outcomes, said Dr Zafar. He described his prospective study in which equipping patients with understandable information on the burden of costs of cancer care reduced OOP costs in 57% of cases, without requiring a change in the treatment regimen.

Responding to the suggestion that prices must be high to fuel progress and innovation in drug development, he said, “Making progress in the long run is not a reason for prices to be at the profiteering level.”

Dr Zafar introduced the concept of financial toxicity in oncology into patient care, calling on all oncologists to discuss cost issues with their patients to enhance outcomes and reduce pain.

See article in the November 2014 issue of Value-Based Cancer Care (www. valuebasedcancer.com/vbcc-issues/ 2014/november-2014-vol-5-no-9/25781financial-toxicity-beginning-to-gainoncologists-attention-finally). 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%

60

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

9%

4

%

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

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

0

8

2

0

2

0

0

9

2

0

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

b

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

© 2014, GlaxoSmithKline group of companies. All rights reserved.

Revised: 01/2014 TFR:4BRS © 2014 GSK group of companies.

All rights reserved. Printed in USA. MEL156R0 July 2014

ASH 2014 Highlights

Immunotherapy the Newest Breakthrough in Hodgkin Lymphoma Impressive response rates with new PD-1 inhibitors

Nivolumab Nivolumab was tested in 23 patients with Hodgkin lymphoma, 87% of whom had received previous treatment with at least 3 regimens, including stem-cell transplant and brentuximab vedotin (Adcetris). In all, 35% of the patients had received at least 6 previous regimens. All tumors had genetic abnormalities involving 9p24.1, leading to overexpression of the PD-1 ligands. Nivolumab 3 mg/kg was administered every 2 weeks until disease progression or severe toxicity.

“Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” said lead investigator Philippe Armand, MD, PhD, Senior Physician, Hematologic Malignancies, Dana-­ Farber Cancer Institute, Boston.

Responses were seen in the 100% of patients who had not undergone a stem-cell transplant and in 80% who had a transplant but did not receive brentuximab. At an average of 40 weeks, the complete response rate was 17% overall, and 60% in brentuximab-naïve patients. Another 13% of patients had stable disease.

The progression-free survival rate was 86% at 24 weeks. At the time of data assessment, 48% of the responses Vol. 5

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“

Treatment [with nivolumab] resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated.

were ongoing, and 43% of patients were still receiving treatment. Some patients have been in remission for >1 year, said Dr Armand.

The safety profile of nivolumab mirrored that in solid tumors. Overall, 22% of patients had grade 3 drug-related adverse events (AEs); no deaths or drug-related grade 4 AEs were reported. Two patients discontinued treatment as a result of AEs. “There was no apparent increase in lung toxicity, which we worry about, because many patients had other treatments that can cause lung injury,” Dr Armand said.

In May of this year, the FDA granted nivo­lumab a breakthrough therapy designation for relapsed Hodgkin lymphoma.

Pembrolizumab Pembrolizumab was evaluated in 29 heavily pretreated patients with classic Hodgkin lymphoma who had progressed after treatment with brentuximab vedotin. Craig H. Mosko­ witz, MD, Clinical Director, Division of Hematologic Oncology, Memorial

”

—Philippe Armand, MD, PhD

Sloan Kettering Cancer Center, New York, presented the results of the trial at the meeting.

© American Society of Hematology. All rights reserved.

San Francisco, CA—Two programmed cell death receptor-1 (PD-1) inhibitors—the investigational drug nivo­ lumab and the recently approved pem­ bro­lizumab (Keytruda)—produced dramatic responses in patients with Hodg­kin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of patients who had exhausted other treatment options, providing solid evidence that targeting the immune system can be effective in hematologic malignancies, similar to solid tumors. The data were presented at the 2014 American Society of Hematology meeting.

“Strategies that target tumor cells using the immune system are extremely exciting,” said Catherine M. Bollard, MBChB, MD, Blood and Marrow Transplant Specialist, Children’s National Health System, and Professor of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC. “I see this as a way forward in how we will revolutionize treatments in hematology.”

© American Society of Hematology. All rights reserved.

By Wayne Kuznar

“

Almost all patients had some evidence of tumor shrinkage….Many patients had stable disease on pembrolizumab.

”

—Craig H. Moskowitz, MD

The response rate was 66%, reported Dr Moskowitz, with complete re-

sponses in 21% of the patients and partial responses in 45%. Responses occurred in 75% of the patients with previous stem-cell transplant and in 44% of those who were transplant-ineligible or who had refused transplant.

The median time to response was 12 weeks, and the median duration of response was not reached. “Almost all patients had some evidence of tumor shrinkage,” Dr Moskowitz said.

The clinical benefit rate, which includes stable disease, was 86%. “Many patients had stable disease on pembrolizumab. In fact, some who have been on treatment the longest had stable disease,” he said.

Pembrolizumab 10 mg/kg was administered every 2 weeks until progressive disease, excessive toxicity, or the completion of 24 months of therapy. Overall, 52% of the patients had received at least 5 previous lines of treatment. All patients had previously failed therapy with brentuximab, and 69% had stem-cell transplant failure.

There were 4 treatment-related grade ≥3 AEs—1 patient each with axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 AEs or treatment-related deaths.

Pembrolizumab and nivolumab have individually demonstrated single-­ agent activity in patients with Hodgkin lymphoma, said Dr Moskowitz, commenting on these results. He noted that future evaluations in combination with standard therapies, or even as maintenance treatment to enhance the posttransplant immune response will be important. n

Venetoclax Moves Forward in Chronic Lymphocytic Leukemia, Acute Myeloid Leukemia

By Phoebe Starr

San Francisco, CA—The results of a phase 1b study of the combination of venetoclax plus rituximab (Rituxan) showed encouraging safety and excellent activity in patients with chronic lymphocytic leukemia (CLL).

Venetoclax will move on to a phase 3

trial comparing venetoclax plus ri­ tuximab versus bendamustine (Treanda) plus rituximab in patients with previously treated CLL. The drug is also being studied in acute myeloid leukemia (AML).

The study included 49 patients with december 2014

I

relapsed/refractory CLL who had a maximum of 3 previous myelosuppressive regimens and no previous transplant. The complete response (CR) rate was encouraging.

“Venetoclax plus rituximab is highly active in relapsed/refractory CLL,

Continued on page 36

www.ValueBasedCancerCare.com

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ASH 2014 Highlights

Venetoclax Moves Forward in Chronic Lymphocytic Leukemia...

Continued from page 35

achieving an overall response rate of 88% and a complete response rate of 31%. The results suggest that rituximab adds to the efficacy of venetoclax,” said lead investigator Andrew W. Roberts, MBBS, PhD, Bone Marrow Transplant Physician and Clinical Hematologist, Royal Melbourne Hospital, Parkville, Victoria, Australia.

“Seventeen patients became minimal residual disease-negative on treatment, which is impressive bone marrow clearance,” Dr Roberts noted.

Venetoclax (formerly ABT-199/GDC-­ 0199) is an oral selective BCL-2 inhibitor that rapidly induces responses in approximately 80% of patients with relapsed/refractory CLL as a single agent. Venetoclax has synergy with rituximab in preclinical models of CD20-positive lymphoid malignancies.

This study was undertaken to determine if the addition of rituximab would improve the efficacy of venetoclax.

The study was designed to identify a maximal tolerated dose of venetoclax and the optimal schedule for using the drug with rituximab and the safety of the combination, but remarkable bone marrow clearance was observed with this combination, said Dr Roberts.

Discontinuations were reported in 10 patients, 1 after the occurrence of

“

Venetoclax plus rituximab is highly active in relapsed/ refractory CLL, achieving an overall response rate of 88% and a complete response rate of 31%.

”

—Andrew W. roberts, MBBS, PHD

tumor lysis syndrome, which led to adjustments in the schedule by modifying the dose of venetoclax and giving 1 dose of rituximab every 4 weeks.

“The new schedule overcomes tumor lysis syndrome,” Dr Roberts said.

Venetoclax was generally well-tolerated, with mild gastrointestinal toxic­ ity and grade 3 or 4 myelosuppression (47% neutropenia, 16% thrombocytopenia, and 14% anemia).

The overall response rate was 88%; 31% of patients achieved CR or CR with incomplete platelet recovery, 45% showed partial response (PR), and 12% showed unconfirmed PR. “Good responses to the combination were observed in patients with del17p,

known to have poor prognosis,” Dr Roberts said.

Overall, 9 of the 15 patients who achieved CR showed no minimal residual disease, and 1 patient with CR showed no minimal residual disease at 14 months. Of the patients with PR, 8 had no minimal residual disease. Of the 5 patients who achieved CR and discontinued therapy, none has progressed to date (up to 26 weeks).

Based on toxicity and efficacy data, 400 mg is the recommended dose.

Slightly more neutropenia, gastroin-

“

AML is an aggressive cancer with low survival rates, and there is a high need for new, effective treatment options. The results of this trial of venetoclax are encouraging.

”

—Marina Y. Konopleva, MD, PhD testinal toxicity, and dose reductions were observed at higher doses.

During the question and answer

session, Dr Roberts was asked about biomarkers for venetoclax. He said that most patients with CLL express BCL2 and are sensitive to this drug, and, in his opinion, biomarkers for response are not needed in this setting.

Acute Myeloid Leukemia A separate presentation showed encouraging first results from a phase 2 clinical trial evaluating venetoclax in patients with AML, justifying further investigation of this drug in AML. Venetoclax achieved an overall response rate of 15.5%; there were 5 patients who achieved CR, 4 of whom had incomplete platelet recovery.

These responses were in patients with relapsed/refractory AML or patients who received venetoclax as frontline therapy but who were unfit for intensive treatment.

“AML is an aggressive cancer with low survival rates, and there is a high need for new, effective treatment options. The results of this trial of venetoclax are encouraging and warrant additional study in patients with AML,” said Marina Y. Konopleva, MD, PhD, Associate Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston. n

INTEGRATING INTEGRA TING COST COST,, QUALITY, ACCESS INTO CLINICAL DECISION-MAKING IN ONCOLOGY

Features: • AVBCC Conference Highlights • VBCC Perspectives

• VBCC Videos • Cancer Drug Updates

• Clinic Profile • Economics of Cancer Care

www.ValueBasedCancer.com

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VBCC_WebFiller_101414

Vol. 5

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No. 10

Christine Celgene Patient Support® Specialist

Your single source for personal support

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

Celgene Commercial Co-pay Programa

Financial assistance through third-party organizations

Celgene Free Medication Programa

Help with locating transportation assistance

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

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

Subject to eligibility requirements.

Celgene Patient Support® is a registered trademark of Celgene Corporation. © 2014 Celgene Corporation

08/14

US-CELG140179a

VBCC Perspective

Financial Toxicity in Patients with Cancer: The Sixth Vital Sign Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care, San Francisco, CA

P

ain is often thought of as the fifth vital sign; namely, pain is such a prevalent problem in patients with cancer, that we should strive to measure it at every visit and minimize it as part of patient-centered care. The job of the oncologist is to cure (when possible), prolong survival while maintaining quality of life (when possible), and to minimize pain and suffering, particularly for our patients who are not going to be cured of their malignancy.

Financial instability, economic uncertainty, and personal bankruptcy— each intimately associated with the ever-rising and unsustainable costs of cancer treatment—induce great individual, familial, and societal pain and suffering.

Much has been written lately about financial toxicity among patients with cancer, which represents a very real and growing problem in the United States, affecting large numbers of patients with cancer. Financial toxicity can be caused by the loss of income or personal assets related to patients’ efforts to pay the costs of cancer care; the loss of a job or a house; or what is becoming more common, “medical bankruptcy” after a diagnosis of or the progression of cancer; or any other cancer-related element that lowers a patient’s ability to earn a living.

Financial toxicity, however, is often also something we oncologists impose on our patients through the choices we make in selecting treatment for them, either knowingly or unknowingly.

As oncologists, we must be conscious of financial toxicity: assess it as the sixth vital sign, measure it,

and continually strive to minimize it.

Financial toxicity is particularly relevant among the increasing number

A simple question—“How are your finances holding up in all this?”—can quickly assess the patient’s sixth vital sign and help us better care for our patients. of patients who have high-deductible health insurance policies or large copayments.

When choosing between 2 chemotherapy drugs with equal efficacy and similar side-effect profiles, we should always choose the less expensive drug to minimize financial toxicity to our patients. For example, branded epirubicin costs 20 times as much as generic doxorubicin, and because the 2 drugs were equivalent in efficacy and side-effect profiles, branded epirubicin had markedly greater person-

Quote of the Month

“Next-generation sequencing­­– based tests miss most of the actionable alterations within a given patient.”

—Juliann Chmielecki, PhD

From the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative

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december 2014

al financial toxicity. In a world where we strive to practice patient-centered cancer care, we should logically choose doxorubicin.

The choices we make related to imposing financial toxicity on patients can directly impede our goal of caring for patients. For example, for patients with breast cancer, as copay amounts for adjuvant hormonal therapy increase, adherence drops; even small changes in the patient’s out-of-pocket cost can lead to a decrease in drug adherence, reducing the patient’s chance of being cured of her cancer. Adding financial toxicity to the already full plate of a patient with cancer can result in worse clinical outcomes, thereby reducing our ability to cure the disease, to prolong survival, or to minimize pain and suffering.

Just this week, I saw a patient for a second opinion: a young woman who had a rapidly growing supraclavicular lymph node, with pain in her shoulder and a biopsy that was positive for a high-grade neuroendocrine cancer. Based on her history and physical examination, this was clearly metastatic cancer. Nevertheless, a local academic center had ordered magnetic resonance imaging (MRI) of her neck, as well as a positron emission tomography/computed tomography. She was then hospitalized for 1 week to begin a chemotherapy regimen that could easily and safely be given in an outpatient setting.

Considering that her cancer is metastatic, did a neck MRI add anything to her care, besides financial toxicity?

Instead, hospitalization was imposing additional financial toxicity for the inpatient stay from the high copayment related to the hospitalization.

This financial toxicity was incremental to the psychologic difficulty of a new diagnosis and of being in the hospital away from her husband and children during Thanksgiving week.

Unnecessary imaging and diagnostic tests that do not improve patient care are not “Veblen goods” that patients should covet; as oncologists, we should strive to minimize financial toxicity to our patients in our treatment decisions and minimize the use of diagnostic imaging.

In general, clinical toxicities are similar across different patient demographics: pain is subjective and varies

from patient to patient, but more severe pain is more unpleasant than minor pain, regardless of socioeconomic status. However, financial toxicity is more severe among patients of limited financial resources who have health insurance policies with large copayments or large deductibles.

Financial toxicity is also a key element to consider in caring for medically underserved patient populations. In the United States, race is largely a proxy for socioeconomic status, and the field of racial disparities in cancer is often thought of as a variation in care among persons of lower socioeconomic status.

Patients of lower socioeconomic status are uniquely susceptible to the financial toxicity of cancer and its treatment, often for systemic reasons.

This forms the basis to many solutions of healthcare disparities: by minimizing financial toxicity to patients of low socioeconomic status, we can dramatically improve their care and their health.

This perspective is a call to providers to consider the financial toxicity of our patients as the “sixth vital sign”—to strive to understand it better, to be conscious of the decisions we make in the clinic, and to measure it on an ongoing basis. It requires consideration of the patient, the related health insurance policy, and the healthcare system where care is provided.

As caregivers, we should innovate to minimize financial toxicity for our individual patients, as well as around our entire patient population as health service researchers. Solving this problem starts with measuring it: a simple question—“How are your finances holding up in all this?”—can quickly assess the patient’s sixth vital sign and help us better care for our patients.

The principle of primum non no­ cere is a moral call to minimize unnecessary financial toxicity for our patients with cancer. Our patients depend on us for spiritual and holistic care. Our goal as caregivers is to relieve pain and suffering. We must treat our patients as we would wish to be treated if we had cancer. Being diagnosed with cancer is devastating enough; we should avoid or minimize financial toxicity to our patients whenever possible. n

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Melanoma Management

Favorable Long-Term Survival with Nivolumab Monotherapy in Advanced Melanoma

By Walter Alexander

Zurich, Switzerland—In previously treated patients with advanced melanoma, single-agent nivolumab dem­ onstrated long-term survival that compares favorably with current standard-of-care agents, according to F. Stephen Hodi, Jr, MD, Director, Melanoma Center, Dana-Farber/Brigham and Women’s Cancer Center, Boston.

The CA209-003 phase 1 clinical trial also showed that responses occurring early were durable even after the discontinuation of therapy, said Dr Hodi at the 2014 Society for Melanoma Research International Congress.

Study Details Investigators enrolled 107 patients with advanced melanoma who had received between 1 and 5 previous lines of systemic therapy. They received ≤96 weeks of nivolumab at doses between 0.1 mg/kg intravenously every 2 weeks and 10 mg/kg intravenously every 2 weeks. The study had safety and tolerability as its primary objectives, preliminary efficacy was a secondary objective, and the protocol was amended to collect overall survival (OS) and retreatment outcomes data.

The mean patient age was 61 years.

Most (62%) patients had received ≥2 systemic therapy regimens, of which 65% were immunotherapies (but not CTLA-4 or programmed cell death [PD]-1 inhibitors). At baseline, visceral metastases were present in 78% of patients, and elevated lactate dehydrogenase levels were present in 36%.

Dr Hodi emphasized that, with a median follow-up of 55 months, the follow-up in this study is longer than that of any other anti–PD-1 agent.

The overall response rate (ORR) for all doses was 32%, with a median response duration of 23 months. For the 3-mg/kg dose that was selected for phase 3 studies, the ORR was 41%, and the median duration of response was 22 months.

Dr Hodi also noted that 15 (44%) of the 34 patients with responses to nivolumab showed a response at week 8, the first tumor assessment.

Among responders who discontinued therapy for reasons other than disease progression, the responses lasted ≥16 months in 21 patients, 14 of whom have ongoing responses.

The OS rates with the 3-mg/kg dose (N = 17) at years 1 to 4 are 65%, 47%, 41%, and 35%, respectively, and for all cohorts, the responses are 63%, 48%, Vol. 5

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“

There is a suggestion of a plateau in the curve at this point [years 1-4]….We need prospective analyses to evaluate the efficacy and safety of nivolumab retreatment.

”

—F. Stephen Hodi, Jr, MD

42%, and 32%, respectively. “There is a suggestion of a plateau in the curve at this point…but further confirmation will obviously be needed in continued follow-up,” Dr Hodi noted.

The median OS is 17.3 months (95% confidence interval [CI], 12.5-37.8) for all cohorts and 20.3 months for the 3-mg/kg dose. The median progression-free survival was longest in the 3-mg/kg group (10 months; 95% CI, 2-16); the median OS in this cohort was 20 months.

Treatment with nivolumab was generally well-tolerated, and with all patients having ≥1 year of follow-up, no new safety signals have been observed. Treatment-related immune-­ mediated adverse events were reported in 58% of patients, with 5% of grades 3 to 4. Adverse reactions included skin (38%), gastrointestinal (19%), endocrinopathies (14%), and

infusion reactions (6%). Dr Hodi noted that immune-mediated adverse events with potential immunologic etiologies require more frequent monitoring and/or unique interventions.

Concluding that long-term survival with nivolumab was comparable with current standard-of-care agents, Dr Hodi said that responses occurred early and were durable even after treatment discontinuation. As reported in earlier research, nivolumab was well-tolerated.

Dr Hodi noted that 3 ongoing phase 3 trials are evaluating nivolumab 3 mg/kg in patients with advanced melanoma.

Retreatment An exploratory retreatment analysis was conducted among patients who entered the follow-up period with ongoing disease control (com-

at a glance ➤ Long-term survival with nivolumab was comparable with current standard-of-care ➤ Responses occurred early and were durable even after treatment discontinuation ➤ The median response duration with nivolumab was 23 months ➤ Among responders who discontinued therapy for reasons other than disease progression, the responses lasted ≥16 months in 21 patients, 14 of whom have ongoing responses ➤ Immune-mediated adverse events require more frequent monitoring and/or unique interventions plete response, partial response, stable disease). Retreatment was permitted in these patients subsequent to confirmed disease progression at the same dose assigned for up to 3 years (including the initial treatment period). Prolonged response or stabilization of disease was observed among 5 patients who were retreated, with an increased adrenal mass successfully excised in 1 patient. “We need prospective analyses to evaluate the efficacy and safety of nivolumab retreatment,” Dr Hodi said. n

BRAF-Mutated Melanoma: Improved Overall Survival with BRAF/MEK Inhibition “Closes the Book” on Benefit Zurich, Switzerland—For regimens joining BRAF and MEK inhibition in BRAF-mutated melanoma, recent clinical trial data showing unequivocal overall survival (OS) improvements effectively “close the book” on defining clinical benefit, according to Keith T. Flaherty, MD, Director of Developmental Therapeutics, Massachusetts General Hospital Cancer Center, Boston. Increases in complete response (CR) rates, added Dr Flaherty at the 2014 Society for Melano-

ma Research International Congress, suggest that with longer-term follow-up, increases in durable responses will also be demonstrated.

The call to explore 2-pathway solutions went out even before phase 3 clinical trial data were available on BRAF monotherapy inhibition, when translational research suggested reactivation of the MAP kinase pathway for BRAF and MEK, Dr Flaherty said in an interview. “That immediately pointed to the concept of BRAF/ december 2014

I

MEK combination therapy as a strategy, given the ready availability of numerous MEK inhibitors that were already reasonably far along in clinical development.”

Preclinical evidence supported the idea that BRAF/MEK inhibition is safer and more tolerable than either monotherapy, taking advantage of BRAF inhibitors having a very different effect on MAP kinase pathway signaling in tumor tissue versus normal tissue without BRAF mutations.

Continued on page 40

www.ValueBasedCancerCare.com

39

Ovarian Cancer

PARP Inhibitors in Gynecologic Cancer

By Alice Goodman

New York, NY—Poly (ADP-ribose) polymerase (PARP) inhibitors are an intense area of interest in gynecologic cancers. At least 8 PARP inhibitors are currently in various stages of development, with olaparib (Lynparza) and the investigational drug veliparib the most studied, but to date none has been approved by the FDA for gynecologic cancers.

Despite enthusiasm for PARP inhibition in gynecologic cancers, more research is needed to understand their mechanisms of action, to identify predictive and prognostic biomarkers, as well as the patients who will be most responsive to these agents, said Tamar Safra, MD, Head, Oncogynecological Unit, Tel Aviv Sourasky Medical Center, Sackler Medical School, Israel, at the 2014 Chemotherapy Foundation Symposium.

“We don’t have the answers to these questions yet. PARP inhibitors are an important group of drugs in ovarian cancers, and we await the results of several studies. So far, finding the an-

swers to these questions is a ping pong game between basic science and clinical studies,” said Dr Safra.

It is not clear which of the suggested mechanisms associated with ovarian cancer and PARP 1 trapping is the most important. Studies suggest that the patients who benefit from PARP inhibitors are those with germline or somatic BRCA1 and BRCA2 mutations and cancers that display other BRCAlike deficiencies.

In ovarian cancer, “we are in a bad position. We know BRCA1 and BRCA2 are markers, but we don’t know whether any others can be used as selective or predictive biomarkers.

We need further study,” Dr Safra said. “We also need further study on mechanisms of resistance to PARP inhibitors, and once we identify those, we need to find ways to overcome resistance.”

In studies of PARP inhibitors, significant responses are observed in BRCA germline mutation carriers, she continued. The accumulated information

suggests a wider application of PARP in serous ovarian cancer. “We await the results of many studies of these agents,” Dr Safra said.

‘‘

In ovarian cancer, we are in a bad position.

We know BRCA1 and BRCA2 are markers, but we don’t know whether any others can be used as selective or predictive biomarkers. We need further study.

”

—Tamar Safra, MD

Overall, 15% to 18% of ovarian cancers are related to BRCA1 and BRCA2 mutations, and 50% of serous ovarian cancers show disruption of the homol-

ogous repair pathways. These groups of patients may have the best response to PARP inhibition, Dr Safra said.

She reviewed some of the key studies to date. An early phase 2 study of olaparib versus pegylated doxorubicin (Adriamycin) in patients with BRCA mutations and recurrent ovarian cancer had disappointing results in progression-free survival (PFS).1 “We thought these drugs would change the life of BRCA carriers,” Dr Safra said. “An important point here is that olaparib was more effective in BRCA carriers.”

Olaparib as maintenance therapy in platinum-sensitive relapsed serous ovarian cancer (ie, high-risk patients) reduced the risk for disease progression versus placebo by 65%, but had no effect on overall survival (OS).2 In a subset of patients with BRCA mutations, olaparib maintenance therapy achieved an 82% reduction in risk of progression versus placebo, a median PFS of 11 months versus 4 months, which was highly significant (P <.001).3 Continued on page 41

BRAF-Mutated Melanoma: Improved Overall Survival with... Continued from page 39 Dr Flaherty noted that this separates a BRAF-MEK combination from other 2-drug pairings that could be used in different cancers. “This is a unique phenomenon that we’re taking advantage of,” he said. With dabrafenib (Tafinlar) monotherapy, the rates of cutaneous squamous-cell carcinoma, skin papilloma, and hyperkeratosis

were 19%, 15%, and 30%, respectively, versus 7%, 4%, and 9%, respectively, for patients receiving dabrafenib plus trametinib (Mekinist).

“

This is a unique phenomenon that we’re taking advantage of….It is the overall survival finding that closes the book.…It’s what we celebrated regarding BRAF monotherapy compared with standard therapy.

at a glance ➤ A preclinical evidence has supported the hypothesis that BRAF/MEK inhibition is safer and more tolerable than either monotherapy in patients with BRAF-mutated melanoma ➤ Combined BRAF/MEK inhibition nearly doubles complete response rates and improves progression-free survival and overall survival rates ➤ Research comparing BRAF/ MEK with dabrafenib has shown delayed resistance for the combination, with PFS durations of 9.4 months and 5.9 months, respectively

40

BRIM-3 trial of vemurafenib (Zelboraf) versus dacarbazine (DTIC), with 336 patients in each arm, the hazard ratio (HR) for OS favoring vemu-

”

—Keith T. Flaherty, MD

Combined BRAF/MEK inhibition improved response rates, progression-free survival (PFS), and, according to new data recently presented at the 2014 European Society for Medical Oncology annual congress, OS in evidence accrued in the past year. “It is the overall survival finding that closes the book,” Dr Flaherty said.

“It’s what we celebrated regarding BRAF monotherapy compared with standard therapy.” In the phase 3

Value-Based Cancer Care

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december 2014

rafenib was 0.37.

Dr Flaherty’s research comparing BRAF-MEK combination with da­ brafenib monotherapy showed delayed resistance for the combination, with PFS duration of 9.4 months and 5.9 months, respectively (HR, 0.39).

The best evidence for synergy between BRAF and MEK inhibitors is the near doubling of CR rates, said Dr Flaherty. In the phase 2 trial data on which the FDA had based its acceler-

ated approval for the dabrafenib-­ trametinib combination in BRAF-­ mutated unresectable or metastatic melanoma, the CR rates for the combination and for dabrafenib monotherapy were 9% and 4%, respectively. In a recent study, the CR rates with dabrafenib plus trametinib versus vemurafenib were 13% and 8%, respectively (Robert C, et al. N Engl J Med. 2014 Nov 16. Epub ahead of print).

Dr Flaherty acknowledged that there are doubters who, pointing to the immaturity of the current data, posit that combination therapy may merely be a “temporizing strategy” that fails to create more durable responses. “The counter argument, however, is that we know that complete responders to BRAF inhibitor monotherapy have the most durable responses. So it’s reasonable to expect, based on dabrafenib/trametinib data showing that complete responders shine through as the patients not only who maintain response the long­ est, but clearly also who survive the longest, that another year of follow-up data will likely assuage this concern.”

Dr Flaherty concluded that combined BRAF/MEK inhibition delays the emergence of resistance and improves OS.—WA n

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Ovarian Cancer

PARP Inhibitors in Gynecologic Cancer Continued from page 40 “Maintenance therapy with olaparib is exploring the combination of olapaseems to be a good option in plati- rib plus BKM 120, a PI3K inhibitor. num-sensitive disease,” Dr Safra said.

“Thus far, PARP inhibitors have Several studies have combined proven efficacy as maintenance therolaparib with chemotherapy. In a apy in BRCA mutation carriers and phase 2 study of platinum-sensitive as treatment for active disease. We serous ovarian cancer, olaparib main- know there is single-agent activity tenance therapy after paclitaxel/car- with a good toxicity profile, and boplatin achieved a median PFS of 12.2 months versus 9.6 months with chemotherapy alone.4 “It is still an open question what would have happened if olaparib was given alone,” Dr Safra said.

Two ongoing studies are looking at biologics combined with PARP inhibitors. Interim results of a phase 2 study by Liu and colleagues showed improved PFS with olaparib plus cediranib (an antiangiogenic agent)over Exclusive share of voice reaching 20,000 opt-in Patients, Navigators, versus olaparib alone: the Nurse median Patient Navigators, and Oncology Nurses!

PFS was 17.7 months with the combithe patient voice nation versus 9 months with olaparib alone (P = .005).5 BRCA mutation carriers had a small advantage, whereas noncarriers had a larger benefit in PFS. No OS Conquer advantage was observed for olaparib.5 A second ongoing phase 1 clinical trial

we’ve seen the potential benefit of selected combination therapy with chemotherapy and with cediranib.

We await the results of ongoing trials to tell us the best setting for these drugs, whether single or combination therapy is better, and whether PARP inhibitors can be used as prevention

in BRCA carriers,” Dr Safra said. n References

1. Kaye SB, et al. J Clin Oncol. 2012;30:372-379.

2. Ledermann J, et al. N Engl J Med. 2012;366:1382-1392.

3. Ledermann JA, et al. J Clin Oncol. 2013;31(15 suppl).

Abstract 5505.

4. Oza AM, et al. J Clin Oncol. 2012;30(15 suppl). Abstract 5001.

5. Liu J, et al. J Clin Oncol. 2014;32(15 suppl). Abstract LBA5500.

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Ovarian Cancer

1—Ovarian cancer is the

number 1 cause of death from gynecologic cancers

1 in 72—Number of women who will develop ovarian cancer in their lifetime

5—Ovarian cancer is the 5th leading cause of death from cancer in women

21,980—Number of new

ovarian cancer cases diagnosed in the United States annually

90%—The high-grade serous

subtype is the cause of nearly 90% of ovarian cancer–related deaths

20%

—Percentage of ovarian cancers found at an early stage; diagnosis is complicated because the symptoms are nonspecific and screening is problematic Sources: www.cancer.org; www.cancer moonshots.org; www.ovariancancer.org.

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4th Conference

Pathways-Based Cancer Care Reduces Hospitalizations, Care Variation, and...

Continued from the cover

debunked frequently recommended solutions to the crisis in cancer care delivery, including “value not volume” payment models, strategies to enhance physician competency, patient decision-sharing efforts, and health information technology upgrades.

Social and Economic Pressures “The evidence is…quite clear that the shifting site of care could be doubling cost of care in certain populations like cancer care. But we have a fragmented system, and so there may not be any one stakeholder who is able to really do what’s necessary to prevent that shift in site of care, as we saw with the shift in the COA [Community Oncology Association] map earlier with the migration of oncology. Which probably now is somewhere from 80% of oncology care being delivered in the community, to about 60% being delivered in the community in a fee for service private oncology practice,” said Dr Feinberg.

In addition to the shifting site of care, rising drug costs, longer treatment cycles as a result of life-threatening diseases becoming chronic diseases, and innovation in drug therapies that enable us to treat patients we were unable to treat before are stress-

at a glance ➤ A pathways-based decisionsupport tool instituted as a collaboration between payers and oncologists can modify physician behavior and reduce costs ➤ Overall, 66% of patients with cancer are hospitalized in their last month of life, and 25% are admitted to an intensive care unit in the final month of life ➤ Evidence shows that singleagent sequential therapy is the best way to reduce toxicity ➤ The key to changing providers’ behavior is to evaluate pathways compliance on the 20% of diagnoses responsible for 80% of costs in oncology ➤ At Cardinal Health, oncology pathways have realized a 15% decrease in costs in the first year, and a 7% reduction in hospitalizations/emergency department visits

42

“

We’re not dealing with mathematics when we deal with the science of medicine; we’re dealing with mostly shades of grey, and very little black and white.

”

—Bruce Feinberg, DO

ing cancer care and the healthcare system, said Dr Feinberg. “The end result of this is social, scientific and economic pressures on cancer care, and all health cares, have stressed the system,” he said.

Many proposed solutions to the crisis in cancer care delivery have not been effective, he said. In general, evidence does not seem to be driving physician behavior. Dr Feinberg provided the example of the divergence in the use of Oncotype DX testing by oncologists who treat patients with breast cancer. Appropriate patients for Oncotype DX are those with T1, T2, N0, estrogen receptor–positive, or HER2-negative disease.

In a practice of 41 physicians, the percentage of eligible patients tested by physicians who had ≥10 eligible patients for Oncotype DX testing ranged from 0% to 71%. “We’re not dealing with mathematics when we deal with the science of medicine; we’re dealing with mostly shades of grey, and very little black and white,” Dr Feinberg said.

Clinical Pathways Change Oncologists’ Behavior Reimbursement methodology may not be the answer to changing behavior, he said. Dr Feinberg’s group conducted a retrospective analysis of a pilot program that offered physicians

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in an oncology medical home a reimbursement model that shifted the source of revenue from drug reimbursement margin to professional charges for cognitive services. The team observed no significant change in physician behavior by the shift, including no change in chemotherapy prescribing and no increase in the use of generic regimens compared with a matched control group.

Pathways that eliminate unnecessary medical interventions would decrease drug and nondrug expenses for patients who are managed based on pathways, with no negative effect on survival. In a study by Temel and colleagues (N Engl J Med. 2010;363:733742), an early palliative care pathway integrated with standard oncologic care for patients with lung cancer improved quality of life and survival despite less aggressive treatment compared with standard cancer care alone.

Such a strategy has not been embraced, as evidenced by the uniformly substandard use of hospice care in Medicare beneficiaries with cancer. In the final month of life, only approximately 50% of patients with cancer are enrolled in hospice, and the ones who are spend only 8 days in hospice.

Overall, 66% of patients with cancer are hospitalized in their last month of life, and 25% are admitted to an intensive care unit in the final month of life.

Cardinal Health Pathways: Improved Outcomes, Reduced Costs To mitigate the more relevant behavioral and cultural issues that preclude effective cancer care, Dr Feinberg showcased Cardinal Health pathways (PathWare), which are digital pathways-based decision-support tools. The software helps oncologists choose evidence-based, cost-effective therapies for patients with common cancers, as well as implement timely end-of-life care. The tool is user-friendly and can be navigated in <2 minutes.

The key to changing providers’ behavior is to evaluate pathways compliance on the 20% of diagnoses responsible for 80% of the cancer care costs, Dr Feinberg said, and to focus on behaviors with the greatest impact on cost and quality.

“

What we’ve seen in our claims data is that two thirds of the [drug] regimens that are given in the third line of cancer care are complex. Yet, every bit of evidence says single agent sequential is the way to go, because all you’re doing with complex regimens is incurring more toxicity that fragile patients cannot tolerate, and putting them in the emergency department and in the hospital.

”

—Bruce Feinberg, DO “What we’ve seen in our claims data is that two thirds of the [drug] regimens that are given in the third line of cancer care are complex,” he said.

“Yet, every bit of evidence says single agent sequential is the way to go, because all you’re doing with complex regimens is incurring more toxicity that fragile patients cannot tolerate, and putting them in the emergency department and in the hospital.”

The payer-supported oncology pathways programs for breast, colon, and lung cancer have been evaluated with 5 payers and have realized a 15% decrease in the cost of cancer care in the first year, along with a 7% reduction in hospitalizations and emergency department visits. n

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

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4th Conference

Diagnostic Tests Will Face Value-Based Pricing Under Payment Reform Cost will be based on payers’ assessment of evidence and outcomes

By Wayne Kuznar

“

Los Angeles, CA—Major coding changes in cancer tests are ahead, including the elimination of stacked coding and the creation of new codes by the Centers for Medicare & Medicaid Services (CMS), which should improve the clinical application of cancer test choices. Speaking at the Fourth Annual Conference of the Association for Value-Based Cancer Care, Marc Samuels, JD, MPH, President and CEO at ADVI, a healthcare consulting company, Washington, DC, said that value-based testing is important for healthcare cost containment.

Cost of Diagnostics Rising Cancer costs are rising at 3 times the rate of inflation, and the cost of cancer diagnostics is rising even faster than overall cancer costs, Mr Samuels said.

Diagnostics is the fastest growing line item in the Medicare budget. “The diagnostic companies know that in order to evolve and to get the price they want—largely because the market is changing—stacked coding is going away,” said Mr Samuels.

“Payers on both sides, Medicare and the private payer market, will be able to tell the price, the outcome, and the value of individual tests.” With this knowledge, diagnostics companies will need to show greater overall value to their tests.

The diagnostic companies know that in order to evolve and to get the price they want… stacked coding is going away. Payers on both sides, Medicare and the private payer market, will be able to tell the price, the outcome, and the value of individual tests.

”

—Marc Samuels, JD, MPH In a shift from the current fee-forservice model to pay-for-value, profitability will depend on increasing and managing utilization. “Today, the only real sort of contracting tool we’ve used, other than the bigger labs that have had some degree of capitation, has been adhering to guidelines,” Mr Samuels said.

The unknown is whether the FDA will ultimately regulate all products, he said. From the payer perspective, clinical utility of testing needs to be established, along with knowing the comparative and clinical effectiveness of testing. On the public payer side,

Table CMS to Create New Codes After FDA Approval of Advanced Tests New tests • CMS now required to adopt temporary HCPCS codes to identify new advanced tests and new tests that are cleared or approved by the FDA • These are only in effect until a permanent HCPCS code is created, not to exceed 2 years Existing tests • Existing tests that do not have a unique HCPCS code (ie, tests paid under a miscellaneous code) will be assigned a unique HCPCS code by the Secretary by January 1, 2016 CMS indicates Centers for Medicare & Medicaid Services; HCPCS, Healthcare Common Procedure Coding System.

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evidentiary standards are also being set. “CMS will begin to come out with guidance that basically standardizes and makes transparent what they’re going to look for in terms of evidence for covering tests,” said Mr Samuels.

Advanced and Nonadvanced Tests Mr Samuels also spoke about putting laboratory test coding into the hands of CMS by establishing advanced and nonadvanced diagnostics. An advanced diagnostic is defined as a test furnished and sold for use by a single laboratory, and is an analysis of multiple biomarkers combined with a unique algorithm to yield a single patient-specific result, or is cleared or approved by the FDA. Advanced tests will be evaluated much like cancer drugs are evaluated now, Mr Samuels predicted.

Non–FDA-approved tests, such as panel tests and single analytes, will continue to generate the same payment rates and coverage. The rates for nonadvanced tests (ie, newer tests that essentially have the same value as the older version) “will be crosswalked or

gap-filled, essentially the way Medicare does those tests today,” he said.

“At some point, both of these groups will move to being valued-based on commercial payer rates.”

Diagnostics Pricing Advanced tests will be paid a “list price” for the first 3 quarters, but manufacturers may be subject to penalty if the list price exceeds 130% of the market rate. If it does, the tests will be priced by the medical director at the Medicare Administrative Contractor.

“After 9 months, you are going to be given a pricing based on the median weighted average of all of your commercial payer reimbursement,” Mr Samuels said.

Mr Samuels foresees that by 2017, all tests will be based on commercial payers’ rates, whether through contract or

“

CMS will begin to come out with guidance that basically standardizes and makes transparent what they’re going to look for in terms of evidence for covering tests.

”

—Marc Samuels, JD, MPH established rates. “We essentially are putting the power back into commercial payers to look at the evidence, help Medicare decide what the payment and coverage should be, and setting up the paradigm that way,” he said.

New Diagnostic Codes CMS will be asked to create codes that are based on evidence and outcomes (Table).

“Just like they create Q codes for drugs, and then they have J codes, we’re going to ask them to create essentially a D code for diagnostics,” explained Mr Samuels. “On top of that, we’re asking that they overlay that with either a Z code [proprietary to a company] or by a modifier.”

The program would be evidence-based, with pricing based on inputs provided to the contractor. A Z code would be provided instead of stacking codes. n

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4th Conference

Providing Financial Incentives for Patients with Cancer to Participate in Their Care Improves Efficiency

By Wayne Kuznar

Los Angeles, CA—A new patient incentive program aligns patient behaviors and choices with financial incentives in an effort to reduce the financial burden of cancer care for patients.

The program was introduced to attendees at the Fourth Annual Conference of the Association for Value-­ Based Cancer Care by Gordon Kuntz, Senior Director of Payer Solutions at ION Solutions.

Patients with cancer represent an average of well under 1% of patients in a health plan yet account for 10% to 15% of the plan’s costs, creating management challenges, said Mr Kuntz.

The average cost of care in the 6 months after the first round of chemotherapy is approximately $125,000. “That’s a big deal for the payers, but for members, it’s a bigger deal,” he said.

Patients with cancer earning ≤$60,000 (the average annual income in the United States is $51,000) can expect to spend 25% of their annual gross pay on health-related issues in the year they are diagnosed. Patient payment responsibility has been increasing by 5% to 6% annually.

Although copays may encourage higher member financial responsibility and more rational decision-making in healthcare purchasing, “when you have cancer, there’s not a lot of discretion involved in your treatment,” said Mr Kuntz. “There’s not a lot of shopping involved. There are not a lot of comparisons to be done.”

This creates an imbalance in which some patients will have to make choices that no one should have to make, he said, creating significant financial stress.

Other major unintended consequences of increased patient financial responsibility are treatment avoidance and reduced adherence, which can paradoxically increase the cost of treatment for the payer as the disease progresses and becomes more costly to treat.

“We look at this as an opportunity for change,” said Mr Kuntz. In an initiative that began at ION Solutions, payers and self-funded employers reward patients with cancer for program compliance. The goal is to reduce health plan costs, including those related to oral drug waste, emergency department utilization, and unwanted services, while mainVol. 5

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Table Behavior Triggers and Potential Benefits Behavior triggers

Expected benefit for sponsor

Patient completes disease-specific Ensures orientation to optimal treatment education, including (as appropriate) expectations clinical trial options

“

When you have cancer, there’s not a lot of discretion involved in your treatment. There’s not a lot of shopping involved. There are not a lot of comparisons to be done.

”

—Gordon Kuntz

taining cancer care quality and patient satisfaction.

“Patients will respond to financial incentives for steerage in oncology, physician selection, and program compliance,” Mr Kuntz said.

Once a patient is identified in the practice, a list of behaviors expected of the patient is generated, with a list of “triggers.” The triggers range from behaviors expected at the initial diag-

Patient’s caregivers complete training also (plus their role)

Ensures patient support during treatment; increases compliance with treatment regimen

Participate in patient distress screening

Identify potential roadblocks to successful treatment

Discuss written treatment plan

Defined and documented treatment plans help patients to understand the intent of care and to make more practical choices

Participate in advance care planning discussions

Minimizes unwanted treatment at end of life; aligns treatment with patient wishes

Understand home care instructions for symptom management

Minimizes emergency department visits and resulting inpatient admissions

Successfully complete MTM program with >90% adherence and compliance to oral drugs (monthly)

Reduces drug waste from therapy holidays and reduces hospitalizations

No emergency department visits without call to practice first

Minimizes emergency department visits and resulting inpatient admissions

Set up account on patient portal and visit weekly (or monthly)

Ensures continuing patient education and communication with practice

Complete satisfaction survey

Improve program and network credentialing

Participate in a survivorship program Ensure optimal posttreatment follow-up and care MTM indicates medication therapy management.

nosis through therapy (Table). Examples of triggers include completing disease-specific education and having a caregiver present at the training, participating in distress screening, and discussing a written treatment plan.

As the patient completes the triggers related to cancer treatment, he or she receives monetary credit. The credit is applied to a credit card that can be used for any healthcare expense, including copays. ION reports to the employer or the health plan how the patient’s participation in this activity

contributed to lower cost for that patient, as well as the employer or the health plan.

“We’re not saying that patients shouldn’t go to the emergency department. If you need to go to the emergency department, you need to go to

“

Patients will respond to financial incentives for steerage in oncology, physician selection, and program compliance.

”

—Gordon Kuntz

the emergency department,” Mr Kuntz said. “But you need to communicate with your oncologist and the office before you do. You need to make sure that you’re calling the office for support along the way.”

This program results in an alignment of stakeholders to provide superior cancer care. “The patient is the beneficiary, but also an integral part of that alignment,” said Mr Kuntz. n december 2014

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4th Conference

Medical Stop-Loss Insurance About to Get Riskier as Oncology Drug Pipeline Gets Pricier

By Wayne Kuznar

Los Angeles, CA—As more high-cost cancer therapies become available, traditional stop-loss insurance becomes riskier for employers and for payers.

Pharmaceutical companies, employers, and benefits design managers are expected to partner to mitigate this economic risk and enhance end-payer coverage for new drugs using the stop-loss risk management tool for self-funded health plans, said Ryan Siemers, CEBS, a risk management insurance expert at Aegis Risk in Alexandria, VA. “Specialty pharmacy is creating a new risk dynamic for self-funded health plans,” Mr Siemers said at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Most large employers have self-­ funded health plans and are ultimately at risk. Reinsurance is insurance for health insurance programs, typically for self-funded employer health plans, said Mr Siemers, but it is just as necessary for other risk bearers, such as accountable care organizations and other health plan payers.

These entities need to be insured for new risks, such as catastrophic therapies that can cost $100,000 or more annually and may be ongoing over multiple years.

Medical stop-loss insurance is a risk management tool designed to protect employers from large catastrophic claims. In exchange of premium, it covers excessive variability in self-funded medical plan expense; in essence, it is a budgeting tool that protects self-funded plans from financial calamity.

Two Types of Stop-Loss Pricing There are 2 types of medical stoploss insurance (Table). The “specific” stop-loss model is the common form: it guards against the volatility of an individual high claimant.

For example, a self-funded health

46

edical Stop-Loss Insurance: A Risk Management Tool for Self-Funded Table M Health Plans

“

Specialty pharmacy is creating a new risk dynamic for self-funded health plans….Stop-loss pricing will need to account for both expense and duration of costly specialty therapies.

Specific (or individual)

Aggregate

Guards against the volatility of individual high-cost claimants

Protects against overutilization of the entire health plan

• The common form of stop-loss • Reimburses claims beyond a specified deductible—as low as $50,000 and up to $1 million • The contract stipulates the covered claims based on dates of incurral and/or payment (eg, 12/15, paid) • Reimburses expense for an individual contract year (ie, it is not ongoing) • Premiums vary widely by deductible

• More common with smaller (<1000 employees), risk-averse employers • Reimburses if overall plan expense exceeds a threshold (eg, 125%) —Based on an expected claims rate per covered employee • Premiums are lower, because claims are uncommon • Typically, it augments “specific” stoploss —No double indemnity

tion of the entire plan. Reimbursement will kick in only if an overall plan expense exceeds a specific threshold, often at 125%.

The New Dynamics in Specialty Drugs Specialty pharmacy will test the traditional stop-loss insurance, said Mr Siemers. With traditional stop-loss —Ryan Siemers, CEBS pricing, catastrophic claims are generally paid for episodes of care within 1 year. “Pricing is based on the next 12 months of these ‘pop-up’ claimants,” plan may have a medical stop-loss he said. “Stop-loss underwriting does pricing at $300,000. If the employer has not account well for ongoing liability in an employee who exceeds the $300,000 future periods. Stop-loss pricing will deductible within a policy year, the need to account for both expense and stop-loss coverage reimburses the ex- duration of costly specialty therapies.” pense of that claimant. In this case, the The new dynamic with some spestop-loss pricing cuts the volatility. cialty drugs is the potential need for In the “specific” form, “You’re ex- treatment lasting many years, as forchanging monthly, regular premium merly fatal cancer diagnoses become payments, for an unpredictable oc- chronic conditions, adding to the trend currence of an event that needs that of increasing $1 million claimants over re­imbursement,” Mr Siemers said. “It time. This trend may accelerate as the smooths it out, and that’s why self-­ Affordable Care Act removes health funded employers have been using it plan annual or lifetime cost limits. for quite some time.”

As stop-loss underwriters, “we are The “aggregate” form of the medical trying to look more at the future,” said stop-loss pricing is typically only used Mr Siemers. “We’re trying to get an by smaller employers (under 1000 em- employer to find value in this coverployees). It guards against overutiliza- age, as these therapies start to hit.”

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Premiums may potentially be higher, but so is the newfound risk.

Underwriters will welcome collaboration with the pharmaceutical industry to manage drug costs.

“It’s key for the provider in the pharmaceutical community to be aware that the underwriting commu-

As stop-loss underwriters, we are trying to look more at the future.

We’re trying to get an employer to find value in this coverage as these therapies start to hit.

‘‘

”

—Ryan Siemers, CEBS nity and the payer community, particularly on the employer side, need to have a better sense of what’s in your pipeline…so that we can perhaps work with underwriters to have a coverage,” said Mr Siemers.

“The risk is in the future, but we need to act now to get a better understanding of therapies in the pipeline,” he emphasized. n

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New Oncology Models Emerging with Shift from Volume-Based to Value-Based Reimbursement

By Wayne Kuznar

Los Angeles, CA—Radical changes are resulting from the recent shift from volume-based to value-based reimbursement and care. The fundamental shift in reimbursement models is proving disruptive, as providers and payers are exploring integration opportunities with their continuum partners that may redefine the current reimbursement paradigm, said Jonathan Bluth, MBA, Vice President, Healthcare Investment Banking, Deloitte Corporate Finance LLC, Los Angeles, CA, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

“Health reform initiatives and incentives provide a potential tipping point to accelerate the existing momentum for physician practice consolidation,” stated Mr Bluth (Figure).

The result of the underlying shift in reimbursement is uncertainty facing the oncology community. With the rise of accountable care organizations (ACOs), physician practices, whether independent or small group practices, and potential investors of practices are asking if they can “manage the game,” said Mr Bluth, “or will they just have to accept whatever the larger ACO pushes down their throats?”

Many physician groups are wondering whether they should sell their practices, and other physician practices are actively pursuing or are considering merger and acquisition approaches from financial or strategic buyers.

Why Are Oncology Practices Pursuing Mergers and Acquisitions?

The reasons for this are different for each practice group but have common themes, which include: • Liquidity at attractive valuations: the window is open • Concern over uncertainty in the future: to preserve income • To gain access to outside capital • To grow through acquisition • For information technology and infrastructure investment • To pursue opportunistic new revenue areas • To gain access to a larger platform • Greater size and scale creates relevance in the market and with payers • More sophistication regarding new payment models • To potentially accelerate growth in income • To better compete with larger comVol. 5

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“

Health reform initiatives and incentives provide a potential tipping point to accelerate the existing momentum for physician practice consolidation.

”

—Jonathan Bluth, MBA

petitors in the market now and in the future • To be more efficient at taking advantage of growth opportunities.

Oncology Merger and Acquisition Frenzy Oncology merger and acquisition activities have seen consolidation within and across a variety of sectors.

Suppliers, physician groups, and pharmaceuticals are no longer independent, and are getting closer with consolidation, said Mr Bluth. “Individual companies that had been focused on pharmaceuticals or have been suppliers are moving into other aspects of the value chain, or specific industry-focused physician practice management companies are moving into other clinical specializations,” he noted.

A variety of acquisition strategies have been used across oncology. One strategy is to acquire more volume to drive down per-unit costs or perhaps to improve on the ability to drive decision-making within an ACO. Another approach is to cross over to other markets in an effort to offer greater value and quality. Private equity investment in oncology is also continuing, despite the reimbursement uncertainties. The interest by the public market will be tested with the initial public offering of 21st Century Oncology, which has been in an acquisition spree, with Oncure being a recent acquisition.

21st Century Oncology “is continuing to look for more investments across the country, and now even internationally,” Mr Bluth said. With the Oncure transaction, 21st Century

Oncology operates 165 treatment centers, including 132 centers located in 16 states.

In 2011, with the financial backing of Oak Hill Capital Partners, Physician Oncology Services and Vantage Oncology merged to create one of the largest networks of outpatient radiation oncology centers in the country.

Vantage Oncology then expanded its presence with the acquisition of Radiation Oncology Services of America, adding 17 new treatment centers across 5 states. Vantage Oncology’s desire to establish a national model and expand into new markets may provide a new opportunity for merger and acquisition activity in the Northwest and Mountain West, said Mr Blum.

“

Individual companies that had been focused on pharmaceuticals or have been suppliers are moving into other aspects of the value chain, or specific industryfocused physician practice management companies are moving into other clinical specializations.

”

—Jonathan Bluth, MBA

Figure H ealthcare Reform Accelerates Momentum for Physician Practice Consolidation Volume-focused • Reimbursed

per admission and/or units of work • Physicians seeking employment models for income security and lifestyle reasons • Limited incentives to prevent admissions or coordinate care • Continuum lacks integration • Declining reimbursement for hospitals and physicians • Significant uninsured and underinsured • “Pay-for-compliance” rather than true outcomes-based reimbursement • Limited access to capital for technology investments required to meet HITECH • Regulatory issues that restrict integration (eg, Stark, Anti-Kickback, Private Inurement)

Health Reform Value-focused • Competing on quality, patient safety, cost-

effectiveness, and coordination of care

• Episodic/bundled payments mechanisms • Shift of large groups of uninsured to capitated

Medicaid population

• HITECH dollars technology use and integration • Improved documentation of care and

information sharing through information exchanges • Accountable care organizations/medical homes • Demonstration projects are factoring more into reimbursement and government payments • New focus on prevention and population health

HITECH indicates health information technology.

Copyright © 2014 Deloitte Development LLC. Used with permission.

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With the acquisition of e+CancerCare, Kohlberg & Company (a US private equity firm) has invested in expanding its outpatient cancer center group.

One acquisition that did not work as intended was AstraZeneca’s purchase of Aptium Oncology, a provider of outpatient oncology management and consulting services, which was eventually sold to Mount Sinai Medical Center.

“All of these groups are still on the prowl, and it’s all of the large national players that are still hungry for acquisitions to feed that engine,” said Mr Bluth. “Many of these companies are privately held today, but 21st Century Oncology is going public, and, I expect, Vantage’s Oncology will soon. There will be so much more transparency behind their business models.” n

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Interview with the Innovators

Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era With the Breast Cancer IndexSM Assay:

An Interview With Stephen C. Malamud, MD, and Susan K. Boolbol, MD, of Mount Sinai Beth Israel Hospital

W

Stephen C. Malamud, MD

Susan K. Boolbol, MD

ith the advent of gene expression profiling, we have gained the ability to objectively advise patients with breast cancer, among other cancers, on their risk of recurrence and potential benefit of therapies through the administration of assays designed to provide predictive and prognostic data. This is welcome news for a patient who has successfully endured treatment for cancer and remains fearful of the risk of relapse.

Also welcome news for patients with estrogen receptor–positive (ER+) breast cancer, recently presented data suggest a survival benefit for some patients by extending endocrine therapy to 10 years, rather than stopping at 5 years. But the question remains, which subset of ER+ patients stands to benefit?

Physicians have a variety of choices on the assays to apply to their patients. There are many genetic expression profiling and expanded immunohistochemistry (IHC) tests to guide the adjuvant therapy of women with breast cancer, including Breast Cancer Index (BCI), MammaPrint, Oncotype DX, and Prosigna. In this in-

PMO Thank you for talking with us today about guiding the adjuvant therapy of women with breast cancer using the Breast Cancer Index (BCI).

To begin, can you describe the circumstance in which you would use this test?

Dr Malamud At the time of diagnosis, a woman with breast cancer will come to the office to make that critical decision on how to move forward with their adjuvant therapy. There are many parameters we will use to ascertain risk and determine what the best treatment might be.

First and foremost is the clinical presentation in the stage of the cancer.

Second comes a variety of these biomarkers that we now use to help differentiate who needs chemotherapy, hormone therapy, or combinations of those therapies and predictions in terms of outcome of treatment and the benefits of those same therapies.

The markers we have considered to date include the estrogen or progesterone receptor by IHC, but more importantly, as we enter the era of per-

sonalized medicine, we look at the genomic analysis of the tumor to decide what needs to happen in the first 5 years. If they are hormone positive, do they need chemotherapy in addition to their hormone therapy? Secondly, what should we do when those patients have survived without a recurrence for their first 5 years and we need to decide how to move forward?

We now have genomic analysis for both of those scenarios. The most critical new question is what to do at that fifth year when we have been relatively stuck with information that tells us that only a small percentage of women will benefit from an additional time on anti-estrogen therapy beyond the fifth year.

The Breast Cancer Index (BCI), a newly developed second-generation genomic assay, will tell us who is likely to benefit with the additional ther-

Value-Based Cancer Care

apy (Figure 1). Other women, who have a low likelihood of benefit, may be absolved from continuing therapy.

We can look at BCI to determine not only the risk of recurrence but the likelihood of benefit from additional therapy. We determine the risk of recurrence over those next 5 years, defined as low or high risk, and use that information as a segue to the discussion of the potential additional benefit of therapy. Based on data from the MA.17 study, those patients who have anything other than a low BCI predictive are more likely to benefit from an additional 5 years of therapy.

Dr Boolbol This field has changed enormously over the past 20 years.

We wouldn’t think of treating a patient now without information from the initial biopsy, IHC of estrogen and progesterone, and Her2 status. And now we need genomic information

Figure 1 Predictive and Prognostic Indications

Dr Malamud is Associate Professor of Medicine, Hematology and Medical Oncology at Mount Sinai Hospital in New York, New York. Dr Boolbol is Chief of Breast Surgery, Appel-Venet Comprehensive Breast Service at Mount Sinai Beth Israel Hospital in New York, New York.

48

stallment of Interview With the Innovators, we focus on BCI – the only validated test available to physicians and patients that provides guidance on the benefit of extending endocrine therapy for an additional 5 years.

BCI is a biomarker test that assesses distinct biological pathways for breast cancer. It predicts both early recurrence (0-5 years) and late distant recurrence (5-10 years) as well as the likelihood of benefit from extended endocrine therapy. About two-thirds of breast cancer patients are ER+, and the risk of late distant recurrence is a concern, with more than 50% of recurrences occurring after 5 years.

The publishers of PMO had the unique opportunity to discuss the utility of BCI with Dr Stephen Malamud and Dr Susan Boolbol of Mount Sinai Beth Israel Hospital about their collaboration as a medical and surgical oncology team to employ a test such as BCI in the treatment decision-making process for patients. What follows are highlights from their thoughtful exchange. To view the video of their discussion, please visit www.personalizedmedonc.com.

BCI Predictive

Predicts Likelihood of Benefit From Endocrine Therapy (5-10 yrs)

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december 2014

BCI Prognostic

Assesses Individual Risk of Late Recurrence (5-10 yrs)

when we’re discussing the potential benefit of chemotherapy. We now have assays to help guide us in treatment decisions.

We have several clinical trials showing that 10 years of endocrine treatment is better than 5 years. That benefit for the overall population of women with breast cancer is relatively small, single digits. But, with BCI, we now have an assay to give us more information, to personalize the treatment for individual patients. We can tell a patient, we’ve run this assay on you and you are not likely to derive much benefit from an additional 5 years or, you will likely derive benefit. It’s a paradigm shift of great benefit to patients.

PMO Can you discuss the importance of the multidisciplinary treatment team and the value of gene expression profile tests to the team?

Dr Boolbol A critical part of taking care of women with breast cancer is the team approach. A surgeon cannot take care of a breast cancer patient alone, a medical oncologist cannot do it alone, and a radiation oncologist cannot do it alone. It really is a working, functioning team that needs to take care of the individual patient. In doing that, part of the surgeon’s job as potentially the first interaction with the patient is educating the patient on how their team functions and all the treatment options, from surgery to

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systemic therapy.

Considering these new genomic tests and patients’ involvement with the multidisciplinary team, it’s important that the patient understands that there are tests that the treatment team uses for early and late treatment. The patient should anticipate interaction with all of the team members, and that will make a difference to their overall care. In fact, studies have shown that patients treated at high-volume centers, meaning centers that take care of a lot of breast patients, treat patients in a multidisciplinary fashion, and the patients have better outcomes.

Dr Malamud Dr Boolbol and I are very fortunate in that when patients come in for their first visit after they’ve had a diagnosis established, we have the opportunity to see patients together or within several days of each other.

Patients really pick up on that, and they understand that there is a multidisciplinary collaborative effort to maintain their health and continue their care for years. I’m not going to take care of you only for these couple of months and then I’m gone and will turn you over to this person. It is a team that continues for at least 5 years and usually more. That kind of interaction is appreciated, and having us both in the same room sometimes at the same time where you’re talking about the surgical aspects and the postoperative care and introducing the concept of genomic testing, prognostic testing, hormonal therapy, chemotherapy, etcetera. The treatments segue into my role quite nicely, and then if at the end of the day they still have some questions, the fact that we can assure them that the following day their case is going to be presented at an even larger, multidisciplinary session again affords some relief because now they’re going to have 20-odd heads discussing their case, hopefully getting a check mark of approval to what we’ve already discussed.

Dr Boolbol As I tell patients, breast cancer is too big for them to handle alone. They need support. And it’s the same thing for those of us caring for them. As a multidisciplinary team we support each other in order to take care of the individual patient. It’s important for patients to know how the team interacts and functions. For example, since I am the first one seeing the patient postoperatively and seeing their pathology first, I’m the one who orders any genomic test that will aid in the decision of chemotherapy.

As the patient moves through treatment and follows up with me and with Vol. 5

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Figure 2 BCI Validation Studies

BCI Validation Studies MA.17 RCT Predictive

J Natl Cancer Inst, 2013

Stockholm RCT Prognostic

Multiinstitutional Prognostic

TransATAC RCT Prognostic

Clinical Cancer Research, 2013

Clinical Cancer Research, 2013

Lancet Oncology, 2013

Validation in Prospective RCT Cohort

Validation in Multi-institutional Cohort of Consecutive Cases

Validation in Prospective RCT Cohort & Head to Head with Oncotype Dx

249 Patients

317 Patients

358 Patients

665 Patients

Post-menopausal

Post-menopausal

Pre- and Postmenopausal

Post-menopausal

ER+ LN- and LN+

ER+ LN-

ER+ LN-

ER+ LN-

Extended AI

Adjuvant TAM

Adjuvant TAM

Adjuvant TAM or AI

Validation in Prospective RCT Cohort

Case-control design to enrich for recurrences

Over 1,500 patients across 4 study cohorts

Dr Malamud, then we start discussing other tests that will aid in the decision of long-term treatment, specifically endocrine treatment such as BCI. PMO BCI touts the unique ability to predict risk of both early and late recurrence, as well as likelihood of benefit from extended endocrine therapy in early ER+ breast cancer. In your experience, are these performance characteristics unique for BCI compared with the other assays?

Dr Malamud Yes, BCI testing has become an important adjunct in our care of patients, especially as we make decisions about therapy beyond 5 years. Normally it’s been the paradigm in the adjuvant treatment of breast cancer that the endocrine treatment continue for 5 years, and we’ve been hard-pressed to find data to support going past the 5-year mark.

Recently, however, several trials, including the ATLAS, MA.17, and others, have shown that there is an advantage for some women to go on with extended adjuvant treatment beyond the fifth year.

The BCI test can help us decide which of those women are actually likely to see benefit from an additional 5 years. If one looks at those trials that were done years ago and now beyond the 10-year mark, the absolute benefit for most of the women if one looks at the mean is only about 5% or 6%, which means that most women do not benefit from being on 5 years of additional therapy. Our goal is to try and isolate those patients who are going to benefit from treatment and not give extended 5 or 10 more years of hormonal therapy to those women who are not likely to

realize benefit.

So BCI is a test that separates those patients who are more likely to ben­ efit from those who are unlikely to benefit. It offers a genomic profile of the tumor using a genomic panel completely distinct from the one that they may have had 5 years earlier and looks at the likelihood of benefit from continuing that treatment.

We are able to explain to the patient that this test is designed to help tell us whether or not there’s more therapy that’s likely to work for them in preventing this disease from coming back. It will help tell us whether or not you need to be treated beyond that fifth year or if we can just stop and be comfortable with that idea.

The idea of being able to stop potentially problematic hormonal therapy that they’ve endured for the 5 years prior is an amazing relief for these women who do not have to continue therapy. And for the women who are likely to benefit from continuing therapy, knowing that there is something that’s going to help them if they are at high risk is again almost of the same benefit.

Dr Boolbol If you compare how we treated patients 10 years ago to now, it’s vastly different. That was really just a cookie-cutter mold. You have breast cancer, it’s this size, it’s this stage, this is what you get. We still have a long way to go, but we really have moved so far past that, and it’s because of these genomic tests.

If the patient is not likely deriving any benefit and this treatment is not helping them, why would we put them at risk for any side effect? I only want to give a patient treatment if december 2014

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they will benefit. The studies show that there is a small benefit for longer than 5 years of treatment, up to 10 years of endocrine treatment. When we exclude the low-benefit patients and treat the patients who stand to benefit, we’re making strides in treating their disease.

When we look at chemotherapy, we see the same thing. When we look at the overall benefit of chemotherapy, it was only about 4% for the individual patient. But when you remove the lowrisk patients and you just treat the highrisk patients with chemotherapy, you’re now seeing benefits of over 25%. That’s what we’re doing now in the extended endocrine phase of their treatment.

If we eliminate the low-risk patients who really are not likely to derive any benefit, and we’re only treating the high-risk patients who are likely to benefit, that’s where we’re going to see an enormous difference in outcome.

Dr Malamud To take data from 10,000 people and point to the 3% or 5% that may benefit and guess that you might be in that 5% is now an unnecessary gamble. That’s 5 years of treatment with the side effects of anti-estrogen therapy for a potential 5% difference in outcome. It is a big deal for a 40-year-old to continue another 5 years of tamoxifen or for a 60-year-old to continue another 5 years of an aromatase inhibitor (AI).

There can be consequences of the treatments that may be in excess of that 5% to 6% difference in the longterm survivorship, or disease-free survivorship.

Dr Boolbol It’s no longer one size fits all – we’re really treating the individual patient. Ten years ago I could tell a patient with a tumor measuring greater than 1 centimeter they were getting chemotherapy. We’ve moved into the era of genomic testing that looks at the individual cancer to determine if the patient will benefit from chemotherapy.

Now my discussion with a patient includes educating them on a test to help with the decision for chemotherapy, and at 4½ to 5 years we’ll be implementing another test to help us with the decision of continuing endocrine or anti-estrogen treatment for another 5 years.

Dr Malamud BCI testing has now become a critical part of our decision making in that 4-, 4½-year mark and provides another opportunity to educate the patients. It behooves us as physicians to stay educated because breast cancer patients come in with that information. I relish that discussion be-

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Interview with the Innovators

Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era...

Continued from page 49

cause this is something that’s going to help us decide who gets treated.

PMO Please describe the prognostic and predictive characteristics of this assay.

Dr Malamud The Breast Cancer Index has 2 unique qualities. The first is that it is prognostic in terms of the recurrence of breast cancer in those second 5 years of disease-free state, and secondly, it will give us a prediction in terms of the value of the additional hormonal therapy for the additional 5 years. Those data are actually the only validated data for any test in demonstrating likelihood of benefit for some patients in treating beyond 5 years (Figure 2).

Those data actually come from a very large multicenter trial, a randomized trial done from the NCIC in Canada called the MA.17, which looked at continued adjuvant therapy, continuing an AI after the first 5 years of tamoxifen. When that patient population was analyzed, there was a demonstrable benefit for those patients who received the additional AI therapy 2 years or more. In fact, at the 2-year mark, when the code was broken, it already was such a dramatic difference that the patients were unblinded and offered cross-over, which has been a criticism of that protocol.

But when one looks at that protocol and looks at the outcome, again the results were relatively small for the overall population. When that tumor population was looked at and classified by BCI analysis, it was quite clear there were 2 groups – those that were benefiting and those that were not.

Those that were benefiting had a 15% or more, perhaps even 16% difference in terms of likelihood of benefit, or likelihood of recurrence versus the group that was statistically not getting any benefit at all.

PMO How has BCI changed the discussions you have had with your patients?

Dr Malamud Using those data and the discussion with the patient regarding risk and benefits, we’re able to separate out those patients who are more likely to be getting an increased benefit from that additional time on drug. Without that, we were obliged to offer at least the discussion regarding continued adjuvant therapy, and patients would look at those data relatively quizzically and wonder whether or not they were going to be in that small subgroup of patients

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6% difference is not helpful to me because it also means that they’re also at risk for all the complications of treatBCI Result Treatment implications ment that take place beyond the fifth year; whether that’s a continued Low likelihood of benefit May allow you to confidently stop endocrine therapy menopausal symptomatology of ta­ after year 5 – and avoid unwanted side effects Low risk of recurrence moxifen or the potential risk of osteoHigh likelihood of benefit May allow you to strongly recommend extending porosis, and other complications of High risk of recurrence and adhering to endocrine therapy the aromatase inhibitors.

It’s also worth noting that BCI can be used to revisit a previously made who are actually benefiting and know you are likely to benefit from treatment decision. For example, if whether or not converting from a this, they may be much more likely to you have a 42-year-old patient, 7 years tamoxifen to an AI was worth that be compliant with the next 5 years of postdiagnosis, who opted to disconlittle incremental gain and the toxici- treatment. tinue tamoxifen 2 years ago at the ties associated with the AIs. The Dr Malamud If one has that infor- 5-year point, you can obtain the BCI Breast Cancer Index has made that mation and it’s there in black and test to provide reassurance of that discussion not only objective but white, and anyone tells them that this treatment decision. If the test result for more acceptable at the patient’s level. test was devised just for this purpose this patient shows a high likelihood of Dr Boolbol You hit on some key and there is a strong likelihood that benefit from an additional 5 years of points, especially that this now gives you’re in this category that will bene- therapy, the patient can be offered to us objective evidence. BCI allows us to fit from treatment, it turns an hour- restart endocrine treatment. The rehave this objective discussion with our long discussion as to risks and ben­ verse is also true; you may have a papatients and move away from that one efits into something much more tient who decided to continue anti-­ size fits all to where we have a validat- manageable and focused such that the estrogen treatment for an additional 5 ed test to show us that you are not patient who thought, “Gee whiz, I’m years, but obtaining the BCI test at the likely to benefit or that you are likely all finished,” now can at least be seventh year yielded a result of low to benefit. And we know that 50% or given some objective data that there is likelihood of benefit. For this patient, more of patients are of low benefit for value for more.

I may recommend discontinuation of extended treatment, and that makes a PMO Extending endocrine therapy therapy at this point. big difference to those patients. past 5 years is a notion recently studDr Boolbol I think that the Breast Dr Malamud To be able to point to ied in the ATLAS and MA.17 trials. Cancer Index and really the ATLAS the other bar graph and say look, Can you please discuss this develop- trial and the MA.17 trial are pivotal you’re going to be one of the women ment, the role BCI plays in making changes or paradigm shifts in how who’s more likely to benefit from ad- the decision of whether to continue we’re taking care of patients. Prior to ditional therapy; you’ve already done therapy, and the impact on patients? the release of these studies I would the first 5 years, let’s go the full-court Dr Malamud BCI occupies a pivotal tell a patient that they were on endopress. We have the evidence that role now in our decision making when crine treatment for 5 years. Again, you’re in the potential group that’s a woman receiving hormone adjuvant this goes on during their initial congoing to benefit from treatment, let’s therapy reaches the fourth to fifth year sult as part of their overall treatment move forward. of their treatment. That has been the plan. Now I tell them that they’ll be That kind of objective information paradigm and the therapy for women on it for 5 to 10 years depending on will oftentimes convince the patient with hormone-positive breast cancer the results of this test. to get off the fence and to move for- such that they remain on anti-estrogen I do not know whether they will ward. That’s incredibly important for therapy for 5 years. We’ve been strug- benefit from extended therapy or not. us now at that fifth year where we’re gling to find that population of women I have trials to say yes, the population sort of stuck in terms of weighing the who will benefit from extended adju- at large benefits, but sitting in front benefits without data. The Breast vant, meaning continuing that anti-­ of that patient, they’re really not inCancer Index has provided the data estrogen therapy onto the fifth and terested in the population at large. that allow for an objective discussion. now into the tenth year.

They’re interested in what will benefit Dr Boolbol We know with endoSeveral clinical trials showed defin- them, and I now can sit there and say crine treatment compliance is an issue itively that there is improvement in we have a test, BCI or Breast Cancer with most of our patients. Patients a population of women to be treated Index, that we’ll be doing around 4½ have heard for years that you take 5 beyond that fifth year. Both the years to tell us and give us that inforyears of endocrine treatment and ATLAS and MA.17 trials demonstrate mation of whether you are likely to you’re done. But then we’re asking an improvement somewhere between benefit from extended therapy. for another 5 years because we have 3% and 6% for the overall population.

If there is a low likelihood of benefit, studies to show that an additional 5 However, the woman sitting in front I may recommend that you don’t need years may be of benefit, many pa- of you at that fourth to fifth year is not it. No one wants to be taking a medicatients think “I’m not doing this anoth- really interested in the general popu- tion with potential side effects for little er 5 years. I’ve endured side effects lation of 5000 or more women. They to no benefit. If there is benefit, you from this for 5 years.” really want to know what the likeli- will want to take it, and that’s really But if we tell a patient, listen, we’ve hood is that they’re going to benefit, what we’ve gotten down to. It’s a pardone the BCI test for you, and we and pointing out that there is a 3% to adigm shift in how we’re treating pa-

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Interview with the Innovators

tients with breast cancer (Figure 3).

Dr Malamud We always think that it’s relatively easy to convince somebody to take their medication that’s going to be potentially lifesaving for the first 5 years. Compliance in the first 5 years is critical. Convincing someone who’s already endured some considerable discomfort for those first 5 years to consider going on for another 5 years can be difficult.

It’s nice, in fact, it’s critical to have this information that justifies the continuation of therapy.

PMO Can you share your thoughts on how BCI affects patients in terms of their notions of survivorship or the psychological impact of stopping versus continuing treatment?

Dr Malamud The Breast Cancer Index is an important tool to help at the decision point at that 4½- to 5-year mark. Clearly, it’s important for the patient to know whether additional therapy will be beneficial for them over the next 5 years. But probably, almost of equal importance, is the reliance on Breast Cancer Index in helping us decide to stop after 5 years.

A breast cancer patient, when she hits that 4½-year mark, is looking toward that goal line as the time that they can finally stop treatment. They need to go on with their life off of medication, be assured their disease is under control and likely to stay under control for the next 5 to 10 years.

In the past, we were reluctant to do that without testing that could help us, especially after the recent trials of the ATLAS or MA.17 and the extended adjuvant trial to tell us more might be better. But more is only better in a few patients. Being able to tell a patient with more confidence that I think it is safe to stop, that I think it’s safe to go on with your life without additional medication, that it’s safer to perhaps not have any of these side effects that are destined or at least likely to happen over these next 5 years is very important.

I often tell the patient they’re a survivor from the minute they meet me.

But that 5-year mark has become a goalpost for many women with breast cancer and, frankly, for many people with all sorts of cancer, that 5-year mark has been their unofficial guidepost, and now being able to actually tell them in an objective way that after the fifth year, I think it’s safe to stop.

You don’t need to go on. Breast cancer is a scary disease for many women, and stopping therapy is every bit as difficult as continuing treatment and being able to show them with reliance that their likelihood of recurrence is small and their likelihood of benefit is Vol. 5

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equally small gives us the ammunition to support that decision.

Dr Boolbol It’s interesting how patients fall into 1 of 2 camps, and as a surgeon, at the 4-, 4½-year mark this discussion really is ramping up where you have the patient who cannot wait to get off their endocrine treatment and they’re marking it on their calendar. And then you have the other camp of patients that this is really their crutch, and they feel like taking this pill everyday is really helping them – it’s saving their life. We really do now have objective data with BCI to help them through this period at the 5-year mark – we now can say this will continue to help you or this is not likely to give you any additional benefit.

And it helps both camps of patients, because for the women who really feel as though this pill is making an enormous difference and they never want to stop it, we now have a test in BCI to say we’ve run this test and we know that the likelihood of benefit is small for you. At that point the risk/benefit ratio switches. There may be more risks than benefits. That helps them.

For the other patients where the benefits outweigh the risks, that helps them. So really, every step along the way we as physicians are weighing the risk/benefit profile along with the patients to help determine the best, most ideal treatment for them.

Dr Malamud The best survivorship with the best quality of life. That’s what we’re trying to do.

PMO How does the use of this test (BCI) impact patient confidence in their treatment plan and ensure adherence to medication? How difficult is it to explain gene expression profiling and BCI to patients and how this technology will impact their care?

Dr Boolbol It comes down to risk/ benefit. If we have a test result telling us that there’s low likelihood of benefit to continued treatment, the patients, knowing that this is a validated test, are going to go along with that.

And the reverse is true. If we have a test telling us that they will derive benefit from continued treatment, although they may not be thrilled about continuing endocrine treatment for another 5 years, they will willingly go along with it and are more likely to be compliant.

Dr Malamud For the 5 years prior we’ve talked about survivorship and getting through the treatment. We tell our patients to win the battle, fight the battle today to survive the next couple of years so when the next test or next treatment becomes available, you’re there to participate.

Had we not been in clinical trials, had we not stored your tumor, had we not survived these 5 years, we wouldn’t be having this discussion, so here we are, here’s the information, and it is individualized.

Dr Boolbol We have to remember it’s validated, predictive data, and that’s critically important. I talk to patients about short term and long term and we want to get through the short term so that we have the long term, and that’s really what it comes down to.

PMO How can payers be educated on the value of these technologies to ensure patient access and cost reimbursement?

Dr Malamud Medicare has recently provided coverage for patients receiving testing with the Breast Cancer Index. This is clearly appropriate in my mind, and I would certainly support that it extends onto the other private insurers because, frankly, anyone receiving hormonal therapy, whether they’re Medicare eligible or not, should have the opportunity for this sort of test to be applied to them when they hit the appropriate time frame. Medicare is often the first to adopt new technologies and new treatments, but they’re also a signpost for the third-party coverage to look with a critical eye at the test and appropriately adopt them into their treatment plans as well.

Clearly, if one looks at the advantages to them, the Breast Cancer Index score that would indicate a patient should come off of therapy is advantageous not only to the patient in terms of their side effects and risks, but also advantageous to the insurer to avoid having not only to pay for the course of the drugs over the next 5 years but also to potentially deal with risks and complications over those 5 years to come.

Dr Boolbol I think that insurance coverage really goes back to personalized medicine and now we have coverage for BCI from Medicare, it really seems as though every insurance company out there should follow suit. Just as we want to individually take care of our patients, insurance companies should want the same. There is no medication without potential side effects, and limiting access to a test such as BCI that’s out there and available to tell us whether or not a patient will benefit from therapy or withhold coverage really does not make any sense and it is not in the patient’s best interest.

PMO What are the next steps in comprehensive personalized medicine for patients with breast cancer. december 2014

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Dr Malamud As we move forward in the treatment of women with breast cancer, we will continue to see increasing use of a personalized approach.

We’ve seen personalization of treatment, first in the development of the estrogen and progesterone receptor for those women who would benefit from hormone therapy. After that came Her2 testing to figure out who required anti-Her2 therapy. Now we have genomic testing that looks at the production and expression of genes associated with risk of recurrence and value of endocrine therapy in years 5-10. And now with the Breast Cancer Index, helping us to decide what to do when they hit that fifth-year mark.

There are a variety of other genomic tests out there to determine the interactions or potential resistance mechanisms for chemotherapy, resistance mechanisms in Her2, mTOR inhibition, PI3 kinase. There are companies where you can send tumors for complete geno­mic analysis to find actionable mutations with the hope that if there’s a mutation for which we have an appropriate drug, we can use that drug to target that mutation.

Dr Boolbol The way in which we treat patients 10 years from now will be completely different from what we’re doing today. Systemic issues, local treatment of breast cancer, how we do surgery, when we do surgery, what options we’re offering the patients, all these will be very different 10 years down the road.

I think that we’re going to be taking a minimally invasive approach to surgery such as cryoablation as opposed to excising the patient’s cancer in the operating room. We’re making advances in all of the arenas of how we treat breast cancer.

Radiation, for instance, there will be fewer patients who receive radiation.

We’re also moving into the era of determining who will benefit from radiation rather than just treating every patient who has undergone breast conservation with radiation.

In every discipline of our multidisciplinary team, we’re making advances in the treatment of breast cancer, all taking a personalized approach. If you look at genetic testing, we’ve made incredible advances; so many advances that we don’t have answers to everything that we know right now.

That’s one of the things that clinical trials will help us with.

PMO Thank you both very much for your time today, and our best to you and your continued success in your treatment of patients with breast cancer. n

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51

Drug Update

Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable or Metastatic Melanoma

By Lisa A. Raedler, PhD, RPh

M

elanoma, although not the most common skin cancer in the United States, is the most deadly.1 Based on data collected between 2004 and 2010, the 5-year survival rate for Americans with metastatic melanoma remains very low—only 16%—for all ages and races, and both sexes.2 The National Cancer Institute has estimated that 21.3 in 100,000 people will be diagnosed with melanoma of the skin in the United States in 2014.2 More than 9700 patients are estimated to die from melanoma in the same time frame.2 The incidence of melanoma is increasing in the United States, particularly among children and adolescents.2,3 An analysis of first-time melanoma diagnoses in patients aged 18 to 39 years between 1970 and 2009 showed that the incidence of melanoma increased 8-fold among young women and 4-fold among young men.3 A study analyzing data from 1973 to 2009 documented an average increase of 2% annually in melanoma in children aged between 0 and 19 years, particularly in girls and those aged between 15 and 19 years.4 These trends in melanoma diagnosis rates are concerning in light of their potential impact on healthcare resource consumption. An assessment of Medicare claims data from 1991 to 2005 demonstrated that patients with melanoma, particularly those with metastatic disease, utilize substantial healthcare resources.5 In this study, patients with metastatic melanoma consumed an average of more than $11,000 monthly in total healthcare costs, the majority of which was related to inpatient hospital services.5 Of note, this cost analysis was conducted before the new targeted therapies for metastatic melanoma became available.

Because tumor cells can spread to distant lymph nodes and to other organs, metastatic melanoma can be difficult to cure.6 Surgery and radiation therapy can be considered for tumors on the skin or for tumors that are localized to the lymph nodes. Metastases in internal organs can be surgically removed, depending on their number and location.6 Copyright © 2014 American Health & Drug Benefits. All rights reserved.

Used with permission.

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The development of novel agents has significantly altered the management of patients with advanced disease. Today’s armamentarium of systemic treatments for metastatic melanoma includes immunotherapies, BRAF inhibitors (ie, vemurafenib, dabrafenib, trametinib), and chemotherapy.6 Many of these newer agents offer superior efficacy compared with chemotherapy.6 Specifically, immune checkpoint blockade with immuno-oncology agents that are directed toward cytotoxic T-lymphocyte antigen (CTLA)-4 (eg, ipilimumab), as well as programmed death (PD)-1 and PD-ligand 1 (PD-L1), has emerged as a successful treatment approach.7 Ipilimumab was the first CTLA-4 inhibitor to demonstrate an overall survival benefit and durable objective responses in patients with metastatic melanoma.7 In patients with metastatic melanoma and BRAF V600 mutation, a striking contrast has been observed between BRAF inhibition, which offers higher response rates with limited response durability, and CTLA-4 inhibition, which offers a relatively low response rate but very durable responses.7 To increase the number of patients with melanoma who benefit from durable responses with immunotherapy, researchers are exploring potential synergies between immune checkpoint inhibitors that target CTLA-4, PD-1, and PD-L1, and kinase-targeted therapies, as well as the concurrent and sequential use of CTLA-4 and PD-1/PD-L1 inhibitors.7 Pembrolizumab Approval On September 4, 2014, the US Food and Drug Administration (FDA) approved pembrolizumab (Keytruda; Merck Sharp & Dohme Corp) for the treatment of patients with unresectable or metastatic melanoma and disease progression after receiving ipilimumab and, in patients with BRAF V600 mutation melanoma, a BRAF inhibitor.8 Pembrolizumab is the first human PD-1–blocking antibody approved for use in the United States.9 Pembrolizumab, which is administered via intravenous infusion, was approved under the accelerated approval program based on surrogate end points of confirmed overall re-

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sponse rate (ORR) and duration of response.8 Improvements in survival or disease-related symptoms have not yet been established.10 According to Jeffrey S. Weber, MD, PhD, Director of the Donald A. Adam Comprehensive Melanoma Research Center of Excellence at the Moffitt Cancer Center, Tampa, FL, “Pembro­ lizumab is…a clearly effective drug that will prolong survival for many patients with metastatic melanoma.

This approval is a real advance and a major milestone in the treatment of the disease.”11

“

Pembrolizumab is…a clearly effective drug that will prolong survival for many patients with metastatic melanoma.

This approval is a real advance and a major milestone in the treatment of the disease.

”

—Jeffrey S. Weber, MD, PhD

As a condition for this accelerated approval, the manufacturer is required to conduct a multicenter, randomized trial to establish the superiority of pembrolizumab over standard therapy and to verify its clinical benefit in patients with metastatic melanoma.8 Currently, 2 ongoing multicenter, randomized, controlled, therapeutic confirmatory trials are under way in patients with metastatic melanoma: Trial P002 in ipilimumab-refractory patients and Trial P006 in ipilimumab-naïve patients. In both trials, the coprimary end points are progression-free survival and overall survival.8 Mechanism of Action Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor and blocks interaction with its ligands, PD-L1 and PD-L2. This binding results in the activation of T-cell–mediated immune responses against tumor cells.

Blocking PD-1 activity resulted in decreased tumor growth in genetically identical mouse tumor models.10

Dosing and Administration The recommended dosage of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks; it should be reconstituted and diluted before infusion. Pembrolizumab should be used until disease progression or until unacceptable toxicity.10 No dose adjustment of pembroliz­ umab is needed for patients with renal impairment or for patients with mild hepatic impairment, defined as a total bilirubin of the upper limit of normal or less, and aspartate aminotransferase (AST) of more than the upper limit of normal, or a total bilirubin of >1 to 1.5 times the upper limit of normal and any AST. Pembrolizumab has not been studied in patients with moderate or severe hepatic impairment.10 KEYNOTE-001 Clinical Trial: Relapsed Metastatic Melanoma The accelerated approval of pembrolizumab was based on the results of a multicenter, open-label, randomized, dose-comparative, activity-estimating cohort conducted within the phase 1b KEYNOTE-001 trial (Trial P001).10 Of the 411 patients with treatment-naïve or with previously treated unresectable or metastatic melanoma who enrolled in the KEYNOTE-001 trial, 173 had disease progression within 24 weeks of the last dose of ipilimumab and, in those with BRAF V600 mutation melanoma, after previous treatment with a BRAF inhibitor. These 173 patients were randomized to receive 2 mg/kg (N = 89) or 10 mg/kg (N = 84) of intravenous pembrolizumab once every 3 weeks until disease progression or until unacceptable toxicity.10 The primary efficacy end points were confirmed ORR according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review and duration of response.10,11 The patients’ tumor status was assessed every 12 weeks.10 The secondary outcome measures included investigator-assessed immune-related response criteria.11 The KEYNOTE-001 trial excluded patients with autoimmune disease, medical conditions that required immunosuppression, or a history of severe immune-mediated adverse events with ipilimumab. The latter was de-

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Drug Update

fined as any grade 4 toxicity requiring treatment with corticosteroids or grade 3 toxicity requiring corticosteroid treatment for ≥12 weeks.10 Patient Population Among the 173 patients with previously treated unresectable or metastatic melanoma in KEYNOTE-001, the median age was 61 years (61% were aged <65 years).10 Most patients were male (60%) and white (97%). All of the patients in the trial had an Eastern Cooperative Oncology Group performance status of 0 or 1. The patients’ disease characteristics included stage M1c (82%), having had ≥2 previous therapies for advanced or metastatic disease (73%), elevated lactate dehydrogenase (39%), BRAF V600 mutation (17%), and brain metastases (9%).10 Efficacy The ORR associated with 2-mg/kg pembrolizumab was 24% (95% confidence interval, 15%-34%) in patients with unresectable or metastatic melanoma who were previously treated with ipilimumab and, if relevant, a BRAF inhibitor.10 Of the 21 patients with an objective response to pembrolizumab, 1 patient achieved a complete response and 20 patients achieved a partial response.10 Of these 21 patients, 3 (14%) patients had disease progressions 2.8 months, 2.9 months, and 8.2 months (respectively) after the initial response to pembrolizumab therapy.

The remaining 18 (86%) patients had ongoing responses after the initial response to therapy, with response duration ranging from ≥1.4 months to ≥8.5 months; this group included 8 patients with ongoing responses of ≥6 months. Objective responses were observed in patients with and without BRAF V600 mutation melanoma.10 The ORR associated with 10-mg/kg pembrolizumab was similar (26%) to the ORR with 2-mg/kg pembrolizumab.10,12 Safety The cohort of 89 patients with previously treated unresectable or metastatic melanoma in KEYNOTE-001 who received pembrolizumab (2 mg/ kg) had a median of 9 doses (range, 1-23 doses).10 The median duration of exposure for this cohort was 6.2 months (range, 1 day-15.3 months). Of these 89 patients, 51% were exposed to pembrolizumab for >6 months, and 21% were exposed for >1 year.10 The Table summarizes the adverse reactions that occurred in ≥10% of patients in this cohort.

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Among the 411 patients who received pembrolizumab in KEYNOTE-001, serious adverse reactions occurred in 36%. The most common serious adverse drug reactions reported in ≥2% of the 411 patients receiving pembrolizumab were renal failure, dyspnea, pneumonia, and cellulitis.10,12 Pembrolizumab was discontinued because of adverse reactions in 9% of the 411 patients receiving 2-mg/kg or 10-mg/kg doses in KEYNOTE-001.

Among the 89 patients with unresectable or metastatic melanoma who received 2 mg/kg of pembrolizumab, the discontinuation rate associated with adverse reactions was 6%.

The adverse reactions that led to the discontinuation of pembrolizu­ mab included pneumonitis, renal failure, and pain.10 Pembrolizumab has no contraindications.

Warnings and Precautions Immune-mediated pneumonitis.

Pneumonitis occurred in 12 of the 411 patients with unresectable or metastatic melanoma who received pembroliz­ umab in the KEYNOTE-001 trial. The median time to the development of pneumonitis was 5 months (range, 2 days-9.9 months), and the median duration of pneumonitis was 4.9 months (range, 1 week-14.4 months). In 5 of the 8 patients with grade 2 pneumonitis and 1 patient with grade 3 pneumonitis, initial treatment with high-dose systemic corticosteroids (≥40 mg prednisone or equivalent daily) was required and was followed by a corticosteroid taper. Pembrolizumab was discontinued in 3 patients with pneumonitis. In 7 of the 9 patients with grade 2 or 3 pneumonitis, the condition completely resolved.10 Patients receiving pembrolizumab should be monitored for signs and symptoms of pneumonitis and should undergo radiographic imaging if pneumonitis is suspected. Corticosteroids are appropriate if grade ≥2 pneumonitis is detected. Pembrolizumab should be withheld for moderate (grade 2) pneumonitis, and should be permanently discontinued for severe (grade 3) or life-threatening (grade 4) pneumonitis.10 Immune-mediated colitis. Colitis, including microscopic colitis, occurred in 4 of the 411 patients in the KEYNOTE-001 trial. Grades 2 and 3 colitis were observed in 1 and 2 patients, respectively. The median time to onset of colitis was 6.5 months (range, 2.3-9.8 months). All 3 patients with grade 2 or 3 colitis were treated with high-dose

dverse Reactions in ≥10% of Patients with Unresectable or Metastatic Table A Melanoma Receiving Pembrolizumab 2 mg/kg Pembrolizumab 2 mg/kg every 3 weeks (N = 89) All grades, % Grade 3,a % General disorders and administration site conditions Fatigue

47

7

Peripheral edema

17

1

Chills

14

0

Pyrexia

11

0

Nausea

30

0

Constipation

21

0

Diarrhea

20

0

Vomiting

16

0

Abdominal pain

12

0

Cough

30

1

Dyspnea

18

2

Pruritus

30

0

Rash

29

0

Vitiligo

11

0

26

0

Arthralgia

20

0

Pain in extremity

18

1

Myalgia

14

1

Back pain

12

1

Headache

16

0

Dizziness

11

0

14

5

14

0

11

1

Gastrointestinal disorders

Respiratory, thoracic, and mediastinal disorders

Skin and subcutaneous tissue disorders

Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders

Nervous system disorders

Blood and lymphatic system disorders Anemia Psychiatric disorders Insomnia Infections and infestations Upper respiratory tract infection

No grade 5 adverse reactions were reported. Of the ≥10% adverse reactions, none was grade 4.

Source: Keytruda (pembrolizumab) for injection prescribing information; September 2014.

a

corticosteroids followed by a corticosteroid taper. One patient permanently discontinued pembrolizumab as a result of colitis. All 4 patients with colitis experienced complete resolution of the condition.10 Patients receiving pembrolizumab should be monitored for signs and symptoms of colitis. Corticosteroids should be used for grade ≥2 colitis.

Pembrolizumab should be withheld for moderate (grade 2) or severe (grade 3) colitis, and should be permanently december 2014

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discontinued for life-threatening (grade 4) colitis.10 Immune-mediated hepatitis. In the KEYNOTE-001 trial, hepatitis, including autoimmune hepatitis, occurred in 2 of the 411 patients, including 1 patient with grade 4 hepatitis. The time to onset was 22 days after initiating pembrolizumab for the patient with grade 4 hepatitis. This patient permanently discontinued pembrolizumab and was treated with highdose systemic corticosteroids folContinued on page 54

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Drug Update

Keytruda (Pembrolizumab): First PD-1 Inhibitor Approved for Previously Treated Unresectable...

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lowed by a corticosteroid taper. Both patients with hepatitis experienced complete resolution of the event.10 Patients receiving pembrolizumab should be monitored for changes in liver function. Corticosteroids should be administered for grade ≥2 hepatitis.

Pembrolizumab should be withheld or discontinued based on the severity of liver enzyme elevations.10 Immune-mediated hypophysitis. Inflammation of the pituitary gland (hypophysitis) occurred in 2 of the 411 patients in the KEYNOTE-001 trial.

One of these events was grade 2 and 1 was grade 4. The time to onset was 1.3 months for the patient with grade 2 hypophysitis and 1.7 months for the patient with grade 4 hypophysitis.

Both patients were treated with highdose corticosteroids followed by a corticosteroid taper and continued receiving physiologic replacement doses of glucocorticoids.10 Patients receiving pembrolizumab should be monitored for signs of hypophysitis. Corticosteroids should be used for grade ≥2 hypophysitis. Pembrolizumab should be withheld for moderate (grade 2) hypophysitis, withheld or discontinued for severe (grade 3) hypophysitis, and permanently discontinued for life-threatening (grade 4) hypophysitis.10 Renal failure and immune-mediated nephritis. In the KEYNOTE-001 trial, nephritis occurred in 3 of the 411 patients, including 1 case of grade 2 autoimmune nephritis and 2 cases of interstitial nephritis with renal failure (1 case of grade 3 and 1 case of grade 4). In the patient with autoimmune nephritis, the time to onset was 11.6 months after the first dose of pembrolizumab and 5 months after the last dose. This patient did not undergo a kidney biopsy. Acute interstitial nephritis was confirmed by biopsy in 2 patients with grade 3 or 4 renal failure.10 All 3 patients with nephritis fully recovered their kidney function after treatment with high-dose corticosteroids followed by a corticosteroid taper.10 Patients receiving pembrolizumab should be monitored for changes in renal function. Corticosteroids should be administered for grade ≥2 nephritis.

Pembrolizumab should be withheld for moderate (grade 2) nephritis and should be permanently discontinued for severe (grade 3) or life-threatening (grade 4) nephritis.10 Immune-mediated hyperthyroidism and hypothyroidism. Hyperthyroid-

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ism occurred in 5 of the 411 patients (2 patients with grade 1, 2 with grade 2, and 1 with grade 3) receiving pembrolizumab. The median time to onset was 1.5 months (range, 0.5-2.1 months) after pembrolizumab initiation, and the median duration was 2.8 months (range, 0.9-6.1 months). One of the 2 patients with grade 2 hyperthyroidism and the patient with grade 3 hyperthyroidism required treatment with highdose corticosteroids followed by a corticosteroid taper. Only 1 patient permanently discontinued pembroliz­ umab as a result of hyperthyroidism.

Hyperthyroidism resolved completely in all 5 patients.10 Hypothyroidism occurred in 34 (8.3%) of the 411 patients who received pembrolizumab in the KEYNOTE-001 trial. The median time to the onset of hypothyroidism was 3.5 months (range, 5 days-19 months). All but 2 patients with hypothyroidism were treated with long-term thyroid hormone replacement therapy. The other 2 patients required short-term thyroid hormone replacement therapy. None of the patients received corticosteroids or discontinued pembrolizumab secondary to hypothyroidism.10 Because thyroid disorders can occur at any time during treatment with pembrolizumab, patients should be monitored for changes in thyroid function at the initiation of treatment, periodically during treatment, and as indicated based on clinical evaluation.10 Isolated hypothyroidism can be managed with thyroid hormone replacement therapy without treatment interruption and without corticosteroids. Corticosteroids should be administered for grade ≥3 hyperthyroidism. Pembrolizumab should be withheld for severe (grade 3) hyperthyroidism and should be permanently discontinued for life-threatening (grade 4) hyperthyroidism.10 Other immune-mediated adverse reactions. Other clinically important immune-mediated adverse reactions can occur while patients with unresectable or metastatic melanoma are receiving pembrolizumab.10 Clinically significant, immune-mediated adverse reactions that occurred in <1% of the 411 patients treated with pembrolizumab in the KEYNOTE-001 trial included exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, and adrenal

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insufficiency.10 In clinical studies of 2000 patients with various diagnoses who received pembrolizumab, other clinically significant immune-mediated adverse reactions included myasthenic syndrome, optic neuritis, and rhabdomyolysis.10 If an immune-mediated adverse reaction is suspected, patients receiving pembrolizumab must be evaluated to exclude other causes. Pembrolizumab should be withheld and corticosteroids should be administered based on the severity of the reaction. Upon improvement of the reaction to grade ≤1, a corticosteroid taper can be initiated and continued for at least 1 month.10 Pembrolizumab can be restarted if the adverse reaction remains at grade ≤1. Pembrolizumab should be permanently discontinued for any severe or grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.10 Embryofetal toxicity. Pembroliz­ umab may cause fetal harm when administered to a pregnant woman. If pembrolizumab is used during pregnancy, or if a patient becomes pregnant while taking the drug, she should be made aware of the potential hazard to the fetus. Women of childbearing age should use effective contraception during treatment with pembrolizu­ mab and for at least 4 months after the last dose of the drug.10 Specific Populations Pediatric patients. The safety and efficacy of pembrolizumab in pediatric patients have not been established.10 Geriatric use. Of the 411 patients with relapsed unresectable or metastatic melanoma who received pembroliz­ umab, 39% were aged ≥65 years. No meaningful differences in efficacy were observed among the age cohorts.10 Pregnancy. Pembrolizumab has been assigned pregnancy category D. Women should avoid becoming pregnant while being treated with pembrolizumab.10 Nursing mothers. Nursing should be discontinued during treatment with pembrolizumab.10 Conclusion Pembrolizumab, the first FDA­ approved PD-1 inhibitor, is a safe and effective immunotherapy for patients with unresectable or metastatic melanoma and disease progression after ipilimumab and, if BRAF V600 mutation melanoma, after a BRAF inhibitor.

The FDA approved pembrolizumab under its accelerated approval program based on tumor response rate and duration of response data. As a condition of this accelerated approval, the FDA required that a multicenter, randomized trial be conducted to establish pembrolizumab’s survival superiority over standard therapy, and to verify its clinical benefit in patients with metastatic melanoma.8 The 2 ongoing trials of pembroliz­ umab, Trial P002 in ipilimumab-refractory patients and Trial P006 in ipilimumab-naïve patients, are currently investigating the potential survival benefit with pembrolizumab in patients with advanced melanoma.

The safety and efficacy of pembro­ lizumab are also being evaluated in other solid and liquid tumors, including advanced non–small-cell lung cancer, renal-cell carcinoma, recurrent head and neck cancer, and multiple myeloma.13 n References

1. Skin Cancer Foundation. Melanoma. www.skincan cer.org/skin-cancer-information/melanoma. Accessed October 17, 2014.

2. National Cancer Institute. SEER stat fact sheets: melanoma of the skin. http://seer.cancer.gov/statfacts/ html/melan.html. Accessed October 17, 2014.

3. Reed KB, Brewer JD, Lohse CM, et al. Increasing incidence of melanoma among young adults: an epidemiological study in Olmsted County, Minnesota. Mayo Clin Proc. 2012;87:328-334.

4. Wong JR, Harris JK, Rodriguez-Galindo C, Johnson KJ. Incidence of childhood and adolescent melanoma in the United States: 1973–2009. Pediatrics. 2013;131:846-854.

5. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked database. Appl Health Econ Health Policy. 2009;7:31-41.

6. American Cancer Society. Treatment of melanoma skin cancer by stage. Revised September 5, 2014. www.cancer. org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-by-stage. Accessed October 17, 2014.

7. Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res. 2013;19:5300-5309.

8. US Food and Drug Administration. Drugs: pembrol­izumab. Updated September 5, 2014. www.fda.gov/ Drugs/InformationOnDrugs/ApprovedDrugs/ucm 412861.htm. Accessed October 17, 2014.

9. Loftus P. FDA approves Merck’s new-wave cancer drug: new treatment, which costs $150,000 a year, is aimed at bolstering the body’s immune system. Wall Street Journal. Updated September 4, 2014. http://online. wsj.com/articles/fda-approves-mercks-cancerdrug-1409856320. Accessed October 17, 2014.

10. Keytruda (pembrolizumab) for injection [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; September 2014.

11. Inman S. FDA approves pembrolizumab for advanced melanoma. OncLive. September 4, 2014. www. onclive.com/web-exclusives/FDA-Approves-Pembro lizumab-for-Advanced-Melanoma#sthash.hAnbLPqJ. dpuf. Accessed October 17, 2014.

12. National Cancer Institute. Melanoma treatment (PDQ®): unresectable stage III, stage IV, and recurrent melanoma treatment. Updated September 19, 2014. www. cancer.gov/cancertopics/pdq/treatment/melanoma/ HealthProfessional/Page9#Section_896. Accessed October 20, 2014.

13. ClinicalTrials.gov. Pembrolizumab. Search results. http://clinicaltrials.gov/ct2/results?term=pembroliz umab&Search=Search. Accessed October 21, 2014.

Vol. 5

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No. 10

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

“Better informed teams provide better care.”

Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

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.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2014 All rights reserved.

VBMKsize_Mitchell_81214

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.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002506000 Printed in USA.

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

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