VBCC April 2015 | Vol 6 | No 3 by Value-Based Cancer Care

APRIL 2015 VOL 6 NO 3

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

NCCN Panel Addresses Value-Based Care in Oncology By Wayne Kuznar

IOM Strategies for Lowering Out-of-Pocket Costs of Cancer Drugs By Rosemary Frei, MSc

t a June 2014 Institute of Medicine (IOM) workshop on patient access to oncology drugs, several cancer experts discussed various strategies on how to lower out-of-pocket (OOP) costs of oncology drugs for patients with cancer. It is essential for oncologists to engage patients in discussions about the OOP

costs of their medications, suggested S. A. Mark Fendrick, Yousuf Zafar, MD MD, MHS, Associate Professor of Medicine, Duke Cancer Institute, and Duke Clinical Research Institute, Durham, NC. In an interview with Value-Based Continued on page 9

GYNECOLOGIC ONCOLOGY HIGHLIGHTS

Hollywood, FL—Value-based decision-making at the bedside can be fraught with obstacles, with no clear agreement on what constitutes value, and for whom. In addition, the myriad insurance plans preclude uniform

treatment strategies, despite clinical pathways and guidelines intended to reduce variation in care. Finally, value is becoming more difficult to achieve in oncology as each benefit becomes more expensive, with the cost of new Continued on page 8

ASCO’s Annual Report: Major Advances in Oncology and the Challenge of ValueBased Care By Eileen Koutnik-Fotopoulos

ignificant gains in cancer research and prevention have led to longer survival, improved quality of life, and decreased disease burden. The 2015 annual report on “Clinical Cancer Advances” from the American Society of Clinical Oncology (ASCO) outlines the biggest advances made in oncology, and

for the first time designates one cancer as the Advance of the Year, as well as emphasizing the ongoing challenge of value-based care (Masters GA, et al. J Clin Oncol. 2015;33:786-809). “Clinical Cancer Advances is a comprehensive overview of advances across the cancer care continuum—from preContinued on page 40

Immunotherapy Vaccine Prolongs Recurrence-Free Survival in Advanced Ovarian Cancer By Alice Goodman Chicago, IL—Immunotherapy holds promise for the maintenance treatment of late-stage ovarian cancer, according to results of a phase 2 clinical trial. The vaccine, made from the patient’s own tumor cells, was able to prolong recurrence-free survival compared with standard of care.

Among 20 patients who received immunotherapy, the median time to recurrence has not yet been reached, whereas among 11 patients who received standard of care, the median time to recurrence was 14.5 months. The investigators say that the majority of patients in the immunotherapy arm have gone “well Continued on page 23

INSIDE FDA NEWS . . . . . . . . . . . . . . . . . . . . . Unituxin approved for high-risk neuroblastoma

VALUE PROPOSITIONS . . . . . . . . . . 7 Targeted therapies for pancreatic cancer ECONOMICS OF CANCER CARE . . . Sunitinib associated with higher costs than pazopanib in RCC Prolaris test shows substantial cost-savings

NCCN CONFERENCE HIGHLIGHTS . . . . . . . . . . . . . . . . . . 14 New smoking-cessation guidelines for patients with cancer Updated prostate cancer guidelines

GYNECOLOGIC ONCOLOGY HIGHLIGHTS . . . . . . . . . . . . . . . . . . 23 Bevacizumab prolongs survival in ovarian cancer ABSTRACTS . . . . . . . . . 28 Abstracts to be presented at the 5th Annual AVBCC Conference HEALTH POLICY . . . . . . . . . . . . . . . 41 ASCO’s report on cancer care in America PATIENT INFORMATION . . . . . . . . . . What is a navigator?

DRUG UPDATE . . . . . . . . . . . . . . . . 43 Lenvima approved for differentiated thyroid cancer

NEW FDA APPROVAL CYRAMZA® (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDAapproved therapy for these aberrations prior to receiving CYRAMZA.

ADVANCING THE SECONDLINE TREATMENT OF METASTATIC NSCLC1 CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.1

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

Warnings and Precautions Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE.

•

Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

•

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation.

•

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

•

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

•

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL1 OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA + docetaxel (n=628)

1.0

OS PROBABILITY

MAJOR OUTCOME MEASURE

10.5

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)1

15% INCREASE IN MEDIAN OS

MONTHS

0.8

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 1

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

527

415

329

231

156

103

501

386

306

197

129

• ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progressionfree survival; ORR=objective response rate. *ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.2 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253) The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.1

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

Use in Specific Populations •

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

•

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

•

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

Most Common Adverse Reactions •

•

The most commonly reported adverse reactions (all grades; Grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colonystimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel.

•

Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%).

•

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions •

No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

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NO. 3

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page. RB-L HCP ISI 17DEC2014 References: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 2. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

APRIL 2015

www.ValueBasedCancerCare.com

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

INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA.

in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3.

CONTRAINDICATIONS None.

Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3

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

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZAtreated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

CYRAMZA plus docetaxel (N=627) All Grades Grade 3-4 (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 Neutropenia 55 49 Thrombocytopenia 13 3 Gastrointestinal Disorders Stomatitis/Mucosal 37 7 inflammation Eye Disorders Lacrimation increased 13 <1 General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 Peripheral edema 16 0 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 Vascular Disorders Hypertension 11 6 Adverse Reactions (MedDRA) System Organ Class

Placebo plus docetaxel (N=618) All Grades Grade 3-4 (Frequency %) (Frequency %) 10 46 5

10 40 <1

50 9

11 <1

Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent antiramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel.

CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intratumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST)

CYRAMZA® (ramucirumab) injection

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

RB-L HCP BS 17Dec2014

based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

FDA News Unituxin First FDAApproved Therapy for Patients with High-Risk Neuroblastoma

The FDA approved dinutuximab (Unituxin; United Therapeutics), an antibody that binds to the surface of neuroblastoma cells, as part of firstline therapy for pediatric patients with high-risk neuroblastoma. This rare cancer occurs mainly in children aged ≤5 years; they have a 40% to 50% chance of long-term survival despite therapy. The FDA approved dinutuximab to be used as part of a multimodality regimen that includes surgery, chemotherapy, and radiation therapy in patients who had at least a partial response to previous first-line multimodality therapy. “Unituxin marks the first approval for a therapy aimed specifically for the treatment of patients with high-risk neuroblastoma,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “Unituxin fulfills a critical need by providing a treatment option that prolongs survival in children with high-risk neuroblastoma.” Dinutuximab was approved under the FDA’s priority review process and was designated as an orphan drug. Furthermore, the FDA issued a rare pediatric disease priority review voucher to the manufacturer for a subsequent drug application for this drug. This is the second rare pediatric disease priority review voucher granted by the FDA since the inception of this voucher program, which is designed to encourage the development of new therapies for rare pediatric diseases. The safety and efficacy of dinutuximab were demonstrated in a clinical trial of 226 pediatric patients with high-risk neuroblastoma. The patients were randomized to the oral retinoid drug isotretinoin or to dinutuximab in combination with interleukin-2 and granulocyte-macrophage colony-stimulating factor, which enhance the activity of dinutuximab. After 3 years of treatment, 63% of patients receiving the dinutuximab combination were free of tumor growth or disease recurrence compared with 46% of patients receiving isotretinoin. In addition, the survival rate was 73% versus 58%, respectively, in an updated analysis. The most common side effects associated with dinutuximab were severe pain, fever, low platelet counts, infusion reactions, hypotension, hyponatremia, elevated liver enzymes, anemia, vomiting, diar-

rhea, low potassium levels, capillary leak syndrome, neutropenia, lympho penia, hives, and low blood calcium levels. Dinutuximab is associated with serious adverse events; it was approved with a boxed warning about its potential for irritating nerve cells, causing severe pain, as well as nerve damage and life-threatening infusion reactions. (March 15, 2015)

Rindopepimut, an Immunotherapy Vaccine, Designated as Breakthrough Therapy for Glioblastoma

The FDA granted a breakthrough therapy designation for rindopepimut (Celldex Therapeutics), an investigational immunotherapy vaccine, for the treatment of adults with glioblastoma and the epidermal growth factor receptor (EGFR) variant III (EGFRvIII), which promotes cancer growth. The EGFRvIII mutation occurs in 25% to 40% of glioblastoma cases; the presence of this mutation is associated with poorer prognosis than glioblastoma without the mutation. The FDA’s designation was based on data from 3 phase 2 clinical trials of patients with newly diagnosed or recurrent EGFRvIII-positive glioblastoma. In these trials, rindopepimut prolonged overall survival beyond what has been achieved in this difficult-to-treat patient population with other treatments. One of these trials was the ACT III phase 2 clinical trial. In ACT III, the overall survival was 21.8 months in patients receiving the vaccine compared with 16 months in the arm of historical control patients. Furthermore, the results of the 3 phase 2 trials showed that rindopepimut is also well-tolerated. The results of ACT III have shown that immunotherapy may be effective in targeting the brain. Discussing this vaccine, David A. Reardon, MD, Coinvestigator of ACT III and Clinical Director of the Center for Neuro-oncology at the Dana-Farber Cancer Institute in Boston, MA, said, “The bottom line is that patients survive longer….This is the first vaccine that has actually shown a survival benefit for patients.” Dr Reardon added, “Six months may not sound like a big improvement, but for people who are familiar with this type of cancer, people who’ve been doing research and trying to come up with a better treatment, 6 months is a huge improvement.” (February 23, 2015) n

RB-L HCP BS 17Dec2014 CYRAMZA® (ramucirumab) injection

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www.ValueBasedCancerCare.com

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

FDA NEWS

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com

Unituxin first FDA-approved therapy for high-risk neuroblastoma More…

Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com

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Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino

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Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 11 times a year by Engage Healthcare Communica tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2015 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.

VALUE-BASED CANCER CARE

ABSTRACTS

Abstracts to be presented at the 5th Annual AVBCC Conference

ECONOMICS OF CANCER CARE

INTERVIEW WITH THE INNOVATORS

NCCN panel addresses value-based care in oncology IOM strategies for lowering out-of-pocket cancer drug costs More…

Confirming diagnoses and identifying biomarkers linked to targeted treatments with bioT3

HEALTH POLICY

ASCO’s report on the state of cancer care More…

NCCN CONFERENCE HIGHLIGHTS

PATIENT INFORMATION

New smoking-cessation guidelines for patients with cancer More…

What is a navigator

DRUG UPDATE

IN THE LITERATURE

Lenvima approved for patients with differentiated thyroid cancer

Frontline bortezomib effective in mantle-cell lymphoma More…

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP 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, Anthem, Inc John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd Albuquerque, NM Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT 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

Bevacizumab prolongs survival in recurrent ovarian cancer More…

Targeted therapies may hold the key for pancreatic cancer therapy More…

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

GYNECOLOGIC ONCOLOGY HIGHLIGHTS

APRIL 2015

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

Genetic Mutations Rampant in Pancreatic Cancers: Targeted Drugs Hold Key to Therapy A new genetic analysis led by researchers from the University of Texas (UT) Southwestern Medical Center suggests that the majority of pancreatic cancers have genetic alterations that could be treated by current targeted drugs, using a precision medicine approach to pancreatic cancer, the fourth leading cause of cancer-related deaths among men and women in the United States. “Pancreatic cancer will surpass breast and prostate to become the third-leading cause of cancer-related deaths in the next 15 years. If we want to change the death rate, we need to increase the investment in understanding the biology of pancreatic cancer and identifying novel treatment strategies,” said study coinvestigator Michael Choti, MD, Chairman of Surgery, and the Hall and Mary Lucile Shannon Distinguished Chair in Surgery, at the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center. Using a comprehensive DNA sequencing of pancreatic tumors showed many mutated genes and potential diagnostic biomarkers. “We identified a wealth of genetic diversity, including multiple mutated genes that were previously unknown to pancreatic cancer—an important step in gaining a better understanding of this difficult and particularly deadly disease,” said lead investigator Agnieszka Witkiewicz, MD, Associate Professor of Pathology, the Harold C. Simmons Comprehensive Cancer Center. “The team was able to identify several genes that may be able to help us to predict outcomes in certain circumstances or serve as good candidates for therapeutic efforts.” The genetic analysis of 109 different pancreatic tumors showed that the genetic makeup of pancreatic cancer is complex, and each tumor is unique. The genetic features uncovered in this study show how pancreatic cancer develops, helps to define survival factors, and points to potential targets for therapeutic intervention. “I am considerably more optimistic of the utility of a genetically targeted therapy for pancreatic cancer today than when we began this work,” said senior investigator Erik Knudsen, PhD, Dr Charles T. Ashworth Professor in Pathology, the Harold C. Simmons Comprehensive Cancer Center. Pancreatic cancer is often diagnosed late, when it can no longer be removed by surgery. Chemotherapy has a modest effect, but most patients experience disease progression and death. The study identified many tumor-related events that could be selectively targeted, depending on the specific genetic mutations. For example, some tumors had the BRAF gene mutation, for which there are FDA-approved drugs that can also be selectively effective for BRAF-mutated pancreatic cancer cells. “Most pancreatic cancers exhibit multiple genetic alterations; therefore, it is likely that combination approaches targeting multiple pathways will be required for effective disease control,” Dr Witkiewicz said. UT Southwestern Medical Center Press Release; April 9, 2015

Tetanus Booster Against Cytomegalovirus Enhances the Immune System, Improves Survival in Glioblastoma

The results of a new study published in Nature (Mitchell DA, et al. 2015;519:366-369) outline a novel way to enhance the effects of immunotherapy in patients with glioblastoma, a rare but aggressive type of brain cancer, and possibly improve patient outcomes. The investigators studied the use of dendritic cells to fight cancer cells. Dendritic cells are specialized immune cells that help other components of the immune system, such as T-cells, to fight off foreign invaders, including cancer cells. “The promise of dendritic-cell–based therapy and other immunotherapies for brain cancer has been upheld for some time, but an important implication of this work is a demonstrated capacity to significantly improve the clinical impact of immunotherapy for patients with this very difficult disease,” said co-lead investi-

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gator Duane A. Mitchell, MD, PhD, Director of the Brain Tumor Immunotherapy Program, the University of Florida, Gainesville. Dendritic cells have been used in immunotherapy to target different types of tumors. These cells are taken from the patient’s own immune system and are then engineered to express antigens from the tumor to create a vaccine. The vaccine is injected back into the patient, and the engineered dendritic cells then activate the patient’s T-cells, which can kill the tumor cells. The objective of the study was to see whether increasing the dendritic-cell migration to the patient’s lymph nodes would improve the effects of the vaccine on patients with glioblastoma. The researchers randomized patients with glioblastoma to receive a tetanus booster shot before getting the tumor antigen–expressing dendritic-cell vaccine. The tetanus booster prepared the patient’s immune system to fight the cancer cells. The patients in the control group received an injection with their own dendritic cells instead of the tetanus shot, after which they received the tumor antigen–expressing dendritic-cell vaccine. The vaccine was targeted against cytomegalovirus (CMV). Studies have shown that CMV is found in glioblastoma tumors, but it is unknown if CMV causes the tumor or only contributes to its progression. The administration of the tetanus booster before the vaccine increased dendritic-cell migration to the patient’s lymph nodes and improved outcomes. The median survival among patients who received the tetanus booster was >36.6 months versus 18.5 months in those who received dendritic cells without the vaccine. “We did not expect that enhancing dendritic-cell migration would be associated with such a dramatic improvement on clinical outcomes in our patients,” said Dr Mitchell. “Dendritic-cell vaccines targeting glioblastoma can be very effective by enhancing migration of dendritic cells.” “These new findings, and especially the dramatic survival rates, suggest that the virus may be an effective target for immune therapy. The results…should stimulate more basic research on CMV and its potential therapeutic role in brain tumors and possibly other cancers,” said Jane Fountain, PhD, Program Director, National Institute of Neurological Disorders and Stroke (NINDS). This study was supported by grants from the NINDS and the National Cancer Institute. National Institutes of Health Press Release; March 18, 2015

Polygenic Risk Score for Breast Cancer on the Horizon

A team of researchers from the UK Institute of Cancer Research and the University of Cambridge, United Kingdom, found a link between a “polygenic risk score” and a woman’s risk for breast cancer. Using the world’s biggest database of genetic information, the Collaborative Oncological Gene-Environment Study, the team analyzed 77 DNA changes that have been previously associated with a slight increase in risk for breast cancer. The risk is much smaller than other known risks, such as BRCA1 and BRCA2 genetic mutations. The findings suggest that a DNA-based genetic test may help to identify women who are at risk for breast cancer, regardless of BRCA mutation status. Nell Barrie, Senior Science Communications Manager at Cancer Research UK, said, “This study shows how the genetic map of breast cancer that scientists have been building up over the years might be used to identify women most at risk, so we can take steps to reduce their chances of developing the disease, or catch it at the earliest possible stage.” A woman in the top 20% of the polygenic risk score was 1.8 times more likely to develop breast cancer than women with a lower score. A woman in the top 1% of the score was >3 times more likely to develop breast cancer. Women with a family history of breast cancer had a 24.4% risk of developing breast cancer if they were in the fifth highest scoring group, and only 8.6% if they were in the fifth lowest scoring group. The study co-leader Professor Douglas Easton, Director of the Centre for Cancer Genetic Epidemiology, University of Cambridge, said, “There’s still work to be done to determine how tests like this could complement other risk factors, such as age, lifestyle, and family history.” Cancer Research UK, in collaboration with Press Association; April 9, 2015 n

APRIL 2015

www.ValueBasedCancerCare.com

Economics of Cancer Care

NCCN Panel Addresses Value-Based Care in... Continued from the cover

“

therapies outpacing inflation. These were some of the themes raised by a panel of oncology experts who discussed value-based cancer care at the bedside during the 2015 National Comprehensive Cancer Network (NCCN) conference.

Most of the pathways have some of the most expensive therapies on them, but you do see ranges in cost of therapy. If…we move toward practicing value-based care, we will see not that we save dollars, but the cost of care won’t rise as rapidly.

Pathways Can Improve Quality of Care

Guidelines and pathways are a shared decision support tool that provides an opportunity to document how clinical decisions are made, especially when a decision falls outside of a guideline, said Stephen B. Edge, MD, Director, Baptist Center for Cancer Care, Memphis, TN. Most cancer treatments given at the bedside are in concordance with guidelines, but Peter B. Bach, MD, Director, Center for Health Policy and Outcomes, Memorial Sloan Kettering Cancer Center, New York, contends that many guidelines have been created to merely reflect clinician behavior. “There’s a sort of tautology that the entities and institutions that develop the guidelines are essentially codifying what they currently do,” said Dr Bach. “Although there may be high concordance, it’s not clear which direction this information is flowing.” Guidelines may not be appropriate at the bedside, because they incorporate all potential alternatives, said Jennifer Malin, MD, PhD, Medical Director of Oncology, Anthem (previously WellPoint). The intent of clinical pathways in most situations is to assist the practicing clinician in selecting the most effective regimen among the choices for a particular patient. “Another way to look at pathways is you’re enabling your physicians to deliver a smaller number of treatments, which should improve the quality of that delivery,” said James L. Mohler, MD, Chair, Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, and Chair, NCCN Prostate Cancer Treatment Panel. “Most of the pathways have some of the most expensive therapies on them, but you do see ranges in cost of therapy,” said Dr Malin. “If on average, as a community we move toward practicing value-based care, we will see not that we save dollars, but the cost of care won’t rise as rapidly.” Pathways can be considered “a form of sophisticated formulary management conducted by payers or intermediaries that essentially tiers treatments as preferable or not. This is a logical response

”

—JENNIFER MALIN, MD, PHD

“

There’s a big disconnect between how patients define value and how health economists define value.

”

—LINDA HOUSE, RN, BSN, MSM

to large variations in the cost of therapies,” said Dr Bach. “To the extent that things are really interchangeable, it’s highly efficient to have pathways that incentivize doctors to use the cheaper of the available interchangeable regimens.” There may be a transparency concern, however, when physicians are being incentivized to follow pathways, and patients don’t know about it. Value for Whom?

According to Linda House, RN, BSN, MSM, President of the Cancer Support Community Global Headquarters, Washington, DC, despite being aware of guidelines and receiving information about their diagnosis and potential treatments, more than 50% of patients say that they are unprepared to make a treatment decision.

VALUE-BASED CANCER CARE

APRIL 2015

“

In the case of radiation doubling the cost of care for prostate cancer, the insurers all know that. They have the data, yet they have been unwilling to go to case rates or restrain practice.

”

—JAMES L. MOHLER, MD

Although guidelines may list toxicities of the various treatment options, patients may weigh these toxicities differently from clinicians, making treatment decisions difficult. The disconnect that happens during the decision-making moment also pertains to the value of care received. “There’s a big disconnect between how patients define value and how health economists define value,” said Ms House. “We have to define value, and we have to be honest about who we are looking for value for,” said Dr Edge. The pressure that clinicians are under to maximize revenues implies

that value-based decision-making may favor the payer or the institution over the patient. The medical community does not “value the data that patients would need for these decisions the same way we value data we traditionally care about,” said Dr Bach, using the example of the recent approval of nivolumab (Opdivo) for the treatment of metastatic squamous non–small-cell lung cancer. Although quality of life was an end point in the clinical trial submitted to the FDA for the New Drug Application for nivolumab, only the gain in survival was mentioned in the company press release touting the approval, and the final data have not yet been published. Patients are being asked to make a treatment decision without these important data, Dr Bach said. Patients can make reasonable choices if presented with the full level of information, according to Ms House. Physicians can be incentivized to provide such information to patients with a fee for quality-based care management that would include distress screening, treatment decision counseling, and overall care planning, she said. Economics Impacts Care Quality

Because physicians are largely not equipped to speak about costs, costs rarely direct a shared decision about cancer treatment, said Dr Mohler. Instead, clinical practice may be influenced by the ownership of technology (ie, radiation machines) that needs to be paid for. “In the case of radiation doubling the cost of care for prostate cancer, the insurers all know that,” he said. “They have the data, yet they have been unwilling to go to case rates or restrain practice.” Patients are also known for wanting the newest technology, which is also the most expensive. When asked how he copes with economics in the examination room, Dr Edge noted the difficulty in providing accurate information about out-ofpocket costs when there are 50 to 100 different insurance products. Cancer drugs approved in 2015 cost at least $15,000 monthly, yet some patients cannot keep appointments or fill their prescriptions because of a $75 copay, said Dr Malin. “We are all implicitly making trade-offs and spending more on healthcare that isn’t often producing value,” she said. The plans under the Affordable Care Act also encourage trade-offs by varying the amount of outContinued on page 10

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Economics of Cancer Care

IOM Strategies for Lowering Out-of-Pocket Costs of Cancer... Continued from the cover

Cancer Care (VBCC), Dr Zafar said that discussions about cost are becoming more necessary than ever. Financial Toxicity a Continuing Theme in Oncology

“Patients are experiencing financial toxicity as a result of their cancer treatment. We talk to patients about the physical side effects, but we don’t often acknowledge the financial side effects,” said Dr Zafar. “It is the healthcare team’s responsibility to bring it up at least once with each patient.” He is currently developing an app to help patients with cost discussions. At the IOM workshop, Dr Zafar pointed out that the rapid rise of OOP cancer care costs has been accompanied by a cost-sharing increase in most health insurance plans: premiums increased by 182% between 1999 and 2013, and worker contributions to premiums nearly doubled in the United States. In a 2013 survey conducted by Dr Zafar and colleagues, almost 50% of the patients with cancer surveyed had reduced their spending on food and cloth-

By the Numbers $124 billion—Current

annual direct cost of cancer care in the United States

$158 billion

— Projected cost of cancer care in the United States in 2020

182%—Increase in health

insurance premiums between 1999 and 2013

50%

—Patients with cancer reducing their spending on food and clothing to pay for cancer care

24%—Patients with cancer

not filling a prescription because of cost

20%

—Patients with cancer taking less than the prescribed amount of a medication

“

ing to allow them to pay for cancer-related costs. Moreover, 24% of the patients did not fill their prescriptions, and 20% took less than the prescribed amount.

We talk to patients about the physical side effects, but we don’t often acknowledge the financial side effects….Encouraging communication around cost is a first and fairly easy step.

Changes Needed

Dr Zafar also noted that the power of private payers, hospitals, and oncologists and other healthcare providers pales in comparison to that of Medicare. Therefore, all their efforts “won’t make a lick of difference if we don’t have Medicare involved in this as well,” Dr Zafar said at the IOM workshop. Increasing frequent drug shortages, along with the rise in the use of oral formulations and of biologics, are among the main drivers of increased oncology drug costs, said IOM workshop participant, Alex Bastian, MBA, of GfK Bridgehead, San Francisco. Within the past year or two, biologics already comprised 55% of cancer drugs, Mr Bastian said.

”

—S. YOUSUF ZAFAR, MD, MHS

“

This one-size-fitsall benefit design fails to acknowledge the differences in clinical value among medical interventions and makes no sense.

”

Value versus Cost

Cost-sharing arrangements in insurance plans are also far from optimal, noted workshop participants. A. Mark Fendrick, MD, Director, Center for Value-Based Insurance Design, University of Michigan, Ann Arbor, said that most beneficiaries pay the same per-

—A. MARK FENDRICK, MD

centage for every drug within a formulary tier, regardless of efficacy.

Table I OM Workshop Take-Away Points on Lowering Out-of-Pocket Costs on Cancer Drugs

Physicians should consider the following steps: • Prescribing generic or biosimilar drugs • Suggest to patients that they split higher-dose oral medications • Buy medicines in bulk • Review patients’ prescriptions to weed out those they no longer need • Offer patients discount cards

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Physician–Patient Interaction Is Key

The Centers for Medicare & Medicaid Services is prohibited from negotiating prices Some of the pilot programs of the Affordable Care Act prohibit the consideration of QALY incremental cost-effectiveness ratios or other measures of a drug’s survival benefit Physicians should be educated on the importance of prescribing generic or other less expensive alternative agents Strategies are needed to allow patients who do not respond to a lower-cost drug to not pay the maximum copay for a next-tier, more expensive drug Patients should be encouraged to select high-performing providers, institutions, and clinics Reimbursement should be separate for the chemotherapy administration fee and the drug fee IOM indicates Institute of Medicine; QALY, quality-adjusted life-year.

APRIL 2015

“This one-size-fits-all benefit design fails to acknowledge the differences in clinical value among medical interventions and makes no sense,” Dr Fendrick said, noting that more widespread use of value-based insurance design would rectify this problem. Some of the many other points made by workshop participants are listed in the Table.

Dr Zafar was persistent about the physician–patient interaction as an impor tant factor toward lowering the use of high-cost cancer drugs. “Until we can get prices under control, encouraging communication around cost is a first and fairly easy step,” Dr Zafar emphasized. The web-based app Dr Zafar is pilot- testing points to patient support programs and other resources to help patients with staggering large copays, and educates them on communication theory. “For example, instead of saying to your doctor, ‘I can’t afford my care,’ which can be a difficult point to tackle, because it’s so broad, a better statement may be, ‘I have difficulty paying for my copay for the drug,’” Dr Zafar told VBCC. n

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Economics of Cancer Care

Sunitinib Associated with Higher Costs Compared with Pazopanib in Patients with Renal-Cell Carcinoma By Chase Doyle

Hollywood, FL—Sunitinib and pazopanib have long battled for supremacy in treating advanced renal-cell carcinoma (RCC). According to findings presented at the 2015 National Comprehensive Cancer Network (NCCN) conference, the newer drug, pazopanib, may have some advantage in terms of total cost of care, but survival outcomes were exactly the same. An independent study from Humana comparing costs and health outcomes in initial therapy for RCC showed that sunitinib had a $12,000 higher mean total cost of care than pazopanib. “Survival and treatment characteristics were similar for both index medications, but medication and total healthcare costs trended higher with sunitinib treatment, despite higher preindex total costs in the pazopanib group,” said co investigator Laura E. Happe, PharmD, MPH, Strategic Consultant, Humana, Louisville, KY. “Nonadherence with sunitinib was associated with significantly higher total healthcare costs, which may indicate unfavorable tolerability with sunitinib treatment.” She emphasized that this is a hypothesis that was not proved in this study. Sunitinib and pazopanib are 2 tyrosine kinase inhibitors (TKIs) approved by the FDA as first-line options for the treatment of patients with advanced RCC; clinical evidence and national guidelines do not differentiate between these therapies. Two comparative cost

studies based on data from the COMPARZ and PISCES trials showed that pazopanib was less costly and more cost-effective than sunitinib, but these findings were based solely on clinical trial data.

“

Survival and treatment characteristics were similar for both index medications, but medication and total healthcare costs trended higher with sunitinib treatment, despite higher preindex total costs in the pazopanib group.

”

—LAURA E. HAPPE, PHARMD, MPH First Real-World Comparison

“To our knowledge,” said Dr Happe, “this is the first head-to-head comparison of these 2 TKIs in a real-world setting. We are looking at our Humana global universe of millions of lives. This study was not funded by either manufacturer… which makes it a very unique analysis.” The study was an observational retrospective cohort with up to 12 months of follow-up for 241 patients receiving sunitinib and 112 receiving pazopanib for at least 6 months. Treatment interruptions were defined as therapy gaps >30 days. Adher-

ence was quantified using proportion of days covered, which was calculated as days prescribed divided by total days of follow-up. “We saw no difference in overall survival, which supports the COMPARZ trial,” said Dr Happe. “About 55% of patients remained alive after 1 year. Treatment interruptions and adherence were also the same. From everything we can garner from claims, in terms of efficacy, the drugs were the same.” Treatment Cost Comparison

The investigators examined the mean total healthcare costs, broken down by component medical and pharmacy costs and stratified by adherent status. “Total costs were the same,” Dr Happe reported. “Sunitinib was higher numerically ($76,624 vs $64,432), but this was a nonsignificant trend. The only component approaching statistical significance was pharmacy index medication, which reflects the price of the drug. Sunitinib was $5000 more expensive ($26,984 vs $21,404)….All other costs were the same.” Although not statistically significant, pazopanib was numerically less expensive in total medical and pharmacy costs. According to Dr Happe, one of the study’s most interesting findings was the significant difference in costs between drugs within the nonadherent sub group. These were $82,730 for sunitinib and $65,040 for pazopanib (P = .01), she reported.

One suggestion for this difference was a possible increase in side effects with sunitinib, leading to greater cost of care. “We don’t know what’s driving this difference in cost,” acknowledged Dr Happe. “Clinical trials have shown some differences in tolerability, meaning sunitinib may be less tolerable than pazopanib.”

“

Nonadherence with sunitinib was associated with significantly higher total healthcare costs, which may indicate unfavorable tolerability with sunitinib treatment.

”

—LAURA E. HAPPE, PHARMD, MPH

Given the lack of difference in efficacy between sunitinib and pazopanib by NCCN or clinical trials, the higher costs of sunitinib will be an important consideration in choice of treatment, the investigators of this study concluded. “We validated no clinical difference between these drugs,” said Dr Happe. “And from a medical standpoint, you are only looking at the price of the drug. If your health plan gets a good discount on one of these drugs, you might consider these drugs interchangeable.” n

NCCN Panel Addresses Value-Based Care in... of-pocket costs according to the monthly premium. “High coinsurance, particularly for things like drugs for CML [chronic myeloid leukemia], are a byproduct of high unit prices for those drugs,” said Dr Bach. “We have population data showing that as coinsurance rises, people leave their Gleevec at the counter. This is one of the biggest disappointments that we can experience. We have maybe the biggest cancer breakthrough in our lifetime being left at the pharmacy counter because of economics.” The 8% inflation-adjusted growth in the cost of cancer drugs “equates to a

“

We have population data showing that as coinsurance rises, people leave their Gleevec at the counter….We have maybe the biggest cancer breakthrough in our lifetime being left at the pharmacy counter because of economics.

”

—PETER B. BACH, MD

100-fold increase in the monthly cost of cancer drugs since the dawn of the

VALUE-BASED CANCER CARE

APRIL 2015

Medicare program in 1965,” said Dr Bach, without a corresponding 100-fold

Continued from page 8

increase in value. “Each year we get a new cancer drug at a cost of a year of life gained, that drug goes up by $8500,” he said. “This is a classic version of spending with diminishing returns.” With health insurance premiums costing approximately 50% of the average person’s take-home pay, there is no room for premiums to increase, suggested Dr Malin; and this makes future choices even more difficult. “Can we encourage value-conscious care in a way that preserves the clinician’s ability to work with the patient and do shared decision-making?” Dr Malin asked. n

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NO. 3

Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration

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

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014.

©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40582 January 2015.

Economics of Cancer Care

Insurance Status Impacts Ability to Travel for Care By Chase Doyle

Orlando, FL—Patients undergoing complex oncologic procedures, such as rad ical cystectomy, radical prostatectomy, or percutaneous nephrolithotomy, are more likely to travel outside of their re-

gions if they have private insurance, potentially reflecting better access to care based on income, according to findings presented at the 2015 Genitourinary Cancers Symposium.

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

VALUE-BASED CANCER CARE

APRIL 2015

“Through the Affordable Care Act, insurance coverage is increasing, with financial incentives for primary care providers,” noted lead investigator Matthew Mossanen, MD, of the Department of

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

Urology, University of Washington, Seattle. “However, many subspecialty fields, like urology, lack monetary motivation caring for newly insured patients.” “An influx of new patients may potentially be challenged by a lack of access to subspecialty services that is not necessarily improved under the new system,” stated Dr Mossanen. Dr Mossanen’s study sought to examine the potential impact of these healthcare changes on the travel for care based on insurance type for urologic procedures. Included in the analysis were the following procedures—radical cystectomy, radical prostatectomy, transurethral resection of prostate, shockwave lithotripsy, nephrectomy, percutaneous nephrolithotomy, retroperitoneal lymph node dissection, and pyeloplasty. Patients were grouped into 1 of 4 insurance types—Medicaid, Medicare, private/HMO, and other (charity care). Hospital service areas were defined as areas where the majority of local patients are hospitalized, and hospital referral regions were defined as where most patients received tertiary care. According to data collected between 2011 and 2012, 600 Medicaid patients, 3806 Medicare beneficiaries, 4998 patients with private insurance, and 554 patients with other insurance underwent urologic surgery in Washington State. Dr Mossanen emphasized the following results: • Of Medicaid patients undergoing radical cystectomy, 13.3% left their region for care versus 29.9% for Medicare beneficiaries and 39.8% for private insurance • Similarly, 10.8% of radical prostatectomy patients with Medicaid coverage traveled outside of their region for care versus 19.5% for Medicare beneficiaries and 24.6% for private insurance • Of patients with private insurance undergoing percutaneous nephrolithotomy, 21.9% traveled outside of their region versus only 12% of Medicare beneficiaries and 17.2% of Medicaid patients • Nonwhite patients are significantly less likely to travel to an outside hospital (odds ratio, 0.66; P <.001) • Patients with increased comorbidities are significantly less likely to travel to an outside hospital. “As the Affordable Care Act takes effect,” concluded Dr Mossanen, “attention to access to subspecialty care is critical and may help inform quality improvement initiatives designed to promote greater access to urologic surgery.” n

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Economics of Cancer Care

Millions in Savings by Using Prolaris Test in All Men with Localized Prostate Cancer By Alice Goodman

Orlando, FL—Significant cost-savings in treating patients with prostate cancer could be achieved in the US healthcare system with the use of the cell-cycle progression (CCP) gene-expression assay called Prolaris (from Myriad Genetics Laboratories), according to a poster from E. David Crawford, MD, Professor of Surgery and Radiation Oncology, University of Colorado, Aurora, and colleagues, presented at the 2015 Genitourinary Cancers Symposium. The use of appropriate treatment in patients with localized prostate cancer based on disease aggressiveness remains a challenge; lack of disease stratification by high- and low-risk disease leads to overtreatment of patients with low-risk prostate cancer and undertreatment of patients with high-risk disease. Having a strategy that could better differentiate between low- and high-risk localized prostate cancer could improve the use of appropriate treatment, thereby saving costs of eliminating overtreatment. Prolaris Testing Reduces Costs

In a US commercial health plan with

10 million members, the use of Prolaris could reduce the cost per patient tested by $2850 over 10 years, translating to a cost-savings of $16 million, according to

published clinical data and interviews with board-certified physicians. The study compared reference scenarios and test scenarios.

In a US commercial health plan with 10 million members, the use of Prolaris could reduce the cost per patient tested by $2850 over 10 years, translating to a cost-savings of $16 million. —E. DAVID CRAWFORD, MD, AND COLLEAGUES

an evidence-based economic model with a hypothetical group of patients with localized prostate cancer. Based on this model, 67% of the savings would occur in the first year of instituting Prolaris testing. A net reduction of $2850 in cost per patient accrued over 10 years after the initial cost for the assay (approximately $3400). The model applied assumptions about management and progression based on

“Total cost of care was calculated for a reference scenario [current clinical practice] and a test scenario where patient management was altered based on CCP test results,” noted Dr Crawford and colleagues. Comparisons between the scenarios were made for the following patient management groups—active surveillance, radical prostatectomy only, radiation therapy only, androgen-deprivation therapy only, radical prostatectomy and

radiation therapy, and radiation therapy and androgen-deprivation therapy. The costs of the test scenario never exceeded the costs in the reference scenarios. The savings were attributable to 2 key factors, with the majority of the savings attributed to the increased use of active surveillance for low- and intermediate- risk patients, as defined by the American Urological Association. In these 2 risk-based groups, 15% and 5% of patients, respectively, would have received active surveillance according to current clinical practice. When the test scenario clinical treatment paradigm was applied, these percentages increased to 69% and 27% of active surveillance in these respective groups. Additional savings came from reduced disease progression rates in high-risk patients with more aggressive disease who moved on to multimodality therapy. The Prolaris test was added to the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology in October 2014, calling for the use of the test in all men with localized prostate cancer, regardless of the risk category. n

Choice of Hospital for Readmissions Influences Mortality Risk in Men with Urologic Cancer By Chase Doyle

Orlando, FL—Patients with urologic cancer who are readmitted after a surgery to a second hospital and not to their original hospital are more likely to have complications than patients readmitted to their original surgical hospital, according to findings presented at the 2015 Genitourinary Cancers Symposium. “Approximately 1 in 10 patients will require hospital readmission within 90 days of a major urologic cancer surgery,” said lead investigator Jasmir G. Nayak, MD, Department of Urology, University of Washington, Seattle, “and up to 40% of these patients will present to a secondary hospital.” Although 40% may sound innocuous, the choice of hospital could mean the difference between life and death, according to Dr Nayak’s analysis. “For patients undergoing surgery in a high-volume center,” he cautioned, “complications managed at secondary hospitals are almost 7 times more likely to be associated with mortality.” VOL. 6

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Urologic cancer surgery is often linked with significant morbidity and mortality. Although outcomes vary among hospitals, this may be partly attributed to differences in failure-to-rescue complications. “Given the regional variation in urologic surgery,” said Dr Nayak, “the institution that patients present to for complication management may affect outcomes. Specifically, presenting to a different hospital than where surgery took place may result in healthcare that is less familiar and thus less prepared to properly identify and manage complications.” This retrospective analysis was based on 1998-2007 and 2009-2013 data from the Washington State Comprehensive Hospital Abstract Reporting System. The sample size consisted of 31,498 surgeries (including radical prostatectomy, radical cystectomy, radical nephrectomy, and partial nephrectomy) with 10% (N = 3113) of readmissions occurring within 90 days of surgery. Of the 3113 total readmissions, 1196 patients were diagnosed with a “rescu

“

For patients under going surgery in a high-volume center, complications managed at secondary hospitals arealmost 7 times more likely tobe associated with mortality.

”

—JASMIR G. NAYAK, MD

able” complication. “Complication rates were based on readmission diagnoses,” said Dr Nayak, “and included cardiac, respiratory, bleed, sepsis, venothrombotic event, or renal failure.” Complication rates were the highest for patients who had undergone radical cystectomy or radical nephrectomy, but these rates differed between those patients admitted to primary versus secondary hospitals. APRIL 2015

“For those patients readmitted to secondary hospitals following radical cystectomy, the FTR [failure-to-rescue] rate was 9.1% compared with 7.4% for those readmitted to their primary hospital,” said Dr Nayak. Overall, the complications rate was 6.1% for patients readmitted to secondary hos pitals compared with 4.1% for those readmitted to their original surgical hospital. “Conversely,” Dr Nayak elaborated, “when surgery is performed in a low-volume center, there is a trend towards a protective benefit of having complications managed at an alternate institution.” He noted that the reasons for these disparities warrant further investigation. “Understanding the impact that site of readmission has on health outcomes will inform clinical behaviors around discharge disposition and patient transfers in order to ensure optimization of healthcare value after major cancer surgery,” he concluded. n

www.ValueBasedCancerCare.com

NCCN Conference Highlights

Treatment for CLL Will Incorporate More Targeted Therapies in the Near Future By Wayne Kuznar

Hollywood, FL—Watch and wait remains the standard of care for patients with asymptomatic early-stage chronic lymphocytic leukemia (CLL), even for high-risk patients, but once therapy is indicated, targeted agents may supplant chemotherapy in the first-line treatment setting, said William G. Wierda, MD, PhD, Center Medical Director, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at the 2015 National Comprehensive Cancer Network (NCCN) annual conference. In his NCCN update of the CLL guideline, Dr Wierda noted that the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) could soon replace conventional chemotherapy with the combination of fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab (Rituxan) as first-line therapy. Age, comorbidities, and cytogenetics on fluorescence in situ hybridization are important considerations in selecting first-line therapy (with chemotherapy under the current guideline) once patients show disease progression symptoms, said Dr Wierda. High-risk features include chromosome 17p deletion (del[17p]), 11q deletion, or unmutated IgVH genes. “We do watch those patients more closely,” he said. “If I have a patient with 17p deletion who doesn’t have an indication to start treatment, I’ll watch him more closely than I would a patient who has a 13p deletion as his sole abnormality and/ or an unmutated IgVH. But we don’t start early treatment for those patients.”

The current standard frontline therapy for a fit younger patient with CLL is the combination of fludarabine, cyclophosphamide, and rituximab. This combination regimen was shown superior to

sive chemotherapy regimens that are currently the standard of care,” Dr Wierda said. Chlorambucil plus a CD20 monoclonal antibody, either obinutuzumab (Gazyva) or ofatumumab (Arzerra), is currently

“

If I have a patient with 17p deletion who doesn’t have an indication to start treatment, I’ll watch him more closely than I would a patient who has a 13p deletion as his sole abnormality and/or an unmutated IgVH. But we don’t start early treatment for those patients.

”

—WILLIAM G. WIERDA, MD, PHD

bendamustine (Treanda) plus rituximab as first-line therapy in a recent study of patients aged ≤65 years with active untreated CLL without del(17p). The updated version of the NCCN guideline states that patients who are free of minimal residual disease in the peripheral blood have better progression-free survival if residual splenomegaly is not clinically significant. The goal in fit, younger patients with IgVH mutations, therefore, should be minimal residual disease–negative complete remission with minimal chemotherapy. In the elderly population or in patients with comorbidities, “We have less inten-

preferred for this group in the guideline. The randomized clinical trial RESONATE 2 that is in progress is comparing chlorambucil with ibrutinib as frontline therapy in elderly patients. “We all expect that trial to be a positive trial and show superior outcomes for those patients who receive ibrutinib in the frontline setting,” Dr Wierda said. In high-risk patients, such as those with an unmutated IgVH, “We’re working on a non–chemotherapy-based regimen, because we know that even if we can get those patients into a good remission, they’re going to relapse, and most likely the benefit to them in delaying exposure

to chemotherapy,” said Dr Wierda. “So strategies that include ibrutinib and some of the new molecules are where we’re moving with the younger patients with an unmutated VH gene,” Dr Wierda said. Ibrutinib was recently approved as frontline therapy in patients with CLL and del(17p); it previously received an indication for the treatment of patients with CLL who have received ≥1 previous therapies. In the salvage setting, 2 drugs have been approved over the past year—ibrutinib and the oral PI3 kinase (PI3K) inhibitor idelalisib (Zydelig), which is given with rituximab. Most responses with idelalisib in this setting are partial responses, and its median progression-free survival is 19.4 months. Idela lisib has shown efficacy in patients with relapsed CLL and del(17p). Several other BTK inhibitors are in development, as well as several PI3K inhibitors, most targeting the delta isoform or the gamma and delta isoforms of PI3K. Spleen tyrosine kinase inhibitors are also in early-phase study, although the data with them “are less compelling” than the early data with ibrutinib, said Dr Wierda. Another class of promising agents is the BCL-2 inhibitors. Venetoclax, the first in this class, is in registration phase 3 trials. It has produced complete responses in patients with relapsed or refractory CLL, and it has activity in patients with very high-risk CLL, such as patients with relapsed or refractory CLL and del(17p). n

NCCN Issues New Smoking-Cessation Guidelines for Patients with Cancer

“

Hollywood, FL—A new clinical guideline for smoking cessation in patients with cancer encourages the use of evidence-based pharmacotherapy, behavioral therapy, and close follow-up with retreatment if needed, said Peter G. Shields, MD, Deputy Director, Comprehensive Cancer Center, James Cancer Hospital, Columbus, OH, at the 2015 National Comprehensive Cancer Network (NCCN) conference. According to the American Association for Cancer Research Task Force on

VALUE-BASED CANCER CARE

Brief counseling, even as short as 3 minutes, is better than no counseling….Sometimes smokers require repeated quit attempts with the same therapies, as smoking slips and relapses are common.

”

—PETER G. SHIELDS, MD

Tobacco, “Virtually no institutions reported systematic and consistent mechanisms for fostering cessation,” Dr Shields said. Many patients with cancer still smoke, and those who do have worse outcomes when treated for their cancer, Dr Shields said, citing at least 1 study on the negative influence of smoking on the efficacy of radiation therapy in head and neck cancer. Dr Shields noted that patients with cancer who smoke are typically more dependent on nicotine and probably have a

Continued on page 15

APRIL 2015

VOL. 6

NO. 3

NCCN Conference Highlights

Immune Checkpoint Blockade Shows Durable Responses in Lung and Kidney Cancers, Metastatic Melanoma By Wayne Kuznar

Hollywood, FL—The National Comprehensive Cancer Network (NCCN) now recommends nivolumab (Opdivo) as subsequent therapy for metastatic squamous non–small-cell lung cancer (NSCLC) after its recent FDA approval. In patients with advanced renal-cell carcinoma (RCC), immune checkpoint blockade may provide a new approach to treat this disease, with durable responses achieved in some patients in a phase 2 clinical trial. At the 2015 NCCN annual conference, presenters provided an update of immunotherapy for the treatment of melanoma as well as lung and kidney cancers.

CTLA-4 antibody ipilimumab (Yervoy) in patients with lung cancer. Nivolumab given as a second-line to fifth-line treatment produced an overall response rate

Nivolumab given as a second-line to fifth-line treatment produced an overall response rate of 18% and in 76 evaluable patients, of the responses, 20 of 31 lasted more than a year, and toxicity was quite mild, with all grade 3 or 4 events being 1% or less.

“

”

Lung Cancer: Nivolumab Now FDA Approved

The experience with immunotherapy in lung cancer is minimal, said Gregory A. Otterson, MD, Professor of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus. Checkpoint blockade (humanized antibodies against PD-1 or its ligand 1 [PDL1]) with nivolumab offers a better immunotherapy strategy than the anti–

mous-cell NSCLC demonstrated a 15% overall response rate, a median overall survival (OS) of 8.2 months, and a 1-year OS rate of 41%. This study led to

—GREGORY A. OTTERSON, MD

of 18% in 76 evaluable patients, “and of the responses, 20 of 31 lasted more than a year, and toxicity was quite mild, with all grade 3 or 4 events being 1% or less,” said Dr Otterson. A single-arm phase 2 study of nivolu mab in the third-line setting in squa-

a phase 3 trial comparing nivolumab versus docetaxel (Taxotere) in previously treated patients with advanced squamous-cell NSCLC. The study was stopped early when, at the planned analysis in January 2015, the OS was 9.2 months in the nivolum-

at a glance ➤ Nivolumab is now indicated as subsequent therapy for metastatic squamous non– small-cell lung cancer (NSCLC) ➤ In the third-line setting in squamous-cell NSCLC, nivolumab demonstrated a 15% overall response rate, a median overall survival (OS) of 8.2 months, and a 1-year OS rate of 41% ➤ High-dose interleukin-2 is an option in select patients who have good performance status, clear-cell renal-cell carcinoma, and low-grade disease

ab arm versus 6 months in the docetaxel arm, for a hazard ratio of 0.59 (P = .002). The FDA recently approved nivolumab for advanced squamous-cell NSCLC, and on this basis, in March 2015. the NCCN recommended nivolumab as Continued on page 16

NCCN Issues New Smoking-Cessation Guidelines... history of unsuccessful attempts to quit. According to the NCCN guidelines, the most effective approach to smoking cessation is a combination of pharmacologic therapy and counseling. Nicotine replacement therapy (NRT) alone may be no better than unaided quitting, and a dose– response relationship exists between the amount of therapy and success. “Brief counseling, even as short as 3 minutes, is better than no counseling,” said Dr Shields. Behavioral therapy can take the form of individual in-person counseling, phone counseling, or group counseling. Smoking status should be documented and should be updated at regular intervals. Oncologists should discuss smoking relapse and provide guidance for patients. Smoking relapse may warrant a change in therapy. “Sometimes smokers require repeated quit attempts with the same therapies, as smoking slips and relapses are common,” Dr Shields said. VOL. 6

NO. 3

Smoking-Cessation Therapy

In addition to NRT, varenicline (Chantix) is considered a first-line pharmacologic treatment. Second-line options include varenicline plus NRT and bupropion (Zyban) plus NRT. Thirdline options include varenicline plus bupropion with or without NRT, the tricyclic antidepressant nortriptyline (Pamelor), and the alpha-2 adrenergic receptor agonist clonidine (Catapres). Bupropion is contraindicated in patients at risk for seizures, and users of varenicline and bupropion should be monitored for the worsening of serious neuropsychiatric issues.

Evaluate Smoking Status

The guideline calls for an evaluation of patients’ current smoking status, and “prioritizes those likely to relapse,” said Dr Shields. “Current smokers and those smoking within 30 days are treated the same.” These patients should have their

readiness to quit assessed. The patients who are ready to quit should be given a personalized quit plan that includes the smoking-cessation therapies noted above. Patients who are not ready to quit should be counseled on the risks of smoking and the benefits of quitting. Barriers to quitting should also be addressed, and educational resources provided. Encouraging these patients to reduce the number of daily cigarettes could pay dividends, said Dr Shields, because they may be more apt to try to quit altogether if they can successfully reduce the number of cigarettes smoked each day. Risk for Smoking Relapse

Former smokers and those who quit recently (within 30 days) should be evaluated for their risk for relapse. Patients at high risk for smoking relapse should be considered for pharmacotherapy and behavioral therapy and be offered support resources. In patients APRIL 2015

Continued from page 14

at a glance ➤ Many patients with cancer still smoke, and this results in worse cancer treatment outcomes ➤ According to the new NCCN guidelines on smoking, the most effective approach to smoking cessation is a combination of pharmacologic therapy and counseling

deemed to be at low risk for relapse, the success and importance of remaining abstinent should be reinforced, and their risk for relapse reassessed. The guideline does not recommend electronic cigarettes as an aid for smoking cessation, because of insufficient evidence to support their use.—WK n

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NCCN Conference Highlights

Updated NCCN Guideline for Prostate Cancer Allows Early Treatment with Docetaxel By Wayne Kuznar

Hollywood, FL—The updated National Comprehensive Cancer Network (NCCN) guideline allows for the upfront use of docetaxel (Taxotere) in some men with castration-resistant prostate cancer (CRPC). This and other systemic therapies represent the most significant changes in the updated guideline for the treatment of patients with metastatic CRPC, said Andrew J. Armstrong, MD, ScM, CoLeader, Genitourinary Oncology Research Program, Duke Cancer Institute, Durham, NC, at the 2015 NCCN annual conference. First-line therapy options in the updated guideline include docetaxel plus prednisone, enzalutamide (Xtandi), and abiraterone (Zytiga) plus prednisone.

“

The castration-sensitive guideline allows for the early use of docetaxel in highvolume men who present with metastatic disease. Now, instead of just giving ADT, we have 6 cycles of docetaxel, and that’s associated with about a 17-month improvement in survival.

”

—ANDREW J. ARMSTRONG, MD, SCM

“The castration-sensitive guideline allows for the early use of docetaxel

high-volume men who present with in metastatic disease,” said Dr Armstrong.

“Now, instead of just giving ADT [androgen-deprivation therapy], we have 6 cycles of docetaxel, and that’s associated with about a 17-month improvement in survival.” The data to which he is referring come from the CHAARTED trial, and have not been published but were presented at the 2014 American Society of Clinical Oncology annual meeting. In that study, the median overall survival (OS) was 13.6 months longer when docetaxel was added to ADT compared with ADT alone; in men with high-volume metastatic disease, the median OS was 17.0 months longer with the addition of docetaxel. In addition, the guideline now reflects level I evidence (from the PREVAIL Continued on page 17

Immune Checkpoint Blockade Shows... subsequent therapy for metastatic squamous-cell NSCLC. Renal-Cell Carcinoma: Anti–PD-1 Promising

“As a field, renal-cell carcinoma is probably 3 or 4 years behind” in immunotherapy, said Eric Jonasch, MD, Associate Professor, Department of Geni tourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX. High-dose interleukin (IL)-2 is an option in a select group of patients who have good performance status, clear-cell RCC, and low-grade disease. “It’s the one cytokine, or immunotherapy, currently approved for RCC,” Dr Jonasch said. High-dose IL-2 is associated with better response rates than interferon, but no survival advantage has been shown with high-dose IL-2 in randomized clinical trials. Carbonic anhydrase IX failed as a biomarker to improve the selection criteria for high-dose IL-2. The retrospective measurement of tumor PD-L1 expression was successful as a marker of response in recipients of high-dose IL-2, and further study of this biomarker is warranted. A number of vaccine strategies have been tried or are being tested in RCC, including vitespen, an autologous heat shock 90 protein plus peptide extract. Vitespen, however, did not improve recurrence-free survival in an adjuvant setting. A multipeptide cancer vaccine is currently under study in pa-

The PD-1 checkpoint inhibitor nivolumab was associated with an overall survival as long as 25 months in patients with previously refractory renalcell carcinoma. —ERIC JONASCH, MD

tients receiving sunitinib (Sutent) for advanced RCC. Checkpoint blockade using a CTLA4 inhibitor and an anti–PD-1 antibody is in ongoing clinical studies in patients with previously treated metastatic RCC. The PD-1 checkpoint inhibitor nivolumab was associated with an OS as long as 25 months in patients with previously refractory RCC, said Dr Jo-

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APRIL 2015

In patients receiving CTLA4 inhibitors in the secondsome of line setting, these patients have been followed for over 10 years without relapse for metastatic melanoma.

“

”

—ANTHONY J. OLSZANSKI, MD, RPH

nasch, and a subset of patients had durable response to nivolumab. Metastatic Melanoma: Durable Disease Control with Nivolumab

To date, no vaccine therapy has been found useful as adjuvant therapy for melanoma, said Anthony J. Olszanski, MD, RPh, Director, Medical Oncology Melanoma Program, Fox Chase Cancer Cen-

Continued from page 15

ter, Philadelphia. Interferon remains the only adjuvant systemic option for patients at risk for melanoma, with the choice being high-dose interferon or pegylated interferon, which is easier to tolerate. Although anti–CTLA-4 therapy extends recurrence-free survival in this setting, the rate of adverse events is high, and an OS analysis is awaited. Ipilimumab is currently indicated for the treatment of unresectable or metastatic melanoma. Anti–PD-1 therapy (ie, pembrolizumab [Keytruda], nivolumab) is indicated for the treatment of patients with unresectable or metastatic melanoma and for patients with disease progression after therapy with ipilimumab, and in combination with a BRAF inhibitor if the patient has a BRAF mutation. CTLA-4 inhibitors are associated with durable disease control in the first- and second-line settings for metastatic melanoma. In patients receiving CTLA-4 inhibitors in the second-line setting, “some of these patients have been followed for over 10 years without relapse for metastatic melanoma,” said Dr Olszanski. Anti–PD-1 treatment with nivolumab was recently shown to be superior to da carbazine as first-line therapy for the treatment of metastatic melanoma, with a 1-year OS rate of 72.9% in the nivolumab group versus 42.1% for dacarbazine. “The median survival for nivolumab has not been met,” Dr Olszanski said. In this study, the superior OS with nivolumab was irrespective of PD-L1 tumor status, he noted. n

VOL. 6

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NCCN Conference Highlights

Updated NCCN Guideline for Prostate Cancer...

at a glance ➤ The updated NCCN guideline calls for the upfront use of docetaxel in men with metastatic CRPC ➤ First-line therapy options for men with CRPC in the guideline now include docetaxel plus prednisone, enzalutamide, and abiraterone plus prednisone ➤ The updated guideline reflects level I evidence for using enzalutamide in metastatic CRPC, which had an 81% risk reduction and a 29% mortality risk reduction versus placebo ➤ Sipuleucel-T extended OS by 4.1 months relative to placebo

VOL. 6

plus prednisone (16.5 vs 8.3 months), representing a 48% reduction in risk with abiraterone. The median OS was also significantly superior with randomization to abiraterone; the median OS was not yet reached in the abiraterone group and was 27.2 months in the place-

bo group, corresponding to a hazard ratio of 0.57. Several ongoing phase 3 trials in CRPC have the potential for practice-changing results, said Dr Armstrong, including ipB:7.625 in ilimumab use in the predocetaxel setting, T:7.375 in rilimogene galvacirepvec plus rilimogene

glafolivec (PROSTVAC) and granulocyte-macrophage colony-stimulating factor before doce taxel in asymptomatic patients with CRPC, the novel immunomodulator tasquinimod (also in the predocetaxel setting), and novel hormonal therapies such as orteronel. n

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.

T:9.75 in

trial) for the use of enzalutamide, said Dr Armstrong. In PREVAIL, which was conducted in men with metastatic CRPC before chemotherapy, the median radiographic progression-free survival (PFS) had not yet been reached in enzalutamide recipients compared with 3.9 months in the placebo group. The rate of radiographic PFS at 12 months was 65% in the enzalutamide group versus 14% among patients receiving placebo, for an 81% risk reduction with enzalutamide. Furthermore, enzalutamide reduced the risk for death by 29%, and in subsets of men with visceral disease, in whom outcomes are generally worse, enzalutamide delayed PFS. “We also have a little more stratification based on visceral disease” metastases, said Dr Armstrong. “There are some drugs we can’t use in visceral disease. We have multiple lines of therapy now, so there’s a new page that goes over the appropriate options as the disease progresses.” The recommendations about immunotherapy in the form of sipuleucel-T (Provenge) also find their way into the guideline, courtesy of the IMPACT trial, in which the median OS was extended by 4.1 months with sipuleucel-T relative to placebo, for a 22% reduction in the risk for death. The newest version of the guideline also addresses the use of abiraterone acetate plus prednisone, and reflects data from the COU-AA-302 phase 3 registration trial. At the third interim analysis, radiographic PFS was doubled in the abiraterone plus prednisone group compared with the group receiving placebo

Continued from page 16

mCRPC = metastatic castration-resistant prostate cancer; AST = aspartate aminotransferase; ALT = alanine aminotransferase.

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

NO. 3

APRIL 2015

Date: 03/16/15

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Customer Code: 029979-150220

Group 360 Job #: 725462

In the Literature Bortezomib Shows Efficacy as Frontline Therapy in Mantle-Cell Lymphoma

For patients with previously untreated mantle-cell lymphoma who are either ineligible for or are not candidates for intensive chemotherapy and stemcell transplantation, the standard of care is the combination regimen of rituximab (Rituxan), cyclophosphamide (Cytoxan), doxorubicin (Adriamycin),

vincristine (Oncovin), and prednisolone (R-CHOP). Studies showed that this could produce complete responses in up to 48% of patients, but progression-free survival (PFS) is limited. The proteasome inhibitor bortezomib (Velcade) was initially approved by the FDA for the treatment of relapsed mantle-cell lymphoma. Now, in a phase 3 trial, researchers assessed the efficacy and safety of bortezomib as frontline

therapy in a regimen of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus R-CHOP in patients with newly diagnosed disease (Robak T, et al. N Engl J Med. 2015;372:944-953). For the study, 487 patients with newly diagnosed mantle-cell lymphoma who were ineligible B:7.625 in for or who are not candidates for stem-cell transplanT:7.375 in tation were randomized to 1 of 2 com-

bination regimens. Patients could receive six to eight 21-day cycles of R-CHOP (N = 244) intravenously on day 1 (with prednisone administered orally on days 1-5) or VR-CAP (N = 243; R-CHOP regimen, but substituting vincristine with bortezomib at a dose of 1.3 mg/m2 of body surface area on days 1, 4, 8, and 11). The primary end point was PFS. The secondary end points included complete response rate,

For men with mCRPC who progressed on ADT

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

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

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

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.

T:9.75 in

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2015 3/15 029979-150220

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APRIL 2015

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VOL. 6

Customer Code: 029979-150220

NO. 3

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In the Literature duration of complete response, time to progression, time to next antilymphoma therapy, treatment-free interval, overall survival, and safety. After a median follow-up of 40 months, 61% of patients had disease progression or died. The median PFS was 14.4 months in the R-CHOP group compared with 24.7 months in the VRCAP group (hazard ratio [HR], 0.63; P <.001), a relative improvement of 59%.

On the basis of investigator assessment, the median durations of PFS were 16.1 months and 30.7 months, respectively (HR, 0.51; P <.001). The secondary end points were consistently improved in the VR-CAP group versus the R-CHOP group, including the complete response rates (42% vs 53%, respectively), median of comB:7.625 duration in plete response (18.0 T:7.375 invs 42.1 months, respectively), median time to progres-

sion (16.1 vs 30.5 months, respectively), median time to next antilymphoma therapy (24.8 vs 44.5 months, respectively), and the median treatment-free interval (20.5 vs 40.6 months, respectively). The researchers noted that overall survival was not mature at the time of the report; however, there was a difference in 4-year survival between the VR-CAP and R-CHOP cohorts (54% vs 64%, respectively).

Adverse events (AEs) of any grade and discontinuation as a result of AEs were similar in both treatment groups, but patients in the VR-CAP group had higher rates of serious AEs. Hematologic toxic effects were the most common AEs, with grade ≥3 AEs for neutropenia and thrombocytopenia higher in the VR-CAP group (85% and 57%, respectively). Overall, VR-CAP prolonged the duration of PFS and showed improveContinued on page 20

B:10 in

T:9.75 in

003307-150130

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 enzymes CYP2D6 and CYP2C8. 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 a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Learn more today at

www.zytigahcp.com.

VOL. 6

Every day tells a story.

NO. 3

Date: 03/16/15

APRIL 2015

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In the Literature Bortezomib Shows Efficacy as Frontline... Continued from page 19

ments in secondary end points compared with R-CHOP in patients with newly diagnosed mantle-cell lymphoma. This improvement was accompanied by increased hematologic toxicity.

Goserelin Prevents Ovarian Failure in Breast Cancer

Early ovarian failure is a common

long-term side effect of chemotherapy. Patients with cancer and premature ovarian failure are at an increased risk for menopausal symptoms, osteoporosis, and infertility. Studies of the use of gonadotropin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to protect ovarian function have shown mixed results and lack data on pregnancy outcomes. In a new study, researchers evaluated whether adminis-

tration of the GnRH agonist goserelin (Zoladex) with chemotherapy would reduce the rate of ovarian failure after adjuvant or neoadjuvant treatment of hormone receptor–negative early breast cancer (Moore HC, et al. N Engl J Med. 2015;372:923-932). The Prevention of Early Menopause Study (POEMS) is an international, randomized, phase 3 study that included 218 premenopausal women aged 18 to 49

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 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].

VALUE-BASED CANCER CARE

APRIL 2015

years with stage I to IIIA operable hormone receptor–negative breast cancer. Patients were randomized in a 1:1 ratio to goserelin with chemotherapy (N = 105) or chemotherapy alone (N = 113). The dose of goserelin was 3.6 mg administered subcutaneously every 4 weeks beginning 1 week before the initial chemotherapy dose and was continued to within 2 weeks before or after the final chemotherapy dose. An anthracycline-based

ZYTIGA® (abiraterone acetate) Tablets 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 ≥2.5 XULN 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 infection 11.5 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 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

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In the Literature chemotherapy was used in a total of 91% of patients. Patients with human epidermal growth factor receptor 2–overexpressing tumors were permitted to use trastuzumab (Herceptin). The primary end point was the rate of ovarian failure at 2 years, with ovarian failure defined as the absence of menses in the preceding 6 months and levels of follicle-stimulating hormone in the postmenopausal range. The secondary end points included preg-

nancy outcomes, disease-free survival, and overall survival. After 2 years of treatment, the rate of ovarian failure was 8% in the goserelin group compared with 22% in the chemotherapy-alone group. In addition, at least 1 pregnancy occurred in more women in the goserelin group compared with the chemotherapy- alone group within the first 5 years of posttreatment (21% vs 11%, respectively). The rates of

disease-free survival and overall survival were also higher in the goserelin group than in the chemotherapy-alone group (89% and 92% vs 78% and 82%, respectively). Grade 3 AEs occurred in 6 patients in each group. Grade ≥2 AEs were observed in 48% of patients in the goserelin group versus in 24% of patients in the chemotherapy-alone group. Although incomplete enrollment and missing data restricted the inter-

pretation of the findings, the use of goserelin with chemotherapy appeared to protect against ovarian failure, reducing the risk for early menopause and improving prospects for fertility.

Regulation of E-Cigarettes and Other Electronic Nicotine Delivery Systems Needed

The American Cancer Society and Continued on page 22

ZYTIGA® (abiraterone acetate) Tablets

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,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % 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

Musculoskeletal discomfort, and Musculoskeletal stiffness 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 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 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

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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 Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis 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].

APRIL 2015

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In the Literature Regulation of E-Cigarettes and Other... Continued from page 21

the American Society of Clinical Oncology issued a joint statement outlining recommendations for policymakers as they work to ensure the safety of electronic cigarettes (e-cigarettes) and other electronic nicotine delivery systems (ENDS), and to minimize the potential negative consequences (Brandon TH, et al. J Clin Oncol. 2015;33:952-963).

Some state and local governments have enacted e-cigarette regulations; however, federal regulations have yet to be adopted. Unlike combustible cigarettes and many other tobacco products, the FDA does not currently regulate e-cigarettes and other ENDS. Manufacturing standards and quality controls on e-cigarettes also have yet to be implemented. Smoking is responsible for 30% of all

cancer deaths in the United States and is associated with an increased risk for at least 18 types of cancer. E-cigarettes and ENDS, which are capable of delivering nicotine in an aerosolized form, have been advocated as harm-reduction devices and smoking cessation aids; however, these products can also be harmful if they increase the likelihood of nonsmokers using combustible tobacco products or if they discourage smokers

ZYTIGA® (abiraterone acetate) Tablets

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. 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 a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information]. 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.

VALUE-BASED CANCER CARE

APRIL 2015

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 ©Janssen Biotech, Inc. 2012 Revised: January 2015 028959-150203

from quitting. Insufficient data exist on the health consequences of using ENDS and on their value as tobacco cessation aids. Therefore, a key recommendation is for additional research on these products, including assessing the health impact of ENDS, understanding the patterns of use for ENDS, and determining what role ENDS have in cessation. In addition to underscoring the need for more research to inform the regulation of e-cigarettes and ENDS, key policy recommendations include:

Smoking is responsible for 30% of all cancer deaths in the United States and is associated with an increased risk for at least 18 types of cancer. • The FDA should regulate all ENDS that meet the statutory definition of tobacco products • Manufacturers should be required to register with the FDA and report all product and ingredient listings, as well as the nicotine concentration in the ENDS solution • Packaging and advertising should be required to carry safety labels that include a warning regarding nicotine addiction • All youth-oriented ENDS advertising and marketing should be prohibited • Internet and other mail-order sellers of ENDS should be required to check the age and identification of customers at the point of purchase and delivery • ENDS use should be prohibited in places where combustible tobacco product use is prohibited by federal, state, or local law until the safety of secondhand and thirdhand aerosol exposure is established • Childproof caps should be required for all e-liquid containers • ENDS and ENDS liquid–containing candy, along with other products targeted at youth, should be banned, unless there is evidence showing that these products do not encourage youth uptake • Funding generated through tobacco product taxes, including any potential taxes levied on ENDS, should be used to help support research on ENDS and other tobacco products • All data related to ENDS composition, use, and health effects should be disclosed for dissemination and should inform policy decisions for ENDS product regulation • State and local government should implement ENDS regulations that are appropriate for protecting the public health. n

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Gynecologic Oncology Highlights

Immunotherapy Vaccine Prolongs RecurrenceFree Survival in Advanced Ovarian... Continued from the cover

beyond 14.5 months” without a recurrence. The vaccine was well-tolerated. “This is cutting-edge medicine for ovarian cancer. The immunotherapy may keep the cancer away longer. This preliminary study with promising results may give women with advanced ovarian cancer an option for a maintenance regimen,” stated lead investigator Jonathan C. Oh, MD, of Texas Oncology, P.A., Dallas, in an official news release. Dr Oh presented the study results at the 2015 Society of Gynecologic Oncology annual meeting. Most patients with ovarian cancer are diagnosed with stage III or IV ovarian cancer, when it is no longer curable. First-line standard of care for advanced ovarian cancer (optimal debulking surgery and chemotherapy)

“

This is cutting-edge medicine for ovarian cancer. The immunotherapy may keep the cancer away longer. This preliminary study with promising results may give women with advanced ovarian cancer an option for a maintenance regimen.

”

—JONATHAN C. OH, MD

is associated with an 80% recurrence rate. In this phase 2 trial, 31 patients

at a glance ➤ Immunotherapy made from the patient’s own tumor cells prolonged recurrence-free survival versus standard of care in women with late-stage ovarian cancer ➤ Of 20 patients receiving the vaccine, the median time to recurrence was not reached and was 14.5 months in 11 patients receiving standard of care ➤ Most of the patients in the immunotherapy arm went well beyond 14.5 months without a recurrence

with advanced ovarian cancer underwent standard of care and were entered into the trial. Of these patients, 20 received the FANG vaccine (granulocyte-macrophage colony-stimulating factor/bi-sh RNAi furin vector-transfected autologous tumor cells), which is manufactured from their own tumor cells. The vaccine was previously shown to elicit the desired immune response in a phase 1 trial, Dr Oh said. The other 11 patients received standard of care alone. Based on the safety of the vaccine, the high rate of T-cell activation in this population that correlates with the immune response, and the marked delay in time to regression, the phase 2 trial was discontinued and phase 3 testing of 382 patients is now being pursued. n

Bevacizumab Prolongs Survival in Recurrent Platinum-Sensitive Ovarian Cancer By Alice Goodman

Chicago, IL—The addition of bevaciz umab (Avastin) to standard chemotherapy extended survival in women with platinum-sensitive recurrent ovarian cancer compared with chemotherapy

at a glance ➤ Adding bevacizumab to standard chemotherapy extended overall survival in women with platinumsensitive recurrent ovarian cancer by 5 months compared with chemotherapy alone ➤ Progression-free survival was extended by 3.4 months, from 10.4 months with chemotherapy alone to 13.8 months with bevacizumab ➤ The addition of bevacizumab to chemotherapy reduced mortality risk by 17% and disease progression risk by 39%

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alone in the phase 3 randomized controlled GOG0213 trial. The results were presented at the 2015 Society of Gynecologic Oncology annual meeting. The median overall survival was 42.2 months for women randomized to receive bevacizumab plus chemotherapy versus 37.2 months for those assigned to chemotherapy alone. Progression-free survival was improved by nearly 3.4 months with the addition of bevacizumab—13.8 months versus 10.4 months with chemotherapy alone. Bevacizumab reduced the risk for death by 17% and the risk for progression by 39%. “Most women whose ovarian cancer is recurring want every edge to extend their lives. This trial, while not completely definitive, builds on previous data, offering hope that we can hone in on treatments to achieve that goal,” said lead investigator Robert L. Coleman, MD, Vice Chair, Clinical Research, Department of Gynecologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, TX. Platinum-based doublets are a standard of care for women with plati-

“

Most women whose ovarian cancer is recurring want every edge to extend their lives. This trial, while not completely definitive, builds on previous data, offering hope that we can hone in on treatments to achieve that goal.

”

—ROBERT L. COLEMAN, MD

num-sensitive recurrent ovarian cancer. The GOG0213 trial was designed to evaluate the role of the addition of bevacizumab to standard chemotherapy and the role of secondary cytoreductive surgery. At the meeting, the results of the first part of the study were presented. The study randomized 374 women to standard chemotherapy with paclitaxel (Taxol) plus carboplatin (Paraplatin) APRIL 2015

and 374 women to standard chemotherapy plus bevacizumab. Both arms received 6 cycles of chemotherapy, and the study arm continued to receive bevacizumab maintenance therapy. This is the first clinical trial of bevacizumab in the setting of ovarian cancer with overall survival being the primary end point. Both treatment arms were well-balanced for demographic and disease characteristics. The patients’ median age was 60 years, and 81% of patients had serous histology. Patients who received bevacizumab had significantly more grade ≥3 adverse events, including gastrointestinal necrosis fistula (1% vs 1.8%, respectively; P = .05), infections (5.8% vs 13%, respectively; P = .002), joint pain (4.6% vs 15.1%, respectively; P <.001), and proteinuria (0% vs 8.1%, respectively; P <.001). However, these events were consistent with the known side effect profile of bevacizumab. The ongoing study will assess quality of life of women in both arms of the trial, as well as the role of secondary cytoreductive surgery before receiving chemotherapy. n

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Gynecologic Oncology Highlights

PARP Inhibitor Maintenance Too Pricey for Ovarian Cancer? By Charles Bankhead Chicago, IL—Poly (ADP-ribose) polymerase (PARP) inhibitor maintenance therapy with olaparib (Lynparza) for

relapsed, platinum-sensitive ovarian cancer would meet conventional standards of cost-effectiveness only if the

drug price decreased by ≥66%, according to a modeling study. Assuming a $7000 monthly cost for

olaparib would lead to an incremen tal cost-effectiveness ratio (ICER) of $135,672 if treatment were limited to

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Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome.

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VALUE-BASED CANCER CARE

APRIL 2015 I78618ha_b.indd 1-2

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Gynecologic Oncology Highlights patients with BRCA1/BRCA2 mutations. Using the drug as maintenance for BRCA wild-type tumors would drive the ICER to $315,840. PARP inhibitor maintenance with olaparib would far exceed the conventional $50,000 willingness-to-pay threshold and even the more generous $100,000 threshold used in some recent discussions of cost-effectiveness, said

PARP inhibitor maintenance with olaparib would far exceed the conventional $50,000 willingness-to- pay threshold. —HALLER J. SMITH, MD

Haller J. Smith, MD, of the University of Alabama, Birmingham, at the 2015 Society of Gynecologic Oncology annual meeting. “At a cost of $7000, olaparib is not cost-effective, regardless of the BRCA status,” said Dr Smith. “Restricting olaparib use to patients with BRCA1/2 mutations decreased costs, but to achieve an acceptable ICER, the cost

of olaparib must be $2500 or less.” In December 2014, the FDA approved olaparib for the treatment of patients with relapsed, platinum-sensitive ovarian cancer with BRCA mutation who were previously treated with ≥3 lines of therapy. In approving the drug, the FDA overruled the Oncologic Drugs Advisory Committee (ODAC) recommenContinued on page 26

Events of renal impairment were reported in 14% of LENVIMA-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure / impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMAtreated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms.

6% of e after hold de 2.

Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage.

tor ment e or e

LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed.

3 or tudied

LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.

AST MA. or ence

Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%).

for rine esume me.

Please see Brief Summary of Prescribing Information on the following pages. LENVIMATM is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2015 Eisai Inc. All rights reserved. Printed in USA/February 2015 LENV0185

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Gynecologic Oncology Highlights

PARP Inhibitor Maintenance Too Pricey... dation, which voted against approval. ODAC members had expressed concern about an excess of hematologic malignancies and an approval request based on a phase 2 trial subgroup analysis (of patients with BRCA muta-

The FDA did stipulate that the approval is contingent on the outcome of 2 ongoing phase 3 trials of olaparib maintenance in relapsed, BRCA-mutated ovarian cancer.

LENVIMA™ (lenvatinib) BRIEF SUMMARY – See package insert for full prescribing information. 1 INDICATIONS AND USAGE LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food. Continue LENVIMA until disease progression or until unacceptable toxicity occurs. Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration. Severe Renal or Hepatic Impairment The recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockroft-Gault equation) or severe hepatic impairment (Child-Pugh C). 2.2 Dose Modifications Hypertension • Assess blood pressure prior to and periodically during treatment. Initiate or adjust medical management to control blood pressure prior to and during treatment. • Withhold LENVIMA for Grade 3 hypertension that persists despite optimal antihypertensive therapy; resume at a reduced dose (see Table 1) when hypertension is controlled at less than or equal to Grade 2. • Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction or hemorrhage • Discontinue for a Grade 4 event. • Withhold LENVIMA for development of Grade 3 event until improved to Grade 0 or 1 or baseline. • Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of the adverse event. Arterial thrombotic event • Discontinue LENVIMA following an arterial thrombotic event. Renal failure and impairment or hepatotoxicity • Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade 0 to 1 or baseline. • Either resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the severity and persistence of renal impairment or hepatotoxicity. • Discontinue LENVIMA for hepatic failure. Proteinuria • Withhold LENVIMA for ≥2 grams of proteinuria/24 hours. • Resume at a reduced dose (see Table 1) when proteinuria is <2 gm/24 hours. • Discontinue LENVIMA for nephrotic syndrome. Gastrointestinal perforation or fistula formation • Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT prolongation • Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. • Resume LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade 0 or 1 or baseline. Reversible posterior leukoencephalopathy syndrome (RPLS) • Withhold for RPLS until fully resolved. • Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. Manage other adverse reactions according to the instructions in Table 1. Based on the absence of clinical experience, there are no recommendations on resumption of dosing in patients with Grade 4 clinical adverse reactions that resolve. Table 1

Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa Adverse Reaction

Modification

Adjusted Doseb

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

20 mg (two 10 mg capsules) orally once daily

Second occurrencec

Interrupt until resolved to Grade 0-1 or baseline

14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily

Third occurrencec

Interrupt until resolved to Grade 0-1 or baseline

10 mg (one 10 mg capsule) orally once daily

Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of LENVIMA Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hypertension In Study 1 hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group. Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension. 5.2 Cardiac Dysfunction In Study 1, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMAtreated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo. Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction. 5.3 Arterial Thromboembolic Events In Study 1, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMAtreated patients and 1% in the placebo group. Discontinue LENVIMA following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 5.4 Hepatotoxicity In Study 1, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST. Across clinical studies in which 1108 patients received LENVIMA, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient. Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until a b

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tions) showing improved progression-free survival (PFS) but not overall survival. However, the FDA did stipulate that the approval is contingent on the T:14.625” outcome of 2 ongoing phase 3 trials of S:14.375”

resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. 5.5 Proteinuria In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome. 5.6 Renal Failure and Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. 5.7 Gastrointestinal Perforation and Fistula Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. 5.8 QT Interval Prolongation In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. 5.9 Hypocalcemia In Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. 5.10 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. 5.11 Hemorrhagic Events In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. 5.12 Impairment of Thyroid Stimulating Hormone Suppression LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 5.13 Embryofetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions sections in the full prescribing information. • Hypertension • Cardiac Dysfunction • Arterial Thromboembolic Events • Hepatotoxicity • Proteinuria • Renal Failure and Impairment • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation • Hypocalcemia • Reversible Posterior Leukoencephalopathy Syndrome • Hemorrhagic Events • Impairment of Thyroid Stimulating Hormone Suppression 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. Safety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions. The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months. The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinerefractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAtreated patients than patients receiving placebo in the double-blind phase of the DTC study.

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Table 2

Adver Vascu Hy Hy Gastro Di Na St Vo Ab Co Or Dr Dy Gener Fa Ed Muscu Ar Metab W De De Nervo He Dy Di Renal Pro Skin a Pa Ra Al Hy Respir Dy Co Ep Psych Ins Infect De Ur Cardia

Ele

Inclu blood b Includ c Inclu abdo d Inclu e Inclu f Includ g Inclu h Inclu and t A clinical receiving 2%, resp a

Table 3

Labora

Chemi Cr Al As Hy Hy Lip Hema Pla

With b Subje In additio patients a increased hypercho 7 DRU 7.1 Effe No dose breast ca 8 USE 8.1 Preg Risk Sum Based on when adm during or teratogen pregnant a

on the

Gynecologic Oncology Highlights olaparib maintenance in relapsed, BRCA-mutated ovarian cancer. PFS is the primary end point in both trials, and results are expected later this year. Dr Smith and colleagues performed a cost-effectiveness analysis, using a model based on 6 cycles of carboplatin plus paclitaxel chemotherapy, followed by olaparib maintenance therapy. T:14.625” Cost was defined as the total cost of S:14.375” Table 2

Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% All Grades or Greater than or Equal to 2% Grades 3 and 4 LENVIMA 24 mg N=261 All Grades Grades 3-4 (%) (%)

o e

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IMA

% n nt in

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Adverse Reaction Vascular Disorders Hypertensiona 73 Hypotension 9 Gastrointestinal Disorders Diarrhea 67 Nausea 47 41 Stomatitisb Vomiting 36 Abdominal painc 31 Constipation 29 d Oral pain 25 Dry mouth 17 Dyspepsia 13 General Disorders and Administration Site Conditions e Fatigue 67 Edema peripheral 21 Musculoskeletal and Connective Tissue Disorders Arthralgia/Myalgiaf 62 Metabolism and Nutrition Disorders Weight decreased 51 Decreased appetite 54 Dehydration 9 Nervous System Disorders Headache 38 Dysgeusia 18 Dizziness 15 Renal and Urinary Disorders Proteinuria 34 Skin and Subcutaneous Tissue Disorders Palmar-plantar erythrodysesthesia 32 21 Rashg Alopecia 12 Hyperkeratosis 7 Respiratory, Thoracic and Mediastinal Disorders Dysphonia 31 Cough 24 Epistaxis 12 Psychiatric Disorders Insomnia 12 Infections and Infestations h 10 Dental and oral infections Urinary tract infection 11 Cardiac Disorders Electrocardiogram QT prolonged

Placebo N=131 All Grades Grades 3-4 (%) (%)

44 2

16 2

4 0

9 2 5 2 2 0.4 1 0.4 0.4

17 25 8 15 11 15 2 8 4

0 1 0 0 1 1 0 0 0

11 0.4

35 8

4 0

13 7 2

15 18 2

1 1 1

3 0 0.4

11 3 9

1 0 0

3 0.4 0 0

1 3 5 2

0 0 0 0

1 0 0

5 18 1

0 0 0

1 1

1 5

0 0

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain d Includes oral pain, glossodynia, and oropharyngeal pain e Includes asthenia, fatigue, and malaise f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia g Includes rash macular, rash maculo-papular, rash generalized, and rash h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively). a b

Table 3

Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa

Laboratory Abnormality

Chemistry Creatinine increased Alanine aminotransferase (ALT) increased Aspartate aminotransferase (AST) increased Hypocalcemia Hypokalemia Lipase increased Hematology Platelet count decreased

LENVIMA 24 mg N=258b Grades 3-4 (%)

Placebo N=131b Grades 3-4 (%)

3 4 5 9 6 4

0 0 0 2 1 1

With at least 1 grade increase from baseline Subject with at least 1 post baseline laboratory value In addition the following laboratory abnormalities (all Grades) occurred in greater than 5% of LENVIMA-treated patients and at a rate that was two-fold or higher than in patients who received placebo: hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia, hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and hyperkalemia. 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. a b

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$312.37 for a chest computed tomography (CT), $482.89 for CT of the abdomen and pelvis, and $7000 for a 30-day supply of olaparib. The cost of the PARP inhibitor was de rived from costs of similar types of drugs. The remaining drug costs were based on 2014 wholesale acquisition costs. The model’s assumptions included 1110 patients with recurrent, platinum-

The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose based on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies. Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5 times the recommended human dose based on BSA). Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA). 8.2 Lactation Risk Summary It is not known whether LENVIMA is present in human milk. However, lenvatinib and its metabolites are excreted in rat milk at concentrations higher than in maternal plasma. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA. Data Animal Data Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma. 8.3 Females and Males of Reproductive Potential Contraception Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. Infertility Females LENVIMA may result in reduced fertility in females of reproductive potential. Males LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration. 8.4 Pediatric Use The safety and effectiveness of LENVIMA in pediatric patients have not been established. Juvenile Animal Data Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth retardation (decreased body weight gain, decreased food consumption, and decreases in the width and/or length of the femur and tibia) and secondary delays in physical development and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats. 8.5 Geriatric Use Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. 8.6 Renal Impairment No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg taken once daily. Patients with end stage renal disease were not studied. 8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg taken once daily. 10 OVERDOSAGE There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Hypertension: Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated. Cardiac Dysfunction: Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles. Arterial Thrombotic Events Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke. Hepatotoxicity: Advise patients that they will need to undergo lab tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure. Proteinuria and Renal Failure/Impairment: Advise patients that they will need to undergo regular lab tests to monitor for kidney function and protein in the urine. Gastrointestinal perforation or fistula formation: Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain. Hemorrhagic Events: Advise patients that LENVIMA can increase the risk for bleeding and to contact their health care provider for bleeding or symptoms of severe bleeding. Embryofetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. Lactation: Advise nursing women to discontinue breastfeeding during treatment with LENVIMA.

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sensitive ovarian cancer with BRCA mutations who were treated each year. Observation would cost $5.5 million and result in a PFS of 4.3 months. Olaparib maintenance for the same patients would result in a PFS of 11.2 months at a cost of $91.3 million, which translated into an ICER of $135,672 per progression-free life-year saved. An analysis of patients with BRCA wild-type tumors showed that an estimated 4439 patients would be treated at a cost of $22.1 million and result in a PFS of 5.5 months. Olaparib maintenance therapy would cost $244.1 million and yield a PFS of 7.4 months.

“

At a cost of $7000, olaparib is not costeffective, regardless of the BRCA status. Restricting olaparib use to patients with BRCA1/2 mutations decreased costs, but to achieve an acceptable ICER, the cost of olaparib must be $2500 or less.

T:10” S:9.5”

sume at tinue

the strategy, and effectiveness as the improvement in PFS arising from the strategy. The ICER represented the cost per progression-free life-year saved. Cost components of the treatment strategy consisted of $121.67 per cycle of paclitaxel, $51.81 per cycle for carboplatin, $386.22 for premedication, $100.73 for a level 4 office visit, $112.20 for CA-125 assessment,

”

—HALLER J. SMITH, MD

Sensitivity analysis showed that if BRCA1 or BRCA2 mutations accounted for 10% (instead of 20%) of patients with recurrent, platinum-sensitive ovarian cancer, the cost of the olaparib strategy would decrease by half, to $46.1 million. The analysis showed that the greatest cost impact would come from a reduction in the estimated cost of olaparib. If the price of a 30-day supply were $5000, the 11.2-month PFS would be associated with an ICER of $97,404 per progression-free life-year saved, decreasing to $49,584 per progression-free life-year saved if the price of the PARP inhibitor were $2500. n

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5th Conference Abstracts Abstracts to Be Presented at the Fifth Annual Conference of the Association for Value-Based Cancer Care May 3-6, 2015 Omni Shoreham, Washington, DC

Category: Employer Issues in Oncology

4-Year Employer Trends and Value-Based Oncology Coverage–Related Findings from a National Employer Survey FR Vogenberg,1 C Larson,2 M Rehayem,2 L Boress2 1 Institute for Integrated Healthcare, Greenville, SC; and University of IllinoisChicago, Department of Pharmacy Systems, Outcomes and Policy; 2Midwest Business Group on Health, Chicago, IL Background: Healthcare costs are a continued concern among employers and other purchasers and extend especially to biologics or oncolytics that are being increasingly scrutinized to demonstrate value over time. A significant cost challenge to employers, these drugs create logistical issues for patients, physicians, pharmacies, and manufacturers because of their unique approval requirements, dosing, side effects, and distribution methods. Costs and outcomes of biologics and oncolytics are also hard to track, because they show up in both medical and pharmacy benefit claims. Objectives: The National Employer Initiative on Biologic & Specialty Drugs survey objectives are to assess the change in level of knowledge and benefit design gaps of employer plan sponsors in the area of specialty pharmacy and biologic products for conditions such as cancer and immune disorders, and to identify opportunities for future benefit coverage innovation. Methods: An online survey instrument was developed through an advisory council comprising self-funded employers for distribution in late (fall) 2014 to early 2015. The survey was disseminated to employers and through 15 business coalitions across the United States, and was completed in March 2015. Results were then analyzed by the Midwest Business Group on Health and the Institute for Integrated Healthcare. Results: The 2014 survey had a total of 81 employers of varying sizes and representative Standard Industrial Classification types that completed the survey and represented more than 1.5 million employee lives, with an average employer size of 19,600. The key findings in 2014 indicate that the majority of employers (77%) reported having an above average to average level of understanding of specialty drugs, with 17% having a high level of understanding. This is a slight decrease from 2013, when the survey had a higher proportion of large employer respondents. Although most employers continue to use traditional drug benefit tactics for management of specialty drugs, they understand the need for oncology-based plan design strategies, with 37% of respondents using an integrated pharmacy benefit management (PBM), 25% requiring the use of specialty pharmacies, and 21% using a physician-based model using prior authorization from a select list. None of the respondents reported offering an oncology carve-out or a narrow formulary to include preferred oncology drugs, but that may change in the future. Nearly 80% of respondents indicate they are concerned about the new drug pipeline, and many support drug innovation for chronic or life-threatening diseases. In addition, most are concerned about quality and cost outcomes management, as well as incorporating wellness strategies across the continuum of patient care. The survey results over a 4-year period indicate that larger-sized companies have a higher knowledge base versus the 2011 findings, which indicated that 78% of small- to midsized employers had little to moderate understanding of specialty drugs or biologics. Similar to 2011, the 2012-2014 results showed that many employers did not know whether their company’s claim costs for specialty drugs had increased over the past several years. In previous years, as well as in 2014, most employers have been using traditional benefit plan design (eg, tiered formularies, copayments, and coinsurance) instead of innovative benefit designs (ie, value-based) that may be more appropriate for biologic or specialty/oncology drugs. In addition, there continues to be an increasing use of high-deductible plans, which will continue to result in more cost-shifting to the consumer. Vendor performance is consistently highly valued, yet the majority of employers only agree or somewhat agree that their PBM does a good job in managing costs. In addition, the majority of benefit designs continue to omit an incentive to ensure the proper compliance to drug therapy or adherence to treatment. Conclusions: There remains a knowledge gap among commercial plan sponsors, especially in clinical outcomes, that is important to those who manage oncology services or risk, among other specialty drug categories. The survey findings demonstrate employers’ relatively low knowledge of biologic drugs, appropriate support technologies or incentives, and vendor contracting options available to their plan for effective management of oncology/specialty drugs. The employers who can improve their understanding of the many challenges in managing this area will be able to more effectively manage total costs and improve related patient outcomes.

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Category: Exploring Barriers and Opportunities in Patient Access

Willingness to Pay for Treatment Among Women with Metastatic Breast Cancer Jacqueline Hall, MSPH1; Marco daCosta DiBonaventura, PhD2; Ronda Copher, PhD1; Shu Huang, BA2; Enrique Basurto, MSc2; Safiya Abouzaid, PharmD, MPH1 1 Eisai Inc.; 2Kantar Health Objectives: Treatment for metastatic breast cancer (mBC) focuses on extending survival, promoting quality of life, and ensuring adequate symptom management. Although many of the available treatment options can be quite costly, few studies have examined the point at which out-of-pocket costs become so high as to not be worth the expense from the patient’s perspective. The present study addressed this gap. Methods: Data were collected through a cross-sectional Internet survey of 175 adult women diagnosed with mBC who had been treated with at least 2 hormone and/or chemotherapy agents. Respondents provided demographic and health history information. Respondents were also presented with an mBC treatment profile and asked their willingness to take the medication with varying levels of per-cycle outof-pocket costs (ranging from $0 to $3000). A hierarchical Bayesian logistic regression was then conducted to predict willingness to take the treatment (willing vs unwilling) from levels of per-cycle out-of-pocket costs. Results: The mean age was 53.5 years (standard deviation, 10.1), and women were predominantly non-Hispanic white (90.9%). The adjusted probability of being willing to pay decreased consistently from 0.94 (at $0 per cycle) to 0.05 (at $3000 per cycle). Once the per-cycle costs exceeded $100 (0.79 adjusted probability of being willing to pay), the willingness disproportionately decreased. The probability of being willing to pay dropped from 0.79 at $100 to 0.59 at $200, the largest decrease observed after a $100 change in costs (eg, the probability of being willing to pay dropped from only 0.59 at $200 to 0.49 at $300). Post-hoc analyses of willingness to pay by different demographic strata revealed a consistency in results. Although low sample sizes precluded meaningful comparisons in some cases, willingness to pay did not vary by age, household income, or education group, among other variables. Discussion: Despite the treatment advancements in mBC, affordability remains an important factor in patients’ decision to use a medication. The results suggest that the sharpest decline in willingness to pay occurs after $100 per cycle, a potential “walking away” point for women. Willingness to pay was generally consistent across demographic (eg, age, income) and health history strata. Healthcare decision makers should be aware of the influence that out-of-pocket costs can have on patient’s willingness and ability to pursue treatment options. This study was funded by Eisai, Inc. Category: Impact of Personalized Medicine on Patient Outcomes

Current Practices in the Use of Next-Generation Sequencing: A Steep Learning Curve? Manjari Pandey,1 Matthew K Stein,2 Jason C Chandler,1 Bradley G Somer1 1 West Cancer Center; 2Department of Internal Medicine, University of Tennessee Health Science Center Background: Next-generation sequencing (NGS) is a relatively recent technology that performs the processes of DNA fragmentation and resynthesis in a parallel fashion, thus amplifying the output and enabling the sequencing of large fragments of DNA in a single run. NGS was rapidly accepted by the field of oncology and has been used to identify hereditary susceptibility to cancers, to understand tumor biology, and to identify “targetable” mutations or predict responses to therapy. Currently, there are no clear guidelines or standards for NGS and the clinician’s abilities to interpret and use the information effectively remain questionable. As the popularity of “personalized” or “precision” medicine grows, we describe the patterns of use of NGS in patient care at the West Cancer Center at Memphis, TN. Methods: We performed a retrospective chart review using the electronic medical records at the West Cancer Center and identified all patients for whom NGS testing through a particular vendor was ordered from October 2009 through August 2014. We collected data on demographics, diagnosis, previous treatments, and reasons cited for ordering NGS. We then determined whether the results led to any change in the management (ie, choice of therapy or enrollment in a trial). Results: A total of 179 patients had NGS testing performed on their tumor samples; 70% were white, and 72% were women. In all, 68% of the patients had private insurance, whereas 26% had Medicare as their primary insurance. All the testing

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5th Conference Abstracts was in the setting of metastatic disease, there were more than 20 different cancer types, of which 34% were gynecologic malignancies; among them, the most common diagnosis was ovarian cancer (79%). The other most common tumors were lung (14.5%), breast (13.4%), and colorectal (8.9%). The indication for testing was documented for 65.9% of cases; the most common reason cited for testing was to “guide therapy” (43.2%), followed by “molecular profiling” (32.2%) and to “evaluate for clinical trials” (24.6%). Of the 38 patients who had NGS for molecular profiling, 12 had the testing done to look for specific targetable mutations with approved therapies available. The results led to a change in management for 47 (26.3%) patients; 18 patients enrolled in trials, 22 received on-label therapy, and 5 patients received off-label therapy. Conclusions: The availability of NGS led to testing in a wide variety of cancers and led to a change in management in a number of patients, including enrollment in clinical trials. However, the patterns of NGS use and documentation differed widely between physicians and reflect a need for standardization. Category: Initiatives to Improve Patient Adherence & Exploring Barriers and Opportunities in Patient Care

Using Data to Improve Quality of Care and Process Sheryl Riley Director of Clinical Programs, SAI Systems International, Inc Contact: Sheryl Riley at sriley@saisystems.com or 908-397-1706 Background: Using data to improve quality of care, patient adherence, quality of life, and process of care, comprehensive data analysis should lead to identifying barriers to patient care and to improving patient adherence. Objectives: To understand the key data components that are needed to identify barriers and adherence concerns of patients, to identify the substance behind utilizing an algorithm to stratify and calculate member risk, and to delineate what can be done with the data that are collected to improve adherence and patient quality of care. Discussion: Nonadherence can have profound clinical consequences, and medication nonadherence in patients with cancer is a growing concern today because of the increasing availability of new oral medications. There are many factors contributing to patient nonadherence to treatment regimens, but many times these factors are not identified until it is too late. Understanding the potential barriers and factors that affect patient adherence will help providers develop strategies to promote patient adherence to cancer treatments, especially oral regimens. Optimal patient outcomes require adherence, education, communication, ongoing monitoring, and follow-up. Many of these potential problems need to be identified and discussed with the patient before they start a cancer treatment program. For oncology, published studies reflect highly variable adherence rates of 17% to 27% for hematologic malignancies, 53% to 98% for breast cancer, and 97% for ovarian cancer. When looking at data, we can calculate the “member risk” and delineate which data elements can improve quality and the process of care. We can also begin to understand the barriers that prevent patients from adhering to treatment plans and care, while utilizing the data to create a cohesive plan of care that can guide patients and their families to wellness and self-management. Also, this process will reduce costs to hospitals and doctors through decreasing the gaps in care and ultimately improving quality of life. Conclusion: There are many barriers regarding adherence; hence, we should utilize the data to jump-start the process and also create strong, trusting patient relationships to get us the rest of the way. Comprehensive care management programs utilize data to improve patient adherence and to decrease barriers, but this information is also vital to hospitals, doctors, and other healthcare professionals working with patients to improve care and cost. Category: Models of Cancer Care Delivery

Treatment-Sequencing Patterns of Novel Agents in Patients with Prostate Cancer Elisabetta Malangone-Monaco,1 Kathy Foley,1 Kathleen Wilson,1 Helen Varker,1 Alison Binder,1 Scott McKenzie,2 Lorie Ellis2 1 Truven Health Analytics, Ann Arbor, MI; 2Janssen Pharmaceuticals, LLC, Horsham, PA Objective: Guidelines from the National Comprehensive Cancer Network recommend chemotherapy, immunotherapy, or antiandrogen therapy for the treatment of advanced castration-resistant prostate cancer (CRPC). This study evaluated treatment sequencing of recently approved agents for CRPC (abiraterone [ABI], enzalutamide [ENZ], docetaxel [DOC], cabazitaxel [CAB], or sipuleucel-T [SIP]) among men with prostate cancer.

Methods: This retrospective, observational study evaluated adult men with prostate cancer in the MarketScan Oncology EMR Database, which includes data from more than 900 contributing oncologists from greater than 100 community practices. Inclusion required a diagnosis of prostate cancer (International Classification of Diseases, Ninth Edition, Clinical Modification diagnosis code 185) from July 1, 2011, to March 31, 2014, no treatment with ABI, ENZ, DOC, CAB, or SIP before September 1, 2012, no other primary cancers, and 6 months of medical record history before the index date. The index date was the date of first prescription of ABI, ENZ, DOC, CAB, or SIP between September 1, 2012, and March 31, 2014. First-, second-, and subsequent-line treatments were evaluated before the end of the data availability or the end of the study. Results: In total, 812 patients with prostate cancer were identified; the mean patient age was 75 years, and 68% of the patients had recorded metastasis. A single line of therapy was observed for 544 (67%) patients. ABI was the most common first-line treatment (N = 443 [55%]), followed by DOC (N = 167 [21%]), ENZ (N = 113 [14%]), SIP (N = 82 [10%]), and CAB (N = 7 [1%]). A second line of therapy occurred in 268 (33%) patients and third line in 8% of patients. The Table describes the first-line therapy and the 2 most common second-line therapies for the men who moved to second-line therapy. Patients with single line of therapy with the agent, N

Patients with 2 lines of therapy after initiation of the agent, N

Second therapy (N)

ABI

335

108

ENZ (63), DOC (40)

DOC

ABI (44), ENZ (23)

ENZ

ABI (23), DOC (8)

SIP

ABI (21), DOC (12)

CAB

ABI (3), ENZ (1)

Agent

ABI indicates abiraterone; CAB, cabazitaxel; DOC, docetaxel; ENZ, enzalutamide; SIP, sipuleucel-T. Acknowledgment: This study was supported by Janssen Scientific Affairs, LLC. Contact the primary author at LEllis@its.jnj.com, lellis@its.jnj.com, or 443-640-4744.

Conclusion: Of the 5 agents of interest, ABI was the most frequently prescribed first-line medication for advanced prostate cancer in this patient cohort. First-line treatment with DOC was more common than first-line treatment with CAB or SIP. Further studies with longer follow-up and other treatments are warranted. Category: New Molecular Diagnostics and Targeted Therapies

Prostate Cancer Assay Improves Treatment Decisions for Patients with Early-Stage Disease John W. Peabody,1-3 Diana Tamondong-Lachica,3 Trever Burgon,3 Megan Chen,3 Lisa M. DeMaria3 1 University of California, San Francisco; 2University of California, Los Angeles; 3 QURE Healthcare, San Rafael, CA Background: Of the 240,000 men in the United States diagnosed annually with prostate cancer, the majority have indolent tumors. Distinguishing between aggressive and indolent cancers is an important clinical challenge. The current approaches for assessing tumor aggressiveness are insufficient. ProMark is a novel protein-based assay with a demonstrated ability to predict tumor aggressiveness at biopsy. Objective: To measure the clinical utility of ProMark in the management of early-stage prostate cancer. Methods: A total of 86 board-certified urologists were enrolled in a randomized, 2-arm experiment that collected data using Clinical Performance and Value (CPV) vignettes, which are simulated cases wherein doctors are provided with results to any tests or procedures they choose to order and are asked to make a treatment plan based on their investigations. To measure changes in practice, the participants completed 3 CPVs at baseline (R1) and 3 CPVs at round 2 (R2). After the baseline data were collected, the urologists randomized to the intervention arm received a 15-minute webinar on ProMark and then, for their R2 cases, were given the results from the ProMark assay. The cases were all newly diagnosed patients with Gleason 3+3 and 3+4 prostate cancer. Each case had a treatment course of either active surveillance (AS) or active treatment (AT), which was determined from the literature and the guidelines from the National Comprehensive Cancer Network. We measured clinical utility for 3 archetypes: (1) cases for whom ProMark scores confirm the evidence-based treatment indicated by the patient’s clinical presentation, (2) cases where ProMark would indicate the need to switch therapeutic apContinued on page 30

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5th Conference Abstracts Prostate Cancer Assay Improves Treatment Decisions... Continued from page 29 proach from AS to AT or from AT to AS, and (3) cases where the treatment course was indeterminate by the current guidelines. The outcome measure was the appropriate treatment, which was defined as urologists who ordered a biopsy and correctly indicated AS or AT according to the individual case. The analyses were done using difference-in-difference estimations. Results: The introduction of ProMark resulted in a marked increase in the number of urologists instituting the correct treatment. Although the control group scores for appropriate treatment stayed virtually the same across the rounds (P >.1), the appropriate treatment in the intervention group increased from 12% in R1 to 28% in R2. This change was most marked in the confirmatory (23%; P <.01) and switch cases (21%; P <.01), but was not statistically significant for the clinically indeterminate cases. Conclusions: In a randomized, experimental study, a novel protein-based assay significantly increased the number of patients who were given the appropriate treatment and suggests that this type of testing has demonstrable clinical utility and may generate significant savings. Category: Quality Measurement in Oncology

Defining Value in Oncology: Perspectives from Patients with Metastatic Breast Cancer Longacre ML,1 Charap ES,2 Buzaglo JS,1 Kennedy V,1 House L1 1 Cancer Support Community; 2inVentiv Health, Adheris Behavioral Insights Group Objectives: Value, as defined by the Institute of Medicine, is the “best care at lower cost.” Yet value may be differently interpreted among healthcare stakeholders (Porter, 2010). We explored the understandings of value among patients with metastatic breast cancer (mBC). By understanding how patients define value when considering their cancer experience, we can identify ways to bridge gaps between healthcare theory and practice. Methods: Using the Cancer Support Community’s Cancer Experience Registry, an online initiative to capture the experiences of those impacted by cancer, we asked patients the following question: “When considering your cancer experience, how would you define value?” We focused on patients with mBC (n = 769), because of these patients’ likely high number of health interactions and consistency of cancer stage. Two researchers coded open-ended responses in vivo by thematic category. The interrater reliability was 85%. Results: The average patient age was 56 years (standard deviation, 9.91; range, 24-93 years). All percents refer to the total sample; 45.9% did not respond, 8.97% did not understand the question, 2.34% were unclear, and 2.73% reported “no value.” The remaining responses were categorized broadly as personal value (38.4%) or exchange value (7.41%). Personal value responses fit into the following subcategories: relational, practical, or existential benefit (“I learned to cherish every day and know who my friends are,” 25.4%); preference (“quality of life,” 8.06%); and guiding principle (“live with no limitations,” 4.94%). Exchange value responses were general (“value should always exceed price paid,” 1.95%) and health-specific (“the cost/ benefit of treatment,” 5.46%). Of those with a health-specific response (n = 42), most (76.2%; n = 32) described treatment benefit as being engaged by or feeling close to their healthcare provider (HCP), while financial cost relative to benefit was mentioned rarely (n = 7). Conclusion: “Value” is multivalent; only 5.46% of patients with mBC in our sample conceived value as having any exchange-based meaning. When defining value relative to healthcare, patients emphasized the importance of their relationship with HCPs rather than the benefit of cost-effective treatment. Although quality, efficiency, and cost transparency in value-based care are essential, patients may be more focused on quality care as it relates to the HCP–patient relationship than on value relative to efficiency/cost. Patient engagement can help build on patients’ focus on value as relationship, while promoting the principles of the Value Initiative. This work is supported through contributions to the Cancer Support Community’s Cancer Policy Institute. Category: Quality Measurement in Oncology

Examining Experiences of Patients Currently Being Treated with Abiraterone Acetate for Metastatic Castrate-Resistant Prostate Cancer Ahmad B. Naim,1 Barbara Roland,2 Susan Wyant,2 Lorie A. Ellis1 1 Janssen Scientific Affairs LLC, Horsham, PA; 2The Dominion Group, Reston, VA Contact: Lorie A. Ellis, at lellis@its.jnj.com or 443-640-4744 Objective: Targeted treatments for advanced prostate cancer have been available for 2 to 3 years. Abiraterone acetate (AA) is a prodrug of abiraterone, which is a novel oral androgen biosynthesis inhibitor that is approved for metastatic castration-resistant prostate cancer (mCRPC). This study examines the overall experienc-

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es of patients currently being treated with AA therapy for mCRPC. Methods: A total of 100 patients with mCRPC who were being treated with AA completed a 30-minute survey in the fourth quarter of 2013. In all, 48 patients were receiving AA for >6 months. The majority (n = 62) of patients were aged ≤62 years; 55 patients were employed full time. A total of 57 patients had received chemotherapy before starting AA, whereas 43 patients had not received chemotherapy in the past. Results: When asked about their experiences with AA therapy, 76% of the patients reported that they feel more positive about their disease condition, and 91% reported that friends and family have a more positive view of their disease. Furthermore, 86% of the patients said they are less reliant or less dependent on others, 78% said they have greater control over their life and treatment, 78% reported they are better able to continue working and/or doing their daily activities, 76% said they are less restricted in being able to plan and participate in social activities, and 72% said they are better able to do the things they want to do. The vast majority of patients (86%) reported that their fatigue has not worsened since they started receiving AA. A total of 35% of patients reported that their fatigue has improved. In all, 49% of patients reported that their pain has not worsened since they started receiving AA. Conclusions: The results from this self-reported patient survey show that the majority of patients view their treatment experiences with AA therapy to be mostly positive. After receiving AA, the patients felt that their fatigue was stable or did not worsen. Furthermore, they had favorable perceptions of well-being, and felt that they had more control over their disease and life. More research is needed to further understand the patient-centered benefits of treatment with AA. Category: Quality Measurement in Oncology

Myeloid Growth Factor Utilization in a Commercial and Medicare Population: Phase 1 of a Quality Improvement Initiative Edward Li, PharmD, BCOP1; Barry Peterson2; Cecilia Tran2; Michael Sturgill2; Dudley Gill2; Stanley Forston2; Romano Bastianpillai2 1 University of New England College of Pharmacy; 2New Century Health Contact: Edward Li, PharmD, BCOP, at eli@une.edu or 207-221-4120 Background: Some clinical practice guidelines encourage the judicial use of myeloid growth factors (MGFs) in the prevention of chemotherapy-induced febrile neutropenia (FN) because of efficacy and safety concerns. For example, the American Society of Clinical Oncology (ASCO) guidelines state that a dose reduction of myelosuppressive chemotherapy in patients with incurable disease rather than prescribing an MGF for secondary prophylaxis is a reasonable alternative. Because there is wide variation in MGF prescribing, New Century Health (NCH) conducted a quality improvement analysis of MGF requests in a commercial and Medicare population. Objectives: To describe the cohort demographics, identify areas of improvement to promote cost-effective use, and measure the economic impact of interventions. Methods: The MGF authorization requests for oncology indications to NCH in 2013 were analyzed for cohort demographics, such as age, weight, tumor diagnosis, and treatment intention (eg, metastatic/palliative, curative, etc). The requests were analyzed for concurrent use with chemotherapy, approval status of the request (including reason for withdrawal), and cost-savings associated with the interventions. Results: There were 7958 requests for an MGF; 81% were for pegfilgrastim and 19% for filgrastim. The average age of the cohort was 66 years; weight-based dosing (>70 kg) was appropriate in 43% of patients receiving 300 mcg, and 72% of patients receiving 480 mcg. MGFs were most frequently requested in: breast (18%), lung (17%), lymphoma (14%), and gynecologic (8%) tumors. A total of 40% of the requests were for metastatic or recurrent disease, and 38% were for curative intent. In all, 6724 (84%) of the requests were authorized based on established-use criteria. The main reason for not authorizing was the lack of compendia support for primary and secondary prophylaxis; this resulted in approximately $3.5 million in cost-savings. Conclusions: There is an opportunity to improve the efficiency of MGF use in this population through a dose-rounding protocol and by promoting chemotherapy dose reductions, as advocated by the ASCO guidelines. Further analysis will assess the concordance of MGF use with the guidelines, specifically in regard to chemotherapy regimens and their risk for FN. Category: Quality Measurement in Oncology

Improving the Awareness, Identification, and Management of Sarcopenic Obesity: An Evidence-Based Toolbox Sarah Lindsey, MSN, APN, ACNS-BC, AOCNS; Kim Astroth, RN, PhD Mennonite College of Nursing, Illinois State University

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5th Conference Abstracts Background: Sarcopenic obesity, a loss of muscle mass coupled with an increase in fat mass, places the more than 14 million cancer survivors at greater risk for recurrence, new cancers, and long-term morbidity. Body mass index alone is not accurate enough to identify either muscle wasting or obesity. Sarcopenic obesity can be found in average-weight individuals. Research Questions: Will the use of an educational toolbox increase the advanced practice nurses’ perceived ability to identify and manage patients who are at risk for sarcopenic obesity? Will the introduction of the educational toolbox increase the documentation of patients’ baseline risk factors, education provided, and referrals made for the management of risk factors related to sarcopenic obesity? Participants: The convenience sample of participants included a group of advanced practice nurses (N = 15) from a large Midwest oncology practice. Method: One-group pretest/posttest using a controlled intervention “toolbox.” Instrument: Survey to assess awareness, identification, and monitoring of sarcopenic obesity. Intervention: An educational presentation that defines the problem and explains the implications for cancer survivors; educational resources that detail expert recommendations for nutrition, weight management, and physical activity; evidence-based practice guidelines adapted from the National Comprehensive Cancer Network Guidelines for Survivorship on healthy lifestyles, SARC-F rapid-scoring tool to assess the risk for sarcopenic obesity; a list of local referral resources for the expert management of functional impairment, physical disability, and nutritional counseling; a documentation template for practitioners to consider after providing an assessment or intervention; and a patient education handout. Framework used was the ACE Star Model of Knowledge Transformation. Preliminary Results: An educational toolbox provides an opportunity for advanced practice nurses to improve the awareness, identification, and monitoring of adult cancer survivors who are at risk for sarcopenic obesity. This opportunity could potentially improve the quality of life of cancer survivors. Category: Patient and Survivor Care

Measuring the Value of Telephone Distress Screening and Referral on Resource Utilization and Distress in Patients with Multiple Myeloma Kennedy V, Buzaglo JS, Goldberger S Cancer Support Community, Washington, DC Contact: Vicki Kennedy at vicki@cancersupportcommunity.org or 202-650-5379 Objectives: Although distress screening is known to reduce distress, little is known about its impact on service utilization. The Cancer Support Community (CSC), in collaboration with Onyx Pharmaceuticals, Inc, has established an integrated patient assistance program to screen and refer patients and caregivers facing advanced multiple myeloma for psychosocial services. We sought to measure the impact of distress screening on the utilization of resources and the effect on patient distress. Methods: Patients were asked 4 distress screening questions by an Onyx 360 Nurse Advocate during an initial phone call. For each question, patients self-reported a level of distress on a scale from 0 to 10 (0-lowest, 10-highest). Patients were then offered enrollment in Onyx 360 services, which include reimbursement and clinical support, transportation assistance, and real-time referrals to key resources. Consenting callers were transferred to the CSC, whose licensed mental health professionals conducted further assessment and offered free counseling, resource referral, and treatment decision counseling. Patients were rescreened 30 days after the initial call. Results: A total of 227 patients were screened for baseline distress. For each question, 70%-80% of patients expressed some level of distress (ie, ≥1). A total of 172 (76%) patients responded with a distress level of ≥4 for ≥1 of the screening questions; of the patients who were also new to the program, 86% subsequently enrolled in ≥1 Onyx 360 service, including 72% enrolling in transportation services and 27% enrolling in copay assistance. Referral rates to the CSC increased when screening was performed compared with when it was not. A total of 145 (64%) patients completed a follow-up call; 74% reported lower levels of distress for ≥1 question since the initial call. Among patients who initially reported a distress level of ≥4 on ≥1 of the screening questions, 79% reported lower levels of distress for ≥1 question since the initial call. Conclusion: The inclusion of distress screening into a pharmaceutical patient assistance program made a significant difference in identifying patients with distress and linking them to resources. Patients utilized these free professional resources at a higher rate when distress screening was implemented compared with when it was not. Distress levels, especially for those with the highest levels, decreased after patients engaged with these resources and services. Patient satisfaction with the services provided was extremely high. These results demonstrate that

a simple distress screening, referral, and follow-up program can improve psychosocial outcomes in patients with advanced multiple myeloma in a unique telephonic setting. Further research is needed to determine whether reduced levels of distress will translate into increased duration of therapy and increase in value to the patient and healthcare system. This work is supported through an unrestricted grant by Onyx Pharmaceuticals, Inc, an Amgen subsidiary. Category: Symptom Management and/or Supportive Care

Demonstrating Return on Investment for Stakeholders in a Care Coordination Program Sheryl Riley Director of Clinical Programs, SAI Systems International, Inc Contact: Sheryl Riley at sriley@saisystems.com or 908-397-1706 Background: Too many patients are being hospitalized for side effects and adverse drug reactions that can and should be managed by their doctors and nurses. When looking at the reasons for readmission, 33% of these result from potentially preventable problems, such as nausea, vomiting, dehydration, and postoperative pain. Objectives: To show that stratifying and assigning acuity to patients based not only on cost but also on disability, functional, and cognitive weights and measures can assist in creating a better plan of care for patients, which improves symptom management and decreases the use of emergency department and hospital admissions; and that by utilizing data analysis, you place tools into the hands of the treating physicians that can improve care and cost-effectiveness. Discussion: The early identification of members who may benefit from care coordination is critical to ensure quality outcomes and to have a positive impact on healthcare costs. Our proprietary algorithm synthesizes demographics; laboratory, medical, behavioral, and pharmaceutical claims; as well as health risk assessment responses to stratify patients into risk categories, which allows proper placement in the best level of care to achieve the best patient and cost outcomes. Through comprehensive care coordination, we are able to drill down further on each patient to identify those who are at a greater risk for complications (eg, patients aged >65 years; patients who have comorbidities; those with gastrointestinal cancer; and those with late-stage cancers who have a greater risk of rehospitalization after cancer surgery). Once these risks are identified, the care coordinators will develop a plan of care that includes building a relationship with the patient and the family, following the patient at home, and frequent, consistent communication to focus on proactive education regarding treatment and side effects, all the time working as a physician extender to assist the oncologist and the rest of the healthcare team. Conclusion: By working directly with patients and their families to keep them informed, educated, and out of the hospital, comprehensive, well-managed care coordination programs can aid patients, physicians, and health plans regarding symptom management and care support, which are clinical and financial wins for stakeholders. Category: Utilization and Cost-Effectiveness

Budget Impact Analysis of Abiraterone Acetate plus Prednisone versus Enzalutamide for the Treatment of Patients with Metastatic CastrationResistant Prostate Cancer Lorie A. Ellis, PhD1; Dominic Pilon, MA, MD2; Patrick Lefebvre, MA2 1 Janssen Scientific Affairs, LLC, Horsham, PA; 2Groupe D’Analyse, Ltée, Montreal, QC, Canada Contact: Lorie A. Ellis at Lellis@its.jnj.com or 443-640-4744 Objective: Previous studies have shown that abiraterone acetate plus prednisone (AA+P) is the most frequently prescribed first-line therapy for advanced prostate cancer among therapies that offer a survival benefit (ie, AA+P, enzalutamide [ENZ], docetaxel, cabazitaxel, and sipuleucel-T). The objective of this study was to model the financial impact of an oral treatment mix for antineoplastic metastatic castration-resistant prostate cancer (mCRPC) in the pharmacy budget from a commercial health plan perspective. Methods: An analytic model was developed for a hypothetical million-member commercial health plan to estimate the costs incurred by different treatment mixes of AA+P and ENZ for patients with mCRPC. The prevalence and incidence rates of prostate cancer were derived from US surveillance data, and mCRPC progression data were obtained from published trials to estimate the number of patients with mCRPC. The base-case treatment mix was obtained from studies of physician prescribing patterns observed from retrospective health claims studies. The pharmacy costs were calculated from the wholesale acquisition costs (wholesale acquisition price effective on August 7, 2014) of a 30-day supply of AA ($7376.68) plus prednisone ($10.85) or ENZ ($8355.03). The budgetary impact of increasing the proporContinued on page 32

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5th Conference Abstracts Budget Impact Analysis of Abiraterone Acetate plus... Continued from page 31 tion of patients receiving first-line AA versus increasing the number of patients receiving first-line ENZ was evaluated. Results: A total of 256 patients with mCRPC per million members was estimated; 65% of these patients were assumed to be treated with an oral agent in the first-line setting. The 30-day treatment costs per patient were higher for ENZ ($8355.03) than for AA+P ($7387.53). Assuming 50% of patients were treated with first-line AA+P and 15% were treated with first-line ENZ, the total pharmacy costs were $10,171,600 and $15,257,400 for 8 months and 12 months of therapy, respectively. Decreasing first-line therapy with AA+P by 10%, 20%, or 30% with a corresponding increase in first-line ENZ resulted in $193,500, $394,740, and $588,240 of additional spending over an 8-month period. Likewise, decreasing first-line therapy with AA+P by 10%, 20%, or 30% with a corresponding increase in first-line ENZ resulted in $290,250, $592,110, and $882,360, respectively, of incremental pharmacy expenditures over a 12-month period. Conclusion: The model demonstrates the financial impact of a treatment mix of oral antineoplastic therapies for mCRPC. For each 10% of first-line AA+P replaced by ENZ, pharmacy spending increased by approximately $200,000 over an 8-month period and by approximately $300,000 over a 12-month period. These results have important implications for population health decision makers who are evaluating the relative value of therapies for this patient population. This study was funded by Janssen Scientific Affairs, LLC. Category: Utilization and Cost-Effectiveness

Budget Impact Analysis of Ibrutinib for Patients with Previously Treated Mantle-Cell Lymphoma Schenkel B,1 Dandappanavar A,2 O’Day K,2 Queener M1 1 Janssen Scientific Affairs, LLC, Horsham, PA; 2Xcenda, Palm Harbor, FL Contact: Brad Schenkel at bschenk9@its.jnj.com or 215-325-3614 Objective: In the United States, approximately 4000 cases of mantle-cell lymphoma (MCL) and 1000 attributed deaths occur annually. The management of previously treated MCL is challenging, because responses to second- and third-line chemotherapies are often incomplete and are not durable as a result of the highly toxic regimens. Ibrutinib is approved by the US Food and Drug Administration (FDA) for the treatment of MCL in patients who have received at least 1 previous therapy. Because of the increased healthcare costs, health plans are interested in the budget impact of new treatments. The objective of this analysis was to estimate the budget impact of adding ibrutinib to a US health plan formulary over a 1-year time horizon. Methods: An Excel-based budget impact model was developed to evaluate the budget impact of ibrutinib in a hypothetical 1-million-member US health plan. The comparators included FDA-approved and category 2A National Comprehensive Cancer Network–recommended regimens for patients with previously treated MCL. The dosing, administration, mean duration of therapy (DOT), and adverse event (AE) rates were based on package inserts for the approved drugs and on published literature for NCCN-recommended regimens. The drug and administration costs were based on RED BOOK and on the Centers for Medicare & Medicaid Services Physician Fee Schedule, respectively. The AE costs were based on the Agency for Healthcare Research and Quality’s Healthcare Cost and Utilization Project data and on published literature. The estimated treatment-eligible population was estimated from epidemiologic data and a large claims database analysis. The market share was estimated for each treatment with and without ibrutinib. The incremental per-treated-member per-month (PTMPM) cost and incremental per-member per-month (PMPM) cost were calculated. A one-way sensitivity analysis was also performed. Results: The model estimated a treatment-eligible population of 17 previously treated patients with MCL for a 1-million-member health plan. The 1-year incremental budget impact of adopting ibrutinib for previously treated patients with MCL was $838 PTMPM, or $0.014 PMPM. The model results were most sensitive to ibrutinib DOT, followed by ibrutinib market share, and proportion of treated population aged ≥65 years. Conclusions: The model estimates a small treated population and indicates that the budget impact of ibrutinib is estimated to be modest from a US health plan perspective. This is important for healthcare decision-making, considering the efficacy and safety benefits for ibrutinib in this orphan disease with a high unmet need. This study was funded by Janssen Scientific Affairs, LLC.

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Category: Utilization and Cost-Effectiveness

Cost-Effectiveness of Octreotide LAR versus Lanreotide Depot in the Treatment of Metastatic Gastrointestinal Neuroendocrine Tumors Rajeev Ayyagari, PhD1; Maureen Neary, PhD, MS2; Shang Li, MS3; Chen Zhao, PhD3; Keiko Higuchi, MPH2; Jipan Xie, MD, PhD3; Al B. Benson III, MD, FACP, FASCO4 1 Analysis Group Inc., Boston, MA; 2Novartis Pharmaceuticals, East Hanover, NJ; 3 Analysis Group Inc., New York, NY; 4Northwestern University, Chicago, IL Background: The long-acting somatostatin analogs octreotide LAR and lanreotide depot are recommended in guidelines by the National Comprehensive Cancer Network (NCCN) for the treatment of functional and nonfunctional metastatic gastrointestinal neuroendocrine tumors (GI-NETs). This study estimated the cost and effectiveness of treating metastatic GI-NETs with long-acting octreotide versus lanreotide from a US payer perspective. Methods: An economic model was constructed to compare octreotide versus lanreotide on effectiveness and costs among functional and nonfunctional patients with GI-NETs over 3-year and lifetime horizons. The model estimated costs, lifeyears, and quality-adjusted life-years (QALYs) using an annual discount of 3%. A partitioned survival structure was used. Patients were distributed among stable disease, progressive disease, and death with breakthrough symptoms possible for functionally active patients. The efficacy inputs for octreotide were obtained from the PROMID trial. The efficacy for lanreotide was assumed to be the same as that of octreotide because of lack of data comparing these drugs. The equal efficacy assumption is supported by the fact that the NCCN guidelines do not differentiate between these drugs and treat them as interchangeable. Utilities for stable and progressive disease, which are used for estimating QALYs, were obtained from a published study estimating the utilities for NET. The costs for treatments, hospitalizations, physician visits, procedures, and end-of-life treatment were considered and were obtained from standard sources and the literature. Results: The total life-years and QALYs were identical for the 2 drugs because of equal efficacy assumptions. Over the 3-year horizon, on average, patients lived 1.8 years with stable disease and 0.8 years with progressive disease, and spent 0.2 years with breakthrough symptoms requiring additional treatment. The estimated QALY was 1.8 years. Over 3 years, the overall cost was $250,547 for patients receiving lanreotide and $223,437 for patients receiving octreotide. Patients lived 7.9 years on average, with patients receiving octreotide incurring $84,875 less in lifetime costs than patients receiving lanreotide. Conclusions: For patients with metastatic GI-NETs, the cost of treatment with octreotide LAR was considerably lower than the corresponding cost for treatment with lanreotide depot over the 3-year and lifetime horizons. Category: Utilization and Cost-Effectiveness

Patterns of Utilization of Bortezomib Retreatment in Patients with Relapsed and/or Refractory Multiple Myeloma Who Received ≥3 Lines of Therapy: Analysis of Physician Chart Data from US Community Oncology Practices S. Jagannath,1 A. Roy,2 J. Kish,3 D. Globe,2 E. Kuriakose,2 D. Siegel4 1 Mount Sinai Hospital, New York, NY; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Xcenda, Palm Harbor, FL; 4John Theurer Cancer Center, Hackensack, NJ Background: The introduction of “novel” agents, including bortezomib (BTZ) and the immunomodulatory drugs (IMiDs) lenalidomide, thalidomide, or pomalidomide, as treatments for multiple myeloma (MM) has significantly prolonged patient survival. Physicians can choose from older agents or novel agent–based induction therapies as well as carfilzomib and pomalidomide, in later lines. Retreatment with BTZ or an IMiD after their initial use is common in patients who have had a durable response before relapse. Guidelines offer many options for induction therapy and in patients with relapsed and/or refractory MM (RRMM), leading to widely varying anticancer regimens and sequencing patterns in real-world settings. Objective: To describe baseline treatment patterns and real-world utilization of BTZ and IMiDs through multiple regimens of therapy in RRMM, and to better understand which retreatment and sequencing scenarios are preferred in clinical practice. Methodology: A retrospective chart review was conducted among patients treated for MM in 30 large US community oncology practices, between January 1, 2007, and the data cutoff on March 31, 2014. From an original patient sample of 4729 patients with an International Classification of Diseases, Ninth Edition–coded diagnosis for MM, the final RRMM study population was a cross-section of 589 patients at various treatment stages who had received ≥3 treatment regimens in a community setting by the cutoff date. Results: Of the 589 patients with RRMM who were studied, 261 (44%) had at

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5th Conference Abstracts least 4 regimens and 116 (20%) had at least 5 regimens. From this sample, the first recorded therapy was BTZ with various treatment partners in 55% (324/589) of patients. Of these patients, 58% (187/324) were retreated with BTZ in the next line, whereas 47% (153/324) received BTZ 2 lines later. A total of 28% (92/324) of patients started on BTZ were retreated with BTZ on the next 2 lines, often with companion IMiDs. In addition, a large majority of patients started on IMiDs were switched to BTZ. Conclusion: This chart review shows that a significant fraction of patients with RRMM are being treated with >3 lines of therapy after starting on BTZ or IMiDs. Retreatment with BTZ was common, even before its formal August 2014 approval for reuse. Physicians often start therapy with BTZ to reuse it following early relapses in patients where the tumor is not refractory to BTZ. In this chart review, retreatment with BTZ was more common than switching to IMiDs. The addition of an efficacy-enhancing companion agent to BTZ for retreatment on later lines may further increase the value and efficacy of care delivered. Category: Utilization and Cost-Effectiveness

Utilization Beyond Traditional Oncology Care Management: Utilizing Multiple Data Sets and Clinical Tools to Improve the Care and CostEffectiveness in the Management of Oncology Patients Sheryl Riley Director of Clinical Programs, SAI Systems International, Inc. Contact: Sheryl Riley at sriley@saisystems.com or 908-397-1706 Utilization management evaluates the appropriateness and medical need of healthcare services while applying evidence-based criteria or guidelines. Plans utilize this information to proactively manage the costs relative to high-dollar drugs and/or procedures. This process is not always provider- and patient-friendly, so utilizing retrospective data analysis to view treatment cost and patterns of care can and should be beneficial in controlling cost. The presentation will outline the type of data needed, as well as the role that data elements play in the process; describe in detail how each element of clinical, operational, and financial data can play into the administration of oncology management; and ascertain how each of these elements works to identify, stratify, and engage the right members for the program. We will also outline how comprehensive and proprietary algorithms utilizing the current patient data can be used to engage physicians and health plans to improve overall patient care. The hope is that with this information we can empower oncologists and health plans to better understand where oncology dollars are being spent, who is spending them, and what they are being spent on. In turn, this information can and should be utilized to change and/or improve current practice patterns in the areas of utilization, symptom management, hospital admissions, and emergency department visits, and the use of palliative and hospice care, therefore supporting the link between data and improving patients’ clinical and financial outcomes. Objectives: To outline the data items needed to create the best clinical, operational, and financial analysis; to define how different types of data are utilized to find the right patients for the program; to identify where dollars are being spent, on what services, and by which physicians; and to describe how utilizing assessment data and additional information collected will improve patient outcomes through reducing hospital admissions and emergency department visits. Category: Utilization and Cost-Effectiveness

Utilization of the New Agents Carfilzomib and Pomalidomide in Relapsed and/ or Refractory Multiple Myeloma: Analysis from 30 Large US Community Oncology Practices S Jagannath,1 A Roy,2 J Kish,3 D Globe,2 E Kuriakose,2 D Siegel4 1 Mount Sinai Hospital, New York, NY; 2Novartis Pharmaceuticals Corporation, East Hanover, NJ; 3Xcenda, Palm Harbor, FL; 4John Theurer Cancer Center, Hackensack, NJ Background: The introduction of bortezomib (BTZ) and lenalidomide (LEN) as induction therapies in multiple myeloma (MM) has lengthened progression-free survival in early stages of disease and has increased overall survival. However, for patients previously exposed to both therapies, there are few other available therapeutic options. The recent approval of the proteasome inhibitor carfilzomib (CFZ) and the immunomodulator pomalidomide (POM) adds 2 relatively novel options for patients with relapsed and/or refractory MM (RRMM) to the treatment algorithm. Objective: To evaluate US community oncologists’ prescribing behavior with recently introduced CFZ and POM for RRMM. Methodology: A retrospective chart review was conducted for patients treated for MM in 30 large US oncology practices between January 1, 2007, and the data

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cutoff on March 31, 2014. From an original sample of 4729 patients with an International Classification of Diseases, Ninth Edition–coded diagnosis for MM, the final RRMM study population was a cross-section, with 589 patients at various treatment stages who had received ≥3 treatment regimens in a community setting by the cutoff date. Results: In 589 patients with RRMM who received ≥3 previous treatment regimens, the use of CFZ and POM had increased with each successive treatment: 1 previous treatment, 2%; 2 treatments, 11%; 3 treatments, 27%; 4 treatments, 33%; and 5 previous treatments, 22%. The chart data revealed that patients who received frontline therapy with bortezomib/lenalidomide/dexamethasone (RVD) were started on new therapies after earlier relapses than patients who received doublet induction with bortezomib/dexamethasone (VD) or lenalidomide/dexamethasone (RD). Patients who received VD induction were prescribed CFZ and/or POM less often in later treatment lines than patients who received RD or RVD induction. Of patients receiving induction with VD, RD, and RVD, 19%, 33%, and 44%, respectively, were prescribed new agents after relapse. Conclusion: An analysis of prescribing patterns for new agents for the treatment of RRMM showed that within 1 year to 1.5 years of the launch of CFZ and POM, they were frequently prescribed by community oncologists after 3 previous treatments. Most community oncologists initiated treatment of MM with a doublet, and often retreated once or twice with BTZ and/or LEN/thalidomide before using the new drugs (up to 33% of patients with 3 previous treatments). In contrast, when patients were started on RVD, almost 50% with 3 previous treatments received the new agents. The lower utilization of new therapies after induction with VD, relative to RD and RVD, may reflect physicians’ preferences for early retreatment with BTZ. Category: Value-Based Pricing in Oncology/Cost-Effectiveness

Economic Impact of a Novel Circulating Tumor DNA Test for ThirdGeneration EGFR TKI Biomarker Testing in NSCLC Gary Gustavsen,1 Patrick Kennedy,1 Martha Boylston,1 Maxwell Mean,1 Oanh Dang,2 Vlada Melnikova,2 Mark Erlander2 1 Health Advances, LLC, Weston, MA; 2Trovagene, Inc., San Diego, CA Background: The explosion of targeted therapies in oncology has placed significant pressure on tissue acquisition for companion diagnostic testing. Non– small-cell lung cancer (NSCLC) is a particularly important indication with high demand for molecular testing yet suboptimal tissue access. Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are approaching launch, placing even greater demands on tissue. Eligibility for these therapeutics will be determined by the presence of a T790M resistance mutation, as identified by a repeat biopsy. Given the high expense of a repeat biopsy, the use of a novel circulating tumor DNA (ctDNA) test from Trovagene, based on either blood or urine samples, may provide clinical and economic benefits to the healthcare system. Objective: The purpose of this study was to quantify the economic impact of the ctDNA test for US commercial health plans. Methods: A fact-based economic model was developed for a hypothetical cohort of patients who had progressed on first-line EGFR TKIs and were considering third-generation EGFR TKI therapy (once approved). Costs were assigned to each unit of care based on 2014 Medicare fee-for-service rates and other published costs of care. Patients were followed for 5 years, with management assumptions based on patterns of care and progression data. Costs were calculated for 2 scenarios: a “reference scenario” representing standard practice with a tissue-based repeat biopsy and a “test scenario” utilizing the ctDNA test. The total cost of care was compared between the 2 scenarios. Sensitivity analyses were performed around key inputs to test model robustness. Results: The ctDNA test reduces costs by $12,938 per patient tested. For a health plan with 10 million members, this would translate to more than $26 million. The vast majority of savings is generated by the avoidance of invasive biopsies, which often lead to very expensive complications. In sensitivity analyses, no single input, when altered within a reasonable range, caused the model to show the test was no longer cost-saving. Limitations: Patient care was modeled based on clinical guidelines, published literature, and physician expert opinion. Real-world practice may differ from the modeled care pattern. The costs were based on national Medicare rates, and may vary by individual health plans. Conclusion: Beyond the clinical and logistical improvements seen with a highly accurate liquid biopsy test, the ctDNA test would likely reduce costs for health plans that choose to cover it. n

APRIL 2015

www.ValueBasedCancerCare.com

Gynecologic Oncology Highlights

Comprehensive Cancer Center Designation Trumps High Volume as Predictor for Outcomes in Ovarian Cancer By Charles Bankhead

Chicago, IL—The National Cancer In- ic survival,” said Robert E. Bristow, stitute (NCI) designation of a compre- MD, MBA, Director of Gynecologic hensive cancer center trumps high case Oncology, University of California, volume as a predictor of outcomes in ovarian cancer, according to a single- region analysis.

“

NCI comprehensive cancer center status is an independent predictor of adherence to ovarian cancer treatment guidelines and improved disease- specific survival.

Increased Survival

NCI-designated centers had a median survival of almost 80 months compared with 52 months for patients who received treatment at high-volume centers that were not part of the National Comprehensive Cancer Network (NCCN). Low-volume centers lagged further behind with a median overall survival of 43 months. Similar differences emerged from an analysis of ovarian cancer–specific survival, according to a presentation at the 2015 Society of Gynecologic Oncology annual meeting. “NCI comprehensive cancer center status is an independent predictor of adherence to ovarian cancer treatment guidelines and improved disease-specif-

at a glance ➤ Access to NCI-designated centers may improve clinical outcomes in patients with ovarian cancer ➤ NCI designation of a comprehensive cancer center was more predictive of outcomes in ovarian cancer than high case volume ➤ High-volume centers were 17% less likely to follow all NCCN guidelines and 18% less likely to adhere to chemotherapy versus 44% and 56%, respectively, for low-volume hospitals ➤ Patients treated at an NCIdesignated center had a median survival of 80 months versus 52 months at highvolume centers and 43 months at low-volume centers

or on the basis of case volume, which was defined as fewer than 10 cases annually (low) or more than 10 annual cases

”

—ROBERT E. BRISTOW, MD, MBA

Irvine, Orange. “NCI comprehensive cancer center status is a structural healthcare characteristic correlating with superior ovarian cancer quality- measure performance. Improving access to NCI-designated centers through regional concentration of care may be a mechanism to improve ovarian cancer clinical outcomes.” NCI Designation

NCI designation represents exclusiv ity among the nation’s cancer centers. The designation comes with restrictive entry criteria that include research infrastructure and programs, innovative clinical trials, outreach, and education. NCI-designated centers account for 4% of the nation’s 1500 cancer centers. However, a center’s benefit to the regional cancer population served remains poorly defined, said Dr Bristow.

Study Details

To examine the impact of NCI designation on ovarian cancer care in Southern California, investigators reviewed the clinical records of NCI comprehensive cancer centers serving Los Angeles, Orange, Riverside, San Bernardino, and San Diego counties. They searched rec ords of the California Cancer Registry for the years 1996 through 2006. The search was limited to a first or only diagnosis of epithelial ovarian cancer. Cancer centers in the region were classified according to NCI designation

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(high). The quality of care was assessed on the basis of NCCN guidelines for 1997 through 2005. The study comprised 192 hospitals, including 5 NCI-designated cancer centers (averaging 14.5 cases annually), 29 high-volume facilities (14.6 cases annually), and 158 low-volume facilities (2.6 cases annually). The data analysis comprised 9933 patients who had a median age of 61 years, International Federation of Gynecology and Obstetrics (FIGO) stage III or IV disease in 69.3% of cases, and serous histology in 40.3% of cases. With respect to health insurance, NCI-designated centers had a fairly even distribution of patients covered by managed care plans, Medicare, and Medicaid. A majority of patients in high-volume facilities were in managed care systems, and the low-volume facilities predominantly treated patients covered by managed care plans and Medicare. Socioeconomic Status

Patients in the lowest socioeconomic status (SES-1) accounted for almost 25% of patients in NCI-designated centers, and patients in SES-2 through SES-5 accounted for roughly equal proportions. SES-4 and SES-5 accounted for more than 50% of the patients in high-volume centers; and SES-2, SES-3, and SES-4 constituted approximately 66% of the patients in low-volume centers.

Adherence to NCCN Guidelines

Complete adherence to NCCN treatment guidelines was modest, at 35.7% of the almost 10,000 patients. Adherence to surgery recommendations was 51.2%, and adherence to chemotherapy recommendations was 62.0%. Adherence to all 3 categories decreased from NCI centers to high-volume centers, and from high-volume centers to low-volume centers (P <.0001). By multivariate logistic analysis, high-volume centers were 17% less likely to follow all NCCN guidelines, 17% less likely to adhere to surgical guidelines, and 18% less likely to adhere to chemotherapy recommendations; the corresponding figures for low-volume hospitals were 44%, 32%, and 56%, respectively. The median overall survival for all 9933 patients was 49.9 months, but ranged from 77.9 months at NCI- designated centers to 51.9 months at high-volume centers and 43.4 months at low-volume centers (P <.0001).

“

Improving access to NCI-designated centers through regional concentration of care may be a mechanism to improve ovarian cancer clinical outcomes.

”

—ROBERT E. BRISTOW, MD, MBA

The median ovarian cancer–specific survival times were 46.1 months overall, 67.0 months at NCI-designated centers, 50.8 months at high-volume centers, and 38.5 months at low-volume centers (P <.0001). Dr Bristow acknowledged that there are limitations of the analysis, including its retrospective design, inability to account for uncontrolled variables, a lack of adjustment for survival by NCCN guideline adherence, no evaluation of treating physicians’ specialty, and patient willingness or ability to travel to a specific center. n

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Interview with the Innovators

Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments with the bioT3 Approach

An Interview with Ralph V. Boccia, MD, FACP, of Georgetown University

T Ralph V. Boccia, MD, FACP

he current generation of oncologists has witnessed great advances in our understanding of tumor biology and biomarkers linked to treatments. Those advances started with research, but disseminating this information can be difficult given the myriad of obstacles in adoption to practice. The science behind these advances is fascinating and excites those in medicine with the possibility of providing meaningful, life-altering care to patients. But still there exists the reality of the vetting of each new discovery, starting with niche use among the early users, before it gets adopted more broadly. With the advent of molecular medicine, we have novel options to detect and identify genetic mutations and other biomarkers to assist in selecting the appropriate therapy to target cancer cells. Combining this knowledge with guidelines of how to treat based on tumor type can only serve to improve patient outcomes.

PMO Genomic tools such as next-generation sequencing are not widely adopted in community practices for metastatic patients. In your experience, what are the barriers to adoption? Dr Boccia The low uptake in the community is primarily due to the fact that the first wave of tools was developed to meet the needs of academia and don’t adequately address the needs of community practices. More specifically, when it comes to next-gen sequencing, research-focused oncologists are interested in understanding all mutations associated with a given tumor type, even if no agents are currently available that can target the related pathways. Increasingly, there is interest among these academics in obtaining information across the entire genome in the hope of future actionability, and often in the context of their collaborations with research divisions of pharmaceutical companies. In sharp contrast, treatment-focused oncologists are primarily interested in current actionability and thus interested in biomarkers linked to Food and Drug Administration (FDA)-approved drugs and late-stage clinical trial candidates. Further, they are focused on getting the information fast in a simple and easy-to-

understand tumor-specific report at a reasonable cost. Therefore, the use will increase when the needs of community practices are more directly addressed. PMO Can you discuss the strengths and weaknesses of the various next-gen sequencing tests to detect actionable biomarkers? Dr Boccia In terms of the first wave of tools developed for academia, there are 2

There are many options in selecting tests to gather pertinent information related to a patient’s genetic profile and the biology of their tumor. In this current installment of Interview with the Innovators, and with the intent to assist in the dissemination of impactful information, we focus on the bioT3 approach, which provides a molecular diagnosis for tumors with unclear diagnosis as well as comprehensive biomarker profiling, including mutational analysis and protein expression markers to assist oncologists in selecting site-specific and targeted therapy options for patients with metastatic cancer. The publishers of PMO had the pleasure of meeting with Dr Ralph V. Boccia from the Center for Cancer and Blood Disorders and Clinical Associate Professor at Georgetown University who participated in the research for these products and has first-hand experience with them in the clinic. To view the live interview, please visit www.PersonalizedMedOnc.com/videolibrary.

main approaches: 1) sequencing only, and 2) testing everything independent of tumor type. The strength of the “sequencing-only” approach is that it consumes very little tissue but, unfortunately, it is not a comprehensive platform. For some specific biomarkers, IHC [immunohistochemistry] and FISH [fluorescence in situ hybridization] are the more appropriate platforms versus sequencing. IHC

probes protein expression levels in the tumor, which cannot be performed with sequencing. This is relevant both for traditionally important biomarkers such as HER2, ER [estrogen receptor], and PR [progesterone receptor] expression, which are recognized to be important in breast cancer, as well as relatively new biomarkers such as programmed death-ligand 1 (PD-L1), which may have a growing

Diﬀerent needs related to metasta/c disease management Different needs related to metastatic disease management Research-focused oncologists

Treatment-focused oncologists

•  Research focused, and interested in clinical trial enrollment

•  Focused on patient care

•  Often specialize in specific cancers

•  More often see all cancers, with specialization in select cases

•  Interested in all targets, including those in the discovery stage

•  Interested in targets with FDA-approved drug or late-stage clinical trials candidates

•  Actionable now or in the future

•  Actionable now

•  Cost not usually a limiting factor

•  Cost-focused (especially patient portion)

Dr Boccia is a founder and the Medical Director of The Center for Cancer and Blood Disorders. He is also Clinical Associate Professor of Medicine at Georgetown University, consulting Medical Director of the International Oncology Network (ION) Clinical Research Program, and Chairman of ION’s Medical Advisory Panel.

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Interview with the Innovators bioT3 addresses needs for a broad

Treatment driven by CancerTYPE ID resulted in a Treatment driven by CancerTYPE ID resulted in a 37% increase in overall survival 37% increase in overall survival

bioT3 addresses needs group for a broadof group of metastatic patients patients metastatic Clear Diagnosis?

Rx alone

Overall Survival   (probability)

Dx + Rx

Yes

Oﬀering

Value proposition

•  Help achieve definitive diagnosis of tumor type & subtype •  Biomarkers linked to targeted treatments •  Reimbursement ease •  Logistical ease, minimal tissue use (low QNS) •  Time: 7-10 days

clinical relevance in melanoma, lung cancer, and other solid tumors. Sequencing also probes genetic rearrangements and amplifications in a manner that is inconsistent with approved targeted therapy labels and inclusion criteria of many clinical trials. Recent ASCO/CAP [American Society of Clinical Oncology/College of American Pathologists] guidelines for biomarker testing in lung cancer clearly state that ALK rearrangement testing should be done by FISH, in line with the pivotal studies for crizotinib and the corresponding package insert. Rearrangements, in principle, can also be probed by sequencing, but the cutoff criteria and the test specifics are not identical. Unlike academia, where the remaining tests can be done by inhouse pathology, it is not pragmatic for a community oncologist to work with multiple testing facilities to obtain comprehensive biomarker information. The “testing everything independent of tumor type” approach employs a very large number of biomarker tests. The strength of this approach is that it is extremely comprehensive. However, when you run such a large number of biomarkers independent of the type of cancer, you end up with slower turnaround times, high costs, and significant tissue use, in conflict with the basic needs for a community oncology practice. In addition, many biomarkers are only relevant within specific tumor types, so this approach is not aligned with the clinical evidence behind many biomarkers. High-cost tests like this are better used as a last resort when a patient has exhausted all standard-of-care options. PMO How common is the issue of unclear diagnosis in metastatic cancer? Dr Boccia In clinical practice, patients can present with carcinomas for VOL. 6

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•  Biomarkers linked to targeted treatments •  Concise actionable panel •  Lower cost •  Lower rejection rates (QNS) •  Tumor-speciﬁc reports •  Time: 5-7 days

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Median Survival, months Assay directed (n = 194) Empiric* (n = 396)

12.5 9.1

Time (months) Identiﬁed primary site of tumor in 98% of cases

which we cannot identify their primary site—otherwise called carcinomas of unknown primary site. In addition, there are certain ambiguous presentations where patients appear to have a certain type of tumor; however, the overlap of the clinical presentation with potentially different types of cancer makes the initial diagnosis unclear. Data would suggest that the combination of carcinomas of unknown primary site and the ambiguous presentations probably make up for around 100,000 patients newly diagnosed each year, which is ~15% of all newly diagnosed metastatic patients. So it’s no small number. It is important for clinicians to identify the primary site, because the treatment that we render is dictated by where the tumor started, not where the tumor ends up. Accurate diagnosis of tumor type/subtype is necessary for selecting the proper site-specific chemotherapy and molecularly targeted therapies. It is important to note that molecularly targeted therapies are indicated for specific tumor types. For example, vemurafenib is FDA approved for metastatic melanoma patients harboring a BRAF V600E mutation, but it is not approved in metastatic colorectal cancer with the same mutation and may not be effective in this case. So understanding the biomarker profile in the context of tumor type is important. PMO We understand that you have used bioT3 from bioTheranostics in your clinical practice. Can you share with us the type of patient for whom you use this approach, and how it compares to other offerings that you are familiar with? Dr Boccia I’ve had the opportunity to work with bioTheranostics for a number of years, first in the research setting and now in clinical practice. bioT3 was not commercially available when I first started doing research with them as part of a

* Based on historical control. Hainsworth et al. J Clin Oncol. 2013;31:217-223.

consortium looking at carcinomas of unknown primary site. I currently use bioT3 in my everyday practice for metastatic patients with clear as well as unclear diagnoses, from initial treatment through resistance and recurrence. The bioT3 offering combines tumor type diagnosis and comprehensive biomarker profiling for metastatic tumors. It is made up of 2 components, the first being CancerTYPE ID, a gene expression–based molecular tumor classifier. CancerTYPE ID is necessary when we’re looking to identify a primary tumor type, specifically if we’re confronted with a carcinoma of unknown primary site or potentially one of those ambiguous states where there is a differential diagnosis. An example of that might be metastatic squamous cell carcinoma in the lung that could be a primary bronchogenic squamous cell carcinoma in the lung, or it could be a primary head and neck squamous cell carcinoma metastatic to the lung. If unidentified using regular tools, CancerTYPE ID can help distinguish between these tumor types. Another example might be a patient who presents with abdominal carcinomatosis, and we don’t know if it’s a GI [gastroin testinal] or a GU [genitourinary] primary. CancerTYPE ID can be useful for cases in which the tumor type is unknown, and also in cases where there is diagnostic ambiguity and several tumor type possibilities exist. The second component is CancerTREATMENT NGS+, a comprehensive platform that includes next-generation sequencing, FISH, and IHC that lends us the opportunity to select therapies. The biomarkers tested by CancerTREATMENT NGS+ are based on National Comprehensive Cancer Network and ASCO guidelines and major phase 2 and phase 3 clinical trials, resulting in APRIL 2015

more concise panels and reports. This is in contrast to the complicated reports you receive when you do extensive next-generation sequencing that leave a lot of physicians in a position where they don’t understand where to go next. PMO How do you view the strength of the clinical validation evidence for the CancerTYPE ID, and how does it compare with other gene expression tests? Dr Boccia In comparison to other gene expression tests, CancerTYPE ID covers a significantly larger number of tumor types, 50 tumor types compared with 15 and 42. In addition, several studies have validated its accuracy and clinical utility. Specifically, the Mayo Clinic, University of California Los Angeles, and Massachusetts General Hospital have done a blinded study and documented the accuracy of CancerTYPE ID (Clin Cancer Res. 2012;18:3952-3960). A head-to-head comparison of CancerTYPE ID versus IHC demonstrated that CancerTYPE ID was significantly better (J Mol Diagn. 2013;15:263-269). A prospective study in patients with carcinomas of unknown primary site that we published in the Journal of Clinical Oncology showed a 37% improvement in overall survival in those patients profiled with this assay and then treated based on the tumor type identified compared with empiric standard-of-care chemotherapy (J Clin Oncol. 2013;31:217-223). PMO For what types of patients do you see a role for CancerTYPE ID in clinical practice? Dr Boccia We’ve used CancerTYPE ID in our clinical practice in a number of situations. When we get a pathology report back, the first thing we do is to look to see how they document where the tumor that they’re describing appears to have originated from. Oftentimes there is a long account of immu-

Continued on page 38

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Interview with the Innovators

Confirming Diagnoses and Identifying Biomarkers Linked to Targeted Treatments ...designed to Tumorwith speciﬁcthe panels Continued from page 37

nohistochemical stains describing what they conclude. But sometimes pathology reports have an inconclusive or ambiguous diagnosis from a histologic and immunohistochemical standpoint. An example might be a patient with a suspected diagnosis of non–small cell lung cancer [NSCLC] based on clinical correlation, but the pathology report indicates that the tumor is TTF-1 [thyroid transcription factor-1] negative, whereas most lung cancers, but not all lung cancers, are TTF-1 positive. If we think it is NSCLC but can’t be absolutely certain, that would be a reason to use the CancerTYPE ID. Additionally, if the clinical presentation is atypical, or if there are multiple lesions at a distant point from any organ, and standard workup does not provide a definitive diagnosis, then CancerTYPE ID can be very helpful in these situations. PMO Considering the second component of bioT3, for which patients do you see a role for CancerTREATMENT NGS+ in your clinical practice? Dr Boccia We find CancerTREATMENT NGS+ to be helpful in several situations. The first would be at the time of diagnosis where we’re looking to profile that patient’s tumor and make sure that we have in fact identified actionable targets. An example of that might be NSCLC, the nonsquamous variety, where we want to be sure that we have given the patient the best treatment options since there are several targeted therapies available based on the biomarker profile of the tumor. If, for instance, the tumor is EGFR, ALK-1, or ROS1 positive, that’s not a patient we want to be giving chemotherapy to at the outset, because randomized trials have clearly shown that the tyrosine kinase inhibitors offer the patient better response rates, better progression-free survival, and better overall survival. On the other hand, if these biomarkers are negative, then this patient is best suited for chemotherapy. So patients with a known diagnosis of metastatic NSCLC are candidates for CancerTREATMENT NGS+ in the up-front setting. CancerTREATMENT NGS+ is a great platform because it combines next-gen sequencing with FISH and IHC testing, which is important for NSCLC if you are looking for

optimize cost, turn-around time, QNS Tumor-specific panels designed to optimize cost, turnaround time, QNS rates, and actionability rates, and actionability IHC/FISH tests

Next-Generation Sequencing panel (NGS) NSCLC

CRC

Breast

Melanoma

ALK (FISH)

PTEN (FISH)

HER2 (IHC)

PD-L1 (IHC)

Comprehensive panel

ABL1

EGFR

GNAS

KRAS

PTPN11

AKT

ERBB2

GNAQ

MET

RB1

ALK

ERBB4

HNF1A

MLH1

RET

APC

EZH2

HRAS

MPL

SMAD4

RET (FISH)

PTEN FISH)

ATM

FBXW7

IDH1

NOTCH1

SMARCB1

PDL1 (IHC)

ER (IHC)

EGFR (IHC)

BRAF

FGFR1

JAK2

NPM1

SMO

PR (IHC)

FGFR1 (FISH)

CDH1

FGFR2

JAK3

NRAS

SRC

CDKN2A

FGFR3

IDH2

PDGFRA

STK11

CSF1R

FLT3

KDR

PIK3CA

TP53

CTNNB1

GNA11

KIT

PTEN

ROS1 (FISH)

HER2 (FISH)

ALK (FISH) C-MET (IHC) C-MET (FISH)

HER2 (IHC) HER2 (FISH) RET (FISH) ROS1 (FISH)

PD-L1 (IHC)

VHL

PTEN (FISH)

•  Concise list of FISH and IHC biomarkers for NSCLC, CRC, Breast, and Melanoma based on NCCN® recommended biomarkers and phase 2/3 clinical trials •  In contrast, the comprehensive panel is designed to maximize “shots on goal”

ALK rearrangements because ASCO/ CAP guidelines recommend that ALK testing be performed by FISH. If you’re looking for PD-L1 expression, the best way to assess this is through IHC. CancerTREATMENT NGS+ is also very useful for those metastatic cases in which several lines of therapy have been implemented and the disease progresses. A good example of that would be a breast cancer patient with ER+/PR+ tumor type; we would offer several lines of endocrine therapy before moving on to chemotherapy. Once we’ve gotten beyond those first several lines of therapy and looking for additional actionable targets or clinical trial options, that would be a good time to use CancerTREATMENT NGS+ secondarily. There are times when we would use the 2 components of bioT3 together. An example would be an unknown primary site, let’s say an ambiguous primary site or one that we thought might be lung. CancerTYPE ID would help us confirm this is an NSCLC, and that it is nonsquamous, to allow us to better understand whether there is an actionable target, specifically ALK, ROS1, RET, and EGFR. So combining them in this

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APRIL 2015

instance would be a perfect tool for us to set up a treatment program that we could carry through for many lines of therapy. PMO An important theme at ASCO 2014 is the importance of managing costs of cancer care, particularly for metastatic patients. How important is it to

“

We’re at a point in this society where healthcare costs are clearly out of control. The budget is unsustainable, and it’s important that all of us contribute to controlling costs the best we can.

”

—RALPH V. BOCCIA, MD, FACP

lower cost from the perspective of community practices, and how does bioT3 address this critical need? Dr Boccia We’re at a point in this society where healthcare costs are clearly out of control. The budget is unsustainable, and it’s important that

all of us contribute to controlling costs the best we can. There is ongoing payment reform, and so the whole system is changing in the next several years. What this means is that we’re going to be sharing risks with the carriers, as well as showing value and quality with our treatment selection. Accountable care organizations are forming and will recruit members, and all will share risk. The upside potential here is enormous to begin to control the cost of some of these more expensive tests and provide actionable answers for more effective therapy. In looking at Explanation of Benefits coming in from my patients for the testing we have ordered, I’m sometimes appalled. I’ve seen bills for profiling as high as $30,000, certainly $5000, $6000, $7000, and $8000. As a treatment-focused community physician, it is very important for me to obtain actionable information in a cost-effective manner, and I think the bioT3 approach takes this into account. PMO Thank you very much for your time today, and our best wishes to you for continued success. Dr Boccia Thank you, it was my pleasure. n

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Features:

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

AVBCC Conference Highlights VBCC Perspectives VBCC Videos Cancer Drug Updates Clinic Profile Economics of Cancer Care VBCC_WebKsize_51315

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Health Policy

ASCO’s Annual Report: Major Advances in Oncology and the Challenge of... Continued from the cover

vention and screening to treatment and survivorship—and it covers a broad range of cancer types, including progress against rare cancers,” ASCO President Peter Paul Yu, MD, Director of Cancer Research, Palo Alto Medical Foundation, CA, told Value-Based Cancer Care (VBCC). Dr Yu noted that this report “presents a narrative of the top trends in oncology taking place across disease areas. This narrative highlights exciting areas of cancer research and the growing number of treatment options we have now, that we didn’t have 20, 40, or 60 years ago.” In addition, however, the report emphasized the ongoing challenge of paying for these advances in oncology and the high cost of cancer care, which present barriers for patients and for oncologists, negatively affecting patient outcomes, and making value-based care an urgent topic requiring continuing discussions and new solutions.

the approval of 4 new therapies. These include 2 immunotherapies, obinutuz umab (Gazyva) and ofatumumab (Ar zerra), and the 2 new tyrosine kinase inhibitors, ibrutinib (Imbruvica) and idelalisib (Zydelig).

Advance of the Year: Chronic Lymphocytic Leukemia

“Over a merely 1-year period, patients with CLL gained 4 new treatment options. This marks an unprecedented pace of progress for any single type of cancer. The new therapies have filled an unmet clinical need for those with newly diagnosed or resistant disease, making treatment—and remission—possible for more patients than ever before,” Dr Yu told VBCC.

The biggest advance in cancer research was identified as the transformation of treatment for chronic lymphocytic leukemia (CLL), the most common form of leukemia in older adults, with

at a glance ➤ ASCO’s new annual report on clinical cancer advances shows gains in research and prevention have led to longer survival, better quality of life, and decreased disease burden ➤ Patients with CLL now have 4 new treatment options for newly diagnosed or resistant disease, making treatment and remission possible for more patients ➤ Chemotherapy combined with radiotherapy in patients with low-grade gliomas extended patients’ life span by 5 years compared with radiotherapy alone ➤ ASCO is developing a decision-making tool for value-based care to guide discussions between physicians and patients regarding treatment value and patient-centered care

menopausal women at risk for breast cancer. And the new Medicare reimbursement for lung cancer screening with low-dose computed tomography may help to diagnose lung cancer at an early stage and reduce deaths.

“

Healthcare has become increasingly unaffordable to patients and their families and to society at large, both of whom bear the costs of care. As this happens, increasing numbers of patients face the threat that they will be left behind the advances in cancer care. Disparities in healthcare will widen.

”

Advances in Treatment, Prevention, and Screening

The report highlights advances in combination therapies and targeted therapies for cancer. Of special note are the new combination therapies for patients with brain cancer and those with prostate cancer. The combination of chemotherapy and radiotherapy in patients with low-grade gliomas extended patients’ life span by 5 years compared with radiotherapy alone. For patients with advanced prostate cancer, first-line chemotherapy combined with hormone therapy showed improved patient survival. The new targeted therapies became available for non–small-cell lung cancer, advanced stomach cancer, and radioiodine-resistant differentiated thyroid cancer. Immunotherapies are a main advance in cancer therapy, and many new drugs are targeting rare types of cancer. Two major advances in cancer screening and prevention include the oral drug anastrozole (Arimidex), which showed an almost 50% decrease in the risk for breast cancer in a large study of post-

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—PETER PAUL YU, MD

There has also been exciting progress in understanding tumor biology. “Largescale cancer genome analyses have provided a wealth of new information that may help identify new targets for cancer therapy. This new information may also help identify biomarkers for use in monitoring disease progression, assessing the risk for relapse, and selecting the optimal therapy for each individual patient,”

“

It is critical that patients and physicians understand the value of treatment options.” ASCO is developing a “physicianguided decision-making tool to help physicians discuss with their patients the value of any particular treatment and will support patientcentered care.

”

—PETER PAUL YU, MD

explained Dr Yu. The Challenge of Value-Based Care

The importance of value-based cancer care remains a continuing challenge. “Healthcare has become increasingly unaffordable to patients and their families and to society at large, both of whom bear

the costs of care. As this happens, increasing numbers of patients face the threat that they will be left behind the advances in cancer care. Disparities in healthcare will widen,” Dr Yu told VBCC. “To prevent that from happening, it is critical that patients and physicians understand the value of treatment options. In any treatment situation, the health and individual needs of the patient are paramount, and determining the value of any particular cancer treatments is a highly personalized process that must be determined between a physician and patient,” Dr Yu emphasizes. He added that ASCO is developing a framework for value-based care that will provide a “physician-guided decision-making tool to help physicians discuss with their patients the value of any particular treatment and will support patient-centered care.” The Next 10 Years

The report predicts the trends likely to shape the next 10 years of cancer care. Dr Yu said that faster and less expensive genomic testing (eg, next-generation sequencing) “is poised to revolutionize personalized medicine, both as a diagnostic tool and a way to tailor targeted treatments to individual patients.” He also noted that nanotechnology is another area that has broad potential for improving cancer treatments. “Nanoparticles ‘loaded’ with cancer drugs can be designed to release their cargo only upon docking onto or entering cancer cells. This feature spares healthy tissue of toxic side effects, allowing delivery of higher doses of cancer drugs to the tumor.” The use of liquid biopsies to diagnose cancers from circulating tumor cells and DNA can determine the cancer subtype, estimate how fast the tumor is growing, monitor response to therapy, and detect relapse. “Cancers evolve over time, often becoming resistant to therapies. This will allow us to be more agile in responding by changing our therapeutic strategies. However, it is unknown yet whether such approaches truly translate into improved outcomes for patients,” said Dr Yu. Important advances in health information technology will further improve quality care and outcomes, Dr Yu concluded. “New big-data health information technology will delve into the massive and rapidly growing array of cancer research data and guidelines to help physicians deliver care that is personalized to the unique characteristics of patients and individual tumors,” he said. n

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Health Policy

The State of Cancer Care in America: Advances and Challenges

he recently released American Society of Clinical Oncology (ASCO) annual report, “The State of Cancer Care in America, 2015,” is a mixed bag: the report cites multiple advances in the progress against cancer, but also elaborates on the many hurdles in implementing state-of-the-art cancer care for all Americans (J Oncol Pract. 2015;11:79-113). The report, which was presented at a congressional briefing, lists the current realities of the cancer care system and discusses trends in the oncology workforce and practice environment that affect access to care and care itself. “This year’s report clarifies multiple stresses in our nation’s cancer care system, but there is reason to be hopeful,” stated ASCO President Peter Paul Yu, MD, in a news release from ASCO. “With this knowledge and insight, we can identify ways to ensure that all cancer patients receive high-quality care— and help oncology practices adapt, survive, and succeed in today’s demanding healthcare environment.” Emphasis on New Treatment Options

The report emphasizes the growth in treatment options for many cancers.

at a glance ➤ With 68.5% of patients with cancer living ≥5 years after diagnosis, there is a need for follow-up care to monitor for complications and for future cancer screening ➤ A larger patient population, shortages in the oncology workforce, financial instability, and changing payment models put stress on the US cancer care system ➤ Patients rely on oncologists’ help to find better ways to pay for and incentivize high-quality, value-based care ➤ ASCO is developing and testing an alternative payment approach that reflects the current realities of oncology practices and ensures that patients receive services integral to their care

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In 2014, 10 new treatments were added to the list of 170 FDA-approved anticancer drugs, as well as new medical devices and tests to identify cancers early. More than 770 new cancer therapies are in various stages of research and development. These advances have led to improved survivorship, with 68.5% of all patients with cancer living beyond 5 years from diagnosis compared with 49% in 1975, the report states. The survivors need follow-up care to monitor for complications and side effects, as well as future cancer screening. The changes that affect the delivery of high-quality care include a growing demand for cancer treatment (a 45%

By Alice Goodman

“

With this knowledge and insight, we can identify ways to ensure that all cancer patients receive high-quality care—and help oncology practices adapt, survive, and succeed in today’s demanding healthcare environment.

”

—PETER PAUL YU, MD

increase is expected by 2030), which is partly as a result of an aging population, and increasing obesity, leading to an estimated 500,000 additional cases of cancer over the same time period. Disparities in access to cancer care put additional pressures on the healthcare system; cancer screening and treatment are not evenly distributed among racial and ethnic minorities. The Changing Oncology Workforce

The size of the oncology workforce is another issue; although the supply of oncology personnel remains constant, the demand is expected to outpace the supply. The oncology workforce is aging, and new medical school trainees are not filling the gap. In addition, the makeup of the oncology workforce does not reflect the racial and ethnic diversity of the US population. Rural areas of the country are not well served, and more than 59 million Americans who live in these areas do not have access to modern cancer care. Only 10% of all physicians practice in rural areas currently, whereas only 4.8% of

new physicians are planning to practice in these areas.

“

Patients need us to find better ways to pay for and incentivize high-quality, value-based care. ASCO is currently developing and testing an alternative payment approach that reflects the current realities of oncology practices and ensures that patients receive the full range of services that are integral to their care.

”

—PETER PAUL YU, MD

Professional burnout also threatens the oncology workforce. The report states that at least 33% of oncology APRIL 2015

fellows experience professional burn out and do not plan to work as many hours as their senior colleagues. ASCO calls for addressing burnout and other quality- of-life issues to avoid serious workforce shortages. Moreover, oncology practices have to adapt to financial instability and changing payment models, a continuing trend toward practice consolidation of community-based practices, and the administrative burden imposed by insurance companies and the time spent dealing with patient insurance issues that cut into the time available for providing patient care. Achieving and Incentivizing HighQuality Value-Based Care

In the ASCO news release, Dr Yu said, “Patients need us to find better ways to pay for and incentivize high-quality, value-based care. ASCO is currently developing and testing an alternative payment approach that reflects the current realities of oncology practices and ensures that patients receive the full range of services that are integral to their care.” The report contains specific recommendations addressed to Congress and to stakeholders to address the problems, including repealing the Sustainable Growth Rate formula and replacing it with a sustainable structure that incentivizes the delivery of high-quality care; legislation to ensure interoperability of medical records and provide resources for tracking quality measures; and increasing funding to support for research and innovation by $32 billion for the National Institutes of Health and by $5.32 billion for the National Cancer Institute. n

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Patient Information

What Is a Navigator?

By Sharon S. Gentry, RN, MSN, AOCN, CBCN Breast Cancer Navigator, Novant Health Derrick L. Davis Cancer Center, Winston-Salem, NC

ou have just been diagnosed with cancer, and one of the first people you meet on your healthcare team is introduced as a navigator. “A what?” you think. “I need doctors, not a GPS!” But over time, you will realize this person is a great guide. Because they are positioned inside the healthcare system and know the ins and outs of that world, as well as the community around the system, navigators can be a great resource. According to the dictionary, a navigator is a person who finds out how to get to a place: a person who navigates a ship, an airplane, or a device (such as a computer) that is used to plan or find the route to a place. This is also a concise description of the navigators who work in the oncology healthcare system today. Navigators can get you to where you need to go, and can describe the route or journey you will be traveling as a patient. Your navigator may have a clinical background, such as a nurse or social worker, or he or she may have health education training, such as a community health worker or lay navigator. When you look at the tasks (Table) that many navigators perform, you can realize what questions or concerns you may want to share with them that will help you better navigate your care. Your navigator is knowledgeable about cancer care, and the cancer care system. Navigators view the healthcare system through the eyes of the patient. They are aware of the treatment you expect to get throughout your care, and the community resources that can support you and your family. Navigators communicate with your healthcare team and collaborate on your behalf to facilitate your best care. Think of your navigator as a partner who is focused on your personalized, individual care. If navigators do not know an answer, they can direct you to another team member. They have a defined role, and will transition you to other healthcare team members as needed. Be honest with your navigator, so he or she can make appropriate referrals to enhance your care. One of my favorite quotes comes from an article in Patient Education and Counseling that summed up what patients thought about their experience with navigators: “Having a navigator as someone with personal knowledge of the participant’s overall life situation, while also having direct linkages as an ‘insider’ to the health-

VALUE-BASED CANCER CARE

“”

Think of your navigator as a partner who is focused on your personalized, individual care. Be honest with your navigator, so he or she can make appropriate referrals to enhance your care. —SHARON S. GENTRY, RN, MSN, AOCN, CBCN

care system, helping them through administrative challenges, offering security, comfort, or peace of mind by simply knowing that the navigator was there as a resource, ‘checking in’ with calls or informal visits” [Carroll JK, et al. “Patients’ experiences with navigation for cancer care.” In: Patient Education and Counseling. 2010;80: 241-247]. I hope you will embrace the care of a navigator in your cancer journey. n

Table Tasks of and Questions for Your Navigator Task of a Navigator Questions for Your Navigator Orient patients to the care system

Who do I need to see for care now? Where do I go for care? What type of doctors will I be seeing in the system? Can I stay in my community for care? Who is the expert in this field? What are the contact numbers for my healthcare team? Who do I call in the evenings and on weekends? Can I ask my questions to the healthcare team electronically?

Provide education on your cancer diagnosis

What type of cancer do I have? Are there different types of my cancer? What are good Internet resources? What tests/scans will be performed? What is the treatment for my cancer (surgery, radiation therapy, chemotherapy, immunotherapy, other)? What can I expect after surgery? What can I expect after my first chemotherapy treatment? What is radiation like? What can I expect at the surgeon/medical oncologist/radiation visit? Why am I being sent to a high-risk clinic? What is a survivorship care plan? What did the doctor mean by palliative care?

Provide emotional support for patients

Who can talk to my spouse/partner? What do I tell my children? How can I tell my parents? Is there someone to discuss financial concerns? Will I be able to work? Is there a support group? I do not feel comfortable in groups. Is there someone I can talk with? I cannot grasp all that is happening to me; who can I talk with?

Assist patients with logistics, such as transportation, costs

Is there transportation assistance? I live far away. Is there an affordable place to stay? What are the directions to the appointment/test? Is there an interpreter available for me/my family? Can you help me with the copays? I am overwhelmed with these insurance forms; can you help? Who can stay with my elderly parents while I get care? Who do I see about my short-term or long-term disability forms? Is there child care available? Can someone help me with a living will?

Advocate for the patient

I feel dissatisfied with my care; can you help me? I did not have a good experience with a healthcare team member; can you help me? I did not feel comfortable asking questions; what did the doctor mean? Can you review my care plan with me? My appointments conflict with my work schedule; can you help? I am frustrated with this bill, because another one came from the same visit. Are they all bills? Why do I have to wait so long for an appointment?

Utilize community resources

Is there free legal aid available? Is there an agency to help with medications? Can I get financial help in my community? Are there people/groups that can help with transportation? Can someone clean my house? Are there other survivors I can talk with?

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Drug Update

Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment of Patients with Differentiated Thyroid Cancer By Loretta Fala, Medical Writer

hyroid cancer, cancer that starts in the thyroid gland, accounts for 3.8% of all cancer cases in the United States.1 There were an estimated 62,980 new cases of thyroid cancer and 1890 deaths resulting from thyroid cancer in 2014.1 Thyroid cancer is most common in people aged 45 to 54 years (median age, 50 years),1 and it occurs 2 to 3 times more often in women than in men.2 The incidence of thyroid cancer has risen steadily in recent years.3 Although this increasing rate can be attributed largely to disease detection at an earlier stage, the incidence of larger tumors has also increased.3 Thyroid cancer is classified into 3 types—differentiated (includes papillary, follicular, and Hürthle tumors); medullary tumors; and anaplastic (aggressive undifferentiated tumors).2 Differentiated thyroid cancer accounts for more than 90% of all cases of thyroid carcinoma.2 An estimated 566,708 patients were living with thyroid cancer in the United States in 2011.1 Approximately 68.2% of patients are diagnosed at the local stage of thyroid cancer; for patients with localized thyroid cancer, the 5-year survival rate is currently 99.9%.1 However, 10% to 30% of patients who are thought to be disease-free after the initial treatment will have disease recurrence and/or metastases.4 For patients with differentiated thyroid cancer that is refractory to radioactive iodine [131-isotope, also known as 131I] therapy, the 10-year survival rate is only 10% from the time that metastatic disease is detected.5,6 According to a recent study, the estimated annual US healthcare costs (undiscounted) for thyroid cancer were $1.4 billion in 2010; these costs are projected to reach $2.1 billion in 2015 and to exceed $3.1 billion by 2019.7 The authors noted that thyroid cancer is a major public health issue, particularly for women, given the increasing incidence (especially of papillary carcinoma) of the disease among women.7 According to another study, differentiated thyroid cancer accounted for total societal costs of approximately $1.6 billion annually Copyright © 2015 American Health & Drug Benefits. Used with permission. All rights reserved. VOL. 6

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in the United States in 2013.8 Furthermore, the annual costs attributable to differentiated thyroid cancer were projected to approach $3.5 billion by 2030 in that study.8 The treatment of differentiated thyroid cancer generally includes surgery, when possible, followed by radioactive iodine treatment in appropriate patients, and thyroxine therapy. Systemic therapy, including the recently approved tyrosine kinase inhibitors, may be used for patients with significant disease progression, nonresectable tumors, or tumors that are nonresponsive to radioactive iodine therapy.2 The multitargeted tyrosine kinase inhibitors have demonstrated a clinical benefit in locally recurrent, unresectable and metastatic medullary thyroid cancer

and in radioactive iodine–refractory differentiated thyroid cancer.2 Optimal management of the side effects associated with tyrosine kinase inhibitor therapy and/or dose modification are key considerations when managing thyroid cancer with this class of drugs.2 The tyrosine kinase inhibitors represent an important advancement in the treatment of thyroid cancer, because they target multiple molecular pathways that are involved in the pathogenesis of thyroid tumors.5 Lenvatinib: A New Oral Option for Differentiated Thyroid Cancer

On February 13, 2015, lenvatinib (Lenvima; Eisai), an oral, multireceptor tyrosine kinase inhibitor, was approved by the US Food and Drug Administration (FDA) to treat patients

Table 1 E fficacy Results in the SELECT Study: Lenvatinib versus Placebo in Patients with Progressive Thyroid Cancer Lenvatinib cohort Placebo cohort Efficacy variable (N = 261) (N = 131) Progression-free survivala Events, N (%)

107 (41)

113 (86)

Progressive disease

93 (36)

109 (83)

Death

14 (5)

4 (3)

18.3 (95% CI, 15.1-NE)

3.6 (95% CI, 2.2-3.7)

Median progression-free survival, mo Hazard ratio

0.21 (95% CI, 0.16-0.28)

P <.001c

Objective response ratea Objective response rate, %

65 (95% CI, 59%-71%)

2 (95% CI, 0%-4%)

Complete response, %

Partial response, %

2 P <.001

Overall survival

Deaths, N (%) Median overall survivale Hazard ratiob

71 (27)

47 (36)

0.73 (95% CI, 0.50-1.07) P = .10b

Independent radiologic review. Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). c Log-rank test stratified by region (Europe vs North America vs other), age-group (≤65 vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1). d Cochran-Mantel-Haenszel chi-square test. e Not estimable. CI indicates confidence interval; NE, not estimable; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

with locally recurrent or metastatic, progressive, radioactive iodine–refractory differentiated thyroid cancer.9 Lenvatinib was granted an expedited review by the FDA, using its priority

“

The development of new therapies to assist patients with refractory disease is of high importance to the FDA. Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC.

”

—RICHARD PAZDUR, MD

review process, based on the drug’s potential to provide a significant improvement in safety or effectiveness in treating a serious condition over available medications. In addition, lenvatinib received an orphan drug designation, because it is designated to treat a rare condition.9 Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said, “The development of new therapies to assist patients with refractory disease is of high importance to the FDA. Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC [differentiated thyroid cancer].” 9 Steven I. Sherman, MD, Associate Vice Provost, Clinical Research, M.D. Anderson Cancer Center, and principal investigator of a pivotal phase 3 study on lenvatinib led by researchers at the University of Texas M.D. Anderson Cancer Center, noted that advances in thyroid cancer treatment have been made in recent years, particularly for patients with metastatic disease who do not respond to radioactive iodine therapy.10 Dr Sherman stated, “For decades, in this patient population, the treatment was often to repeat ineffective doses of radioactive ioContinued on page 44

APRIL 2015

www.ValueBasedCancerCare.com

Drug Update

Lenvima (Lenvatinib), a Multireceptor Tyrosine Kinase Inhibitor, Approved by the FDA for the Treatment...

Continued from page 43

dine, and possibly salvage therapy with chemotherapy.” He added, “About 10 years ago, with the growing availability of novel targeted agents and multi-targeted kinase inhibitors, we began to recognize potential for treating this subgroup of patients with antiangiogenic therapy and sought to enroll those with refractory disease in clinical trials.” 10 Mechanism of Action

Lenvatinib is a multireceptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other receptor tyrosine kinases that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including the fibroblast growth factor receptors FGFR1, 2, 3, and 4; and the platelet-derived growth factor receptor alpha, KIT, and RET.11

Dosing and Administration

The recommended dose of lenvatinib is 24 mg orally, once daily. In pa-

tients with severe renal or hepatic impairment, the dose is reduced to 14 mg once daily.11 Lenvatinib is available in a 4-mg and a 10-mg capsule.11 Clinical Studies The SELECT Trial

The safety and efficacy of lenvatinib were evaluated in the SELECT trial, a multicenter, randomized (in a 2:1 ratio), double-blind, placebo-controlled study.5 The study included 392 patients with locally recurrent or metastatic radioactive iodine–refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months before study randomization, as confirmed by an Independent Radiologic Review (IRR).5,11 Radioactive iodine–refractory was defined as (1) ≥1 measurable lesions with no iodine uptake on radioactive iodine scan, (2) iodine uptake with progression within 12 months of radioactive iodine therapy, or (3) having received cumulative radioactive iodine activity of >600 mCi (22 GBq) with the last dose administered at least 6 months before study entry.11

Table 2 Lenvatinib versus Placebo: Adverse Events (All Grades Incidence ≥30%) Lenvatinib 24 mg Placebo (N = 261) (N = 131) Adverse reaction All grades, % Grades 3-4, % All grades, % Grades 3-4, % Hypertensiona

Fatigue

Arthralgia/myalgia

Decreased appetite

Weight decreased

Nausea

Stomatitisd (inflammation of the mouth and lips)

Headache

Vomiting

Proteinuria

Palmar-plantar erythrodysesthesia (hand-foot) syndrome

Abdominal paine

Dysphonia (voice impairment)

Diarrhea c

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure. b Includes asthenia, fatigue, and malaise. c Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia. d Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation. e Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, epigastric discomfort, and gastrointestinal pain. Source: Lenvima (lenvatinib) capsules prescribing information; February 2015. a

VALUE-BASED CANCER CARE

APRIL 2015

In this study, patients were randomized to receive lenvatinib 24 mg once daily (N = 261) or placebo (N = 131) until disease progression. Randomization was stratified by geographic region, previous VEGF/VEGFR-targeted therapy, and age. The median age of the patients was 63 years. Overall, 99% of the patients had metastatic disease.11 The primary efficacy outcome measure was progression-free survival, as determined by a blinded IRR using Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).11,12 Secondary efficacy outcome measures included objective response rate and overall survival. Patients in the placebo group could receive lenvatinib after an independent review confirmation of disease progression.11 As shown in Table 1, a significant prolongation in progression-free survival was demonstrated in patients receiving lenvatinib compared with patients who received placebo. Patients in the lenvatinib group had a 14.7-month longer median progression-free survival than patients in the placebo group. Moreover, 65% of patients in the lenvatinib group had an objective response compared with 2% of patients in the placebo group. Overall survival was not estimable in either group.5,11 Safety

The most common adverse reactions (with an incidence of ≥30%) associated with lenvatinib are shown in Table 2. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%).11 The most common adverse reactions (at least 1%) resulting in discontinuation of lenvatinib were hypertension (1%) and asthenia (1%).11 Lenvatinib has no known contra indications.11

Drug Interactions

Effect of other drugs on lenvatinib. CYP3A is one of the main metabolic enzymes of lenvatinib. No dose adjustment of lenvatinib is recommended when coadministered with CYP3A, P-glycoprotein (P-gp), and breast cancer resistance protein inhibitors and CYP3A and P-gp inducers.11

Warnings and Precautions

Hypertension. Blood pressure should be controlled prior to treatment with lenvatinib. Lenvatinib should be withheld for grade 3 hypertension despite optimal hypertensive therapy. For patients

with life-threatening hypertension, lenvatinib should be discontinued.11 Cardiac failure. Patients should be monitored for clinical symptoms or signs of cardiac decompensation. Lenvatinib should be withheld for grade 3 cardiac

“

For decades, in this patient population, the treatment was often to repeat ineffective doses of radioactive iodine, and possibly salvage therapy with chemotherapy. With the growing availability of novel targeted agents and multi-targeted kinase inhibitors, we began to recognize potential for treating this subgroup of patients with antiangiogenic therapy.

”

—STEVEN I. SHERMAN, MD

dysfunction. For patients with grade 4 cardiac dysfunction, lenvatinib should be discontinued.11 Arterial thromboembolic events. Lenvatinib should be discontinued following an arterial thromboembolic event.11 Hepatotoxicity. Before initiation of lenvatinib and periodically throughout treatment, liver function tests should be monitored. For patients with grade 3 or greater liver impairment, lenvatinib should be withheld. Lenvatinib should be discontinued for patients with hepatic failure.11 Proteinuria. Before initiating lenvatinib therapy and periodically through treatment with lenvatinib, patients should be monitored for proteinuria. Lenvatinib should be withheld in patients with ≥2 g of proteinuria for 24 hours. Lenvatinib should be discontinued in patients who have nephritic syndrome.11 Renal failure and impairment. Lenvatinib should be withheld for grade 3 or 4 renal failure or impairment.11 Gastrointestinal perforation and fistula formation. Lenvatinib should be discontinued in patients who develop gastrointestinal perforation or life-threatening fistula.11 QT interval prolongation. Electrolyte abnormalities should be monitored and corrected in all patients. For patients who develop grade ≥3 QT interval prolongation, lenvatinib should be withheld.11

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Drug Update Hypocalcemia. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during treatment with lenvatinib.11 Reversible posterior leukoencephalopathy syndrome (RPLS). Lenvatinib should be withheld for patients with RPLS until the RPLS is fully resolved.11 Hemorrhagic events. Lenvatinib should be discontinued for patients with grade 3 hemorrhage. Lenvatinib should be discontinued for patients with grade 4 hemorrhage.11 Impairment of thyroid-stimulating hormone (TSH) suppression. TSH levels should be monitored monthly and thyroid replacement medication should be adjusted as needed in patients with differentiated thyroid cancer.11 Embryofetal toxicity. Lenvatinib can cause fetal harm. Women of reproductive potential should be advised about the potential risk to the fetus and the use of effective contraception.11 Use in Specific Populations

Lactation. It is not known whether lenvatinib is present in human milk. Because of the potential for serious adverse reactions in nursing infants from

lenvatinib, women should be advised to discontinue breastfeeding during treatment with lenvatinib.11 Pregnancy. Lenvatinib can cause fetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the fetus.11 Females and males of reproductive potential. Lenvatinib may result in reduced fertility in women of reproductive potential. Lenvatinib may result in damage to male reproductive tissues, which can lead to reduced fertility of unknown duration.11 Pediatric use. The safety and effectiveness of lenvatinib in pediatric patients have not been established.11 Geriatric use. In clinical studies, no overall differences in safety or effectiveness were observed between patients aged ≥65 years and those aged <65 years.11 Renal impairment. No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose of lenvatinib is 14 mg taken once daily. Patients with endstage renal disease were not studied.11 Hepatic impairment. No dose adjustment is recommended in patients

with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose of lenvatinib is 14 mg taken once daily.11 Conclusion

With the FDA approval of lenvatinib, a new, once-daily oral treatment option became available to help slow the progression of differentiated thyroid cancer, the most common type of thyroid cancer, in patients with locally recurrent or metastatic, radioactive iodine–refractory disease.9 Treatment with lenvatinib, a multitargeted tyrosine kinase inhibitor, demonstrated a statistically significant prolongation in progression-free survival in patients with progressive, radioactive iodine–refractory differentiated thyroid cancer. In the SELECT clinical study, the median progression-free survival in the lenvatinib group was 18.3 months versus 3.6 months in the placebo group (P <.001).5,11 n

References

1. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http://seer.cancer.gov/statfacts/html/ thyro.html. Accessed March 10, 2015. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): thyroid carcinoma. Version 2.2014. August

12, 2014. www.nccn.org/store/login/login.aspx?Return URL=http://www.nccn.org/professionals/physician_gls/ pdf/thyroid.pdf. Accessed March 10, 2015. 3. American Cancer Society. What are the key statistics about thyroid cancer? Revised February 13, 2015. www. cancer.org/cancer/thyroidcancer/detailedguide/thyroidcancer-key-statistics. Accessed March 11, 2015. 4. National Cancer Institute. Thyroid cancer treatment (PDQ®). Updated February 25, 2015. www.cancer.gov/ cancertopics/pdq/treatment/thyroid/HealthProfessional/ page9. Accessed March 13, 2015. 5. Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372:621-630. 6. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892-2899. 7. Aschebrook-Kilfoy B, Schechter RB, Shih Y-C, et al. The clinical and economic burden of a sustained increase in thyroid cancer incidence. Cancer Epidemiol Biomarkers Prev. 2013;22:1252-1259. 8. Lubitz CC, Kong CY, McMahon PM, et al. Annual financial impact of well-differentiated thyroid cancer care in the United States. Cancer. 2014;120:1345-1352. 9. US Food and Drug Administration. FDA approves Lenvima for a type of thyroid cancer. Press release. February 13, 2015. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm434288.htm. Accessed March 14, 2015. 10. M.D. Anderson. Lenvatinib shows promise for patients with radioiodine-refractory thyroid cancer. Press release. February 11, 2015. www.mdanderson.org/news room/news-releases/2015/lenvatinib-promise-radio iodine-refractory-thyroid-cancer.html. Accessed March 13, 2015. 11. Lenvima (lenvatinib) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; February 2015. 12. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45: 228-247.

Personalized Medicine

Clinical Utility of Genomic Biomarker Tests Questioned By Alice Goodman

Orlando, FL—An independent review of the literature suggests that 3 biomarker tests developed for prostate cancer have yet to justify their utility in randomized clinical trials. The 3 tests in question—Prolaris, Decipher, and Oncotype DX for prostate cancer—are being used in practices around the country, cost approximately $3500 per test, and are reimbursable by Medicare depending on the state. “These are promising tests, but they need future testing for clinical applicability, and this testing can be done by incorporating them into randomized clinical trials,” stated Meghan Anastasia Cooper, MA, MS-IV, a fourth-year medical student at Lake Erie College of Osteopathic Medicine, Bradenton, FL. Ms Cooper presented these findings at a poster session during the 2015 Genitourinary Cancers Symposium. Most of the studies on these tests are sponsored by the companies that mar ket them. Ms Cooper and colleagues screened the medical literature and found 32 studies of these tests. Only 8 VOL. 6

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met the criteria of adequate sample size for reliable statistical analysis, original and validation studies, utilizing data sets from independent patient cohorts, and studies reporting appropriate statistical evaluations. Hazard ratio, odds ratio, area under the curve, or precision and reproducibility were used to quantify the assays’ predictive capability. “It is difficult to compare directly

performance of these 3 tests, and no prospective studies have been reported to validate these assays,” Ms Cooper stated. About the Genomic Tests

Prolaris (Myriad Genetics) and Oncotype DX for prostate cancer (Genomic Health) are used on the biopsy specimen to identify the presence of a gene panel, and both tests are being market-

at a glance ➤ Prolaris, Oncotype DX, and Decipher are biomarker tests used in practices around the country, cost approximately $3500 each, and may be reimbursable by Medicare ➤ Prolaris and Oncotype DX can identify eligibility for active surveillance, possibly preventing overtreatment and saving healthcare dollars

➤ Decipher can predict disease aggressiveness, thereby helping physicians choose the most appropriate postsurgery management for their patients ➤ The tests are promising, but they need future testing for clinical applicability, which can be done by incorporating them into randomized clinical trials

APRIL 2015

“

These are promising tests, but they need future testing for clinical applicability, and this testing can be done by incorporating them into randomized clinical trials.

”

—MEGHAN ANASTASIA COOPER, MA, MS-IV

ed to identify low- and very low-risk men who can be managed by active surveillance, theoretically preventing overtreatment and saving the healthcare system money. Decipher (GenomeDx Biosciences) is a genomic test that is used on the prostate specimen after radical prostatectomy, and the test can predict aggressive disease or less aggressive disease, thereby helping physicians to choose the most appropriate postsurgery management. n

www.ValueBasedCancerCare.com

Managed Care Payers and Pharmaceutical Oncology Trends

John Fox, MD, MHA Senior Medical Director Associate Vice President Medical Affairs Priority Health

Alex Jung Principal, Global Strategic Advisory Services Ernst & Young LLP

Omni Shoreham Hotel • Washington, DC AN

ANNUAL CONFERENCE

RSARY VE NI

AGENDA

MAY 4, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction to Conference and Opening Remarks John Fox, MD, MHA, Priority Health Alex Jung, Ernst & Young LLP

8:15 am – 9:00 am

Session 1 - The Emerging Role of Personal Medicine – the Business Case Vince Miller, MD, Foundation Medicine

9:00 am – 9:45 am

Session 2 - Pathways versus Personalized Medicine – Never the Twain Shall Meet Michael Kolodziej, MD, Aetna

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - The CMMI Multipayer Oncology Care Model Heidi Schumacher, MD, CMMI

10:45 am – 11:30 am

Session 4 - Practice Accreditation as Oncology Medical Homes Ted Okon, Community Oncology Alliance (Invited) David Eagle, Community Oncology Alliance (Invited)

11:30 am – 12:15 pm

12:15 pm – 1:15 pm

Session 5 - How to Measure Quality in Cancer Michael Kolodziej, MD, Aetna Heidi Schumacher, MD, CMMI David Eagle, Community Oncology Alliance (Invited) Ted Okon, Community Oncology Alliance (Invited) Lunch Presentation - Financial Toxicity Speaker TBD

1:15 pm – 2:00 pm

Session 6 - Keynote Session – IMS Oncology Drug Trends Report Doug Long, IMS Health Inc

2:00 pm – 2:45 pm

Session 7 - Pharma and Defining Value in Cancer Care Sanjeev Wadhwa, Biologist/Life Sciences Consultant for R&D

2:45 pm – 3:30 pm

Session 8 - Comparative Effectiveness and Measuring Value of Drug Therapeutic Options in Cancer Care Robert Bilkovski, MD, Abbott Pharmaceuticals

3:30 pm – 4:15 pm

Session 9 - Perspective on the Future of Oncology Drug and Disease Management Grant Lawless, RPh, MD, FACP, University of Southern California

4:15 pm – 5:00 pm

Session 10 - Limited Distribution Oncology Drug Networks and the Value of Controlled Distribution Alex Jung, Ernst & Young LLP

5:00 pm – 5:45 pm

Session 11 - Specialized Pharmacy and Adding Value of Disease and Patient’s Support in Cancer Care Speaker TBD

5:45 pm – 6:00 pm

Poster Award Q & A

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Welcome Reception/Exhibit Hall

*Agenda subject to change. AVBCC395_Agenda4king022515

AVBCConline.org/conference

Oncology Providers Practice and Personalized Medicine Trends

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center

Barbara L. McAneny, MD Chair, Board of Trustees American Medical Association

Omni Shoreham Hotel • Washington, DC ANNUAL CONFERENCE

MAY 5, 2015

AN RSARY VE NI

AGENDA

7:00 am – 8:00 am

Meet the Experts Breakfast

1:15 pm – 2:00 pm

8:00 am – 8:15 am

Introduction and Opening Remarks Barbara L. McAneny, MD, American Medical Association Sanjiv S. Agarwala, MD, Temple University School of Medicine

Session 6 - Keynote Session - ValueBased Cancer Care: How Do We Get There in the ’Omics Era? Gary Palmer, MD, JD, MBA, MPH, Nanthealth

2:00 pm – 2:45 pm

Session 7 - Can We Afford Personalized Medicine? Michael Kolodziej, MD, Aetna

2:45 pm – 3:30 pm

Session 8 - The Precision Medicine Initiative: Deliverables from Those on the Front Lines of Personalizing Care Harold Varmus, MD, National Cancer Institute (Invited)

3:30 pm – 4:15 pm

Session 9 - Adapting Regulation to Meet the Needs of the Exponential Growth of the Molecular Testing Era Victoria Pratt, MD (Invited)

4:15 pm – 5:00 pm

Session 10 - Role of Pathologist in the Age of Personalized Medicine Pranil Chandra, DO, PathGroup (Invited)

5:00 pm – 5:45 pm

Session 11 - The Role of Immunotherapy in Personalizing Treatment James Allison, PhD, MD Anderson Cancer Center (Invited)

5:45 pm – 6:00 pm

Poster Award Q & A

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Reception in Exhibit Hall

8:15 am – 9:15 am

Session 1 - Win-Win-Win Approaches to Oncology Care: How Providers, Patients, and Payers Can All Benefit from Improving the Way We Pay for Cancer Treatment Harold Miller, Center for Healthcare Quality and Payment Reform

9:15 am – 10:00 am

Session 2 - Pitfalls or Challenges of New Payment Models Bruce Pyenson, Milliman

10:00 am – 10:15 am

Break

10:15 am – 11:00 am

Session 3 - Oncology Medical Home – A Patient-Centric System for Delivering Quality Cancer Care Barbara L. McAneny, MD, American Medical Association

11:00 am – 11:45 am

Session 4 - FDA on Testing and Personalized Medicine Speaker TBD

11:45 am – 12:15 pm

Session 5 - Revamping Research Raju Kucherlapati, PhD, Harvard Medical School

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

*Agenda subject to change. AVBCC395_Agenda5king022515

AVBCConline.org/conference

Government and Employer Trends

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc

F. Randy Vogenberg, PhD, RPh Principal Institute for Integrated Healthcare (IIH)

Omni Shoreham Hotel • Washington, DC ANNUAL CONFERENCE

MAY 6, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction and Opening Remarks Jayson Slotnik, JD, MPH, Health Policy Strategies, Inc F. Randy Vogenberg, PhD, RPh, Institute for Integrated Healthcare

8:15 am – 9:00 am

Session 1 - Oncology Bundled Payments Speaker TBD

9:00 am – 9:45 am

Session 2 - Media Coverage Oncology Panel Speaker TBD

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - Actuary View and Future Market Landscape Speaker TBD

10:45 am – 11:30 am

Session 4 - Coverage Parameter Trends in Health Benefits Impacting Oncology Speaker TBD

11:30 am – 12:15 pm

AN RSARY VE NI

AGENDA

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

1:15 pm – 2:00 pm

Session 6 - Private Health Exchanges Laurel Pickering, Northeast Business Group on Health

2:00 pm – 2:45 pm

Session 7 - Onsite and Retail Clinic Services Expansion Larry Boress, Midwest Business Group on Health

2:45 pm – 3:30 pm

Session 8 - Group Health Benefits 2016 and Beyond Brian Klepper, PhD, National Business Coalition on Health

3:30 pm – 4:15 pm

Session 9 - Panel Discussion: Patient Engagement Patrick McKercher, PhD, Patient Assistance Network Foundation

4:15 pm – 4:30 pm

Closing Remarks

*Agenda subject to change.

Session 5 - Keynote Session – 21st-Century Cures Speaker TBD

AVBCC395_Agenda6king022515

AVBCConline.org/conference

VBCC April 2015 | Vol 6 ­| No 3

VBCC April 2015 | Vol 6 | No 3