VBCC Nov 2014 | Vol 5 | No 9

November 2014 VOL 5 NO 9

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

Quality Care Symposium

Financial Toxicity Beginning Reimbursement Reform in Oncology: to Gain Oncologists’ Moving from Cost Attention, Finally to Quality

By Phoebe Starr

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

O

ncology payment reform is a hot topic in the provider and payer communities. Numerous models and pilots have been introduced to define the value of cancer care, improve the quality, and/or con-

Boston, MA—The good news for patients with cancer is that oncologists are beginning to recognize financial toxicity as a side effect of cancer treatment.

According to S. Yousuf Zafar, MD, MHS, Medical Oncologist, Duke University Medical Center, Durham, NC, financial toxicity should be assessed as a patient-reported outcome as early as possible after a cancer diagnosis so that interventions can be put in place to assist patients in getting expanded coverage for their treatments.

At the 2014 ASCO Quality Care Symposium, Dr Zafar spoke about factors that contribute to financial toxicity and the negative impact it can have on patients’ outcomes if not addressed. Oncologists are often unaware of the exact costs of the treatments they prescribe and typically do not discuss costs of treatment or insurance coverage with their patients.

Continued on page 14

Symptom Management Drives Value in Oncology

By Chase Doyle

San Diego, CA—The development of standardized methods of patient assessment through a symptom management clinic (SMC) leads to better quality care, improved patient satisfaction, and a significant reduction in costs, according to a study presented at the 2014 Association of Community Cancer Centers’ National Oncology Conference.

For Lynn Graze, RN, MSN, OCN, Nursing Director at the DeCesaris

© 2014 Engage Healthcare Communications, LLC

Cancer Institute of the Anne Arundel Medical Center in Annapolis, MD, the idea for the symptom management clinic emerged from a drive to achieve higher-quality care at lower cost.

Establishing the Symptom Management Clinic In 2011 “we started to see that systematic nursing assessments with interventions lead to better quality of life for

Continued on page 25

trol costs. The transition to a system that values outcomes over the quantity of services is driving this reform.

Cancer care has changed a lot and continues to change rapidly, but transparency regarding cost and outcomes Continued on page 26

Avoidable Hospitalizations and Emergency Department Visits Driving Up Costs of Cancer Care

By Kate O’Rourke Boston, MA—Two studies presented at the 2014 ASCO Quality Care Symposium show that patients with cancer have high rates of hospitalizations that are deemed avoidable, as well as high rates of emergency department visits.

Clearly, strategies are needed to in-

Lowell E. Schnipper, MD

crease the value of cancer care for patients and for the healthcare system.

“We all agree that patients want the highest quality of life during the cancer continuum. Our obligation is to invoke the right treatment at the right time. We know that hospitalizations Continued on page 16

inside VALUE PROPOSITIONS . . . . . . . . . . . . . . . .

WHO’s 12 steps to prevent cancer

7

QUALITY CARE SYMPOSIUM . . . . . . . . 8 Choosing Wisely often not followed Radiation safety initiative reduces errors ECONOMICS OF CANCER CARE . . . . 14 Strategies to lower cost of CML Value is not “code” for cost reduction IN THE LITERATURE . . . . . . . . . . . . . . . . . . 17 Biomarker-based drugs reduce toxicity, costs 4TH CONFERENCE . . . . . 35 Private health exchanges rapidly growing Employers view healthcare as investment

PERSONALIZED MEDICINE . . . . . . . . . 40 Assigning value to oncology medical technologies THE PATIENT PERSPECTIVE . . . . . . . 41 12-second TUG test reduces readmissions PROSTATE CANCER . . . . . . . . . . . . . . . . . . 44 Sexual function preserved with vesselsparing radiation DRUG UPDATE . . . . . . . . . . . . . . . . . . . . . . . . . 46 Zydelig: first-in-class treatment for 3 hematologic malignancies PALLIATIVE CARE SYMPOSIUM . . . 50 DNR orders reduce critical care cost of advanced cancer

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

PERSONALIZED MEDICINE

WHO’s 12 recommendations for cancer prevention More…

Assigning value to new oncology technology

QUALITY CARE SYMPOSIUM

A 12-second test that can reduce readmissions

Symptom management inadequately addressed More…

PROSTATE CANCER

ECONOMICS OF CANCER CARE Avoidable hospitalizations drive up cancer costs More…

IN THE LITERATURE

Senoir Production Manager Lynn Hamilton

Biomarker-driven cancer drugs reduce toxicity, costs More…

The Lynx Group President/CEO Brian Tyburski

VBCC PERSPECTIVE

Editorial Assistant Cara Guglielmon

Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz

Oncology reimbursement reform Employers see healthcare as an investment More…

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

Value-Based Cancer Care

Zydelig: First-in-class PI3 kinase inhibitor for the treatment of 3 hematologic malignancies

PALLIATIVE CARE SYMPOSIUM Timing of palliative care impacts outcomes Long-awaited cost analysis of early intervention More…

Biopsies costly and unnecessary in 43% of patients More…

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc 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 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 Ted Okon, BS, MBA Executive Director Community Oncology Alliance, Washington, DC

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

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

6

DRUG UPDATE

VBCC Editorial Board

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

Preserving sexual function

LUNG CANCER

4TH CONFERENCE

Director, Quality Control Barbara Marino

THE PATIENT PERSPECTIVE

I November 2014

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

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com.

Address all editorial queries to: editorial@valuebasedcancercare.com • Telephone: 732-992-1891 • Fax: 732-992-1881.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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VALUE PROPOSITIONS

Advance Care Planning

The WHO’s International Agency for Research on Cancer Issued 12 Steps to Prevent Cancer

In October 2014, the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) issued its 2014 guide for cancer prevention. The updated Code Against Cancer outlines 12 specific recommendations for a healthy lifestyle, with the goal of cutting cancer cases in Europe by half.

“The Code raises awareness of the critical role of prevention in the fight against cancer,” said Christopher P. Wild, PhD, Director of IARC. “By adopting the Code, all European citizens can take concrete actions for themselves, their friends, and families to significantly reduce their risk of developing cancer.”

The 12 recommendations in the Code Against Cancer emphasize the importance of (1) avoiding tobacco, (2) avoiding alcohol, (3) avoiding excessive sun exposure, (4) avoiding exposure to radiation from radon, (5) maintaining a healthy body weight, (6) being physically active, (7-9) screening for bowel, breast, and cervical cancers, (10) vaccinating against human papillomavirus, (11) breastfeeding, and (12) limiting hormone replacement therapy.

“These are all recommendations where you can change your behavior as an individual,” suggested Joachim Schuez, PhD, who led IARC’s research for the WHO. “If you follow [them], you will reduce your cancer risk,” Dr Schuez said in a telephone briefing from IARC’s headquarters in Lyon, France.

Overall, 2.66 million new cancer cases are diagnosed in Europe annually, and 1.28 million deaths are related to cancer annually. Furthermore, the rate of cancer-related complications is increasing, and with it the economic burden of cancer. Smoking remains the leading cause of cancer in Europe, hence the first recommendation is the warning against smoking or being exposed to it. The updated Code Against Cancer advises: “Do not smoke. Do not use any form of tobacco. Make your home smoke free (and) support smoke-free policies in your workplace.”

According to the WHO, in addition to the 6 million people annually who die because of firsthand smoking, an additional 600,000 persons annually die of secondhand exposure to smoking in Europe.

“This new Code is based on the very latest scientific evidence. It is an important tool for cancer prevention for individuals, governments, health advisers, and policy-makers. It provides a foundation for creating healthy environments and adopting healthier lifestyles to prevent cancer,” said John F. Ryan, Acting Director of the Public Health Directorate of the European Commission. The World Health Organization’s International Agency for Research on Cancer; October 14, 2014

New Molecular Tests for Identifying Resistance to Bruton’s Tyrosine Kinase Inhibition in Patients with Chronic Lymphocytic Leukemia or LymphomaRelated Mutations

NeoGenomics, Inc, a provider of cancer-focused genomic testing, has launched the first tests in the United States for the identification of mutations in the Bruton’s tyrosine kinase (BTK) and PLC-gamma2 genes that can predict resistance to BTK inhibitors. The company has also launched a lymphoma profiling test for the prediction of susceptibility to BTK inhibitors and for the detection of mutations in the CXCR4, CD79B, MYD88, and CARD11 genes in several types of lymphoma.

BTK plays an important role in B-cell activation, and its inhibition is key to treatment of B-cell–related hematologic cancers. Although BTK inhibi-

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tors have shown good efficacy in the treatment of patients with chronic lymphocytic leukemia (CLL) and some subtypes of lymphoma, including mantle-cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), the disease eventually becomes resistant to BTK inhibitors in some subpopulations, because of BTK and PLC-gamma2 mutations. Identifying these mutations in patients with CLL, MCL, or DLBCL can help physicians to know when to prescribe a different type of therapy for these patients.

Maher Albitar, MD, NeoGenomics’ Chief Medical Director and Director of Research and Development, said, “Targeting BTK represents a revolutionary approach in the treatment of B-cell neoplasm. We are providing the appropriate means to optimize the utilization of this type of therapy. We believe that this type of testing will make physicians better equipped in their struggle to cure CLL and certain types of lymphoma.”

Commenting on the launch of these tests, Francis Giles, MD, Deputy Director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and Director of Northwestern Medicine Developmental Therapeutics Institute, commented, “BTK inhibitors are a very potent member of a new wave of targeted therapies for the lymphoproliferative disorders. We have learned, in particular based on our experience with BCR-ABL1 inhibitors in chronic myeloid leukemia, that dynamic monitoring of response and resistance are critical to the optimal use of targeted therapies. The NeoGenomics tests are very important in this context, particularly as defining the likelihood of response to BTK inhibitors, or the molecular nature of BTK inhibitors resistance, to help us choose between the increasing array of relevant alternate agents.” NeoGenomics, Inc; October 23, 2014

Anticancer Drugs and Vaccines Have High Value for PhRMA, with First Place in the Current Pipeline

According to a recent report from the Pharmaceutical Research and Manufacturers of America (PhRMA)—Medicines in Development for Cancer, 2014 Report—oncology drugs continue to be the focus of drug manufacturers, with 771 cancer therapies, including drugs and vaccines, currently in various stages of development. “On average, it costs $1.2 billion and takes between 10 to 15 years to bring a new, effective medicine to patients,” the report states.

According to the report, 213 experimental agents in the pipeline are for solid tumors, including 98 for lung, 73 for breast, 48 for ovarian, 47 for brain, 46 for colorectal, 45 for prostate, 39 for pancreatic, 37 for liver, and 24 for stomach cancer. Among hematologic cancers, 87 investigational agents are for leukemia and 78 are for lymphoma. The report suggests that the recent progress in oncology drug development “could echo the success we have seen in HIV/AIDS treatment,” turning cancer into a chronic disease.

A second report released by PhRMA, also on October 7—Researching Cancer Medicines: Setbacks and Stepping Stones—discusses the challenges and progress in cancer drug development: for every drug approved by the FDA, many more fail in clinical trials. But drugs that fail in clinical trials often help researchers gain a better understanding of how cancer works and how to fight it, the report states. Up to 80% of the investigational drugs for cancer have the potential to be first-in-class medicines. Cancers with the most first-in-class therapies in the pipeline are melanoma (91%); colorectal cancer (81%); blood cancer (77%); breast cancer (76%); and bladder, lung, and prostate cancers (75% each). And many “of these medicines target the root cause of cancers at the molecular level and some harness the body’s immune system to attack cancer cells.” This new understanding may be the key to making cancer a chronic disease. Specialty Pharmacy News; October 2014; vol 11, issue 10

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Quality Care Symposium

Are Choosing Wisely Recommendations Being Followed?

New Study Identified Low Levels of Adherence

By Alice Goodman

Boston, MA—The American Board of Internal Medicine Foundation’s Choosing Wisely campaign has the potential to rein in healthcare costs and improve patient care. Each year since 2012, the American Society of Clinical Oncology (ASCO) has listed 5 tests or interventions that should not be used routinely in clinical practice, but so far no data have been published on whether oncologists are following these recommendations.

A team of researchers from the Hutchinson Institute for Cancer Outcomes Research (HICOR) at Fred Hutchinson Cancer Research Center in Seattle, WA, has been tackling that question for the first time. They presented their findings at the 2014 ASCO Quality Care Symposium.

HICOR partnered with Premera Blue Cross to take a first step in determining patterns of care related to ASCO’s Choosing Wisely recommendations. The goal of the research was to characterize adherence to each of the 5 recommendations, and then zero in on opportunities to improve care.

Overall, for 3 of the 5 recommendations, approximately 30% to 50% of patients may have received tests or interventions that were not supported by evidence.

The investigators noted that measuring Choosing Wisely adherence provides a baseline, rather than a quality score, that can guide quality improvement and cancer care delivery and further research.

“It is a huge challenge to measure

“

It is a huge challenge to measure adherence to Choosing Wisely….Our goal in working with Premera and the cancer registry is to identify patterns of care in Western Washington, confer with local oncology providers to address areas where care can be improved, and develop interventions.

”

—Karma L. Kreizenbeck adherence to Choosing Wisely, and that is one of the reasons our work received a lot of attention at the Quality Care Symposium. Our goal in working with Premera and the cancer registry is to identify patterns of care in Western Washington, confer with local oncology providers to address areas where care can be improved, and develop interventions,” said Karma L. Kreizenbeck, Project Director at HICOR, who presented the data at the meeting.

Ms Kreizenbeck and colleagues linked data from the Cancer Surveillance System (CSS), a part of the Surveillance, Epidemiology, and End Results program, which covers 4.5 million people and records approximately 27,000 cases annually, with enrollment and claims data from Premera Blue Cross, a not-for-profit

commercial insurer that covers approximately 1.2 million lives in western Washington State.

The investigators developed algorithms for each of the 5 Choosing Wisely recommendations. The linkage of CSS and health insurance enrollment files identified 24,263 patients with cancer, with some exclusions for lack of data on diagnosis.

Relatively Good Adherence Adherence was relatively good to recommendations 2 and 3. Recommendation 2 says not to use positron emission tomography (PET), computed tomography (CT), or radionuclide bone scans in the staging of patients with early prostate cancer that is at low risk of spreading. Recommendation 3 says to not use PET, CT, and ra-

dionuclide bone scans in the staging of patients with early breast cancer that is at low risk of spreading.

Poor Adherence However, the data showed that adherence to recommendations 1, 4, and 5 was suboptimal.

Recommendation 1 says to avoid unnecessary anticancer therapy and focus on symptom relief and palliative care for patients with advanced cancers that are unlikely to benefit for chemotherapy or radiation at that late stage. Ms Kreizenbeck and colleagues found, however, that 41% of patients with cancer were receiving chemotherapy or radiation in the last 60 days before death.

Recommendation 4 says that routine tests for biomarkers and advanced imaging should not be used routinely for patients who have completed curative breast cancer treatment. The data presented by Ms Kreizenbeck and colleagues showed that 41% of these women were still undergoing testing for biomarkers and advanced imaging.

Recommendation 5 says to avoid the use of colony-stimulating factors (CSFs) in patients undergoing chemotherapy who have a <20% risk for developing febrile neutropenia.

Again, the data presented by the team of researchers showed that 40% of patients with breast cancer and 36% of those with non–small-cell lung cancer were receiving CSFs with chemotherapy that had a <20% risk for febrile neutropenia. n

Stage II/III Colon Cancer Outcomes and Costs Not Associated with Care Setting

By Kate O’Rourke

“

Boston, MA—Results of a new study show that the care setting, whether an academic hospital or a community center, does not affect the cost of colon cancer care or the duration of overall survival (OS). The study was presented at the 2014 ASCO Quality Care Symposium.

“There is no difference in overall survival for stage II or stage III patients based on hospital academic status. Costs of care are similar between academic and nonacademic hospitals, across virtually the full range of the

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Value-Based Cancer Care

There is no difference in overall survival for stage II or stage III patients based on hospital academic status. Costs of care are similar between academic and nonacademic hospitals, across virtually the full range of the cost distribution.

”

—Christine M. Veenstra, MD

cost distribution,” said lead investigator of the study Christine M. Veenstra, MD, Clinical Lecturer, Hematol­ ogy and Oncology, University of Michigan Medical Center, Ann Arbor.

Previous studies have demonstrated that it is more costly to treat patients with medical conditions (eg, stroke, heart disease, hip fracture) at academic medical centers than in community settings (Taylor DH Jr, et al. N Engl J Med. 1999;340:293-299).

And a recent study by Veenstra and colleagues has shown that among

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What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+MP provided an OS advantage over MP that was not regained with subsequent therapies Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration.

Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR §II

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

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE adjacent to this advertisement.

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

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.

Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.

Quality Care Symposium

Stage II/III Colon Cancer Outcomes and Costs Not...

Medicare beneficiaries with stage IV colon cancer, treatment by a provider affiliated with an academic medical center was associated with a 2-month improvement in OS, with no difference in costs, except at the very high end of the cost curve (99.9%; Veenstra

CM, et al. Cancer. 2014;120:3237-3244).

In a new retrospective review of Medicare data, Dr Veenstra and colleagues reviewed OS and 12-month costs of care in patients with stage II or III colon cancer; these results were presented at the meeting.

S:7”

The analysis included 20,118 patients diagnosed from 1996 to 2005.

The researchers compared the outcomes in patients treated at academic centers and nonacademic centers. The results showed no difference in median OS for stage II colon cancer (6.4

Brief Summary

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VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

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

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. V-14-0258 All rights reserved. Printed in USA

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vs 6.3 years, respectively; P = .71) or stage III colon cancer (4.2 years for both; P = .81) among the 2 treatment settings. The median and mean costs of care were similar between academic and nonacademic hospitals.

Dr Veenstra said that treatment guidelines for stage II/III colon cancer, such as those from the National Comprehensive Cancer Network, may help to explain these findings.

“The availability of guidelines to standardize care of patients with nonmetastatic colon cancer may underlie our findings,” she said.

“

We have to assume that the results were affected by reduced variability in adjuvant regimens. Decreased decision-making, when there is less variability, really results in less cost.

”

—Dawn L. Hershman, MD, MS

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

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

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

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

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

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Continued from page 8

Dawn L. Hershman, MD, MS, Associate Professor of Medicine and Epidemiology, and Codirector of the Breast Cancer Program at the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, agreed. “We have to assume that the results were affected by reduced variability in adjuvant regimens. Decreased decision-making, when there is less variability, really results in less cost,” she noted.

Dr Hershman pointed out that there is an abundance of evidence that cancer surgery outcomes are better at National Cancer Institute (NCI)-designated centers. A 2005 study showed that NCI cancer centers had lower adjusted surgical mortality rates than control hospitals for colectomy, pulmonary resection, gastrectomy, and esophagectomy.

A 2008 study showed that median survival after colorectal surgery is better at NCI-designated centers than at community centers for early-­ stage disease and late-stage disease.

The study included almost 34,000 colectomies and more than 8500 proctectomies and showed that long-term mortality was significantly improved after resection at NCI centers for patients with colon cancer (P <.001) and patients with rectal cancer (P = .02). n

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Quality Care Symposium

Patient-Reported Outcomes Suggest Symptom Management Is Inadequately Addressed by Oncologists

By Phoebe Starr

Boston, MA—A patient-reported outcomes study demonstrated that 20% to 45% of patients treated at community cancer centers did not get advice or adequate help for managing common symptoms such as pain, fatigue, and emotional distress. Another important finding of the PROSSES study is that the quality improvement registry-­ based Rapid Quality Reporting System (RQRS) method for assessing patient-reported outcomes is useful in clinical practice and led to improved cancer care at the 17 participating community cancer centers. The results were presented at the 2014 ASCO Quality Care Symposium.

“Symptoms are an important aspect of patient-centered care. Our findings provide the patient’s perspective about unmet needs, which cannot be found in medical records.

The study reveals a clear need for oncologists and the healthcare team to assess symptom management with cancer patients and give advice or suggestions when necessary,” stated lead investigator Tenbroeck Smith, MA, Director, Patient Reported Outcomes Research, American Cancer Society, Atlanta, GA. “Using RQRS incurred a low cancer staff burden, results were consistent across cancer centers, and replicable over time,” Mr Smith said. RQRS pro-

vided each institution with actionable symptom management quality data to improve patient care, he noted.

“

The study reveals a clear need for oncologists and the healthcare team to assess symptom management with cancer patients and give advice or suggestions when necessary.

Study Details The PROSSES study included 2487 patients with locoregional breast or colon cancer 4 to 12 months from diagnosis. The patients were from 17 community cancer centers and completed mailed or online RQRS questionnaires.

Overall, 77% of the patients reported having discussions with clinicians about pain over the past 6 months

“

”

—Tenbroeck Smith, MA

Symptoms are an important aspect of patient-centered care.

Our findings provide the patient’s perspective about unmet needs, which cannot be found in medical records.

”

—Tenbroeck Smith, MA (range at all cancer centers, 63%-89%), and 70% of patients said they received advice on pain management (range, 62%-89%).

In addition, 78% of patients dis-

cussed fatigue with a clinician over the past 6 months (range, 60%-94%), but only 61% received advice on how to manage the pain.

The rates were lowest for emotional distress: 59% reported discussing emotional distress in the past 6 months (range, 50%-87%), and 55% said they were given professional advice (range, 45%-77%).

The proportions of patients who reported being bothered by these symptoms in the past 6 months were: ➤ 61% for pain ➤ 74% for fatigue ➤ 46% for emotional distress.

When only these patients were asked

if they were getting help, the responses were 58% for pain; 40% for fatigue; and 46% for emotional distress.

“Our results reveal that there is huge room for improvement,” Mr Smith noted.

Ethan Basch, MD, MSc, Director, Cancer Outcomes Research Program, University of North Carolina School of Medicine, Chapel Hill, commented on the study. He said that a challenge of patient-reported outcomes research is that the findings reflect the patient’s perceptions, and it is not known if anyone from the healthcare team actually tried to give symptom management advice to the patient. n

Low Use of Oral Chemotherapy in Last 6 Months of Life a Surprising Finding

By Kate O’Rourke

Boston, MA—Excess use of chemotherapy at the end of life has been a major quality and cost concern for the past decade. A new study reported at the 2014 ASCO Quality Care Symposium surprisingly showed low use of oral chemotherapy in the last months of life and a decline in oral chemotherapy as patients approached death. In this study, in the last 30 days of life, roughly 19% of patients received intravenous (IV) chemotherapy compared with only 5% of patients who received oral chemotherapy.

Lead investigator of the study, Jessica A. Zerillo, MD, a fellow in quality and patient safety at Beth Israel Deaconess Medical Center, Boston, said she was surprised at the low use of oral chemotherapy, because other studies Vol. 5

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have shown a consistent high use of IV chemotherapy at the end of life.

Chemotherapy in the last 14 days of life has been a marker of potential overuse of care at the end of life (Earle CC, et al. J Clin Oncol. 2003;21:11331138). Another study evaluating chemotherapy use in 1996 showed that IV chemotherapy was used frequently in the last 3 months of life, hovering between 20% and 25%, and that the cancer’s responsiveness to drugs did not influence whether dying patients received chemotherapy (Emanuel EJ, et al. Ann Intern Med. 2003;138:639-643).

To date, however, there has been little information on oral chemotherapy at the end of life.

To fill this knowledge gap, Zerillo and colleagues investigated chemo-

therapy use in patients at Dana-Farber Cancer Institute who died in 2012 and were covered under Blue Cross Blue Shield of Massachusetts.

“

It does not appear that prescribers are transitioning patients from IV to oral chemotherapy at the end of life within this selected population.

”

—Jessica A. Zerillo, MD

The cohort of 200 patients had different cancers, including gastrointestinovember 2014

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nal (24%), breast (20%), head and neck (13%), genitourinary (9%), thoracic (9%), hematologic (6.7%), gynecologic (2.2%), and other (16%). The researchers compared different administration routes, and analyzed oral chemotherapy use in 3 periods at the end of life— the last 14 days, last 30 days, or last 6 months.

In the last 6 months, 76% of patients were prescribed any chemotherapy, including approximately 64% of patients who were prescribed IV chemotherapy and 22.5% who were prescribed oral chemotherapy (Table).

“Within this cohort of patients, use of any chemotherapy, including oral, sharply declined during the last 30 and 14 days of life, consistent with a shift to palliative end-of-life management,” Continued on page 12

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Quality Care Symposium

Radiation Safety Initiative Promises to Reduce Errors

By Phoebe Starr

Boston, MA—The Radiation Oncology Incident Learning System (ROILS) is a safety initiative developed jointly by the American Society for Radiation Oncology and the American Association of Physicists in Medicine, mainly in response to a scathing report of serious radiation errors published in the New York Times in 2010.

At the 2014 ASCO Quality Care Symposium, Suzanne B. Evans, MD, MPH, Assistant Professor of Therapeutic Radiology, Yale Cancer Center, New Haven, CT, discussed the initiative, which was launched in June 2014.

At participating institutions, radiation oncologists are encouraged to report as many radiation errors (ie, incidents) as possible that compromise patient safety, and reporting is anonymous. The goal is to develop a database of common errors, discover patterns of care, report on them, and develop strategies to make radiation therapy safer.

“Talk to your radiation oncologists about RO-ILS. The initiative is enjoying widespread adoption, and adoption is growing. It is free, it is impor­ tant, and it is going to make your patients receive better care. Participation will improve outcomes in your cancer clinics,” Dr Evans said.

Thus far, 20 institutions have contracted with RO-ILS, and another 31

“

Talk to your radiation oncologists about RO-ILS. The initiative is enjoying widespread adoption, and adoption is growing. It is free, it is important, and it is going to make your patients receive better care.

”

—Suzanne B. Evans, MD, MPH contracts are in process.

Dr Evans showed images of a radiation error that demonstrated just how easily things can go wrong, especially in the case of an obese patient

with cancer, where the planned field fell 3 cm short of the tumor bed, despite modern techniques. Fortunately, the next day this error was corrected.

Incidents are common, approaching 1 in 600, she noted. “An incident is defined as a near-miss, a harmless hit, an actual error reaching the patient, or an unsafe condition. Incident learning is the feedback loop whereby we learn from what is happening,” Dr Evans explained.

The aims of RO-ILS are to provide an infrastructure for the national incident learning system, to disseminate “errors of note,” to encourage incident learning, to identify national patterns, and to learn more about the causes of error. The evidence gathered on RO-ILS is undiscoverable by federal courts, and it appears that is also true of state courts. Reporting is anonymous and free. Enrollment is possible on the RO-ILS website.

Handoffs and transitions can be dangerous times in cancer care, and require multidisciplinary team attention, Dr Evans continued. In this setting, poor communication can lead to errors.

“In radiation, we are so reliant on each other. I can prescribe the perfect radiation treatment plan, but if it is not delivered as prescribed we won’t have quality care. Thus far, data on

incidents of delivery error and outcomes are not readily available,” she told listeners.

Protocol violations are common in the radiation setting. A meta-analysis of 8 separate trials (4 adult, 4 pediatric) showed that the median frequency of radiation therapy quality assurance protocol violations was 32% (range, 8%-71%). These violations significantly increased the hazard ratio for death (1.84; P <.001; Ohri N, et al.

J Natl Cancer Inst. 2013;105:387-393).

Separate analysis of each of the 8 individual trials showed that all but 1 demonstrated an increased incidence of death for protocol variations.

“Incident learning improves staff engagement, creates a safety culture, and reduces the number and the severity of incidents. A team that reports incidents is engaged and wants to promote safety, making our clinics safer. We all know these errors happen, but only a team striving for excellence will report these errors,” Dr Evans stated.

Informal surveys suggest that participation in RO-ILS reduces the number and severity of incidents, she continued. “Studies show that the more reporting an institution does, the few­ er the severe incidents,” Dr Evans emphasized. “Our nonarguable goal is zero errors,” she said. n

Low Use of Oral Chemotherapy in Last 6 Months... said Dr Zerillo. “It does not appear that prescribers are transitioning patients from IV to oral chemotherapy at the end of life within this selected population.”

According to Dr Zerillo, the analysis highlights the need for a more comprehensive understanding of oral chemotherapy use at the end of life.

“With the growing use of oral chemotherapy, the development of measures to define quality of end-of-life

care with these agents is warranted,” she said. “There is an NQF [National Quality Forum] quality measure to limit chemotherapy in the last 14 days of life; however, that measure does not specify what is appropriate for oral chemotherapy.”

Dawn L. Hershman, MD, MS, Associate Professor of Medicine and Epidemiology, and Co-Director of the Breast Cancer Program at Herbert Irving Comprehensive Cancer Center,

Last 6 months, %

Last 30 days, %

Last 14 days, %

Any chemotherapy

76

23

5.5

Intravenous chemotherapy

64

19

4.5

Oral chemotherapy

22.5

5

0.5

First oral chemotherapy

NA

2.5

0.5

NA indicates not available.

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”

—Dawn L. Hershman, MD, MS

Table Chemotherapy Use in the Last 6 Months of Life in 200 Patients Chemotherapy type

“

While the rates are low, we know that there are increasing numbers of oral therapies being studied and approved annually. With increased availability of oral therapy, these rates will need to be monitored.

Columbia University, New York, said that the low rates identified in the study might only be the tip of the iceberg. “While the rates are low, we know that there are increasing numbers of oral therapies being studied and approved annually,” said Dr

Continued from page 11

Hershman. “With increased availability of oral therapy, these rates will need to be monitored.”

Dr Hershman pointed out that a study conducted in the mid-1990s identified an increasing use of aggressive chemotherapy at the end of life (Earle CC, et al. J Clin Oncol. 2004;22: 315-321), and recent data show that aggressive care in the final days is a continuing problem. In one study, researchers identified a significant increase in intensive care unit (ICU) admissions, hospitalizations, and repeated emergency department visits at the end of life in patients with ovarian cancer, even though hospice use increased (Wright AA, et al. J Clin Oncol. 2014;32:3534-3539). This study also demonstrated that patients who receive chemotherapy are more likely to have admissions to the ICU and are less likely to die in their preferred location. n

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Quality Care Symposium

Inappropriate Use of Adjuvant Chemotherapy Common in Patients with Lung or Colon Cancer

By Kate O’Rourke

Boston, MA—Two recent studies have shown that non–evidence-based use of chemotherapy is common in patients with non–small-cell lung cancer (NSCLC) or colon cancer. The results were reported at the 2014 ASCO Quality Care Symposium.

“You do not take medicine you do not need, especially when it is potentially lethal. Yet this is what is going on in these tumor types in the southeastern United States,” said William J. Hrushesky, MD, Chief Scientific Officer and Senior Executive Medical Director, Oncology Analytics, Plantation, FL. The studies were conducted in the southeastern United States by Oncology Analytics.

Oncology Analytics is a cancer decision support company that positions itself between the payer and the oncologist to help clinicians improve the delivery of high-quality cancer care.

Colon Cancer In the first study, Dr Hrushesky and colleagues investigated misuse of chemotherapy in older patients with stage II or III colon cancer. Recent

at a glance ➤ The use of non–evidencebased chemotherapy in patients with NSCLC or CRC is quite common ➤ The most common reason for patients discontinuing adjuvant chemotherapy for CRC is toxicities from oxaliplatin, including neuropathy, diarrhea, nausea, and vomiting ➤ Because adjuvant chemotherapy has no survival benefit and can cause more harm than good, it should not be used in patients with stage I NSCLC ➤ In a study of 264 patients with I NSCLC, 67 requests for adjuvant chemotherapy were for patients with stage I NSCLC ➤ The rate of inappropriate requests increased from 17% in 2011 to 20% in 2012, 30% in 2013, and 34% in 2014 ➤ It is hoped that ASCO’s Choosing Wisely campaign will help oncologists to reduce the misuse of adjuvant chemotherapy

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data from randomized controlled trials have demonstrated that the addition of oxaliplatin to fluorouracil-­ based adjuvant chemotherapy in patients aged >70 years with stage II or III colorectal cancer (CRC) does not improve survival, but adds toxicity.

“

We expected there would be some change when the NSABP study came out or the NCCN guidelines were changed. We detected none. We see this as an important quality issue that needs to be addressed.

”

—William J. Hrushesky, MD

In October 2011, a trial from the National Surgical Adjuvant Breast and Bowel Project (NSABP) demonstrated that the addition of oxaliplatin to fluorouracil plus leucovorin improves overall survival (OS) in patients with stage II or III CRC, but not in patients aged ≥70 years (Yothers G, et al. J Clin Oncol. 2011;29:3768-3774).

In August 2012, the National Comprehensive Cancer Network (NCCN) revised its guidelines supporting the omission of oxaliplatin from adjuvant chemotherapy regimens for older patients with colon cancer.

In September 2012, the international MOSAIC trial showed that there was no benefit in OS or disease-free survival when oxaliplatin was added to fluorouracil with leucovorin as adjuvant treatment in stage II cancer and for elderly patients with stage II or III CRC (Tournigand C, et al. J Clin Oncol. 2012;30:3353-3360).

In the current study, Dr Hrushesky and colleagues examined how this increasing evidence influenced clinical practice in elderly patients with colon cancer. They examined 57 consecutive months of chemotherapy requests for 266 patients aged ≥70 years with stage II/III colon cancer, based on 3 time spans—July 2007-October 2011 (the date of the NSABP publication), October 2011-November 2012 (close to NCCN guidelines changes and MOSAIC trial publication), and November 2012-March 2014.

More than 33% of the doctors re-

3D illustration of lung cancer cells.

quested oxaliplatin-containing combinations for the 266 patients. Despite the strong evidence that oxaliplatin does not benefit elderly patients with CRC, the study found no evidence of a reduction.

“We expected there would be some change when the NSABP study came out or the NCCN guidelines were changed. We detected none,” said Dr Hrushesky. “We see this as an important quality issue that needs to be addressed.”

The most common reason for patients discontinuing adjuvant chemotherapy for CRC is specific oxaliplatin toxicities, including neuropathy, diarrhea, nausea, and vomiting.

“

Treatment of stage I lung cancer should be avoided in the adjuvant setting, as it is likely to do more harm than good.

”

—William J. Hrushesky, MD

“These data represent a delayed/ lost opportunity for less toxic equally effective treatment of elderly patients with colo­rectal cancer in the adjuvant setting,” said Dr Hrushesky.

Lung Cancer In the second study from Oncology Analytics, Dr Hrushesky and colleagues examined chemotherapy requests from oncologists for the adjuvant treatment of patients with stage I/II NSCLC between January 2011 november 2014

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and May 2014.

Overall, 67 of 264 adjuvant chemotherapy requests were for patients with stage I NSCLC and the frequency of requests increased from 17% in 2011, to 20% in 2012, 30% in 2013, and 34% in 2014. Of note, adjuvant chemotherapy has not been shown to improve OS in any randomized controlled trial for stage I disease, and 5 national guidelines recommend against it.

“Adjuvant chemotherapy should not be given to stage I NSCLC patients, since no data demonstrate an overall survival advantage,” said Dr Hrushesky. “Guidelines from ASCO, the European Society for Medical Oncology, the NCCN, the UK, and Canada are unanimous. Each one says that treatment of stage I lung cancer should be avoided in the adjuvant setting, as it is likely to do more harm than good.”

The researchers also found that 52 of 67 chemotherapy requests for stage I/II NSCLC were for carboplatin-­ based regimens; only 19% were for cisplatin-based regimens. All existing level 1 data, which include analysis of 5 cisplatin-based phase 3 trials and 2 carboplatin-based phase 3 trials, demonstrate that only cisplatin-based adjuvant regimens improve OS. Oncologists should attempt to reduce the misuse of adjuvant chemotherapy for the 2 populations studied.

“We think it would be helpful if ASCO supported these opportunities within the Choosing Wisely campaign,” Dr Hrushesky said. “Perhaps that would help enhance high quality, evidence-based cancer care for individuals with colon and lung cancer.” n

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Economics of Cancer Care

Financial Toxicity Beginning to Gain Oncologists’...

There is currently no expert consensus on which healthcare professionals should discuss finances with patients, or what the optimal timing of such discussions should be. However, there is agreement that financial toxicity needs to be addressed.

“Financial toxicity is the elephant in the room. You can begin the discussion by asking your patients one simple question about whether their cancer care is covered by a drug plan,” Dr Zafar suggested. He noted that many patients with cancer who have health insurance often have inadequate coverage for cancer treatment.

A confluence of factors contributes to financial toxicity, including high drug costs, the widespread use of expensive biologics in oncology, increasing reliance on oral chemotherapy, increasing insurance premiums, and much higher copays for cancer treatments.

Regarding the cost of drugs, Dr Zafar noted that 1 month of chemotherapy is estimated to cost $10,000, and the cost of cancer drugs continues to rise. Between 2007 and 2014, the price of erlotinib (Tarceva) increased by 91%, the price of dasatinib (Sprycel) increased by 130%, and the price of imatinib (Gleevec) increased by 158%.

Spending on oral chemotherapy increased by 37% per quarter at the same time that the use of oral chemotherapy increased by 17% per quarter.

In addition, there has been an exponential increase in health insurance premiums in the past decade or so that

can adversely affect patients with cancer. From 1999 to 2013, insurance premiums increased by 182%, and work-

growing list of financial adverse events as a result of the care we are providing.

These include delaying care, nonadher-

“

Financial toxicity is the elephant in the room. You can begin the discussion by asking your patients one simple question about whether their cancer care is covered by a drug plan.

”

—S. Yousuf Zafar, MD, MHS

ers’ contributions to their health insurance increased by almost 200%, on average.

The 4-tiered formularies are now being used in many drug plans, and cancer drugs are among the most expensive drugs to be covered; they are typically falling into tiers 3 and 4, which have significantly higher member copays than drugs in the first 2 tiers.

Patients often experience their cancer treatment as a significant financial burden and stint on basic necessities to pay for their cancer drugs. Some exhaust their savings and file for bankruptcy, Dr Zafar continued.

The fallout from financial toxicity impacts patient well-being, according to several recent studies. “There is a

ence, missed appointments, and taking fewer medications,” Dr Zafar said.

Financial Interventions The glass is not half empty, however. Interventions can be implemented by oncologists and other healthcare providers on the individual, interpersonal, and systemic levels to improve patients’ situations, improve patient adherence to therapy, and avoid the considerable financial hardship on some patients.

On the individual level, patients should be educated about the costs of healthcare so that they can gain healthcare cost literacy. Many patients are unaware of the availability of assistance programs, and that their oncologist can intercede

Continued from the cover

with the payer to request expanded coverage. Providers can help patients get this type of information to help them gain control of the financial burden associated with cancer treatment.

On the interpersonal level, oncologists or other healthcare providers should communicate with patients about the cost of cancer care, and inform patients about programs and other ways to decrease their healthcare costs, including patient assistance programs offered by drug manufacturers and/or by the health insurance plan. Many cancer centers today offer patients some form of financial consultation when requested, but not all patients ask for help. Oncologists should take the initiative to ask patients about their financial situation in relation to their cancer treatment, find out how it may affect their treatment, and offer help when needed.

On a systemic level, identification of patients at high risk for financial toxicity is important before they find themselves deeply in debt. Dr Zafar urged oncologists to make use of existing screening tools to identify patients in financial need, and addressing price transparency with patients. Many oncologists still shy away from discussing costs with patients, which can affect treatment results.

Overall, bringing together resources in health literacy, patient engagement, and healthcare delivery can start to reduce the impact of the ever-rising costs of cancer care and of financial toxicity on patients with cancer. n

Strategies to Minimize the Cost of Treating Chronic Myelogenous Leukemia

By Alice Goodman

New York, NY—Targeted therapy for chronic myelogenous leukemia (CML) is one of the big success stories of personalized medicine; however, continuous lifelong therapy may be required, and it is very expensive. Neil P. Shah, MD, PhD, of the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, discussed strategies for mitigating the expense of treatments for CML at the 2014 National Comprehensive Cancer Network annual congress.

The incidence of CML is likely to increase as the population ages, and by 2024, the incidence is expected to double, but the introduction of the tyrosine kinase inhibitors (TKIs) has changed the prognosis of this cancer.

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“

The wonderful news is that more people are living with CML than any time in the past….

But the not-so-good news is that the cost of 1 year of imatinib has risen to $92,000 in 2013, from $30,000 in 2001. Second- and third-generation TKIs are priced even higher than imatinib.

”

—Neil P. Shah, MD, PhD “The wonderful news is that more people are living with CML than any time in the past. TKIs have also changed the outcomes for patients

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with gastrointestinal stromal tumors,” Dr Shah said. “But the not-so-good news is that the cost of 1 year of imatinib has risen to $92,000 in 2013, from

$30,000 in 2001. Second- and third-generation TKIs are priced even higher than imatinib. One year of ponatinib currently costs $138,000,” he said.

“This is unsustainable. We have to ask ourselves how long this can continue,” Dr Shah stated.

Chronic-phase CML has an excellent prognosis if patients can achieve a BCR-ABL polymerase chain reaction of <10% after 3 months (ie, complete cytogenetic remission [CCyR]), irrespective of which TKI is used, he said.

Patients who fail to achieve that milestone do not do well, no matter which drug they get for treatment.

Second-generation TKIs, such as nilotinib (Tasigna) and dasatinib (Sprycel), are more likely to achieve CCyR than

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Economics of Cancer Care

Value Is Not “Code” for Cost Reduction

By Chase Doyle

San Diego, CA—Although dollars spent on healthcare are an integral part of the value equation, “value should not be a code word for cost reduction,…but should be defined in a framework for performance improvement,” according to Thomas A. Gallo, Executive Director, Virginia Cancer Institute, Richmond. Mr Gallo reviewed the need to award value in cancer care instead of volume, while streamlining accrediting and reporting programs at the 2014 Association for Community Cancer Centers’ National Oncology Conference.

The movement toward quality care has been driven chiefly by increasing healthcare costs, Mr Gallo said. It has been estimated that by 2020, 50% of the US household’s disposable income will go toward healthcare.

Costs of cancer care in particular have risen dramatically, from $72 billion in

at a glance ➤ Value is not a code word for cost reduction; it must include improved outcomes ➤ Payers are beginning to change the payment paradigm from a volume-based to a value-based system ➤ It’s the responsibility of the entire oncology community to create a culture in which everyone is focused on improving patient experience and care ➤ It’s important to create an environment that focuses on improvement, not punishment

“

Value should not be a code word for cost reduction,…but should be defined in a framework for performance improvement….Cost and quality must be considered in tandem when you look at that value equation.

”

—Thomas A. Gallo

2004 to $125 billion in 2010. The National Institutes of Health has projected that cancer care costs will range from $179 billion to $205 billion by 2020.

“What’s more alarming,” said Mr Gallo, “is that the rate of increase in costs is higher in cancer care than other specialties. To put this into perspective, cancer medical costs are increasing by 12% to 18% per year… compared to health care in general, which is increasing by 9% per year.”

The aging of the US population poses challenges specific to oncology, considering that 10,000 people are turning age 65 years daily. Increasing complexity of care and changing patient attitudes are also drivers related to the quality discussion.

“Gone are the days where patients listen to everything the doctor said and don’t question anything. They have much more access to information. They want to be involved and engaged with their care,” he said.

Quality metrics in oncology vary widely across programs, according to

Mr Gallo. “Some people are using patient satisfaction surveys as a proxy for quality in oncology,” he said. “Others are using outcomes in survival.”

Many cancer programs are spending an increasing amount of time and resources to achieve prescribed standards of quality reporting and accreditations. Mr Gallo noted that it requires 200 person-hours to achieve Quality Oncology Practice Initiative certification—hours that could be used to provide patient care. The common denominator across all programs, however, is depleted budgets.

“We are all finding that the dollars we receive for oncology care are being cut, margins are shrinking,” he emphasized.

Value Equals Outcome versus Cost The relationships between cancer practices and payers have often been adversarial. “Payers looking at value is perceived as a code word for ‘reduce cost,’” said Mr Gallo, “but there are other ways to achieve value....Cost and quality must be considered in tandem

Strategies to Minimize the Cost of Treating Chronic... imatinib (Gleevec), although imatinib is less expensive. For example, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST) study showed that 91% of patients receiving nilotinib achieved CCyR at 3 months compared with 67% of patients who received imatinib as front-line treatment, and the Dasatinib versus Imatinib Study in Treatment-Naive CML Patients (DASISION) showed that 81% of patients receiving dasatinib achieved CCyR at 3 months versus 67% of patients treated with imatinib (P <.001). By 12 months, the CCyR rates were 80% for nilotinib and 65% for imatinib, and 83% for dasatinib and 72% for imatinib.

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“Despite the fact that more patients meet the milestone on newer drugs, overall survival and progression-free survival are comparable at 5 years after treatment discontinuation,” Dr Shah stated.

The main clinical benefit of second-­ generation TKIs is a reduction in the rate of transformation to accelerated-­ phase/blast-phase CML versus with imatinib—approximately a 3% absolute modest difference, he said. This should be viewed in the context of at least 20% higher cost compared with imatinib, and this difference is likely to become much bigger when imatinib goes off patent in 2016.

when you look at that value equation.”

Whether changing how they pay for drugs and chemotherapy administration or instituting shared savings pools for keeping patients out of emergency departments, payers are seeking new ways to increase value.

“Payers are starting to design their own programs that look at changing the paradigm from a volume-based system to a value-based system,” said Mr Gallo.

UnitedHealthcare’s pilot project evaluated the potential effectiveness of these new approaches to payment. The results were impressive—a 34% overall reduction in medical costs ($35 million) compared with the control group (Newcomer LN. J Oncol Pract.

2014;10:187-189).

Mr Gallo called for a systemwide approach to achieving efficiency and providing value. “We all agree that it’s the responsibility of the entire organization…[to] create a culture in which everyone is focused on improving patient experience and care,” he suggested. “It’s important to create an environment that focuses on improvement, not punishment.”

In his opinion, the current reimbursement plan fails to properly incentivize many approaches that improve quality, such as multidisciplinary clinics and additional ancillary services, and he believes there are too many accrediting standards and reporting programs.

At the end of the review, Mr Gallo offered his own definition of quality, a more subjective metric for success: “Quality is all about self-examination, trying to improve yourself going forward and making incremental improvements to what you do on a daily basis.” n

Continued from page 14

Thus, the initiation of treatment with imatinib, reassessing response at 3 months, and switching patients with a suboptimal response to a second-generation TKI are prudent approaches.

Approximately 50% to 66% of patients will be able to continue receiving imatinib, Dr Shah said.

Another possible approach is to initiate second-generation TKIs in newly diagnosed patients, get them to CCyR more quickly, and to consider a clinical trial of a lower dose of imatinib, interferon alfa plus grapefruit juice (potentiates response), or other investigational agents.

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the discontinuation of therapy once a complete molecular response is achieved. This could reduce any side effects as well as reduce the therapy’s cost. Treatment discontinuation trials are ongoing. One of them, the Stop Imatinib (STIM) trial, has enrolled 100 patients with a sustained complete molecular response for 2 years. TKIs are discontinued and are reinitiated if there is disease recurrence.

“Strategies to reduce treatment cost warrant clinical trials. These include dose modification and treatment discontinuation, but clinical trials and pharmacoeconomic studies are needed,” Dr Shah said. n

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Economics of Cancer Care

Avoidable Hospitalizations and Emergency Department Visits Driving Up Costs of...

Continued from the cover

and emergency room visits are inevitable, but we can develop a care system that obviates the need for many of them,” said Lowell E. Schnipper, MD, Clinical Director, Beth Israel Deaconess Medical Center Cancer Center, Boston. Dr Schnipper served as the discussant of the 2 studies.

Emergency Department Visits The first study from researchers at the University of California, Davis, compared the use of the emergency department by cancer survivors, patients with other chronic conditions, and individuals without chronic conditions.

Survivorship was defined as from the time of the cancer diagnosis through the rest of life. Few studies have examined cancer survivors’ use of the emergency department. The researchers analyzed data from the 2008-2011 Medical Expenditure Panel Survey (MEPS) and MEPS Experiences with Cancer Survivorship Supplement. MEPS is one of the most complete sources of data on healthcare cost, utilization, and health insurance coverage.

The study included 5217 cancer survivors, 29,617 patients with chronic conditions, and 27,759 individuals with no chronic conditions. The annual rate of any emergency department visit was 18.6% among cancer survivors, 15.5% in patients with chronic conditions, and 9% in individuals with no chronic conditions; the average number of visits was 1.5, 1.4, and 1.3, respectively. Undergoing active cancer treatment had no influence on the emergency department visit rate.

“As a group, cancer survivors had substantially more emergency department visits and number of visits among those who had any visits,” said lead investigator of the study Rebecca S. Lash, RN, MSN, MPP, a PhD candidate at the University of California, Davis, in Sacramento. “However, these visits were not adjusted for a number of things such as age, gender, insurance status, which did vary by group. Importantly, 85% of cancer survivors reported at least one other chronic condition.”

Compared with patients without chronic conditions, the odds of any emergency department use were higher in cancer survivors and those with chronic conditions. Other factors that predicted higher emergency department use included: ➤ Having more than 1 chronic condition ➤ Public insurance rather than private insurance

16

“

We know that hospitalizations and emergency room visits are inevitable, but we can develop a care system that obviates the need for many of them.

”

—Lowell E. Schnipper, MD

“

There are potentially avoidable hospitalizations....Some potential interventions… would be early integration of palliative and psychosocial care and more robust outpatient acute care systems.

”

—Gabriel A. Brooks, MD

“”

As a group, cancer survivors had substantially more emergency department visits and number of visits among those who had any visits.

—Rebecca S. Lash, RN, MSN, MPP

➤ Less than a college education.

These factors have also been identified in other studies.

The average annual expenditures were similar for patients with cancer ($1406), individuals with no chronic conditions ($1406), and patients with other chronic conditions ($1553). On the surface, said Ms Lash, these numbers may be surprising, but if you dig deeper, they are not.

“In MEPS, when a patient is admitted to the hospital, expenditures get wrapped up into their admission expenditures, and they are not included in MEPS emergency department expenditures,” said Ms Lash. So, the data show “people who went to the emergency room and got discharged. When you consider that, you wouldn’t expect the groups to vary much. We are prob-

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ably vastly underestimating the expenditures. Oncology patients are a group likely to be admitted to a hospital. I would point out, however, that $1500 is a lot of money for an episode of care that doesn’t result in an admission.”

Avoidable Cancer-Related Hospitalizations The second study focused on the rate of potentially avoidable hospitalizations in patients with a solid tumor who were admitted to Brigham and Women’s Hospital in Boston and had ≥2 outpatient cancer-related visits to Dana-Farber Cancer Institute in the 6 months before hospitalization.

The researchers interviewed the outpatient oncologist, inpatient attending physician, and an inpatient resident/physician assistant, asking

them whether on the day of admission, the patient could have been safely and effectively managed as an outpatient rather than an inpatient, and was the hospitalization preventable with different medical management during the 30 days before admission.

Of 103 hospitalizations, 21% were rated as potentially avoidable by 2 clinicians, and 28% were deemed potentially avoidable by 1 clinician. Only 2% of hospitalizations were rated avoidable by all 3 clinicians. Hospitalizations were more likely to be perceived as avoidable when psychosocial factors contributed to the reason for hospitalization (odds ratio, 2.9; 95% confidence interval, 1.2-7.3).

The most common psychosocial factors contributing to hospitalization were depression/anxiety and inadequate home support. The median length of stay was shorter for potentially avoidable hospitalizations than for other hospitalizations—2 versus 4 days.

“There are potentially avoidable hospitalizations out there, and we really ought to believe that we can do something about those,” said Gabriel A. Brooks, MD, a medical oncologist at Dana-Farber Cancer Institute, who presented the study.

“Some potential interventions that strike me as valuable to reduce avoidable hospitalizations would be early integration of palliative and psycho­ social care and more robust outpatient acute care systems.” Dr Brooks said that better identification of patients at risk for chemotherapy toxicity and chemotherapy-related hospitalization may also help.

Improving Quality Care Dr Schnipper pointed out that studies have shown that early palliative care can help reduce hospitalizations and emergency department visits. A Canadian study, for example, showed that early palliative care for patients with cancer and other conditions reduced hospitalizations by roughly 33% and reduced emergency department visits by 25% (Seow H, et al. BMJ. 2014;348:g3496).

Dr Schnipper also believes that oncology medical homes, by providing better care, could help keep patients out of the emergency department and the hospital. A recent study demonstrated that oncology medical homes can reduce emergency department visits and hospital admissions by 50% (Sprandio JD, et al. J Oncol Pract. 2013; 9:130-132). n

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In the Literature Molecular Profiling Not Cost-Effective for Adjuvant Chemotherapy DecisionMaking in Patients with Node-Negative Breast Cancer

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probability of being the most cost-effective strategy; systematic chemotherapy had a 6% (4% in the patients with ER-positive disease) likelihood of being the most cost-effective strategy; and the MammaPrint genomic test had only a 2% (20% in patients with ER-positive NNBC) B:7.625 in probability of being the most cost-effective strategy.

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These results indicate that the use of the MammaPrint test to determine which patients with NNBC are at high risk for disease recurrence and would benefit from adjuvant chemotherapy is not cost-effective. The health outcomes in this study were almost identical among the 3 strategies evaluated. The high cost of the Continued on page 18

In mCRPC therapy…

Is there more to the story?

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials.

Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly. mCRPC=metastatic castration-resistant prostate cancer; AST=aspartate aminotransferase; ALT=alanine aminotransferase.

Please see additional Important Safety Information on the next page.

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

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The use of adjuvant chemotherapy in patients with node-negative breast cancer (NNBC) has a negative impact on quality of life, serious side effects, and increased overall costs of therapy.

However, the use of chemotherapy has favorable outcomes in patients with NNBC, which accounts for the majority (70%-80%) of breast cancers identified in screening programs. In a new study, researchers analyzed the economic impact of using the genomic test MammaPrint, a 70-gene signature, versus 2 other strategies to guide the clinical decision to use adjuvant chemotherapy in patients with NNBC (Bonastre J, et al. J Clin Oncol. 2014; 32:3513-3519).

The study was conducted in France and was supported by the French National Cancer Institute. Data were taken from the TRANSBIG consortium validation study conducted with the MammaPrint genomic test. A total of 307 patients with NNBC who did not receive any systemic adjuvant therapy were included in the study.

Eligibility criteria included age <61 years at diagnosis and a tumor size of <5 cm. The majority (69%) of the patients had estrogen receptor (ER)-positive breast cancer; 41% had a grade 2 or 3 tumor.

In the base-case analysis, 3 strategies were used to decide whether to use adjuvant chemotherapy, including (1) the genomic test MammaPrint, (2) the prognostic diagnosis Adjuvant! Online, and (3) using systematic chemotherapy in all patients. The time horizon for overall survival (OS) was 10 years. In the first 2 strategies, only women at high risk for recurrence were assumed to receive chemotherapy. In the systematic chemotherapy strategy, all patients were assumed to receive chemotherapy, regardless of risk for recurrence.

The costs were based on the French National Insurance Scheme, lifeyears, and quality-adjusted life-years (QALYs), and were calculated for each of the 3 strategies for the 10-year time horizon. Without the use of adjuvant chemotherapy, the 10-year OS for patients with NNBC is 77% (95% confidence interval [CI], 71%-81%).

The mean differences in life-years and QALYs were similar among the 3 strategies. The MammaPrint genomic test was associated with a higher cost than the other 2 strategies: the mean difference was an additional €2037 (range, €1472-€2515) for MammaPrint compared with Adjuvant! Online and

€657 (95% CI, –€642 to €3130) compared with systematic chemotherapy.

However, when the cost of the genomic test was reduced, the test became a more cost-effective strategy.

Based on a €50,000 per QALY willingness-to-pay threshold, the Adjuvant! Online strategy had a 92% (76% in patients with ER-positive NNBC)

In the Literature Molecular Profiling Not CostEffective... Continued from page 17

MammaPrint genomic test renders it less cost-effective than the other 2 options for routine use to determine the benefit of adjuvant chemotherapy in patients with NNBC. If the cost of the test were lower, however, it would become more cost-effective.

Biomarker-Driven New Anticancer Drugs Reduce Toxicity and the Associated Costs

The new drugs approved by the FDA for the treatment of patients with cancer often result in prolonged survival and improved quality of life; however, increasing reports have

noted rare but serious adverse events linked to new therapies, and managing these events further increases the cost of therapy. A recent study evaluated anticancer drugs approved by the FDA between 2000 and 2011 to identify grade 3 or 4 adverse events and their associatedB:7.625 costsin (Niraula S, et al.

J Clin Oncol. 2014;32:3634-3642).

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In this meta-analysis of 41 studies related to anticancer drugs in development, researchers analyzed the frequency and costs of 12 grade 3 or 4 adverse events. They calculated the estimated incremental drug prices and the incremental costs associated with the management of these common events based on the type of a

For men with mCRPC who progressed on ADT

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

More than 1,000 days.

And every day tells a story.

MEDIAN OVERALL SURVIVAL FOR ZYTIGA plus prednisone† 35.3 vsMONTHS 30.1 MONTHS with placebo plus prednisone (active compound).‡ IMPROVEMENT IN MEDIAN OVERALL SURVIVAL 5.2 MONTHS compared with placebo plus prednisone. ®

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached.

Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

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IMPORTANT SAFETY INFORMATION (cont) Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken.

Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter.

Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function. *Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N=1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH) agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the co-primary efficacy end points were overall survival (OS) and radiographic progression-free survival.

ADT=androgen-deprivation therapy.

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In the Literature new drug and target specificity. The 41 studies included a total of 27,539 patients. The studies involved 19 experimental anticancer drugs, of which 12 were targeted agents and 7 were chemotherapies.

Drugs that target a specific molecular mutation or a specific target on the cancer cells were associated with a

lower incidence of grade 3 or 4 adverse events compared with controls (P = .22); by contrast, other drugs, including angiogenesis inhibitors and chemotherapy agents, were associated with increased toxicity compared with controls (P <.001). In the latter, the risk for toxicity regardB:7.625increased in less of whether T:7.375 the control arm conin

tained an active or inactive treatment.

In addition, the median monthly drug cost was higher for the experimental drugs compared with the controls, regardless of the type of drug.

The median incremental drug price for the experimental drugs was $6000 (range, –$620 to $32,900) per patient per month (PPPM). The PPPM medi-

an cost was lowest, at $4610 (range, –$620 to $9150), for targeted drugs with the greatest specificity; followed by chemotherapy, at $5730 (range, $2780-$7790); and highest, at $6690 (range, $2870-$32,900), for the less-­ specific targeted agents. The median cost of managing adverse events was higher for the new drugs than for the Continued on page 20

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003307-130924

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

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In the Literature Biomarker-Driven New Anticancer... Continued from page 19

controls in drugs with less-specific molecular targets and in chemotherapies. However, in drugs with specific molecular targets, the cost of managing toxicity was lower than for the controls.

Overall, the investigators conclud-

ed, the new anticancer drugs are associated with increased toxicity, unless the drugs have a specific molecular target on cancer cells. The additional toxicity leads to a small increase in the overall cost of treatment. According to the researchers, these results suggest that developing biomarker-­ driven drugs should be encouraged

as a way to reduce toxicity and the associated costs and to improve overall outcomes.

Panobinostat Improves Outcomes in Relapsed/ Refractory Myeloma

Panobinostat is a potent, oral histone deacetylase (HDAC) inhibitor

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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that has shown synergistic antitumor activity when combined with bortezomib (Velcade) and dexamethasone (Decadron). HDAC inhibitors could help overcome the acquired resistance to proteasome inhibitors, such as bortezomib, by blocking the aggresome pathway (an escape route for myeloma cells as they evade the ubiquitin

ZYTIGA® (abiraterone acetate) Tablets is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

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

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

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In the Literature proteasome pathway). The multicenter, randomized, double-blind phase 3 clinical trial known as PANORAMA1 compared the use of panobinostat plus bortezomib and dexamethasone to placebo plus bortezomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma (San-Miguel JF, et al. Lancet

Oncol. 2014; 15:1195-1206).

PANORAMA1 enrolled 768 patients with relapsed and/or refractory myeloma from 215 centers in 34 countries.

Patients with disease refractory to bortezomib were excluded. The patients were randomized to panobinostat or to placebo, both in combination with bortezomib and dexamethasone, for a

maximum of 12 cycles. Patients were followed for a median of approximately 6 months.

The primary end point was median progression-free survival (PFS), which was significantly longer in the panobinostat group (11.99 months) than in the placebo group (8.08 months), a 27% reduction in the risk for disease progres-

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) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable.

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

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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

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sion. The 2-year PFS was 20.6% with panobinostat versus 8.4% with placebo.

For patients who achieved a complete response or near-complete response, the median PFS was 19.38 months in the panobinostat group and 15.21 months in the placebo group. The addition of panobinostat to the combination of bortezomib and dexamethasone also led to

Continued on page 22

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In the Literature Panobinostat Improves Outcomes in Relasped...

Continued from page 21 longer median duration of response and longer time to first disease pro­ gression, relapse, or myeloma-related death. These results were consistent across all subgroups, suggesting a clinical benefit with the addition of the

HDAC to the treatment regimen, regardless of any previous treatment or baseline patient characteristics.

At the time of this analysis, the overall survival data were not yet mature, but the median survival duration was 33.64 months with panobinostat and 30.39 months with placebo. Although this 13% mortality risk reduction was

not statistically significant, the panobinostat group had significantly more complete or near-complete responses than the placebo group (27.6% vs 15.7%, respectively; P = .006).

Serious adverse events occurred in 60% of patients receiving panobinostat versus 42% of patients receiving placebo. Neuropathy was not increased in

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

the experimental group, but that group did have more cases of diarrhea, thrombocytopenia, asthenia, and fatigue.

The investigators noted that the results with panobinostat are better than those seen with another HDAC inhibitor, vorinostat (Zolinza), which, when added to bortezomib, did not lead to a significant increase in PFS; panobino­ stat is a more potent pan-HDAC inhibitor, with more potent in vitro inhibitory activity than vorinostat, they noted.

PANORAMA1 is the first phase 3 clinical trial to show a benefit for a 3-drug versus a 2-drug combination in patients with relapsed and/or refractory myeloma.

In an editorial accompanying the article, S. Vincent Rajkumar, MD, Professor of Medicine at the Mayo Clinic, Rochester, MN, wrote that this study “is the first to report on a new class of drugs with meaningful clinical activity in myeloma in nearly 15 years” (Rajkumar SV. Lancet Oncol. 2014;15:11781179). He noted that although the improvement in PFS may seem small, “it will probably increase as we learn how best to use the drug and optimize the dose and dosing schedule.” Dr Rajkumar concluded, “I expect panobinostat to become an important component of myeloma treatment.”

Single-Unit Cord-Blood Transplant Better than 2-Unit Transplant in Patients with Hematologic Cancers

Umbilical cord blood is often used for hematologic stem-cell transplantation. In patients with a large body mass, it is often not possible to use only 1 cord-blood unit, because of the limited number of hematopoietic cells.

Investigators therefore assumed that the use of 2 cord-blood units would improve outcomes, because of the increased number of hematopoietic cells.

They tested their hypothesis in an open-label, phase 3, multicenter clinical trial with children and young adults (Wagner JE, et al. N Engl J Med. 2014;371:1685-1694).

A total of 224 patients aged 1 to 21 years were randomized in a 1:1 ratio to undergo a 2-unit (n = 111) or a 1-unit (n = 113) cord-blood transplantation procedure. The primary end point was 1-year overall survival (OS). The groups were matched for age, sex, race, performance status, degree of donor-recipient human leukocyte antigen matching, and disease type.

The 1-year OS rate was similar among the 2 groups—65% (95% confidence interval [CI], 56-74) with 2 units of cord blood and 73% (95% CI, 63-80) with 1 unit of cord blood, an insignificant difference. The outcomes were also similar between the 2 groups in Continued on page 49

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Economics of Cancer Care

New Reimbursement Models Needed for Vulnerable Populations with Cancer

See also VBCC Perspective, page 1

By Phoebe Starr

Boston, MA—Vulnerable populations with cancer pose challenges to an already strained healthcare system. At the 2014 ASCO Quality Care Symposium, speakers addressed quality care issues related to treating cancer in the elderly and in patients with multiple comorbidities; they all agreed that new reimbursement models are needed to provide patient-centered coordinated care to these populations.

In the United States, we already have a shortage of geriatricians and oncologists, and this is likely to become worse over the next few decades. Fragmentation of the delivery of cancer care and the rising costs of healthcare add to the challenge of cancer care in the elderly and to those with comorbidities.

“The silver oncologic tsunami is coming. Cancer is a disease associated with aging, and meeting the challenges of elderly patients with cancer is a challenge that will only grow in importance over the next few decades,” stated Andrew E. Chapman, DO, Co-Director, Jefferson Senior Adult Oncology Center, Sidney Kimmel Cancer Center, Philadelphia, PA. Older patients have a high disease burden, Dr Chapman said. Of all cancers, 60% occur in people aged ≥65 years, and 69% of cancer-related deaths occur in the same age-group.

at a glance ➤ New reimbursement models are needed to provide patientcentered coordinated care to all patients ➤M odels that promote teambased care and that are specifically geared toward treating the elderly and patients with multiple comorbidities are especially needed ➤ Healthcare training should include a focus on responding to patients’ emotions and fears, fostering patient self-management, information exchange, and decision-making ➤E nsuring patient-centered comprehensive cancer care must become a priority

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The exploding population of elderly people coupled with the rising costs of cancer care and the fragmentation of delivery of complex geriatric care creates a perfect storm.

New Models of Care in the Elderly Dr Chapman presented an urgent “to do” list to meet this challenge: 1. Empower healthcare stakeholders to improve healthcare delivery in the geriatric setting 2. Develop healthcare delivery models focused on the elderly 3. Develop oncology-based relevant data sets 4. Establish new standards of care and implement the data and modeling in clinical practice.

“

The silver oncologic tsunami is coming.

Cancer is a disease associated with aging, and meeting the challenges of elderly patients with cancer is a challenge that will only grow in importance over the next few decades.

”

—Andrew E. Chapman, DO

Empowering healthcare stakeholders entails recognizing the unique needs of elderly patients in terms of comorbidities, nutritional status, cognitive impairment, geriatric syndromes, polypharmacy, psychological status, and social support.

Inadequate assessment of cognitive and functional status in elderly patients can lead to overtreatment and undertreatment, Dr Chapman added.

The healthcare community needs to develop core competencies geared toward treating elderly patients and incorporate them into healthcare training and education. Models to promote team-based care coordination are needed.

Developing deeper data sets depends on more focused clinical trials that include the elderly, Dr Chapman emphasized. Extending drug patents may be a way to incentivize pharmaceutical companies to conduct such trials.

Good communication is needed that is based on understandable, relevant, and evidence-based information

“

ditions; 53% of those aged 50 to 64 years had at least 2 of these conditions, he continued.

I am a 20-year cancer survivor and I find it challenging to coordinate my own follow-up care. I can only imagine what it is like to walk in the shoes of an elderly patient with 5 or more comorbidities.

”

—Neeraj K. Arora, PhD

to engage elderly patients in the new standards of care. The development of decision aids for the elderly needs to involve collaboration with patients and palliative care experts.

At the end of life, many elderly patients are subject to intensive interventions instead of palliative care.

The need for palliative care should be discussed with patients with cancer and their families as early as possible.

Payers need to create a model for reimbursement of these discussions, which can help rein in inappropriate healthcare spending.

Quality Issues in Patients with Multiple Comorbidities Neeraj K. Arora, PhD, Acting Branch Chief, Outcomes Research Branch, National Cancer Institute, Bethesda, MD, addressed quality issues for patients with cancer and survivors with multiple chronic conditions. “Problems related to communication and transitions of patients from in to outpatient care are amplified in individuals with cancer and other chronic conditions,” stated Dr Arora.

“One in 3 individuals enrolled in Medicare have 5 or more other chronic conditions. These people see between 5-16 different physicians per year in 3-9 different practices,” Dr Arora stated. “I am a 20-year cancer survivor and I find it challenging to coordinate my own follow-up care. I can only imagine what it is like to walk in the shoes of an elderly patient with 5 or more comorbidities,” he told listeners.

The experience of living with cancer and other chronic conditions is not limited to elderly people, Dr Arora reminded the audience. In one sample of 3000 people in the United States, 26% of those aged 18 to 49 years had 2 of 7 common chronic connovember 2014

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“Ensuring patient-centered comprehensive cancer care has to be our priority moving forward,” Dr Arora stated.

He gave the following list of actionable goals: ➤ Foster healing relationships ➤ Enable patient self-management ➤ Manage uncertainty ➤ Respond to emotions ➤ Exchange information ➤ Make decisions.

“Studies show that having patient-­ centered systematized coordinated care has a positive influence on self-confidence and the ability to care for oneself,” Dr Arora stated.

“

Ensuring patientcentered comprehensive cancer care has to be our priority moving forward….Now we need a model of how to pay for patient-­­ centered care.

”

—Neeraj K. Arora, PhD

Aspects of care that are relevant to all patients with cancer throughout the trajectory of their illness include: ➤ Planning and counseling before therapy ➤ Use of palliative care and hospice services ➤ Interdisciplinary coordinated care ➤ Comprehensive symptom assessment and treatment ➤ Patient experiences of care.

“Now we need a model of how to pay for patient-centered care,” Dr Arora stated. n

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Economics of Cancer Care

Individualizing Dosing of 5-FU with Pharmacokinetic Test Is Cost-Effective

By Wayne Kuznar

Chicago, IL—Using a commercially available assay to guide the dosing of 5-fluorouracil (5-FU) for the treatment of metastatic colorectal cancer (CRC) is cost-effective based on a survival advantage over dosing related to body surface area, according to an analysis conducted by Daniel Goldstein, MD, a hematology and medical oncology fellow at Emory University, Atlanta, GA. Currently, the standard treatment for metastatic CRC is a regimen of 5-FU given with leucovorin and oxaliplatin (FOLFOX). Dosing is typically calculated by body surface area, but this method may result in substantial interindividual variability in drug exposure, often resulting in high toxicity levels, he said.

The development of an immuno­ assay for 5-FU now allows pharmacokinetic-guided dose adjustments of FOLFOX to individualize chemotherapy treatments. The results of 2 separate studies showed that this method improves overall survival (OS) and decreases toxicity versus body surface area–guided dosing in patients with metastatic CRC. “The issue of personalizing the dosing of 5-FU has been around for quite

some time,” he said. “This is probably one of the first tests that has shown to be validated and have clinical utility, but it’s in its infancy.”

“

The issue of personalizing the dosing of 5-FU has been around for quite some time.

This is probably one of the first tests that has shown to be validated and have clinical utility.

”

—Daniel Goldstein, MD The recognition of the clinical benefits of pharmacokinetic-guided dos­ ing led Dr Goldstein to compare the cost-effectiveness of pharmacokinetic FOLFOX dosing to traditional body surface area FOLFOX dosing in patients with metastatic CRC. “When you use the PK [pharmacokinetic] test to guide the dosing, you do get improved overall survival and decreased toxicity. The test is only

$400 to $500, so we did a cost-effectiveness analysis to see if this extra spending on the test has value.”

Cost Analysis Dose adjustments of 5-FU based on pharmacokinetics can be made using an immunoassay for 5-FU, he said.

However, he said, the test “is not used so much in the US at the moment,” Dr Goldstein noted.

The investigators used a Markov model for their cost-effectiveness comparison of the 2 dosing methods. Published data on progression-free survival (PFS) and OS were used to estimate the impact on disease progression and mortality risk.

The costs for the administration of chemotherapy and the management of adverse events were established based on Medicare reimbursement rates for hospital and physician services. The costs of drugs were based on the Medicare and Medicaid prices. All costs were calculated averages of 2013 price ranges in US dollars.

Calculated into the cost estimation were drug costs, administration costs, and costs for grade 3/4 adverse events. The cost of the test was as-

sumed to be $400.

The primary outcomes were measured in incremental cost per quality-adjusted life-year (QALY) gained.

Pharmacokinetic FOLFOX provided 2.03 additional QALYs at a cost of $50,205 compared with body surface area FOLFOX with 1.46 QALYs at a cost of $37,173.

The incremental cost-effectiveness ratio (ICER) was $22,694 per QALY. This ICER was well below the $50,000 willingness-to-pay threshold in all one-way sensitivity analyses. In probabilistic sensitivity analyses, 99% and 95% of patients had ICERs of <$42,000 per QALY and <$34,000 per QALY, respectively.

The main cost driver was the $400 pharmacokinetic test that was used for 4 cycles to establish optimal doses, said Dr Goldstein. The main drivers of the clinical benefits were improved PFS and OS outcomes.

“Given the cost-effectiveness profile and OS advantage with PK FOLFOX, it should be evaluated further in comparative effectiveness studies,” he noted.

These results were presented at the 2014 American Society of Clinical Oncology meeting. n

Routine Imaging Costly in B-Cell Lymphoma, Rarely Picks Up Relapse After Remission Chicago, IL—Routine surveillance imaging of asymptomatic patients in first remission after treatment for diffuse large B-cell lymphoma offers little clinical benefit at substantial cost, according to Scott F. Huntington, MD, of Abramson Cancer Center, University of Pennsylvania, Philadelphia, and colleagues. Strategies utilizing 2 years of routine computed tomography (CT) or positron emission tomography (PET)/ CT scans were associated with minimal survival benefit compared with follow-up without routine imaging.

“Surveillance imaging limited to 4 scans over 2 years is associated with significant aggregate costs,” noted Dr Huntington at the 2014 American Society of Clinical Oncology meeting.

The goal of routine surveillance imaging is the detection of early relapse, but “there’s increasing data showing that the majority of patients who have diffuse large B-cell lymphoma who relapse will be symptomatic. So, the utility of imaging is questioned,” he said.

24

Dr Huntington and colleagues created a decision analytic Markov model and compared 3 surveillance strategies in cohorts of 55-year-old patients. The baseline model was biased to favor imaging strategies by associating asymptomatic imaging-detected relapses with improved clinical outcome, said Dr Huntington.

Quality-adjusted utility, lifetime costs, and incremental cost-effectiveness ratios were calculated for each follow-up strategy.

“One trial found that patients with image-detected disease were more likely to have lower IPI [International Prognostic Index] scores, so they were basically having more favorable outcomes posttransplant,” he pointed out. “The data from that trial was used to bias toward imaging.”

The benefit of imaging-based follow-up remained small after quality-of-life adjustments. The costs associated with imaging-based surveillance strategies are considerable, and incre-

Value-Based Cancer Care

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November 2014

mental cost-effectiveness ratios were $202,300 per quality-adjusted life-year

“

Surveillance imaging limited to 4 scans over 2 years is associated with significant aggregate costs….Usually, routine surveillance imaging is not picking up those relapses.

Even in the best-case scenario for the utility of imaging, it’s still not likely to be cost-effective.

”

—Scott F. Huntington, MD

(QALY) for CT strategies and $312,600 per QALY for PET/CT strategies.

Incremental cost-effectiveness ratios

for imaging strategies remained at >$100,000 per QALY or were dominated by routine follow-up in multiway sensitivity analyses over clinically relevant ranges.

“The question is if routine surveillance imaging or serial surveillance imaging should be used, and there are providers who suggest against surveillance imaging,” Dr Huntington noted. “Certainly you want to see patients routinely, every 3 to 6 months, and perform a close history and physical exam, because that is actually the majority of relapse—the patient is symptomatic. The patient may have changing symptoms or recurrent night sweats, and we may see new physical exam findings and new laboratory findings.”

He added that, “Usually, routine surveillance imaging is not picking up those relapses. Even in the bestcase scenario for the utility of imaging, it’s still not likely to be cost-effective.”—WK n

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Economics of Cancer Care

Symptom Management Drives Value... patients. We also saw that unrelieved symptoms lead to a decline in physical state, performance status, and increased suffering. So we knew we had to treat these symptoms early,” Ms Graze said.

Untreated symptoms cost payers too. “We knew that if a patient has to go to the ED [emergency department] for oncology symptom management, they have a better than 50% chance of being admitted,” said Ms Graze. “So we really wanted to alleviate these [symptoms] with earlier care for our patients.”

“”

Systematic nursing assessments with interventions lead to better quality of life for patients.

—Lynn Graze, RN, MSN, OCN

Despite this incentive, establishing the symptom management clinic was not easy. Lack of standardized assessment tools, equipment, digital support, and staffing issues all posed barriers. Perhaps the biggest obstacle, Ms Graze said, was psychological.

“Patients do not like to bother their physicians….The communication of symptoms during office visits is

flawed compared with concurrent diaries of symptoms; what patients document as their symptoms is not what they’re telling their physicians.”

Accurate patient assessment is critical to cost-savings by providing the right care at the right time and place, with fewer dose modifications. The symptom management model was developed with the patient perspective in mind. “We needed to find a way to make care easier for the patients,” said Ms Graze. “We wanted to get to symptoms early, treat them, and keep patients out of the ED….

Patient education was critical.”

Run by nurse practitioners (NPs) and triage nurses, the clinic provides rapid access and coordination of care with the oncologists and infusion team. If 1 of 19 criteria is met, a patient can automatically be put on the NP’s schedule. Triage phone lines are answered by infusion nurses and average between 70 and 100 calls daily.

“We didn’t extend the clinic hours,” said Barry R. Meisenberg, MD, Chair for Quality Improvement and Healthcare Systems Research, Anne Arundel Medical Center. “We just made it easier to reach us during clinic hours.”

Significant Results A study conducted by the hospital showed good results for the symptom management clinic in the first 8

Continued from the cover

months. Overall, 41 patients were seen monthly in the clinic for pain, anorexia, nausea, vomiting, diarrhea, swell-

nificant percentage of non–chemotherapy-related admissions could be prevented with little effort, without

“

The financial incentive is there, and we can make the case to our payers that this is important for us to do for more than one reason. It’s also good patient care.

”

—Barry R. Meisenberg, MD

ing, and fever. Of these, 65% of patients were seen the same day and 25% were seen the following day.

Emergency department visits went from 26 to 17 monthly, a 35% reduction.

“We didn’t invent symptom management. There’s probably a description of this in Homer with the Greek army and the gates of Troy….What we were able to do was embed the SMC within the larger oncology clinic, and we achieved a 35% reduction in ED visits,” said Dr Meisenberg.

He said the study proved that a sig-

overhauling the oncology care model.

“We have to expand the concepts so we’re taking care of not only the patients on our clinic schedules, but the patients who are not on our clinic schedule. We basically need an alternative roster of patients that we’re managing via the phone and the triage,” Dr Meisenberg emphasized.

“The financial incentive is there, and we can make the case to our payers that this is important for us to do for more than one reason. It’s also good patient care,” he concluded. 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

Vol. 5

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www.ValueBasedCancerCare.com

25

VBCC Perspective

Reimbursement Reform in Oncology: Moving from Cost to...

Continued from the cover

and the understanding of value has lagged behind.

Cancer care in the 1960s, 1970s, and even the early 1980s, was largely a hospital-based service. Surgery was king; radiation and chemotherapy were in their infancy. The late 1980s and the early 1990s saw tremendous innovation in these fields. These years also saw a migration of medical oncology from hospital-based to office-based practice.

This relocation of services exponentially increased the complexity of the required infrastructure. The office infusion center, specially trained nurses, chemotherapy pharmacy services, and the associated business office support were very expensive. Payment for professional medical oncology services was the same as for any other office-based internal medicine subspecialty.

The buy-and-bill model was born from the need to help pay for infrastructure. Practices began to purchase

chemotherapy drugs at wholesale prices and sell them to payers at increased retail prices. The understand-

Michael Kolodziej, MD

ing that this margin offset the cost of the infrastructure was implicit.

The emergence of new, expensive chemotherapy options in the 1990s dra-

By the Numbers In a recent survey of 57 healthcare leaders on telemedicine: Implementing Telemedicine

90% of respondents report their organizations have begun to develop/ implement a telemedicine program 84% believe that telemedicine services are important (52%) or very important (32%) to their organizations 64% say their telemedicine programs offer remote monitoring 52% of programs have real-time interaction capabilities 50% rank improving quality of care as the top reason for implementing telemedicine 36% are piloting/implementing a program 34% have telemedicine programs under construction or in development 18% are most excited for the opportunity to reach new patients 8% have no telemedicine service at all 3% said telemedicine was unimportant ack of Reimbursement Top Obstacle L

48% rank lack of reimbursement the biggest obstacle to implementing telemedicine 48% rank ensuring physicians see telemedicine as credible first (13%) or second (26%) obstacle 41% of hospitals/health groups are not being reimbursed at all for telemedicine services 36% worry about physicians feeling adequately compensated for using telemedicine 24% rank institutional support and funding as the top obstacle ~25% expect <10% of patients to utilize their telemedicine services 21% receive lower rates from managed care companies for telemedicine than for in-person care 17% rank lack of reimbursement the second obstacle to implementation 11% rank the potential for increased revenue/profitability as a reason to implement telemedicine 6% describe their telemedicine programs as â&#x20AC;&#x153;matureâ&#x20AC;?

Source: Foley. 2014 Telemedicine Survey Executive Summary. November 11, 2014.

26

Value-Based Cancer Care

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November 2014

matically increased the cost of cancer care. Under the buy-and-bill model, the net revenue of oncology practices also

Data have now convincingly shown that therapeutic decision-making by oncologists is not, for the most part, profit driven. But there also is recognition that the current fee-for-service model remains driven by utilization rather than value-based reimbursement.

increased. Some less-than-transparent prescribing practices tied to volume-based rebates caused many within and outside the medical community to characterize the motives of oncologists in prescribing chemotherapy as conflicted at best and perverse at worst.

Because Medicare beneficiaries represent approximately half of all patients treated for cancer, the federal government became involved in the prescribing rebate debate. The resulting Medicare Modernization Act of 2003 tied reimbursement to the actual cost of the drug administered and capped the margin, effectively limiting the profitability of caring for patients with Medicare coverage.

Unfortunately, only the cost of care and the financial incentives tied to chemotherapy administration became the focus of debate, rather than a discussion of value. In response, almost all commercial payers also focused on cost. They migrated to a structure parallel to that of Medicare and increased utilization management, particularly through prior authorization.

Although utilization management had some impact on cost, the rapid pace of innovation and the associated soaring cost have kept cancer care in the spotlight of policymakers and payers. This is understandable when one considers that the cure rate for the most common advanced-stage malignancies in adults has not improved much.

Still, survival has been prolonged for many patients, and the advances in cancer care are undeniable. The task now is to understand and reward good outcomes. Data have now convincingly shown that therapeutic

decision-making by oncologists is not, for the most part, profit driven.

But there also is recognition that the current fee-for-service model remains driven by utilization rather than value-based reimbursement.

The value that is being defined in oncology today is pragmatic. It is rooted in understanding the appropriate evidence-based care for clinical subsets of patients, the associated cost structure of this care, and the subsequent outcomes. This value can be defined objectively, but requires measurement, reporting, and process improvement.

Neither providers nor payers hold all the data elements; progress requires collaboration. The current reimbursement reform proposals that are likely to succeed all share the attribute of continuous quality improvement, with a pay-for-value model as the soul of this transformation.

The current reimbursement reform proposals that are likely to succeed all share the attribute of continuous quality improvement, with a pay-for-value model as the soul of this transformation.

Big data will become an enabling technology to facilitate physician performance, as well as process-of-care modeling. The payers are ready to shift attention from the buy-and-bill model to a model where a high-performing network of providers is recognized and is financially rewarded.

The healthcare system is cost-constrained, so an infusion of cash is unlikely. Quality will be rewarded, however, and high-performing providers will thrive.

Unfortunately, oncology payment reform is not a cure-all. The challenges associated with the cost differential attributable to site of service will require other solutions.

In addition, the high cost of new therapies, particularly considered in the context of rewarding incremental rather than truly innovative advances, will need to be addressed.

Finally, and perhaps most important, the voice of the patient/healthcare consumer has not yet been adequately integrated into the proposed reforms.

We must continue the dialogue. 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

4th Conference

Adoption of Private Health Exchanges by Employers Expected to Grow Rapidly

By Wayne Kuznar

Los Angeles, CA—Private exchanges as platforms for employer health insurance plans under the Affordable Care Act (ACA) are growing rapidly­ —they are already utilized by big corporations and have made some of the biggest strides in the smallerand medium-sized corporate marketplace. Private health exchanges are already offered by several large global companies, including Walgreens, UPS, Sears, Xerox Corporation, Time Warner, Williams-Sonoma, Panera Bread, and Chico’s.

Alex Jung, Principal of Global Strategic Advisory Services at Ernst & Young, LLP, shared her assessment of the changes in the health insurance marketplace at the Fourth Annual Conference of the Association for Value-­Based Cancer Care.

Ms Jung explained that healthcare is a corporate investment to oncologists.

Approximately 50% of the United States is covered by the private insurance sector (ie, employers). Of the 167 million people who have coverage under private insurance markets, corporations have been looking to decrease the costs of benefits that represent 70% of their operating budgets.

“That’s why people’s salaries have stagnated so much,” Ms Jung said.

“You don’t see real income growth in this country, because of the cost of benefits, and, primarily, healthcare.”

With the signing of the ACA, employee benefits consultants entered the arena. Companies such as Aon Hewitt provide private exchange offerings in 2 distinct types: risk-based plans and self-insured plans. The profit margin varies significantly between the 2 offerings, thus making it a key variable in sizing the potential market opportunity, according to Ms Jung. “Exchanges in the private sector are going to be what we see as the primary source of

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F igure Private Exchanges Positioned to Be Among the Fastest Growing Markets in the Next 3 to 5 Years We expect a strong migration to private exchange by employers for active employees and retirees The number of private exchange lives will increase by approximately 90% annually to 2018

Interest is high on the buy and sell sides, driving annual growth

Private exchange industry enrollment Estimated number of lives (in millions)

Private exchange industry enrollment growth Percent growth of number of lives 179%

˜90% 118%

“

Exchanges in the private sector are going to be what we see as the primary source of coverage for employees in this country….The private exchange is actually growing fastest at the bottom of the pyramid, which is employers under 100 employees.

”

—Alex Jung

coverage for employees in this country,” she said.

According to Ms Jung, the huge, traditional employee benefit consultant Aon acquired Hewitt Associates to invest in the infrastructure in these private exchanges. “When Aon acquired Hewitt Associates, they didn’t do it because they wanted to acquire the employee benefits outsourcing business,” said Ms Jung. “They did it because they wanted the platform— the systemic platform for administering health plans—because they had the vision that they would eventually convert that platform into a platform

˜33.0

85% 56% 37%

˜1.5-2 2013

2014 2015 2016 2017 2018

2018

Many industry leaders are forecasting enrollment in private exchanges will exceed public exchanges and could reach approximately 30 million to 40 million lives by 2018 Industry enrollment growth includes both active employees and retirees.

Sources: US Small Business Administration, US Census Bureau, William Blair & Company, consensus estimates, company reports, and Ernst & Young analyses.

that would administer private exchanges for employers.”

What started as an “experiment” between Aon and Walgreens has branched out to the middle market and small employers. Despite their lower risk tolerance, the fastest growth in the private sector is for the middle market and small employers. Companies such as Towers Watson and Buck Consultants are faring well in this market. “The private exchange is actually growing fastest at the bottom of the pyramid, which is employers under 100 employees,” said Ms Jung.

“That’s largely because they can’t afford the premiums that they’re being charged for private insurance.”

That said, the forces that drive private exchanges are the huge benefit consulting firms that can have enor-

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mous influence on the employer plan sponsors that are traditionally relied on for private insurance, said Ms Jung.

Insurance companies have been relegated to the status of intermediaries that are trying to define their role in the future, because they are getting commoditized, she said. Although employers are traditionally risk-averse, the adoption rate of private exchanges will be quick, within a predicted 3- to 5-year span (Figure). “You have mobile and digital platforms that will accelerate the adoption rate,” Ms Jung noted.

According to her, although private exchanges are small today, industry dynamics have primed the market for rapid growth. Given the size of the addressable market, private exchanges could be a $67-billion market by 2025, Ms Jung said. n

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4th Conference

The Changing Healthcare Payment, Regulation, and Delivery Environments

By Wayne Kuznar

Los Angeles, CA—The environment for regulation, payment, and healthcare delivery is changing. In particular, disruptive changes in Medicare reimbursement are on the horizon, said Michael E. Meyers, MPH, Managing Director and Head of Investment Banking, T.R. Winston & Company, Los Angeles, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Mr Meyers started with a discussion of trends in the changing environment of specialty pharmaceuticals. Specialty pharmaceuticals remain an extremely attractive business segment for value-added services and solutions, because providers and payers will continue to require specialty solutions to achieve greater efficiencies, he said.

Clinical care management programs and the use of specialty pharmacies have increased dramatically.

These programs help to maintain patient ad­herence. Through the use of technol­ogy and clinical pathways, firms have the opportunity to assist payers in managing specialty utilization. Specialty pharmaceuticals represent a rapidly growing percentage of drug plan costs, which are now estimated to be 40%. Another trend is the move from covering specialty pharmaceuticals under the medical benefit to covering them under the pharmacy benefit.

A 2014 survey of 72 institutional investors showed that 44% of those surveyed believed that specialty drug prices in the United States will rise by 2020, but at a slower pace than in the past (Table).

Changing Medicare Reimbursement “The ASP [average sales price] reimbursement system continues to be in the crosshairs of Congress,” Mr

36

Meyers said. “The Wall Street perspective is that ASP induces perverse incentives for high drug prices and excess utilization.”

Changing State of Compounding New regulation will take the compounding market upscale, said Mr Meyers. Typically, compounding

“

Along with bundling, these proposals disrupt pricing and provide powerful incentives for manufacturers to favor competitively bid schemes rather than the current Part B model.

”

—Michael E. Meyers, MPH

Current proposals focus on a prospective ASP; however, other ideas, although further off, may be more disruptive. One construct involves blending the medical and drug benefits. Medicare is also aiming for new authorities to engage in tacit forms of reference pricing, such as low-cost alternative authority. “Along with bundling, these proposals disrupt pricing and provide powerful incentives for manufacturers to favor competitively bid schemes rather than the current Part B model,” he stated.

Other disruptive changes in motion are the increasing rate of hospital acquisitions of physician practices and the increasing consolidation of health systems, hospitals, and integrated delivery networks. In addition, drugmakers now consider the new value customer to be the provider, not the insurer.

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pharmacies have been pharmacies that are regulated at the state level as a pharmacy that dispenses 1 compounded product to 1 patient.

“Things changed after a tragedy that occurred with one compounding pharmacy in Massachusetts a couple of years ago,” he said. “Ultimately, Congress took up legislation…called DQSA [Drug Quality and Security Act] to now require—although the FDA is now implementing the legislation as voluntary—registration of compounding pharmacies as manufacturers.”

It is likely that the industry will get rolled up by more capable manufacturers, improving quality and trust, and creating opportunities for reputable manufacturers who can meet the current good manufacturing practice requirements. These manufacturers will have a huge advantage in terms of

Specialty Drug Trends in the Table United States: Survey Responses from 72 Institutional Investors Q: In general, how do you think US specialty drug prices will change by 2020?

Specialty drug pricing will: Rise, but at a slower pace than in the past: 44% Continue to rise at a similar pace as in the past: 18% Stay about the same: 16% Fall approximately 5%: 7% Fall approximately 10%: 5% Fall approximately 15%: 7% Fall approximately 20%: 2% Fall approximately ≥25%: 2% size and economies of scale in providing physicians complex mixtures and compounded products.

The new framework for compounders will probably fall somewhere between new drug applications and abbreviated new drug applications.

The FDA and REMS Program Enforcement The FDA is facing renewed scrutiny over its enforcement of the Risk Evaluation and Mitigation Strategies (REMS) program. In a fragmented supply chain, the FDA is learning that enforcing provisions regulating the use of a REMS program is difficult, especially without legal authority over providers. New REMS requirements and “special medical use” will create additional chokeholds regarding already fairly tightly regulated supply chains.

Special medical use is going to create additional challenges in the management of distributing specialty drugs to select providers based on special certifications and controlled prescribing, said Mr Meyers. n

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

08/14

US-CELG140179a

4th Conference

Cost Levers Increasingly Being Incorporated into Health Benefit Designs

By Wayne Kuznar

Los Angeles, CA—New health insurance benefit designs are being created with various cost levers to help cover expected expenditures. A primer on these designs was offered by Matthew C. Palmgren, PharmD, President, Int’Ovation Healthcare Solutions, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

The fundamental law of insurance is that the revenue generated (ie, premiums) must be greater than the sum of all indemnities (ie, expenses). Actuarial fairness states that a fair premium is the same as the expected expenditure.

An insurer needs to insure a population and not just an individual for an actuarially fair premium to cover the expected health expenditures.

“The reality is that it comes down to revenue versus expenses,” Dr Palmgren said. “Premiums minus costs is equal to profits to healthcare companies.”

The New Benefit Design Landscape Under the Affordable Care Act (ACA), health plans must spend a minimum of 84% of their previous year’s health insurance premiums on healthcare services—the medical loss ratio (MLR). MLR rebates are mandated under the ACA when insurers do not spend at least this minimum percentage on healthcare services. The services offered fall under 10 essential health benefit categories.

Although there may be limits on services, there can no longer be monetary caps within the deductibles on services, said Dr Palmgren. Copayments and deductibles at varying levels are becoming common for some healthcare services, such as inpatient services (ie, skilled nursing facilities, home healthcare) and outpatient services and sites (ie, office visit, mental

38

healthcare, urgent care, ambulatory surgery, rehabilitative services).

“Specialty office visits might have a different copay than primary care,” he said. “You can see how complex this

“

Specialty office visits might have a different copay than primary care….

We’re constantly trying to tweak the system to make it affordable with the premiums.

”

—Matthew C. Palmgren, PharmD gets very quickly. About 10 years ago, we’d probably just assign one copay for all of these [services]. Now, we’re constantly trying to tweak the system to make it affordable with the premiums.”

Using copays to steer patients to desired settings is another trend, said Dr Palmgren. Because emergency care is the most costly care, patients who would normally consider emergency care are being shifted to urgent care when possible.

Services for which limits (and de-

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Table Plan Pharmacy Details Your cost if a Your cost if a Services you network nonnetwork may need provider is used provider is used Limitations and exceptions Level 1— Preferred/lowcost generics

$10 copay (retail) $20 copay (mail order)

Level 2— Nonpreferred generic

$20 copay (retail) Not covered $40 copay (mail order)

See Level 1 for limitations and exceptions

Level 3— $50 copay (retail) Not covered Preferred brands $100 copay (mail order)

See Level 1 for limitations and exceptions

Level 4— Nonpreferred brands

Not covered

Preauthorization may be required; penalty will be 50% 30-day supply (retail), 90-day supply (mail order)

50% coinsurance

Not covered

See Level 1 for limitations and exceptions

Level 5— 50% coinsurance Specialty drugs

Not covered

Preauthorization required; penalty will be 50% Specialty pharmacy discount: 40% coinsurance when filled via a preferred network specialty pharmacy

Source: Healthcare.gov.

ductibles) are often considered include outpatient diagnostics and outpatient ancillary services (ie, hearing services).

In addition to copays and deductibles, other benefit design cost levers include exempted procedures and medications and coinsurance (a percentage of the negotiated price).

The pharmacy benefit is ripe for cost levers. The actual pharmacy cost to a health plan is calculated as the prescription cost minus the coinsurance multiplied by utilization. Drivers of the pharmacy cost are protected classes, mandatory coverage (ie, contraception), and mandatory tier placement.

Pharmacy cost levers include network contracts, manufacturer rebates, deductibles, formularies, and preferred pharmacy copays. Under the ACA, the costs for medications when a nonnetwork pharmacy provider is

used are not covered (Table).

With respect to pharmacy services, more insurers are covering over-thecounter medications, Dr Palmgren indicated, and others are considering coverage of investigatory medications.

Previously, plans were not sophisticated enough to break out the medical and pharmacy deductibles. “They’re very sophisticated now,” he said.

“Now, you can have a medical deductible, a pharmacy deductible, or an integrated deductible.”

Qualified Health Plans Under the ACA, qualified health plans in the Exchange have targets for the coverage of the actuarial value of benefits. For bronze plans, the target is 60%; for silver, 70%; for gold, 80%; and for platinum, 90%. Catastrophic plans are available only to individuals aged ≤30 years who are exempted from the mandate to purchase coverage.

Access to Exchange plans and monthly premiums are established by county. Bronze plans incorporate a 20% coinsurance for a physician visit or generic prescription after the deductible is met, up to the maximum out-of-pocket expense. With most bronze plans, the deductible mimics the maximum out-of-pocket expense, said Dr Palmgren. A silver plan reduces the coinsurance to 10% after the deductible, at the cost of a higher monthly premium but with a lower deductible. n

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4th Conference

Employers Are Now Viewing Healthcare as an Investment Rather than an Expense

By Wayne Kuznar

Los Angeles, CA—The mission of private exchanges that arose with the passage of the Affordable Care Act (ACA) has employers viewing healthcare as an investment rather than an expense, analyzing the competitors’ healthcare offerings, and holding the employee accountable for its use.

“Healthcare is now recognized as an investment to be optimized, not an expense to be minimized,” said John Kahle, Senior Vice President and Chief Wellness Officer at Intercare Insurance Solutions, who spoke on emerging employee perspectives of healthcare at the Fourth Annual Conference of the Association for Value-­ Based Cancer Care.

In considering healthcare as an investment, insurers are realizing that less care is not necessarily less expensive care, and that more care is not necessarily better care. Employers are recognizing that health is one component of a business strategy that may improve productivity and a company’s financial performance, said Mr Kahle.

As part of a business strategy, therefore, healthcare must deliver value.

Private versus Public Exchanges A private health insurance exchange may make sense for some companies, he said. Private exchanges have greater certainty of cost, can increase employee choice, and can accelerate “consumerism” (Table).

The typical profile of an employer opting for a private exchange is an employer that seeks predictability in

cost and budgeting, wants a defined contribution focus, wants improved decision-making technology, wants

“

Healthcare is now recognized as an investment to be optimized, not an expense to be minimized….I can make more money, or I can take it and invest it. Healthcare became a part of a business strategy.

”

—John Kahle

more choice of plans, and that prefers a hands-off enrollment process.

A private exchange is not a way out of the benefits business, said Mr Kahle, and will incur additional cost to implement. Early feedback from employers suggests that most companies want more evidence that private exchanges can deliver greater value for active plans.

In private exchanges, a consequence of ACA surcharges being levied against insurers and employers is a shift in cost to the employee. These surcharges are increasingly being

Table Public versus Private Exchanges Plan variable Public exchanges

Private exchanges

Owned/managed

State and/or federal government

Privately owned and operated

Plans available

Bronze, silver, gold, and platinum

Plan families

Offer subsidies for those eligible

Yes

No

Ideal employee populations

Subsidy-eligible individuals, part-time employees, early retirees, COBRA continuees

Active employees, Medicareeligible retirees, retirees aged <65 years

Size employers

Small employers—up to 2016, for <50 lives

All sizes

Can you leave?

Yes

Yes—consider switching costs

Sponsored by

Federal government

Consultant, carrier, or third party

Offer increased choice

Yes

Yes

Dental, vision, and voluntary benefits

No

Yes

COBRA indicates Consolidated Omnibus Budget Reconciliation Act.

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added to the premiums of tiered healthcare (platinum, gold, silver, and bronze) plans. These charges can in-

clude the Patient-Centered Outcomes Research Institute cost, the transitional fee, and an insurance fee.

Coverage Implications Mid-level employers with 100 to 1000 employees will race to the bronze plan out of financial necessity, said Mr Kahle, which shifts more costs to the employee. Variable employees, defined as those who do not work full time, but who work variable hours, will have their salaried working time closely monitored to ensure that they do not exceed 29 hours, he added.

Additional savings may be obtained by not offering spousal coverage, with the consequence that spouses may qualify for subsidies under the ACA given that an affordable plan was not available to them. This change may be difficult to communicate to employees, who are used to employer-sponsored plans that cover their spouses and dependents, Mr Kahle said.

Although the rise in healthcare costs can be slowed, these costs will continue to increase. With the new “healthcare as an investment” paradigm, a way to offset the increased cost of healthcare is to invest in employees’ preventive healthcare, thereby increasing employee productivity, said Mr Kahle.

As a business strategy, companies are now evaluating their employee healthcare expenses versus those of their competitors. “If I can deliver november 2014

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at a glance ➤ In viewing healthcare as an investment rather than an expense, less care may not be cost-saving, and more care may not mean better quality care ➤ Private exchanges have greater predictability in budgeting, increase employee choice, and improve decisionmaking, but at a higher start-up cost ➤ One way to offset increasing healthcare costs is to invest in preventive healthcare for employees, which can increase their productivity ➤ Patients need to be held accountable for their healthcare choices, including nonadherence and misuse of plan benefits healthcare to my employees at $8000 a year, and my competitor, the one that I’m locked horns with on a regular basis, has a cost of $9000 a year, I have $1000 a year per employee that I can do something with,” Mr Kahle said. “I can make more money, or I can take it and invest it. Healthcare became a part of a business strategy.”

In addition, companies that are involved in acquisitions will examine the cost of healthcare at the company they are looking to purchase.

Patient Accountability Patient accountability is the last paradigm shift, said Mr Kahle, because plans are being designed to incorporate patient responsibility.

The average employer pays 73% of the cost of employees’ healthcare and 100% for preventive care (under the ACA), so employers will want to ensure that employees and their dependents are responsibly using their coverage.

If a patient is nonadherent to treatment or routine screening, the employee could be held accountable for their care. For example, Mr Kahle said, if a patient with a low-deductible plan misuses the plan by creating a lowest value claim (emergency department visit) instead of a high-value claim (preventive care), the health plan could revert to a high-deductible one. n

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Personalized Medicine

Personalized Medicine in Oncology: NICE Grappling with Assigning Value to New Diagnostics and Medical Technologies

By Wayne Kuznar

San Francisco, CA—Personalized med­ icine is evolving to become an integral part of modern medicine, but regulators are grappling with the assignment of value to new medical technologies, said Andrew Stainthorpe, PhD, Associate Director of the UK National Institute for Health and Care Excellence (NICE), who discussed regulatory aspects of personalized medicine in oncology at the Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative.

NICE provides guidance on coverage decisions in the United Kingdom for new therapies, technologies, and diagnostics entering the market. Unlike the FDA, NICE makes its recommendations based not only on safety and efficacy but also on cost-effectiveness and questions of cost versus quality.

Value Considerations “Does the current regulatory landscape work well for manufacturers and researchers?” Dr Stainthorpe asked.

“And does it work well for patients, clinicians, payers, and health technology assessment committees? In some respects it doesn’t, and that’s why, perhaps, you’re seeing from NICE…a number of negative decisions about the cost-effectiveness of diagnostic tests, and for new technologies and the cost-effectiveness of those.”

Healthcare expenditures are outpacing growth domestic product in most countries at a rate that is not sustainable. Key parts of regulatory agencies and health technology assessment committees are the process by which decisions are made with budget constraints in mind.

Payers have a difficult role, because

In some respects, the regulatory landscape does not work well for healthcare stakeholders, and that’s why, perhaps, you’re seeing from NICE…a number of negative decisions about the cost-effectiveness of diagnostic tests, and for new technologies and the costeffectiveness of those.

‘‘

”

—Andrew Stainthorpe, PhD

they work with tightly controlled budgets, said Dr Stainthorpe. They must be convinced of the value of medicines and new technology, especially in the context of current treatment options.

Cancer is not a uniform disease, because there are different molecular subsets of most cancers. In addition, increasingly, new drugs are effective for the treatment of several rare cancers and are receiving approval for a variety of cancers, such as imatinib for chronic myelogenous leukemia with the oncogene BCR-ABL translocation and gastrointestinal stromal tumors with KIT mutations, or trastuzumab for HER2-overexpressing breast cancer and gastric cancer.

Current research is leading to a plethora of different cancers, and questions arise regarding the best way to treat them, “and which technologies work best to treat patients who may have more than one tumor type expressing a range of different mutations,” Dr Stainthorpe said.

Quote of the Month “A biomarker is clinically useful if it tells you what to do or what NOT to do in treating your patient.”

—Sanjiv Agarwala, MD

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

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Cost-Effectiveness NICE typically considers a range of factors in making its guidance. It assesses the evidence provided by manufacturers of technology. A threshold of £20,000 per quality-adjusted lifeyear has been accepted as cost-effective, but NICE may allow higher prices for innovative technologies, Dr Stainthorpe said.

at a glance ➤ Unlike the FDA, NICE makes its regulatory recommendations based not only on efficacy and safety but also on the costeffectiveness of new drugs or medical technologies ➤ NICE also considers the patient perspective in its decisions ➤ Evidence must now show benefit of a treatment on quality of life, not only on the disease ➤ A threshold of £20,000 per quality-adjusted life-year has been accepted as costeffective, but NICE may allow higher prices for innovative technologies

—Andrew Stainthorpe, PhD

NICE operates where a biomarker is featured.”

NICE may give a qualified “yes” to a new technology, usually if in a posthoc review of the data it determines that a subset of the population benefits more than the overall population from the technology. “It may be that there’s a genetic aspect to it,” Dr Stainthorpe said.

“There are still situations in which there’s a good match between a companion diagnostic and its indication, but it’s not cost-effective, and NICE has said that it can’t recommend that treatment,” he pointed out.

The difficulty lies in establishing a transparent process that outlines NICE’s appraisal parameters that enter into its decisions, “so the manufacturers bringing such technology to market will know what evidence to collect, and what actually makes a difference in the technology appraisal,” he said.

“There are technology appraisals for which a manufacturer might bring a companion diagnostic into the process,” Dr Stainthorpe said. “And there’s a diagnostic appraisal program with appraisal of a new diagnostic without it being linked to a drug. Those are the 2 programs where

Patient Perspective NICE also considers the patient perspective in its decisions. Evidence must now show benefit of a treatment on quality of life, not only on the disease.

With personalized medicine, regulators face not only the challenge of small sample size (in some instances, an “n” of 1), but also patients with a number of “n’s” in the form of different genotypes. How that fits into decisions about which therapies to make available, and their costs, is uncertain.

“It’s an exciting time, but I think we need more research and more input in a way that’s digestible for the regulators and the health technology assessment community,” Dr Stainthorpe said. n

“

There are still situations in which there’s a good match between a companion diagnostic and its indication, but it’s not costeffective, and NICE has said that it can’t recommend that treatment.

”

Vol. 5

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No. 9

The Patient Perspective

The 12-Second Free Test that Can Reduce Hospital Readmissions

By Julie K. Silver, MD Associate Professor, Harvard Medical School, Department of Physical Medicine and Rehabilitation, Boston, MA, and founder of Oncology Rehab Partners www.OncologyRehabPartners.com

M

“

ary” is a 67-year-old woman who was diagnosed with cancer and underwent surgery. She was hospitalized and then readmitted to the hospital after falling at home. I see a lot of Marys (or Joes) in my practice, as do most oncologists and physiatrists. It would take 12 seconds to identify many of the Marys and Joes and help to prevent their readmissions.

I can usually spot them as I glance up from the computer I use in the hallway and watch them walking from the waiting room to an examination room with my medical assistant. These are the folks who are slow and, for lack of a better term, wobbly. Identifying these patients can take seconds, with the help of a free, evidence-based test.

Why is this so important? Wobbly patients have a lot of falls that lead to laceration and bone fractures, head injuries, and other problems that require medical treatment, including hospital readmissions. The significant healthcare costs associated with their wobbliness is well-documented. To zero in on the patients at highest risk, as well as the least-expensive solutions that will provide the best possible outcomes (think Triple Aim), let us focus on the elephants in operating rooms.

This was the topic of a 2014 review article titled “Patient Frailty: The Elephant in the Operating Room” and published in the journal Anaesthesia. In this article, Hubbard and Story highlight­ ed what every rehabilitation clinician knows: research has shown that slow gait speed is an excellent way to identify patients who are at risk for falls or other postoperative complications. Wobbly patients slow down to compensate for a lack of strength and balance.

The 12-Second Solution The Timed Up and Go (TUG) test is a validated tool that can be used in the office setting during preoperative evaluations to quickly identify patients who may benefit from a rehabilitation referral before surgery (ie, prehabilitation). Because this is such a fast, easy, and good predictor of which patients would likely benefit from a physiatry or physical therapy referral, when I am giving lectures to oncology healthcare professionals, I often do a demonstration so that they can see just Vol. 5

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No. 9

TUG test can be found at the Centers for Disease Control and Prevention initiative titled “Stopping Elderly Accidents, Deaths & Injuries (STEADI): think steady, not wobbly.” You can find the single-page form and instructions at www.cdc. gov/injury/STEADI.

“

It would take 12 seconds to identify many of the Marys and Joes and help to prevent their readmissions. These are the folks who are slow and, for lack of a better term, wobbly. Identifying these patients can take seconds, with the help of a free, evidence-based tool.

”

how easy this test is to perform.

This has become an “aha” moment in my lectures, where the attendees instantly realize that they can significantly affect outcomes by performing the TUG test. In fact, the average fifth grader could likely learn to perform this test in less than 5 minutes (although the test should be done by trained healthcare professionals). If there is time, the TUG test can be performed with other validated measures that assess things such as patient frailty.

How to Perform the TUG Test 1. The patient should sit in a standard armchair wearing regular footwear and using a walking aid if needed.

2. Ask the patient to stand up from the chair and walk to a line on the floor that is 10 feet away, turn, and come back to the chair and sit down.

3. If this takes the patient 12 seconds or more to complete, the patient is at high risk for falling and should be referred before surgery for a physiatry or physical therapy consultation.

4. A copy of the form used for the

Help Reduce Hospital Readmissions In my practice, when I see patients walking slowly down the long corridors, I can instantly tell if they are wobbly, and if they have tried to solve their own problems. These patients usually have a cane that they picked up at the local drugstore. It is not the right height, and frequently they are using it on the wrong side.

A single visit to a physical therapist is sometimes all that is needed to make the patient much steadier, by adjusting the height of the cane, and teaching the patient how to use it properly, including stepping off curbs and going up and down stairs.

If you want to decrease the incidence

of hospital readmissions and reduce the length of stays, consider adding the TUG test to the preoperative screening protocol at your practice or institution.

Combine the screening with a rehabilitation referral process before surgery if the patient cannot complete the TUG test in less than 12 seconds. n

COMING SOON! Highlights from the 2014 ASH Conference!

A Focus on Chronic Lymphocytic Leukemia and Castleman Disease an e-newsletter brought to you by the publishers of Value-Based Cancer Care

®

www.ValueBasedCancerCare.com november 2014

I

www.ValueBasedCancerCare.com

41

速 速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 Kyprolis Kyprolis (carfilzomib) for Injection Now Has a Permanent J Code: J9047

treatment of patients with multiple myeloma who have received at least 2 prior ForFor thethe treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib immunomodulatory agent have demonstrated disease therapies including bortezomib andand an an immunomodulatory agent andand have demonstrated disease progression on within or within days of completion of last therapy.

Approval is based on response rate. progression on or 60 60 days of completion of last therapy.

Approval is based on response rate.

Clinical benefi t, such as improvement in survival or symptoms, been verifi Clinical benefi t, such as improvement in survival or symptoms, hashas notnot been verifi ed.ed.

THEPOWER POWEROF OF THE SECOND-GENERATION SECOND-GENERATION PROTEASOMEINHIBITION INHIBITION PROTEASOME TAKESFLIGHT FLIGHT TAKES

Important Safety Information Important Safety Information CONTRAINDICATIONS CONTRAINDICATIONS None.

None.

Evaluate cardiac imaging and/or other as indicated.

Evaluate withwith cardiac imaging and/or other teststests as indicated.

Withhold KYPROLIS for pulmonary hypertension Withhold KYPROLIS for pulmonary hypertension untiluntil resolved or returned to baseline consider whether resolved or returned to baseline and and consider whether to to restart KYPROLIS based a benefi t/risk assessment. restart KYPROLIS based on aon benefi t/risk assessment.

Pulmonary Complications: Dyspnea reported in 35% Pulmonary Complications: Dyspnea waswas reported in 35% of of patients enrolled in clinical trials.

Grade 3 dyspnea occurred patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, 1 death (Grade 5) was reported. in 5%; no Grade 4 events, and and 1 death (Grade 5) was reported. safety of KYPROLIS evaluated in clinical studies The The safety of KYPROLIS was was evaluated in clinical studies of of Monitor manage dyspnea immediately; interrupt and and manage dyspnea immediately; interrupt patients relapsed and/or refractory multiple myeloma. Monitor 526526 patients withwith relapsed and/or refractory multiple myeloma.

KYPROLIS symptoms resolved or returned KYPROLIS untiluntil symptoms havehave resolved or returned Cardiac Arrest, Congestive Heart Failure, Myocardial Cardiac Arrest, Congestive Heart Failure, Myocardial to baseline. to baseline.

Ischemia: Death to cardiac arrest occurred within Ischemia: Death due due to cardiac arrest has has occurred within Infusion Reactions: Infusion reactions characterized a day of KYPROLIS administration. onset or worsening Infusion Reactions: Infusion reactions werewere characterized a day of KYPROLIS administration.

NewNew onset or worsening a spectrum of systemic symptoms including fever, chills, of pre-existing congestive heart failure decreased spectrum of systemic symptoms including fever, chills, of pre-existing congestive heart failure withwith decreased left left by aby arthralgia, myalgia, facial flushing, facial edema, vomiting, ventricular function or myocardial ischemia occurred arthralgia, myalgia, facial flushing, facial edema, vomiting, ventricular function or myocardial ischemia havehave occurred weakness, shortness of breath, hypotension, syncope, chest following administration of KYPROLIS. Cardiac failure weakness, shortness of breath, hypotension, syncope, chest following administration of KYPROLIS. Cardiac failure tightness, or angina.

These reactions occur immediately events cardiac failure congestive, pulmonary edema, tightness, or angina.

These reactions can can occur immediately events (e.g.,(e.g., cardiac failure congestive, pulmonary edema, following infusion orto up24 tohours 24 hours administration ejection fraction decreased) reported in 7% of patients.following infusion or up afterafter administration of of ejection fraction decreased) werewere reported in 7% of patients.

KYPROLIS. Administer dexamethasone to KYPROLIS Monitor for cardiac complications manage promptly.

KYPROLIS. Administer dexamethasone priorprior to KYPROLIS Monitor for cardiac complications and and manage promptly. to reduce the incidence and severity of reactions.

Inform Withhold KYPROLIS for Grade 4 cardiac events to reduce the incidence and severity of reactions. Inform Withhold KYPROLIS for Grade 3 or34or cardiac events untiluntil patients of risk the risk symptoms, to contact physician recovery consider whether to restart KYPROLIS based patients of the andand symptoms, andand to contact physician recovery and and consider whether to restart KYPROLIS based if symptoms ofinfusion an infusion reaction occur. a benefi t/risk assessment.

Patients Heart if symptoms of an reaction occur. on aon benefi t/risk assessment.

Patients withwith NewNew YorkYork Heart Association Class III and IV heart failure, myocardial infarction Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) Association Class III and IV heart failure, myocardial infarction Lysis Syndrome: Tumor lysis syndrome (TLS) in preceding the preceding 6 months, conduction abnormalities Tumor in the 6 months, and and conduction abnormalities occurred following KYPROLIS administration in <of 1% of occurred following KYPROLIS administration in < 1% uncontrolled by medications at greater uncontrolled by medications maymay be atbegreater risk risk for for patients.

Patients with multiple myeloma and a high tumor patients. Patients with multiple myeloma and a high tumor cardiac complications. cardiac complications. burden should be considered at greater for TLS. burden should be considered to betoatbegreater risk risk for TLS. to receiving KYPROLIS, ensure patients are well Pulmonary Hypertension: Pulmonary arterial hypertension PriorPrior to receiving KYPROLIS, ensure thatthat patients are well Pulmonary Hypertension: Pulmonary arterial hypertension hydrated.

Monitor for evidence of TLS during treatment, (PAH) reported in 2% of patients treated KYPROLIShydrated.

Monitor for evidence of TLS during treatment, and and (PAH) waswas reported in 2% of patients treated withwith KYPROLIS manage promptly.

Interrupt KYPROLIS until TLS is resolved.

Grade or greater in less 1%patients. of patients. manage promptly. Interrupt KYPROLIS until TLS is resolved. and and waswas Grade 3 or3greater in less thanthan 1% of

WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS

1 1 KYPROLIS is engineered selective inhibition KYPROLIS is engineered forfor selective inhibition 2, 2, • Single-agent KYPROLIS phase 2 study results • Single-agent KYPROLIS phase 2 study results * * - Overall response (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Overall response raterate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, - Median duration of response of 7.8 months (95% CI: 5.6, 9.2)9.2) • Most patients across all phase 2 studies (85%) need to discontinue therapy toadverse an adverse event • Most patients across all phase 2 studies (85%) did did not not need to discontinue therapy duedue to an event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, acute renal failure each) dyspnea, increased blood creatinine, andand acute renal failure (1%(1% each)

ADVERSE REACTIONS ADVERSE REACTIONS safety of KYPROLIS evaluated in clinical trials of 526 patients relapsed and/or refractory TheThe safety of KYPROLIS waswas evaluated in clinical trials of 526 patients withwith relapsed and/or refractory multiple myeloma. multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. most common were pneumonia (10%), • Serious adverse reactions were reported in 45% of patients.

TheThe most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), congestive heart failure (3%) acute renal failure (4%), pyrexia (3%), andand congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), pyrexia (30%) thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), andand pyrexia (30%) PX-171-003 a single-arm, multicenter clinical trial of KYPROLIS in 266 patients relapsed multiple myeloma and whose disease *Study PX-171-003 was awas single-arm, multicenter clinical trial of KYPROLIS in 266 patients with with relapsed multiple myeloma and whose disease had had *Study

response tomost the most recent therapy ordisease had disease progression during or within 60 days the most recent therapy.

Attime the time a ≤ 25% response to the recent therapy or had progression during or within 60 days of theofmost recent therapy.

At the of of a ≤ 25% patients had received a median of 5 prior of therapy.

The primary endpoint was ORR. Response was determined

by Independent studystudy entry,entry, patients had received a median of 5 prior lineslines of therapy.

The primary endpoint was ORR. Response was determined

by Independent Review Committee assessment International Myeloma Working Group criteria.

Review Committee assessment usingusing International Myeloma Working Group criteria.

References: 1. Demo SD,CJ, KirkAujay CJ, Aujay MA, al. Antitumor activity of PR-171, a novel irreversible inhibitor the proteasome.

Cancer Res. 2007;67(13):6383-6391.

References: 1. Demo SD, Kirk MA, et al. et Antitumor activity of PR-171, a novel irreversible inhibitor of theofproteasome.

Cancer Res. 2007;67(13):6383-6391.

2.

KYPROLIS [prescribing information].

South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia ADVERSE REACTIONS Thrombocytopenia: KYPROLIS causes thrombocytopenia ADVERSE REACTIONS with platelet nadirs occurring around Day 8 of each 28-day cycle with platelet nadirs occurring around Day 8 of each 28-day cycle Serious adverse reactions were reported in 45% of recovery to baseline by start the start of next the next 28-day cycle. Serious adverse reactions were reported in 45% of and and recovery to baseline by the of the 28-day cycle. patients. The most common serious adverse reactions were In patients multiple myeloma, of patients experiencedpatients. The most common serious adverse reactions were In patients withwith multiple myeloma, 36%36% of patients experienced pneumonia (10%), acute renal failure (4%), pyrexia (3%), and thrombocytopenia, including Grade in 10%.

Thrombocytopeniapneumonia (10%), acute renal failure (4%), pyrexia (3%), and thrombocytopenia, including Grade 4 in 4 10%.

Thrombocytopenia congestive heart failure (3%). Adverse reactions leading to following KYPROLIS administration resulted in a dose reduction congestive heart failure (3%). Adverse reactions leading to following KYPROLIS administration resulted in a dose reduction discontinuation of KYPROLIS occurred in 15% of patients discontinuation of KYPROLIS occurred in 15% of patients and and inof 1%patients of patients discontinuation of treatment in 1% and and discontinuation of treatment withwith included congestive heart failure (2%), cardiac arrest, dyspnea, KYPROLIS in <of 1%patients. of patients.

Monitor platelet counts frequentlyincluded congestive heart failure (2%), cardiac arrest, dyspnea, KYPROLIS in < 1% Monitor platelet counts frequently increased blood creatinine, acute failure each). increased blood creatinine, and and acute renalrenal failure (1% (1% each). during treatment KYPROLIS. Reduce or interrupt during treatment withwith KYPROLIS. Reduce or interrupt dosedose as as clinically indicated. common adverse reactions (incidence ≥ 30%) clinically indicated.

TheThe mostmost common adverse reactions (incidence ≥ 30%) fatigue (56%), anemia (47%), nausea (45%), werewere fatigue (56%), anemia (47%), nausea (45%), Hepatic Toxicity and Hepatic Failure: Cases of hepatic thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), Hepatic Toxicity and Hepatic Failure: Cases of hepatic thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), failure, including fatal cases, have been reported (< 1%). pyrexia (30%). failure, including fatal cases, have been reported (< 1%). and and pyrexia (30%).

KYPROLIS cause elevations of serum transaminases KYPROLIS can can cause elevations of serum transaminases USE IN SPECIFIC POPULATIONS bilirubin.

Withhold KYPROLIS in patients experiencing USE IN SPECIFIC POPULATIONS and and bilirubin.

Withhold KYPROLIS in patients experiencing Grade or greater elevations of transaminases, bilirubin, Grade 3 or3greater elevations of transaminases, bilirubin, or or Since Since dialysis clearance of KYPROLIS concentrations dialysis clearance of KYPROLIS concentrations has has other enzyme abnormalities resolved or returned other liverliver enzyme abnormalities untiluntil resolved or returned to to not been not been studied, the drug should be administered studied, the drug should be administered afterafter the the KYPROLIS baseline.

After resolution, consider if restarting KYPROLIS is is dialysis baseline.

After resolution, consider if restarting dialysis procedure. procedure. appropriate.

Monitor enzymes frequently. appropriate.

Monitor liverliver enzymes frequently.

Please Brief Summary of the Embryo-fetal Toxicity: KYPROLIS cause harm Please seesee Brief Summary of the fullfull Embryo-fetal Toxicity: KYPROLIS can can cause fetalfetal harm Prescribing Information adjacent pages. when administered a pregnant woman based on its Prescribing Information on on adjacent pages. when administered to ato pregnant woman based on its mechanism of action findings in animals.

There are no mechanism of action and and findings in animals.

There are no adequate well-controlled studies in pregnant women adequate and and well-controlled studies in pregnant women using KYPROLIS. Carfi lzomib caused embryo-fetal toxicity using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in in pregnant rabbits at doses lower in patients pregnant rabbits at doses thatthat werewere lower thanthan in patients receiving the recommended dose.

Females of reproductive receiving the recommended dose.

Females of reproductive Pharmaceuticals, Pharmaceuticals logo, Kyprolis potential should be advised to avoid becoming pregnant while Onyx,Onyx, Onyx Onyx Pharmaceuticals, Onyx Onyx Pharmaceuticals logo, Kyprolis potential should be advised to avoid becoming pregnant while and Kyprolis logoallare all trademarks of Onyx Pharmaceuticals, and Kyprolis logo are trademarks of Onyx Pharmaceuticals, Inc. Inc. ©2013 Pharmaceuticals, Inc., South San Francisco, being treated KYPROLIS. ©2013 Onyx Onyx Pharmaceuticals, Inc., South San Francisco, CA CA being treated withwith KYPROLIS. 0512-CARF-243R1 December 2013 0512-CARF-243R1 December 2013

Prostate Cancer

Preserving Sexual Function in Patients with Prostate Cancer with Vessel-Sparing Radiation Therapy

By Phoebe Starr

San Francisco, CA—In men with prostate cancer undergoing curative radiation therapy, it may be possible to preserve sexual function by using a

vessel-sparing radiation technique, according to the 5-year follow-up results from a study of men who underwent vessel-sparing radiation

therapy in this setting.

At the 2014 American Society for Radiation Oncology meeting, Patrick W. McLaughlin, MD, Professor of Ra-

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing a Cycles 2 and Beyond Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Dosing Dosing Dosing Dosing (27 mg/m2): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.

Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

• • •

• Non-Hematologic Toxicity Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • congestive heart failure; • decreased left ventricular function; • or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

44

Value-Based Cancer Care

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November 2014

• • •

Recommended Action Withhold dose.

If fully recovered before next scheduled dose, continue at same dose level.

If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Recommended Action Withhold until resolved or returned to baseline.

After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

• Restart at the dose used prior to the event or reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

• Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

• After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

diation Oncology, University of Michigan, Novi, presented the results of the 5-year follow-up on patients treated with the technique. In 2005, Dr

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

a

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.

6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

a

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

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prostate Cancer McLaughlin and colleagues defined the vessel-sparing technique.

“Using MRI [magnetic resonance imaging] to define patient’s anatomy, the vessels involved in maintaining an erection can be spared in some patients,” said Dr McLaughlin. “This is not possible in all patients; for example, those with prostate cancer at the apex of the prostate,” Dr

McLaughlin said.

The study included 90 men diagnosed with prostate cancer, approximately 50% of whom underwent external beam radiation therapy (EBRT) alone and 50% who received EBRT plus brachytherapy. None of the patients received androgen deprivation therapy.

All forms of cancer therapy affect

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. 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 Use in Specific Populations].

ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [see Warnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.

Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Event Fatigue Anemia Nausea Thrombocytopenia Dyspnea Diarrhea Pyrexia Upper respiratory tract infection Headache Cough Blood creatinine increased Lymphopenia Edema peripheral Vomiting Constipation Neutropenia Back pain Insomnia Chills Arthralgia Muscle spasms Hypertension Asthenia Hypokalemia Hypomagnesemia Leukopenia Pain in extremity Pneumonia Aspartate aminotransferase increased Dizziness Hypoesthesia Anorexia Pain Hyperglycemia Chest wall pain Hypercalcemia Hypophosphatemia Hyponatremia

All Gradesa 292 (55.5) 246 (46.8) 236 (44.9) 191 (36.3) 182 (34.6) 172 (32.7) 160 (30.4) 149 (28.3) 145 (27.6) 137 (26.0) 127 (24.1) 126 (24.0) 126 (24.0) 117 (22.2) 110 (20.9) 109 (20.7) 106 (20.2) 94 (17.9) 84 (16.0) 83 (15.8) 76 (14.4) 75 (14.3) 73 (13.9) 72 (13.7) 71 (13.5) 71 (13.5) 70 (13.3) 67 (12.7) 66 (12.5) 66 (12.5) 64 (12.2) 63 (12.0) 63 (12.0) 62 (11.8) 60 (11.4) 58 (11.0) 55 (10.5) 54 (10.3)

Patients (N = 526) [n (%)] Grade 3 Events 38 (7.2) 111 (21.1) 7 (1.3) 69 (13.1) 25 (4.8) 4 (0.8) 7 (1.3) 17 (3.2) 7 (1.3) 1 (0.2) 13 (2.5) 84 (16.0) 3 (0.6) 5 (1.0) 1 (0.2) 50 (9.5) 15 (2.9) 0 1 (0.2) 7 (1.3) 2 (0.4) 15 (2.9) 12 (2.3) 14 (2.7) 2 (0.4) 27 (5.1) 7 (1.3) 52 (9.9) 15 (2.9) 5 (1.0) 3 (0.6) 1 (0.2) 12 (2.3) 16 (3.0) 3 (0.6) 13 (2.5) 24 (4.6) 31 (5.9)

Grade 4 Events 2 (0.4) 7 (1.3) 0 54 (10.3) 1 (0.2)b 1 (0.2) 2 (0.4) 0 0 0 1 (0.2) 11 (2.1) 0 0 0 4 (0.8) 0 0 0 0 0 2 (0.4) 1 (0.2) 3 (0.6) 0 1 (0.2) 0 3 (0.6)b 1 (0.2) 1 (0.2) 0 0 0 3 (0.6) 0 8 (1.5) 3 (0.6) 3 (0.6)

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

One event was Grade 5 severity.

a

b

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sexual function, Dr McLaughlin said.

A 2009 study showed that among patients with good baseline erectile capacity, after 36 months of prostate cancer therapy, erectile capacity was present in only approximately 30% of those treated with prostatectomy, 50% of those who received EBRT, and 80% of patients who underwent brachytherapy (Chen RC, et al. J Clin

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS 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. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, 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 KYPROLIS in pediatric patients have not been established.

Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond.

The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated.

OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care.

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.

PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.

Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

november 2014

I

Oncol. 2009;27:3916-3922).

Two patient-reported metrics were used to assess sexual function—Metric A, which measured erections suf­ ficient for sexual intercourse, and Metric B, which was more general regarding any form of sexual activity.

“

Using MRI to define patient’s anatomy, the vessels involved in maintaining an erection can be spared in some patients.

This is not possible in all patients; for example, those with prostate cancer at the apex of the prostate.

”

—Patrick W. McLaughlin, MD

Using Metric A, which only examined erectile function sufficient for sexual intercourse, at 2 years erectile capacity was achieved in 16.5% of patients of the radiation therapy– alone group and in 20.8% in the group receiving radiation therapy plus brachytherapy. At 5 years, 15.4% and 16.9% of patients, respectively, were able to maintain an erection.

Using Metric B, erectile function sufficient for sexual activity with or without aids was preserved in 78.6% of patients receiving radiation therapy alone and in 91.8% who received radiation therapy plus brachytherapy at 5 years.

Dr McLaughlin said that as people age, sexuality changes and many couples engage in sexual activity other than intercourse, which can be painful to women after menopause—this is why he thinks Metric B is more reflective of sexuality in older people.

The cure rates at the 5-year follow-up were excellent. The cure rates were 98% among low-risk men (55% of patients), 96% among intermediate-risk men (30% of patients), and 87% in high-risk men (5% of patients). n www.ValueBasedCancerCare.com

45

Drug Update

Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved by the FDA for the Treatment of 3 Hematologic Malignancies

By Lisa A. Raedler, PhD, RPh

C

hronic lymphocytic leukemia (CLL), a cancer of B-cell lymphocytes, is the most common type of leukemia in Western adult patients.1 According to the Leukemia and Lymphoma Society, more than 15,600 Americans were diagnosed with CLL in 2013.2 CLL is a disease of the elderly.3 The incidence of CLL increases significantly among individuals aged ≥50 years, with only a small fraction of patients diagnosed in their 30s and 40s.2 The majority of patients with CLL are diagnosed without symptoms, and typically learn that they have CLL after routine blood work.4 As it advances, CLL can cause severe fatigue, swollen lymph nodes, enlarged spleen, shortness of breath, and infections.4 The clinical course of CLL is heterogeneous. Although some patients with CLL live for decades with no treatment, others have disease that is rapidly aggressive.3 The survival of patients with CLL ranges from approximately 1 year to more than 20 years.5 According to the American Society of Clinical Oncology, the 5-year overall survival (OS) rate for patients with CLL of all stages is approximately 79%.5 The cost burden associated with CLL is significant. Based on a recent cost analysis conducted in Germany, the total per-patient costs for patients with CLL is €9753 (approximately $12,202) annually compared with €4807 (approximately $6014) annually for individuals in a control group of the same age and sex.6 In this study, the economic burden of CLL was primarily driven by inpatient costs and by drug costs. From a societal perspective, productivity loss was the highest cost associated with a CLL diagnosis.6 Small Lymphocytic Lymphoma According to the World Health Organization, CLL and small lymphocytic lymphoma (SLL) are different clinical manifestations of the same disease.7 The term CLL is used when there is a leukemic component in peripheral blood, whereas SLL is used when lymph nodes or other tissues are infiltrated by CLL cells that appear to be without the leukemic component.2,7 Only 5% of patients present with clinical features of SLL.2 CLL and SLL afCopyright © 2014 American Health & Drug Benefits. Used with permission.

All rights reserved.

46

fect people of the same age-groups, have common signs and symptoms, and are generally slow-growing conditions.8 The treatment for both malignancies is also similar.8 Follicular Lymphoma Follicular lymphoma is the second most common subtype of non-Hodg­ kin lymphoma (NHL), comprising approximately 20% of all NHL cases.8 Follicular lymphoma is characterized by a translocation between chromosome 14 and chromosome 18, which causes the overexpression of BCL-2 and increased resistance to treatment.8 Although an indolent NHL, follicular lymphoma can transform into an aggressive phenotype, at which point it should be managed using therapies that are appropriate for aggressive forms of NHL, including combinations of chemotherapy and anti-CD20 monoclonal antibodies.9 Evolving Treatments for Chronic Lymphocytic Leukemia In the past several years, major advances have been made in understanding the pathophysiology of CLL, including biologic factors that influence its clinical course. As a result, treatment approaches have evolved to target the underlying disease pathology.3 The International Workshop on CLL recommends treating CLL if patients present with active progressive disease manifested as bulky progressive adenopathy or bone marrow failure.2,10 Initial treatment of patients with symptomatic CLL typically includes chemotherapy combined with a targeted drug––either rituximab or another CD20-targeted monoclonal antibody.2,11 Medications that can be used for the treatment of patients with relapsed and/or refractory CLL include alem­ tuzumab, bendamustine, chlorambucil, fludarabine, ibrutinib, lenalidomide, obinutuzumab (in combination with chlorambucil), ofatumumab, and rituximab.12 Several of these are new therapies that were approved in 2013 and 2014 for use in patients with previously untreated CLL and in relapsed or refractory CLL; these include ibrutinib, obinutuzumab, and ofatumumab.13-15 Idelalisib: First-in-Class PI3 Kinase Inhibitor Approved by the FDA On July 23, 2014, the US Food and

Value-Based Cancer Care

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November 2014

Drug Administration (FDA) approved idelalisib (Zydelig; Gilead Sciences), an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, for the treatment of 3 types of hematologic malignancies, including patients with relapsed CLL, to be used in combination with rituximab when rituximab can be used alone because of the presence of comorbidities, as well as patients with relapsed follicular lymphoma or patients with relapsed SLL after 2 previous systemic therapies.16 The FDA approved idelalisib for the treatment of CLL under the prescheduled review process, and used its accelerated approval program to approve the indications for the treatment of patients with relapsed follicular lymphoma and for patients with relapsed SLL, based on the surrogate end points of tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established for idelalisib in these 2 malignancies.16 Idelalisib was approved with a Risk Evaluation and Mitigation Strategy program to ensure that healthcare providers who prescribe idelalisib are informed of the risk for fatal and serious toxicities associated with idelalisib.16 Mechanism of Action Idelalisib is a potent and selective inhibitor of the PI3Kδ, an enzyme that is expressed in normal and malignant B-cells.17,18 Idelalisib inhibits several cell-signaling pathways, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and to the bone marrow.18 In cell lines derived from malignant B-cells and in primary tumor cells, idelalisib induced apoptosis and inhibited proliferation. Inhibition of chemotaxis and adhesion, and reduced cell viability have been observed in lymphoma cells that were treated with idelalisib.18 Dosing and Administration The recommended dosage of idela­ lisib for all 3 indications is 150 mg administered orally twice daily. Idelalisib tablets can be taken with or without food and should be swallowed whole.18 Treatment with idelalisib should be continued until disease progression or

unacceptable toxicity. The optimal and safe dosing regimen for patients who take idelalisib for more than several months is unknown.18 Key Clinical Trials Study 116: Phase 3 Clinical Trial in Relapsed CLL The approval of idelalisib in combination with rituximab for the treatment of patients with relapsed CLL was based on Study 116, a randomized, double-blind, placebo-controlled phase 3 clinical trial.17 This clinical trial enrolled 220 patients with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy as a result of coexisting medical conditions, reduced renal function, or significant neutropenia or thrombocytopenia resulting from previous therapy with cytotoxic agents.17,18 Patients received idelalisib plus ri­ tuximab or placebo plus rituximab until disease progression or unacceptable toxicity. Idelalisib was administered orally at 150 mg twice daily.17,18 Patients in both arms received 8 doses of rituximab (first dose, 375 mg/m2; subsequent doses, 500 mg/m2 every 2 weeks for 4 infusions, and every 4 weeks for 4 infusions). The median duration of exposure to idelalisib was 5 months.17,18 The primary end point was progression-free survival (PFS), which was defined as the interval from randomization to disease progression or death from any cause (whichever came first), using the Kaplan-Meier method.17 The primary end point was assessed by an Independent Review Committee. The secondary end points included overall response rate (ORR) and complete response rates, lymph-node response, and OS. Study 116 was stopped for efficacy following the first prespecified interim analysis.17,18 Patient population. The patients’ median age was 71 years, with 78% of patients aged ≥65 years. The majority of patients were male (66%), and Caucasian (90%). The median time since CLL diagnosis was 8.5 years.17,18 Overall, 40% of patients in Study 116 had moderate-to-severe renal dysfunction, defined as creatinine clearance <60 mL per minute, and 35% of patients had poor bone marrow function, defined as grade ≥3 anemia, thrombocytopenia, or neutropenia. Al-

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Drug Update

most two-thirds of the patients had advanced-stage CLL, and more than 40% had 17p deletion or TP53 gene mutations.17,18 Patients in both arms had received a median of 3 previous therapies, including regimens containing rituximab, fludarabine, cyclophosphamide, and bendamustine.17,18 Efficacy. At 24 weeks, the PFS rate was 93% in patients receiving idelalisib plus rituximab compared with 46% in patients receiving placebo plus ri­ tuximab (Table 1).17 The adjusted hazard ratio (HR) for progression or death in the idelalisib plus rituximab group was 0.15 (95% confidence interval [CI], 0.08-0.28; unadjusted P <.001).17,18 Study 116 was stopped for efficacy following the first prespecified interim analysis.17,18 Results of a second interim analysis continued to show a significant PFS improvement for idel­ alisib plus rituximab over placebo plus rituximab (HR, 0.18; 95% CI, 0.100.32; P <.001; Table 1). In the idelalisib plus rituximab group, the median duration of PFS was not reached; in the placebo plus rituximab group, the median duration of PFS was 5.5 months. The PFS benefit for idelalisib and rituximab was similarly favorable in all prespecified subgroups, including those that were stratified according to the presence or absence of the 17p deletion or TP53 gene mutation and immunoglobulin heavy chain variable mutational status.17,18 At 12 months, the OS rate in the idel­ alisib plus rituximab group (92%) was significantly higher than the OS rate in the placebo plus rituximab group (80%; HR for death, 0.28; 95% CI, 0.09-0.86; P = .02). In the idelalisib plus rituximab group, the ORR was 81% (95% CI, 71%88%) compared with 13% (95% CI, 6%21%) in the placebo plus rituximab group (P <.001). All responses were partial responses (Table 1).17 DELTA Study: Phase 2 Clinical Trial in Relapsed Follicular Lymphoma The safety and efficacy of idelalisib in patients with relapsed follicular lymphoma were evaluated in the DELTA clinical trial, a single-arm, multicenter clinical trial that included 72 patients with relapsed follicular lymphoma.18,19 In this clinical trial, idelalisib was administered orally at 150 mg twice daily until evidence of disease progression or unacceptable toxicity. The study’s primary end point was IndeVol. 5

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pendent Review Committee–assessed ORR. Tumor response was assessed using revised response criteria for malignant lymphoma, as recommended by the International Working Group.18,19 Patient population. The patients’ median age was 62 years.18,19 The majority of the patients were male (54%), Caucasian (90%), and had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (92%). The patients’ median time since diagnosis was 4.7 years. The patients had received at least 2 previous treatments and experienced disease relapse within 6 months after treatment with rituximab and an alkylating agent. The median number of previous treatments was 4 (range, 2-12) and included rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); bendamustine and rituximab; and rituximab plus cyclophosphamide, vincristine, and prednisone.

At baseline, 33% of patients had extra­ nodal disease, and 26% of patients had bone marrow involvement.18,19 Efficacy. Among the 72 patients with relapsed follicular lymphoma who received idelalisib, the ORR was 54% (95% CI, 42%-66%), including 6 complete responses (8%) and 33 partial responses (46%) (Table 2). The median duration of response was not evaluable (range, 0+ to 14.8+ months). The median time to response was 1.9 months (range, 1.6-8.3 months).18 An improvement in survival or disease-related symptoms has not been established for idelalisib in patients with relapsed follicular lymphoma.16,18 The continued approval of idelalisib for the treatment of patients with relapsed follicular lymphoma may be contingent on the verification of clinical benefit in confirmatory clinical trials.18 DELTA Study: Phase 2 Clinical Trial in Relapsed Small Lymphocytic Lymphoma The safety and efficacy of idelalisib in patients with relapsed SLL was also evaluated in the DELTA clinical trial.18,19 Overall, 26 patients with relapsed SLL received 150 mg of idelalisib orally twice daily until evidence of disease progression or unacceptable toxicity.

The primary end point was Independent Review Committee–assessed ORR. Tumor response was assessed using revised response criteria for malignant lymphoma, as recommended by the International Working Group.18,19 Patient population. The patients’

Table 1 I delalisib versus Placebo: Survival and Response Results in Patients with Relapsed CLL in Study 116 Idelalisib plus rituximab Placebo plus rituximab Efficacy parameter (N = 110) (N = 110) P value Median PFS, months

NR (95% CI, 10.7-NR)

5.5 (95% CI, 3.8-7.1)

P <.001

PFS, %

93

46

P <.001

Overall survival, %

92

80

P = .02

Overall response, %

81

13

P <.001

CI indicates confidence interval; CLL, chronic lymphocytic leukemia; NR, not reached; PFS, progression-free survival.

Sources: Zydelig (idelalisib) tablets prescribing information; 2014.

Furman RR, et al. N Engl J Med. 2014;370:997-1007.

ELTA Trial: Response Rate in Patients with Relapsed FL or SLL Table 2 D Receiving Idelalisib Response

Idelalisib 150 mg twice daily, N (%)

Relapsed FL (N = 72) Overall response

39 (54)

Complete response

42 (8)

Partial response

33 (46)

Relapsed SLL (N = 26) Overall response

15 (58)

Complete response

0

Partial response

15 (58)

FL indicates follicular lymphoma; SLL, small lymphocytic lymphoma.

Source: Zydelig (idelalisib) tablets prescribing information; 2014.

median age was 65 years.18 The majority of patients were male (73%), Caucasian (81%), and had a baseline ECOG performance status of 0 or 1 (96%). The patients had received at least 2 previous treatments, and their disease had relapsed within 6 months after treatment with rituximab and an alkylating agent. The patients’ median time since SLL diagnosis was 6.7 years. The median number of previous treatments was 4 (range, 2-9) and included bendamustine plus rituximab; fludarabine, cyclophosphamide, and rituximab; and R-CHOP. At baseline, 27% of patients had extranodal disease.18,19 Efficacy. Among the 26 patients with relapsed SLL who received idel­ alisib, the ORR was 58% (95% CI, 37%77%), and all responses were partial responses (Table 2). The median duration of response was 11.9 months (range, 0+ to 14.7+ months). The median time to response was 1.9 months (range, 1.6-8.3 months).18,19 An improvement in survival or disease-related symptoms has not been established for idelalisib in relapsed SLL. The continued approval of idealisib for the treatment of patients with relapsed SLL may be contingent on the november 2014

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verification of clinical benefit in confirmatory clinical trials.16,19 Adverse Events The majority of adverse events among patients receiving idelalisib plus rituximab were consistent with those expected for patients with relapsed CLL who had received extensive previous therapy.17 In Study 116, serious adverse events were reported in 49% of the patients who received idelalisib plus rituximab.17,18 The most frequent serious adverse events included pneumonia, pyrexia, sepsis, febrile neutropenia, and diarrhea (Table 3). Adverse reactions leading to the discontinuation of idelalisib therapy occurred in 10% of the patients; the most common of these reactions included hepatotoxicity and diarrhea or colitis.17,18 Dose interruption of idelalisib was required in 35% of patients with relapsed CLL.18 Overall, 15% of the patients needed dose reductions as a result of adverse events or laboratory abnormalities; the most common reasons for dose reductions included elevated transaminase levels, diarrhea or colitis, and rash.18 Continued on page 48

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Drug Update

Zydelig (Idelalisib): First-in-Class PI3 Kinase Inhibitor Approved by the FDA for the Treatment of 3 Hematologic...

Continued from page 47

The safety data for idelalisib also reflect drug exposure in 146 adult patients with indolent NHL who received idelalisib 150 mg twice daily in clinical trials. The patients’ median duration of exposure to idelalisib was 6.1 months (range, 0.3-26.4 months). Overall, 50% of these patients experienced serious adverse events, including pneumonia, diarrhea, and pyrexia.18 In addition, dose interruption or discontinuation of idelalisib occurred in 53% of the patients with indolent NHL; the most common reasons for interruption or discontinuation of idel­ alisib included diarrhea, pneumonia, and elevated transaminase levels.18 Contraindications Idelalisib is contraindicated in patients with a history of serious allergic reactions, including anaphylaxis and toxic epidermal necrolysis.18 Warnings and Precautions Boxed warning. Idelalisib carries a boxed warning indicating that the drug may cause fatal and/or serious intestinal perforation, hepatoxicity, diarrhea or colitis, and pneumonitis. Patients should be monitored for the development of these adverse events, and idelalisib therapy should be discontinued if intestinal perforation is suspected.18 Hepatotoxicity. In clinical trials, 14% of patients who received idelalisib experienced fatal and/or serious hepatotoxicity. In addition, elevations in transaminase levels greater than 5 times the upper limit of normal have been observed. These findings were typically noted within the first 12 weeks of treatment with idelalisib and were reversible with dose interruption.18 After resuming idelalisib treatment at a lower dose, 26% of patients experienced recurrence of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations. Idelalisib treatment should be discontinued if recurrent hepatotoxicity occurs.18 The use of idelalisib concurrently with other drugs that may cause liver toxicity is not recommended.18 Transaminase levels should be monitored in all idelalisib recipients according to the following schedule18: • Every 2 weeks for months 1 to 3 • Every 4 weeks for months 4 to 6 • Every 1 to 3 months thereafter.

Weekly monitoring is appropriate if ALT or AST levels rise above 3 times the upper limit of normal until liver toxicity resolves. Idelalisib should be

48

rade ≥3 Adverse Reactions Reported with Idelalisib versus Placebo in Table 3 G Patients with CLL Idelalisib plus rituximab, N (%) (N = 110)

Placebo plus rituximab, N (%) (N = 108)

18 (16)

14 (13)

Sepsis

8 (7)

4 (4)

Diarrhea

6 (5)

0

Rash

4 (4)

1 (1)

Pyrexia

3 (3)

1 (1)

Chills

2 (2)

0

Stomatitis

2 (2)

0

Bronchitis

1 (1)

1 (1)

Headache

1 (1)

0

Adverse event Pneumonia

CLL indicates chronic lymphocytic leukemia.

Source: Zydelig (idelalisib) tablets prescribing information; July 2014.

withheld if ALT or AST levels are greater than 5 times the upper limit of normal. Total bilirubin, AST, and ALT levels should be monitored weekly until abnormalities resolve.18 Severe diarrhea or colitis. Across clinical trials, severe diarrhea or colitis (grade ≥3) occurred in 14% of patients receiving idelalisib. Diarrhea can occur at any time and responds poorly to antimotility agents. Concurrent use of idelalisib and other medications that cause diarrhea should be avoided.18 After interruption of idelalisib therapy and, in some instances, the use of corticosteroids, the median time to resolution of diarrhea ranged from 1 week to 4 weeks.18 Pneumonitis. Patients taking idela­ lisib have experienced fatal and serious pneumonitis. Pneumonitis should be suspected in patients who are taking idelalisib and present with pulmonary symptoms, including cough, dyspnea, hypoxia, interstitial infiltrates on a radiologic examination, or a decline of >5% in oxygen saturation.18 For patients with possible pneumonitis, idelalisib should be interrupted until an etiology for lung symptoms has been determined. Patients with pneumonitis that is believed to be caused by idelalisib have discontinued idelalisib therapy and received corticosteroids.18 Intestinal perforation. In clinical trials, fatal and serious intestinal perforations have occurred in patients taking idelalisib. Some patients had moderate-to-severe diarrhea at the time of perforation. Patients should immediately report new or worsening abdominal pain, chills, fever, nausea, or vomiting. Idelalisib should be permanently discontinued in patients who experience intestinal perforation.18

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Severe cutaneous reactions. Overall, 1 case of toxic epidermal necrolysis was reported in a study of idelalisib plus bendamustine and rituximab. Patients receiving idelalisib have also reported other severe or life-threatening (grade ≥3) cutaneous reactions, including exfoliative dermatitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, exfoliative rash, and skin disorders. Patients should be monitored for the development of severe cutaneous reactions, and idelalisib should be discontinued if they occur.18 Anaphylaxis. Serious allergic reactions, including anaphylaxis, have been reported in patients taking idel­ alisib. Idelalisib should be permanently discontinued if this occurs, and appropriate supportive measures should be instituted.18 Neutropenia. Across clinical trials, 31% of patients receiving idelalisib experienced treatment-emergent grade 3 or 4 neutropenia. Blood counts should be monitored a minimum of every 2 weeks for the first 3 months of therapy and at least weekly in patients whose neutrophil counts are <1.0 Gi/L.18 Embryofetal toxicity. Idelalisib may cause fetal harm when administered to a pregnant woman.18 If idelalisib is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be made aware of the potential hazard to the fetus. While taking idelalisib, women of reproductive potential should avoid becoming pregnant. Effective contraception can be used during idelalisib treatment and for at least 1 month after the last dose.18 Use in Specific Populations Pregnancy. Idelalisib is a pregnancy category D teratogen and may cause

teratogenicity and/or embryofetal lethality. Women should avoid becoming pregnant while taking idelalisib.18 Nursing mothers. Because many drugs are excreted in human milk and because of the potential for idelalisib-related adverse events in nursing infants from idelalisib, nursing or idelalisib should be discontinued based on the importance of the drug to the mother.18 Pediatric use. The safety and effi­ cacy of idelalisib in pediatric patients have not been established.18 Geriatric use. In clinical trials of idel­ alisib for relapsed CLL, relapsed follicular lymphoma, and relapsed SLL, 63% of patients receiving the agent (131 of 208) were aged ≥65 years. No meaningful differences in efficacy were observed among age cohorts.18 When patients aged ≥65 years with relpased CLL were compared with younger patients, older patients had a higher incidence of discontinuation as a result of an adverse reaction (11% vs 5%), higher incidence of serious adverse events (51% vs 43%), and higher incidence of death (3% vs 0%).18 When patients aged ≥65 years with indolent NHL were compared with younger patients, older patients had a higher incidence of discontinuation as a result of an adverse event (28% vs 20%). In addition, older patients had a higher incidence of serious adverse reactions (64% vs 37%) and a higher incidence of death (11% vs 5%).18 Hepatic impairment. Safety and efficacy data are not available in patients with baseline ALT or AST values greater than 2.5 times the upper limit of normal, or bilirubin values greater than 1.5 times the upper limit of normal. Patients with baseline hepatic impairment should be monitored for signs of idelalisib toxicity.18 Conclusion Idelalisib, the first FDA-approved PI3Kδ inhibitor, is an effective and safe treatment option for patients with relapsed CLL, relapsed follicular lymphoma, or relapsed SLL. Based on a significant PFS benefit, idelalisib joins ibrutinib as an FDA-approved oral agent for use in patients with relapsed CLL. In relapsed follicular lymphoma and relapsed SLL, idelalisib was approved under the accelerated approval program based on ORR data. Clinical trials to collect data verifying the clinical benefit of idelalisib in these 2 indolent lymphomas are under way.20 Additional clinical trials are evaluating the combination of idelalisib plus ofa-

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Drug Update tumumab and idelalisib plus obinutuzumab for the treatment of patients with previously untreated CLL. Idelalisib is also being studied in combination with bendamustine and rituximab for the treatment of patients with previously untreated and relapsed hematologic malignancies.20 n

drugtherapy/. Accessed September 11, 2014.

12. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): non-Hodgkin’s lymphomas. Version 4.2014. August 22, 2014. www.nccn.org/professionals/ physician_gls/pdf/nhl.pdf. Accessed October 3, 2014.

13. Gazyva (obinutuzumab) injection [prescribing information]. South San Francisco, CA: Genentech, Inc; June 2014.

14. Imbruvica (ibrutinib) capsules [prescribing infor-

mation]. Sunnyvale, CA: Pharmacyclics, Inc; July 2014.

15. Arzerra (ofatumumab) injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; April 2014.

16. US Food and Drug Administration. FDA approves Zydelig for three types of blood cancers. Press release.

July 23, 2014. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm406387.htm. Accessed September 11, 2014.

17. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib

and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370:997-1007.

18. Zydelig (idelalisib) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; July 2014.

19. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370:1008-1018.

20. ClinicalTrials.gov. Idelalisib. Search results. http:// clinicaltrials.gov/ct2/results?term=idelalisib&Search= Search. Accessed September 11, 2014.

References

1. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia. www.lls.org/#/diseaseinformation/ leukemia/chroniclymphocyticleukemia/. Accessed September 11, 2014.

2. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: incidence. www.lls.org/#/diseaseinforma tion/leukemia/chroniclymphocyticleukemia/incidence/.

Accessed September 11, 2014.

3. Gribben JG. How I treat CLL up front. Blood. 2010; 115:187-197.

4. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: signs and symptoms. www.lls.org/#/ diseaseinformation/leukemia/chroniclymphocyticleu kemia/signssymptoms/. Accessed September 11, 2014.

5. Cancer.net. Leukemia—chronic lymphocytic—CLL: statistics. Reviewed July 2014. www.cancer.net/cancer-­ types/leukemia-chronic-lymphocytic-cll/statistics. Accessed September 11, 2014.

6. Blankart CR, Koch T, Linder R, et al. Cost of illness and economic burden of chronic lymphocytic leukemia. Orphanet J Rare Dis. 2013;8:32.

7. Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17:3835-3849.

8. Leukemia & Lymphoma Society. Non-Hodgkin lymphoma: treating specific indolent subtypes. www.lls. org/#/diseaseinformation/lymphoma/nonhodgkin lymphoma/treatment/indolentnhlsubtypes/specific­ indolentsubtypes/. Accessed September 11, 2014.

9. Leukemia & Lymphoma Society. Treatment for aggressive NHL subtypes. www.lls.org/#/diseaseinforma­ tion/lymphoma/nonhodgkinlymphoma/treatment/ aggressivenhlsubtypes/. Accessed September 11, 2014.

10. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood.

2008;111:5446-5456. Erratum in: Blood. 2008;112:5259.

11. Leukemia & Lymphoma Society. Chronic lymphocytic leukemia: treatment: chemotherapy and drug therapy. www.lls.org/#/diseaseinformation/leukemia/ chroniclymphocyticleukemia/treatment/chemotherapy

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.

Single-Unit Cord-Blood Transplant Better than...

Continued from page 22 terms of rates of disease-free survival, neutrophil recovery time, transplantation-related mortality, and disease relapse. However, several outcomes were better with 1 unit than with 2 units of cord blood, including improved platelet recovery and lower incidence of grade III or IV chronic graft-versus-host disease (GVHD).

The investigators concluded that although many outcomes were similar with 1- or 2-unit cord-blood transplantation, the use of 1-unit cord-blood transplant resulted in improved platelet recovery and a lower risk for GVHD in this population of children and young adults aged <21 years. These results, they noted, indicate that 2-unit cord-blood transplantation “does not confer a survival advantage in children and adolescents.” n Vol. 5

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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 Symposium

Study Quantifies the Cost-Savings of Do Not Resuscitate Orders

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

G. Portman, MD, Chair of the Department of Supportive Care Medicine at Moffitt Cancer Center, Tampa, FL, presented the results.

Dr Portman and colleagues examined the cost of care and the length of stay of patients who died in the intensive care unit (ICU) at Moffitt Cancer Center during 2013, based on whether they had an advance directive without a DNR, an advance directive with a DNR, or no advance directive. The cost of care for a regular hospital bed was compared with a stay in the ICU to determine the potential cost-savings of avoiding the ICU.

“

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

Symposium, is one of the first to quantify the cost-savings that can result when critical care patients with advanced cancer have a DNR. Diane

LASERS PRINTED AT

significant cost reduction in the critical care of patients with advanced cancer. The study, reported at the 2014 Palliative Care in Oncology

100%

Boston, MA—New research provides hard data demonstrating that having an advance directive with a do not resuscitate (DNR) order leads to a

Once you had the living will, you knew what that patient wanted and you could turn to the patient’s family and say, ‘This is what the patient would have wanted. We are now engaging in futile care.’ We curtailed undesired or futile care more rapidly.

”

—Diane G. Portman, MD

Moffitt’s Blood and Marrow Transplant (BMT) program has implemented a protocol to obtain a more detailed advance directive before bone marrow transplant because of the high risk of the procedure.

“Studies from other cancer centers have shown that even if critical cancer patients had advance directives, you got little action from them, and the care kind of rolled along on automatic pilot, was very aggressive and often futile,” said Dr Portman.

“Previous studies have shown that we need much tighter discussions about goals and level of care in the ICU cancer population, and that concrete language is needed in the form of a DNR, rather than a traditional advance directive,”she said.

Of the 103 patients with advanced cancer who died in the ICU at the Moffitt Center, when a patient had an advance directive but no DNR, no real impact was seen on costs. “What was very meaningful was having a living will, which usually then also translated into a DNR. It was less likely to

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Palliative Care Symposium

Timing of Palliative Care Delivery in Patients with Cancer Impacts Quality and Cost Outcomes

By Kate O’Rourke

Boston, MA—Offering palliative care to patients with advanced cancer earlier rather than later in the course of disease can improve outcomes and reduce costs, according to a new study presented at the 2014 Palliative Care in Oncology Symposium. Early palliative care had a dramatic impact on the number of emergency department visits and inpatient deaths, among other measures.

“Patients who have early palliative care consultation have more appropriate care and a higher quality of care at the end of life,” said Michael W. Rabow, MD, Director, Symptom Management Service, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.

The American Society of Clinical Oncology recommends that palliative care be offered alongside standard cancer care for patients with metastatic cancer and/or high symptom burden. Studies have shown that palliative care is associated with improved quality outcomes, reduced costs, and greater patient satisfaction, but there are limited data on how the timing of palliative care impacts the quality, intensity, and cost of medical care at the end of life for patients with advanced cancer.

In this new retrospective analysis, Dr Rabow and colleagues focused on

978 patients who died from cancer between January 2010 and May 2012 at the Helen Diller Family Comprehensive Cancer Center. Patients were in-

“

Among patients getting early palliative care, there is a small increase in outpatient costs, but this is more than outweighed by the decrease in inpatient costs. Early palliative care provides higher quality care for the same or possibly less cost.

”

—Michael W. Rabow, MD

cluded if they had 2 or more oncology visits within 6 months of dying. This cancer center provides inpatient and outpatient palliative care services.

Approximately 30% of patients received palliative care and 30% of these patients qualified as early palliative care. “Early” was characterized as care received more than 90 days before

death, and “late” was defined as care received less than 90 days before death. Gynecology and urology clinics were more likely to refer patients to early palliative care.

Early palliative care was predominantly delivered in the outpatient setting (84%), and late palliative care was mostly delivered in the hospital setting (82.4%).

Quality Outcomes Compared with late palliative care, the use of early palliative care significantly reduced: ➤ Intensive care unit stays in the last 30 days of life: 5% vs 20%, respectively (P = .001) ➤ Proportion of patients who had more than 1 emergency department visit in the last 30 days of life: 4% vs 14%, respectively (P = .007) ➤ Inpatient deaths: 15% vs 34%, respectively (P <.001) ➤ 30-day mortality: 33% vs 66%, respectively (P <.001).

“There is a clear strong trend in all of these numbers. You are having a very, very big impact on the kind of care patients receive and the quality measures we look at,” said Dr Rabow.

Cost Outcomes Cost comparisons showed an important trend that was very close to

Study Quantifies the Cost-Savings of Do Not Resuscitate... Continued from page 50 have a living will and not have a DNR,” noted Dr Portman.

Despite longer lengths of stay, indicating that DNRs were obtained late in their course, patients who had a DNR still had significantly lower costs of care. The average savings for having a living will and a DNR compared

with no advance directive or an advance directive with no living will was roughly $300 per day in the ICU. The savings, said Dr Portman, was realized through reduced spending on testing, supplies, and pharmaceuticals. The cost of care for patients who did not go to the ICU but stayed

at a glance ➤ An advance directive with a DNR order leads to a significantly lower cost of critical care of patients with advanced cancer ➤ Having a living will and a DNR saved approximately $300 daily in the ICU compared with no advance directive or having an advance directive with no living will

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➤ There was a $2000 reduction daily in the cost of care for patients who did not go to the ICU but stayed in a regular hospital bed ➤ A living will is not only cost-saving, but it also alleviates futile and undesired end-of-life care

in a regular hospital bed was reduced by $2000 daily.

“Once you had the living will, you knew what that patient wanted and you could turn to the patient’s family and say, ‘This is what the patient would have wanted. We are now engaging in futile care,’” said Dr Portman. “We curtailed undesired or futile care more rapidly.”

The researchers also found that the BMT program’s advance directive initiative increased the number of patients with an advance directive on their chart from 41% to 83% in 7 months. Among the 38 patients who had a bone marrow transplant and had died, this resulted in a significant reduction in their length of stay in the ICU by aligning their care with their stated goals. “We need to generalize this initiative more broadly to other patients,” said Dr Portman. n november 2014

I

at a glance ➤ Introducing palliative care early to patients with advanced cancer can improve outcomes, reduce costs ➤ Patients receiving early palliative care had reduced intensive care unit stays in the last 30 days of life, less inpatient deaths, and lower 30-day mortality rates ➤ Early palliative care reduced intensive care unit stays by 20% in the last 30 days of life compared with only 5% in patients who received later palliative care ➤ Inpatient costs in the last 6 months of life were approximately $6600 lower when palliative care was introduced early rather than late

being statistically significant in the analysis: inpatient costs were lower for patients who received early palliative care compared with late palliative care.

Patients in the early palliative care group had lower average inpatient direct costs in the last 6 months of life than those in the late palliative care group—$19,067 versus $25,754, respectively; however, the outpatient direct costs were slightly higher—$13,040 versus $11,549, respectively.

“Among patients getting early palliative care, there is a small increase in outpatient costs, but this is more than outweighed by the decrease in inpatient costs. Early palliative care provides higher quality care for the same or possibly less cost,” noted Dr Rabow.

The researchers said that the data are convincing enough that they are trying to change practice at their cancer center.

“We would love to see patients being referred much earlier, because we see the impact it has on the quality of end-of-life care,” Dr Rabow stated.

“The challenge is capacity. We are essentially trying to use this data to convince the cancer center to increase capacity for outpatient palliative care consultation.” n

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Palliative Care Symposium

Long-Awaited Cost Analysis of Early Palliative Care Intervention in Patients with Metastatic Lung Cancer

.29

Outpatient visits (including palliative care visits)

–197

–78

.79

Chemotherapy

757

0

.06

–1053

–878

.11

Hospice services

Positive numbers correspond to cost-savings for early palliative care.

Source: Greer JA, et al. Cost analysis of a randomized trial of early palliative care in patients with metastatic non-small cell lung cancer. Presented at the 2014 Palliative Care in Oncology Symposium; Boston, MA; October 25, 2014. Used with permission.

a

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Eduardo Bruera, MD, Professor and Chair, Department of Palliative Care and Rehabilitation Medicine, M.D. Anderson Cancer Center, Houston, discussed the study at the symposium. Dr Bruera said that the research was important, because it showed that the costs of early palliative care were not higher than standard care, but that the expenses had a different distribution. n

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—Joseph A. Greer, PhD

50

ifferences in End-of-Life Care Costs for Standard Care Compared with Table 2 D Early Palliative Carea Mean Median Variable (last 30 days) difference, $ difference, $ P value

1

Positive numbers correspond to cost-savings for early palliative care.

Source: Greer JA, et al. Cost analysis of a randomized trial of early palliative care in patients with metastatic non-small cell lung cancer. Presented at the 2014 Palliative Care in Oncology Symposium; Boston, MA; October 25, 2014. Used with permission.

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Clinical Outcomes A landmark randomized controlled trial conducted at Massachusetts General Hospital demonstrated that early palliative care improved survival, quality of life, and depression in patients with metastatic NSCLC (Temel JS, et al. N Engl J Med. 2010;363:733742). The study randomized 151 patients with newly diagnosed metastatic NSCLC to receive either standard cancer care alone or early palliative care integrated with standard care.

Patients in the palliative care arm met with palliative care clinicians monthly, whereas patients in the standard oncology arm met with palliative care clinicians only when the patient or family requested it. Although fewer patients in the early palliative care group than in the standard care group received aggressive end-of-life care (33% vs 54%, respectively; P = .05), the median survival was longer among patients receiving early palliative care (11.6 vs 8.9 months, respectively; P = .02).

0.5

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The marginally significant findings show that early palliative care was associated with a lower average total cost per day of $117 compared with standard care. In the final month of life, costs were greater for hospice care, but less for chemotherapy in the early palliative care group compared with standard care.

99

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ifferences in Total Healthcare Costs for Standard Care Compared with Table 1 D Early Palliative Carea Mean Median Variable difference, $ difference, $ P value

group compared with standard care.”

According to an estimate from a 2011 study, the average cumulative total healthcare cost for metastatic lung cancer is $125,849 (Vera-Llonch M, et al. BMC Health Serv Res. 2011; 11:305). Palliative care may be one method of reducing these healthcare costs. Inpatient palliative care consultations have been associated with significant savings for hospital costs (May P, et al. J Palliat Med. 2014;17:10541063), yet little is known about the impact of outpatient early palliative care on the overall costs of care.

75

sociated with a lower average total cost per day of $117 compared with standard care,” said Dr Greer. “In the final month of life, costs were greater for hospice care, but less for chemotherapy in the early palliative care

75

”

—Joseph A. Greer, PhD

75

“

The delivery of early palliative care for patients with metastatic NSCLC does not appear to increase health care expenses over the course of disease or at the end of life.

A New Cost Analysis At the meeting, Dr Greer presented the results of a new, secondary analysis of the original study, which calculated the cost of care throughout the original study and at the end of life in terms of hospitalizations and emergency department visits, outpatient clinic visits, chemotherapy administration, and hospice services.

Although many of the costs showed a trend toward a cost-savings for the palliative care arm, the results did not reach statistical significance (Table 1 and Table 2).

“Although this secondary analysis lacked statistical power, the delivery of early palliative care for patients with metastatic NSCLC does not appear to increase health care expenses over the course of disease or at the end of life.”

Dr Greer said that future studies of early palliative care models need to include sufficiently powered cost analyses that assess relevant inpatient, outpatient, and homecare services.

75

Boston, MA—A long-awaited cost analysis of a randomized trial comparing early palliative care with standard care in patients with metastatic non–small-cell lung cancer (NSCLC) did not produce results that reached statistical significance, but the findings were positive, the researchers said, given that early palliative care has been shown to improve survival and other outcomes.

“Early palliative care has been shown to improve quality of life, mood, and end-of-life care in patients with metastatic NSCLC,” said Joseph A. Greer, PhD, a clinical psychologist at Massachusetts General Hospital, Boston, who presented the study at the 2014 Palliative Care in Oncology Symposium.

“The marginally significant findings show that early palliative care was as-

75K

By Kate O’Rourke

No. 9

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

Lung Cancer

Risk for Second Primary Lung Cancers Remains High in Smokers Overall survival improves in patients who quit smoking

By Phoebe Starr San Francisco, CA—Patients who are diagnosed with lung cancer but continue to smoke are at much higher risk for a second primary lung cancer compared with never-smokers or those who have quit smoking, according to the largest analysis of its kind, which was presented at the 2014 American Society for Radiation Oncology meeting.

“This study, which looked at the relationship between smoking history and developing a second lung cancer, adds to the evidence of the harmfulness of cigarette smoking. We presumed that never-smokers would have a lower risk than current smokers, but we were encouraged to find that quitting smoking lowered the risk of second primary lung cancer and quitters had similar overall survival rates as never-smokers,” said

“

We presumed that neversmokers would have a lower risk than current smokers, but we were encouraged to find that quitting smoking lowered the risk of second primary lung cancer and quitters had similar overall survival rates as never-smokers.

”

—John Michael Boyle, MD

lead investigator John Michael Boyle, MD, a radiation oncology resident at Duke University, Durham, NC. “These findings confirm that smoking cessation is crucial and should be an integral part of patient care for all patients, as well as cancer survivors.”

The study included 1484 patients who underwent surgery for stage I-IIIA non–small-cell lung cancer between 1995 and 2008, including 372 current smokers, 1014 former smokers, and 98 never-smokers. The 5-year incidence of second primary lung

cancer was 13% for current smokers, 7% for former smokers, and 0% for never-smokers (P = .03).

During follow-up, only 1 never-­ smoker developed a second primary lung cancer 7 years later. The risk increased with the number of years of tobacco exposure, equaling an 8% increased risk with every 10 pack-years.

The overall survival (OS) results were quite different among the groups based on the smoking history, Dr Boyle emphasized. “OS was the worst for current smokers. Quitting smoking mitigated increased risk of mortality,” he noted.

The rate of 5-year OS was 39% in current smokers, 46.1% in those who quit >5 years ago, 47.1% in those who quit <5 years ago, and 54.1% in never-­ smokers. n

Lung Biopsies Costly and Often Unnecessary

By Alice Goodman

Chicago, IL—A large study based on Medicare claims data reveals an opportunity to substantially cut costs of lung cancer screening, while improving quality of care. Based on this study, lung biopsies are the most expensive modality used in the diagnostic workup of patients with an abnormal chest computed tomography (CT) scan, and as many as 43.7% of the biopsies according to this study are unnecessary and are in contrast to the National Comprehensive Cancer Network (NCCN) lung cancer screening guidelines recommendations.

The current NCCN guidelines recommend the use of a positron emission tomography (PET) scan after an abnormal CT scan to identify patients who would benefit from a lung biopsy. The study, which was presented at the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology, showed that the diagnostic workup costs after an abnormal CT scan totaled $38.3 million. Of this, 43.1% ($16.5 million) was attributed to the biopsy costs of 761 patients included in the sample who had negative biopsies and were not diagnosed with lung cancer in the following year.

“This study provides a baseline of current costs for the lung cancer diagnostic workup prior to the introduction of major lung cancer screening

54

programs. Biopsy costs comprise a significant proportion of the overall cost of diagnosing lung cancer, and biopsies significantly increase the costs in patients who are diagnosed with lung cancer, and those who aren’t,” said Tasneem Lokhandwala, MS, PhD, a data analyst at Xcenda in Palm Harbor, FL.

“”

We need better identification of patients who need lung biopsy in order to reduce costs and improve patient outcomes.

—Tasneem Lokhandwala, MS, PhD

Study Details The study population was culled from a random sample of Medicare beneficiaries. A total of 8979 eligible patients were identified (aged 65-74 years; mean age, 69.3 years) who had an abnormal chest CT scan between July 1, 2009, and December 31, 2010.

During a 12-month study period, 13.9% (1249) of the patients were diagnosed with lung cancer; the median time from abnormal CT scan to lung

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cancer diagnosis was 11 days.

As part of the diagnostic workup, chest x-rays were ordered for 54.4% (N = 4885) of patients, chest CT scans were ordered for 32.9% (N = 2954), and lung biopsies were done in 19.4% (N = 1742). PET scans were ordered for a mere 0.4% (N = 36) of the patients.

Lung biopsies were negative in 43.7% (N = 761) of the patients who had a biopsy; none of these patients was diagnosed with lung cancer during follow-up.

Cost Impact and Biopsy Complications The average associated Medicare cost of the diagnostic workup totaled $7567 for patients diagnosed with lung cancer and $3559 for those not diagnosed with lung cancer.

Looking at the cost analysis of lung biopsies (procedure costs, and all incidental costs including physician cost, anesthesia services, and adverse events), for each biopsy, the median cost was $3874, and the mean cost was $14,364.

The average cost of a lung biopsy with complications (ie, adverse events) was approximately 4 times higher than a biopsy without complications­—$37,745 versus $8869, respectively. Complications were reported in 19.3% (N = 336) of patients

who underwent a lung biopsy.

“We need better identification of patients who need lung biopsy in order to reduce costs and improve patient outcomes. These could include better

“

It is important to bear in mind the associated costs and potential harms of diagnostic tests. The cost of unnecessary biopsies in patients who did not have lung cancer include adverse events and emotional stress.

”

—laurie E. gaspar, md, mba imaging, follow-up PET, and liquid biopsies,” Dr Lokhandwala stated.

Commenting on the study results, Laurie E. Gaspar, MD, MBA, Chair, Department of Radiation Oncology, University of Colorado, Denver, said, “It is important to bear in mind the associated costs and potential harms of diagnostic tests. The cost of unnecessary biopsies in patients who did not have lung cancer include adverse events and emotional stress.” n

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A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

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

Value-BasedCare

™

November 2013 u 8th IN A SERIES

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

Topics include: • Effective Treatment of Newly

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

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

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

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

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

This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients.

These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

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

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care.

Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

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

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

This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

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

An official publication of

11/15/13 9:58 AM

VIEW THE SERIES ONLINE AT:

www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127_Ksize13114

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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