VBCC March 2015 | Vol 6 ­| No 2

MARCH 2015 VOL 6 NO 2

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

High-Quality Cancer Care Value of New Drugs for Focus of ASCO’s Medicaid Hematologic Cancers— Reform Recommendations Improving Quality,

Extending Survival

By Rosemary Frei, MSc

By Wayne Kuznar

A

lthough often criticized as being overly expensive, innovations in drug development for hematologic malignancies meet standard benchmarks for cost-effectiveness, deliv-

Peter P. Yu, MD, FACP

Blase N. Polite, MD, MPP

ate last year, the American Society of Clinical Oncology ­ (ASCO) issued a policy statement on Medicaid reform, with recommendations on ensuring quality of care for all patients with cancer, including the underserved population, while also improving provider reimbursement to ensure value-based care. ASCO’s poicy statement advo-

cates for the expansion of Medicaid coverage to all Americans with cancer, an increase in Medicaid pay­­ment rates to reach those of Medicare, and a greater emphasis on rewarding providers for the delivery of quality care (Polite BN, et al. J Clin Oncol. 2014; 32:­4162-4167).

“That’s a key take-home point— that you don’t see just us out here say-

L

Continued on page 16

GENITOURINARY CANCERS SYMPOSIUM

ASSURE Trial: No Role for Adjuvant Sorafenib or Sunitinib in Locally Advanced Kidney Cancer

By Phoebe Starr

Orlando, FL—Surprisingly, the use of adjuvant sorafenib (Nexavar) and sunitinib (Sutent) failed to extend disease­free survival (DFS) in patients with locally advanced kidney cancer who are at high risk for recurrence, according to initial results of the ASSURE study.

The ASSURE trial is the first and largest study investigating the use of adjuvant tyrosine kinase inhibitors/vascular endothelial growth factor (VEGF) inhibitors in kidney cancer.

The results surprised the lead investigator, Naomi B. Haas, MD, Cancer Continued on page 10

© 2015 Engage Healthcare Communications, LLC

ering value for their cost, suggest a team of health economics researchers led by Peter J. Neumann, ScD, Director, the Center for the Evaluation of Value and Risk in Health, Tufts Medical Center, Continued on page 8

PERSONALIZED MEDICINE

AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate Cancer New biomarker to guide treatment decisions?

By Phoebe Starr Orlando, FL—Experts are hopeful that the field of prostate cancer will soon be catching up to breast cancer and some other tumor types with regard to genomic markers.

A study featured at the 2015 Genitourinary Cancers Symposium sug­­

gests that the an­drogen receptor (AR) abnormality known as “AR-V7” will turn out to be a predictive marker to

Emmanuel S. Antonarakis, MBBCh Continued on page 15

INSIDE FDA NEWS . . . . . . . . . . . . . . . . . . . . .

Panobinostat first HDAC inhibitor for multiple myeloma VALUE PROPOSITIONS . . . . . . . . . .

Novel test identifies apoptosis from a cancer drug in 16 hours ECONOMICS OF CANCER CARE . . .

Preventing relapse in myeloma reduces overall costs

5 7 8

GU CANCERS SYMPOSIUM . . . . . . 13 Active surveillance for prostate cancer not advised in intermediate risk QUALITY CARE . . . . . . . . . . . . . . . . 15 Foreign-trained physicians less likely to screen for cancer

IN THE LITERATURE . . . . . . . . . . . . 17 Lenvatinib prolongs PFS in advanced thyroid cancer LEUKEMIA . . . . . . . . . . . . . . . . . . . . 23 Vosaroxin extends survival in older patients BREAST CANCER . . . . . . . . . . . . . . .

Lowering dietary fat increases longterm survival

25

CANCER REHABILITATION . . . . . . 26 Interview with a lung cancer survivor DRUG UPDATE . . . . . . . . . . . . . . . . 28 Cyramza for advanced gastric cancer and metastatic NSCLC

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

10.5

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

15% INCREASE IN MEDIAN OS

MONTHS

0.8

OS PROBABILITY

MAJOR OUTCOME MEASURE

(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

3

6

12

15

18

21

24

27

30

33

36

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

9

• 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

527

415

329

231

156

103

70

45

23

11

2

0

501

386

306

197

129

86

56

36

23

9

0

0

• 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 • 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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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.

RB94721 01/2015 PRINTED IN USA © Lilly USA, LLC 2015.

ALL RIGHTS RESERVED. CYRAMZA® is a registered trademark of Eli Lilly and Company.

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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

19

2

5

0

50 9

11 <1

7

<1

5

2

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

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

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.

Eli Lilly and Company, Indianapolis, IN 46285, USA Copyright © 2014, Eli Lilly and Company. All rights reserved.

FDA News First HDAC Inhibitor, Panobinostat, Approved by the FDA for the Treatment of Patients with Multiple Myeloma

The FDA approved panobinostat (Farydak; Novartis Pharmaceuticals) for the treatment of patients with multiple myeloma. Panobinostat works ­­by inhibiting the histone deacetylase (HDAC) enzymes, which slow and/or kill the excess production of plasma cells in the bone marrow that leads to the development of multiple myeloma.

Panobinostat was approved under the FDA’s priority review and accelerated approval programs and carries an orphan drug designation.

Panobinostat is the first HDAC inhibitor approved by the FDA. Panobin­ ostat is approved for the treatment of myeloma in patients who have received at least 2 previous standard myeloma therapies, including bortezomib and an immunomodulatory agent (eg, lenalidomide). Panobinostat should be used in combination with bortezomib and dexamethasone.

“Farydak has a new mechanism of action that distinguishes it from prior drugs approved to treat multiple myeloma, making it a potentially attractive candidate agent for the treatment of multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Farydak’s approval is particularly important, because it has been shown to slow the progression of multiple myeloma.”

The safety and efficacy of panobin­ ostat were based on a clinical trial with 193 patients with myeloma who received at least 2 previous treatments, including bortezomib and an immunomodulatory agent. The patients were randomized to a combination of panobinostat, bortezomib, and dexamethasone, or to bortezomib and dexamethasone alone. The 3-drug combination of panobinostat, bortezomib, and dexamethasone extended the progression-free survival by 4.10 months; it was approximately 10.6 months with the 3-drug combination compared with only 5.8 months with bortezomib and dexamethasone alone. In addition, the response rate was 59% among the patients receiving the 3-drug combination versus 41% among those receiving bortezomib and dexamethasone without panobinostat.

The most common side effects seen with panobinostat were diarrhea, tiredness, nausea, swelling in the arms or legs, decreased appetite, fever, vomiting, and weakness. The most common laboratory abnormalities were hypophosphatemia, hypokale-

CYRAMZA® (ramucirumab) injection

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Palbociclib Approved for Metastatic Breast Cancer in Postmenopausal Women

The FDA granted approval to palbociclib (Ib­ rance; Pfizer) for the treatment of postmenopausal women with metastatic breast cancer. Palbociclib works by blocking the activity of the cyclin-­ dependent kinases 4 and 6, which promotes cancer cell growth.

Palbociclib is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-­ positive, HER2-negative cancer who have not received any endocrine-­based therapy.

According to Dr Pazdur, “The addition of palbociclib to letrozole provides a novel treatment option to women diagnosed with metastatic breast cancer. The FDA is committed to expediting marketing approval of cancer drugs through our accelerated approval regulations.”

The FDA expedited the approval of palbociclib under its accelerated and priority review programs, and designated it as a breakthrough therapy based on the strength of the preliminary clinical evidence, which shows that the drug may offer an improvement for patients compared with current therapies.

Palbociclib’s efficacy was demonstrated in a clinical trial of 165 postmenopausal women with ER-positive, HER2-­negative metastatic breast cancer who had not received treatment for metastatic disease. Patients were randomized to palbociclib plus letrozole or to letrozole alone. Progression-free survival was 20.2 months with the combination of palbociclib and letrozole compared with approximately 10.2 months in patients receiving letrozole alone. Overall survival data are not yet available.

The most common side effects were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, hair loss, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and nose bleeding.

The recommended dose is 125 mg for the first 21 days, followed by 7 days without treatment. Patients’ complete blood count should be monitored before the start of therapy, at the beginning of Continued on page 12

RB-L HCP BS 17Dec2014

VOL. 6

mia, hyponatremia, increased creatinine, thrombocytopenia, leukopenia, and anemia.

Panobinostat carries a boxed warning about the risk for severe diarrhea and fatal cardiac events. The FDA requires a Risk Evaluation and Mitigation Strategy program to inform providers of these risks. (February 23, 2015)

RB-L HCP BS 17Dec2014

MARCH 2015

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

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager 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

FDA NEWS

First HDAC inhibitor, panobinostat, approved for multiple myeloma Palbociclib approved for metastatic breast cancer in postmenopausal women More…

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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

Lenvatinib prolongs progression-free survival in advanced thyroid cancer More…

LEUKEMIA

Blinatumomab attacks minimal residual disease Monitoring response to TKIs by PCR improves outcomes in CML More…

GU CANCERS SYMPOSIUM

History of testicular cancer increases risk for aggressive prostate cancer later on More…

BREAST CANCER

PERSONALIZED MEDICINE

Lowering dietary fat increases long-term survival More…

QUALITY CARE

Conversation with a lung cancer survivor

AR-V7 predicts chemotherapy sensitivity in metastatic prostate cancer

CANCER REHABILITATION

Foreign-trained physicians less likely to screen for cancer, especially among immigrants

DRUG UPDATE

Cyramza for advanced gastric cancer and metastatic lung cancer

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

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

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

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

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

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

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IN THE LITERATURE

ECONOMICS OF CANCER CARE

Quality Control Assistant Theresa Salerno

Director, Creative & Design Robyn Jacobs

High-quality cancer care is focus of ASCO’s Medicaid reform recommendations

Value of new drugs for hematologic cancers: improved quality, extended survival More…

Director, Quality Control Barbara Marino

Director, Production & Manufacturing Alaina Pede

HEALTH POLICY

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MARCH 2015

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

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

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VALUE PROPOSITIONS

Advance Care Planning

CLL Therapy Named “Cancer Advance of the Year” by ASCO

Filgrastim-Sndz First Biosimilar Approved by the FDA

In its 2015 Annual Report Against Cancer, for the first time ever the American Society of Clinical Oncology (ASCO) named the advances made in a specific tumor type as “cancer advance of the year.” That cancer is chronic lymphocytic leukemia (CLL). This new designation highlights the recent FDA approval of 4 new drugs in a span of 12 months for the treatment of patients with CLL, the most common type of leukemia in adults.

“This has truly been a banner year [2014] for CLL and for clinical cancer research as a whole. Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients,” said ASCO President Peter P. Yu, MD, FACP, commenting on the announcement.

“It’s also remarkable that almost one-third of the year’s top studies were made possible by federal research dollars. We cannot underestimate the importance of federal investment for answering critical cancer care questions, particularly in rare, understudied cancers.”

The 4 new drugs include the first 2 immunotherapies to receive FDA approval for leukemia—ofatumumab (Arzerra) and obinutuzumab (Gazyva)—and 2 targeted therapies, idelalisib (Zydelig) and ibrutinib (Imbruvica). Ofatumumab and obinutuzumab are both anti-CD20 antibodies indicated for use in combination with chlorambucil for treatment-naïve patients with advanced CLL. These immunotherapies delay the progression of CLL by approximately 12 months.

Idelalisib and ibrutinib are 2 targeted therapies, and each of them is a first-­inclass oral agent for CLL. Idelalisib is the first PI3K-delta inhibitor approved by the FDA for patients with relapsed or refractory CLL for use in combination with rituximab (Rituxan).

Ibrutinib is the first Bruton’s tyrosine kinase inhibitor approved by the FDA for the treatment of patients with CLL and a deletion in chromosome 17, a marker of poor prognosis in CLL. “These new therapies fill an enormous need for thousands of patients living with CLL,” said Gregory Masters, MD, FACP, FASCO, Co-Executive Editor of the ASCO annual report. “For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle.”

Approximately 120,000 Americans have CLL, and approximately 16,000 new patients are diagnosed with the disease annually. Cancer Network; January 21, 2015

The FDA approved the cancer drug filgrastim-sndz (Zarxio; Sandoz/Novartis) as the first biosimilar agent to ever be approved in the United States. Filgrastim-sndz is biosimilar to filgrastim (Neupogen), and is approved for the same indications as filgrastim, which include several hematologic cancers and severe neutropenia. A biosimilar must demonstrate the same safety and effectiveness that were shown with the original (reference) biologic drug; a biosimilar, however, is expected to be sold at a lower price than its reference biologic drug.

“Biosimilars will provide access to important therapies for patients who need them,” said FDA Commissioner Margaret A. Hamburg, MD. “Patients and the health care community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy and quality standards.”

The Biologics Price Competition and Innovation Act of 2009, which was passed as part of the Affordable Care Act in 2010, created a pathway for the FDA to approve biosimilars in the United States. Based on that act, biosimilars can be approved if they can provide sufficient evidence to show that their efficacy and safety profiles are biologically similar or interchangeable with an FDA-approved biologic agent, which is known as the “reference” drug. The biosimilar must demonstrate that it has the same mechanism of action, route of administration, and dosage form/strength as the reference drug, and it can only be approved by the FDA for the same indications for which the reference drug is approved. US Food and Drug Administration; March 6, 2015

Novel Test Can Identify Apoptosis from Cancer Drugs in 16 Hours

A new test developed by researchers at Dana-Farber Cancer Institute may offer a new direction in personalized or precision medicine. The test, called Dynamic BH3 Profiling (DBP), can predict which drug among a variety of current treatments will be most effective for a specific tumor type. DBP is designed to detect the early signs of apoptosis in a patient using a cancer drug, and the test can assess the efficacy of individual drugs or drug combinations. The DBP usually can begin to detect the self-destruction of cancer cells within 16 hours.

“This measurement can be made in less than a day. It turns out that those drugs that push cancer cells closer to the threshold of apoptosis even over this short time frame are the drugs that eventually kill the cancer cells best, both in the laboratory and in mice, and even humans,” said Anthony G. Letai, MD, PhD, Associate Professor, Harvard Medical School and Dana-Farber Cancer Institute, Boston.

The researchers have tested cancer drugs for a variety of tumors, including melanoma, breast cancer, leukemia, lymphoma, prostate, colon, and ovarian cancer.

According to Dr Letai, the new test is 80% to 90% accurate in predicting which drug is most effective for a specific tumor.

“We can take early pick to see if the cancer cell is being pushed toward death.

What makes this especially powerful is that we’re not restricted to using one drug at a time; it can test the effectiveness in combinations,” said Dr Letai. “This is functional precision medicine, getting the right drugs to the right patient.” ­­FoxNews.com; February 26, 2015

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Type of Health Insurance Affects Clinical Outcomes in Patients with Brain Tumor

According to researchers from the University of Florida Health, the type of health insurance—private versus public—can affect the clinical outcomes of patients with brain tumor. The researchers found that patients with brain tumor who are uninsured or are covered by Medicaid are hospitalized for longer periods and have more complications than patients who have private insurance. In part, this could be related to the late diagnosis that is more typical for this patient population; these patients have less access to care than those with private insurance. And as in most cases of cancer, a late diagnosis is associated with a poorer prognosis than an early diagnosis.

“When private-insurance patients start to have a problem, it gets picked up ­really fast. They go to a primary doctor, who makes a quick referral to a neurologist or neurosurgeon,” said lead investigator Kristopher G. Hooten, MD, Resident, Department of Neurosurgery, University of Florida College of Medicine, Gainesville.

The results of the study were published in February in Neurosurgery.

“It’s both an access-­to-care and a quality-of-care issue before patients are admitted. [Uninsured or Medicaid patients] come in when their brain tumors are more advanced,” Dr Hooten said.

The uninsured and patients covered by Medicaid were at increased risk for developing a new medical condition in the hospital, and their risk for death during hospitalization was 25% greater than those with private insurance. They were also more likely to end up in a nursing home, a rehabilitation center, or hospice than patients with private insurance. These results are based on an analysis of 20022011 National Inpatient Sample data, the largest healthcare database in the United States. The researchers collected information on 566,346 hospital admissions for brain tumor.

“This type of research is important from a global standpoint to understand what goes into quality assessment, how hospitals are ranked based on quality and which patients are potentially high-risk. The true benefit is identifying areas of improvement and making things better for patients,” suggested Maryam Rahman, MD, Assistant Professor, Department of Neurosurgery, University of Florida. University of Florida press release; March 3, 2015 n

MARCH 2015

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Economics of Cancer Care

Value of New Drugs for Hematologic Cancers...

Boston (Saret CJ, et al. Blood. 2015 Feb therefore met this <$50,000 per QALY, 5. Epub ahead of print). regardless of the source of funding for the In their systematic review, Dr Neu- research (ie, industry or no industry). mann and colleagues looked at 29 cost-effectiveness studies of new drugs for hematologic malignancies developed Looking at the price between 1996 and 2012, showing that alone is not sufficient. the mean incremental cost-effectiveness That price has to be looked ratio (ICER) of these targeted therapies was <$50,000 per quality-adjusted lifeat in the context of what year (QALY) in approximately 75% of we’re getting back for it. the studies and <$100,000 per QALY in So if there is a treatment almost 90%.

The <$50,000 per QALY is accepted that really improves as the benchmark used to define cost-­ quality of life or extends effectiveness. The majority of the studies

“

life substantially…that is something that is worthy of a higher price.

at a glance ➤ A systematic analysis of recent targeted therapies for hematologic cancers suggests these agents deliver value for their cost ➤ Among 29 cost-effectiveness studies, the mean ICERs were <$50,000 per QALY in nearly 75% of the studies and <$100,000 per QALY in almost 90% ➤ The median ICER for industryfunded studies was $7000 lower than for non–industryfunded studies ➤ Despite the high costs of new drugs, the cost-effectiveness ratio distributions are comparable with those for cancer overall

”

—JOSHUA T. COHEN, PHD, MA

“Looking at the price alone is not sufficient. That price has to be looked at in the context of what we’re getting back for it,” said coinvestigator Joshua T. Cohen, PhD, MA, Deputy Director of the Center for the Evaluation of Value and Risk in Health. “So if there is a treatment that really improves quality of life or extends life substantially…that is something that is worthy of a higher price, and that’s the point.”

The effects of innovative agents in hematology on length of life, quality of life, and cost, and therefore their value, have been the topic of much heated discussion, said Cayla J. Saret, Research Assistant at the Center for the Evaluation of Value and Risk in Health. “We’ve been doing some research in the area of

interventions for blood cancer, and we weren’t aware of any other reviews of the literature that looked at the cost-effectiveness of these interventions overall,” Ms Saret told Value-Based Cancer Care.

The 29 peer-reviewed studies selected focused on 9 hematologic agents— alpha interferon (Multiferon), alemtuz­ umab (Campath), bendamustine (Treanda), bortezomib (Velcade), dasatinib (Sprycel), imatinib (Gleevec), lenalidomide (Revlimid), rituximab (Rituxan) alone or in combination, and thalidomide (Thalomid). The studies reported 44 ICERs. A total of 73% of the ICERs were <$50,000 per QALY and 86% were <$100,000 per QALY. The highest median-reported ICER was for chronic myeloid leukemia, at $55,000 per QALY, and the lowest was for non-Hodg­­ kin lymphoma, at $21,500 per QALY. The median ICER reported by industry-funded studies was $26,000 per QALY, which was lower than the $33,000 per QALY median reported by studies not funded by the industry, a nonsignificant difference.

“Our review suggests many new treatments for hematologic malignancies may confer reasonable value for money,” the investigators wrote. “Despite the high costs of new drugs, the cost-­ effectiveness ratio distributions are comparable to those for cancers overall and other healthcare fields.”

“As opposed to looking at the price in isolation, or the benefits in isolation, we’re hoping that decision makers also take into account cost-effectiveness, and this is one tool for them as they make decisions,” said Ms Saret. “They may be

Continued from the cover

looking at affordability. They may be look­ing at side effects. They may be looking at overall budget. This isn’t to say that this is the only thing a decision should be based on, it’s just pointing out one more factor to take into consideration.”

An appropriate threshold for cost-­ effectiveness has not been clearly established, said Dr Cohen. The United Kingdom uses a slightly lower threshold than the $50,000 or $100,000 per QALY

“

As opposed to looking at the price in isolation, or the benefits in isolation, we’re hoping that decision makers also take into account costeffectiveness, and this is one tool for them as they make decisions.

”

—CAYLA J. SARET

used in the United States. “There are people who argue the benchmark should be even higher [than $50,000 per QALY] when you look at what is actually spent on healthcare as a proxy for what society effectively deems as acceptable,” Dr Cohen said. He and Dr Neumann and Dr Weinstein had tackled this subject in a separate perspective last year, arguing that no single threshold is appropriate in all decision contexts, but in general, the $50,000 per QALY threshold may be too low (Neumann PJ, et al. N Engl J Med. 2014;371:796-797). n

Preventing Relapse in Myeloma Carries Economic Benefits, Reduces Overall Costs

By Dana Taylor

San Francisco, CA—In what is believed to be the first economic analysis of disease progression of patients with myeloma, researchers found that in patients with newly diagnosed myeloma, the monthly costs are reduced by 68% between the first 4 months through 18 months, but they then rise steeply when the disease relapses. The data were presented at the 2014 American Society of Hematology meeting.

“Few studies have examined the cost patterns of newly diagnosed patients before and after their first relapse, par-

8

ticularly using real-world data,” said Gary Binder, of Celgene Corporation.

“We know about the consequences of disease progression from a clinical perspective, but to our knowledge there’s never been an analysis of what this means from an economic perspective,” he said. “We wanted to examine the patterns of cost in the first-line setting, and see how those compared to the second-­line setting.”

Treatment with bortezomib and lenalidomide, and longer durations of treatment, have prolonged survival in

VALUE-BASED CANCER CARE

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MARCH 2015

p­ atients with myeloma, but this improvement has raised interest in the

“

The findings suggest that the longer you can sustain a patient in first-line status, the longer the patient will be running at below-average cost.

”

—GARY BINDER

cost of treating newly diagnosed patients. An economic analysis could be valuable in informing decisions on the cost-effectiveness and economic benefits of long-term drug therapy for patients with myeloma, including the economic impact of extending time to disease progression and the cost consequences when the disease relapses and the patient moves to second-line therapies.

Mr Binder and his colleagues, in collaboration with the Levine Cancer Institute and the Carolinas HealthCare SysContinued on page 9

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Economics of Cancer Care

Regorafenib in Metastatic Colorectal Cancer: High Cost with Little Benefit

By Chase Doyle

San Francisco, CA—According to a recent cost-effectiveness analysis, thirdline therapy with regorafenib (Stivarga) in patients with previously treated metastatic colorectal cancer (CRC) far exceeded accepted willingness-to-pay ­ thresholds based on incremental cost-effectiveness ratio (ICER) and quality-adjusted life-years (QALYs). Presented at the 2015 Gastrointestinal Cancers Symposium, the results showed that regorafenib provided an additional 0.04 QALYs, at a cost of $39,391.

“The incremental cost-effectiveness ratio was almost $900,000 per QALY, which is way above the benchmark value,” said Daniel A. Goldstein, MD, Hematology Oncology Fellow at the Winship Cancer Institute, Emory University, Atlanta. “Basically, you’re not getting a lot of bang for your buck.”

Regorafenib was approved by the FDA in 2012 for patients with CRC and is now the standard of care as third-line therapy in patients with metastatic CRC, improving the median overall survival by only 1.4 months. Dr Goldstein was quick to note its considerable side-effect profile and high cost.

“It has a lot of side effects—hand-foot syndrome, fatigue, diarrhea—and patients who have already received 2 lines of treatment are often not in a high enough performance status to receive it,” he said.

In addition, when it is administered, there are extraordinary costs to payers.

Citing the lack of any published USbased cost-effectiveness studies of regorafenib for the treatment of metastatic colorectal cancer, Dr Goldstein’s outcomes were obtained by merging publicly available clinical trial data with publicly available cost data for Medicare.

According to estimates from the Centers for Medicare & Medicaid Services, the base-case value for the drug was $11,364 per cycle. (The drug is administered on the first 21 days of a 28-day cycle.) The management of adverse

“

Goldstein, “and they found that regorafenib had a 6-week median overall survival benefit. And so, when you incorporate quality-adjusted life-years into that, because the quality of life for patients who are in third-line treatment is not great, the drug provided patients only 0.04 quality-adjusted life-years gained.”

And those 0.04 QALYs proved costly.

Including adverse events, the price of regorafenib equaled $39,391 for the total treatment duration.

“In all 1-way sensitivity analyses,” noted Dr Goldstein, “the ICER of regorafenib was greater than $700,000 per

If there is not a precise number for willingness-­to­pay value, it’s been approximated in the past at around $50,000 per QALY, perhaps $100,000 per QALY, and maybe even $150,000 per QALY, but this number of $900,000 per QALY is way above that benchmark value.

”

events included in Dr Goldstein’s assessment was based on accepted standards.

“We used the CORRECT trial data that were published for patients who were treated with regorafenib versus placebo in a third-line setting,” said Dr

—DANIEL A. GOLDSTEIN, MD

QALY. And the ICER of regorafenib was greater than $200,000 per QALY in more than 99% of probabilistic sensitivity analyses.”

At a willingness-to-pay threshold of $100,000 per QALY, the use of rego-

“

When we do have patients who have run out of all FDAapproved options, we may offer this drug, although, admittedly, it doesn’t have that much benefit in unselected patients.

”

—DANIEL A. GOLDSTEIN, MD

rafenib in patients with previously treated metastatic CRC is not cost-­effective.

“If there is not a precise number for willingness-to-pay value, it’s been approximated in the past at around $50,000 per QALY, perhaps $100,000 per QALY, and maybe even $150,000 per QALY,” emphasized Dr Goldstein, “but this number of $900,000 per QALY is way above that benchmark value….It’s the highest number I’ve ever seen in any of my personal studies.”

When asked whether this drug is still used at Emory, Dr Goldstein acknowledged, “When we do have patients who have run out of all FDA-approved options, we may offer this drug, although, admittedly, it doesn’t have that much benefit in unselected patients.” n

Preventing Relapse in Myeloma Carries Economic Benefits, Reduces Overall...

Continued from page 8

tem in Charlotte, NC, examined a US database sourced from employer-sponsored health insurance plans and Medicare and Medicaid, covering more than 25 million lives annually. Their analysis included 897 patients newly diagnosed with myeloma and 280 patients with relapsed myeloma who received lenalidomide-based or bortezomib-based regimens between 2006 and 2012.

Cost Spikes with Relapsed Disease

“We found that over time, the cost per month per patient declined, then started to plateau out at 18 months.

When patients relapsed and went on second-line treatment, the cost spiked again, then declined but never to the VOL. 6

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“

Over time, the cost per month per patient declined, then started to plateau out at 18 months. When patients relapsed and went on second-line treatment, the cost spiked again, then declined but never to the same level….Preventing relapses saves money.

same level,” Mr Binder pointed out.

The mean monthly total direct costs (medical and pharmacy-related costs combined) were $15,000 during the first 3 months of treatment and declined each quarter to $4927 monthly at 18 months after starting treatment.

”

—GARY BINDER

At disease relapse, the monthly costs increased to more than $12,000 for the first 3 months and followed a quarterly pattern of reduction, similar to that seen for newly diagnosed patients but never reaching the same low level.

The mean cost stabilized at $5345 MARCH 2015

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after second-line treatment.

By drug, the total monthly cost of treating a newly diagnosed patient averaged $8941 with lenalidomide and $11,139 with bortezomib. For relapsed patients, the mean total costs were $8859 and $10,063, respectively.

The quarterly cost-reduction patterns were consistent for lenalidomide and for bortezomib in newly diagnosed patients (first-line setting) as well as relapsed patients (second-line setting).

“The findings suggest that the longer you can sustain a patient in first-line status, the longer the patient will be running at below-average cost. Preventing relapses saves money,” Mr Binder said in an interview. n

www.ValueBasedCancerCare.com

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Genitourinary Cancers Symposium

ASSURE Trial: No Role for Adjuvant Sorafenib or Sunitinib in Locally Advanced Kidney...

Continued from the cover

Ther­ apeutics Program Co-Leader, Abramson Cancer Center, University of Pennsylvania, Philadelphia. She discussed the results at the 2015 Genitourinary Cancers Symposium.

Disappointing Results

Sorafenib and sunitinib are both widely effective in metastatic kidney cancer, and the investigators of ASSURE hoped that these drugs would also provide benefits for patients in the adjuvant setting. However, the findings of this randomized, placebo-controlled trial suggest that close observation should remain the standard of care, Dr Haas said.

“No one could be more disappointed in these results than me, except for patients with kidney cancer. Even though these drugs provide benefit in the metastatic setting, they did not reduce disease recurrence in the adjuvant setting, while they did increase side effects,” said Dr Haas.

She added that analysis of tumor specimens collected during the trial may provide some clues as to whether specific subsets of patients may derive a treatment benefit from adjuvant therapy with sorafenib or sunitinib.

“

No one could be more disappointed in these results than me, except for patients with kidney cancer. Even though these drugs provide benefit in the metastatic setting, they did not reduce disease recurrence in the adjuvant setting, while they did increase side effects.

”

Study Details

ASSURE enrolled 1943 patients who underwent complete resection and were categorized as having intermediate- or high-risk for disease recurrence according to tumor size and grade, and lymph node involvement. The treat-

—NAOMI B. HAAS, MD

ment arms were well-balanced for the type of kidney cancer, type of surgery,

at a glance ➤ Unexpected results from a new study show that adjuvant therapy with sorafenib or sunitinib does not extend disease-free survival in patients with locally advanced kidney cancer who are at high risk for recurrence ➤ Because these drugs are effective in metastatic kidney cancer, investigators were hoping they would provide benefits in the adjuvant setting

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VALUE-BASED CANCER CARE

➤T he 5-year recurrence-free survival rates for sunitinib (53.8%) and sorafenib (52.8%) were similar to the placebo rate (55.8%) ➤ Overall survival did not differ significantly between the arms ➤ Based on these results, adjuvant sorafenib or sunitinib should not be used for locally advanced kidney cancer after surgery ➤ Close observation should remain the standard of care for patients with advanced kidney cancer

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MARCH 2015

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The fact that this is a negative trial no way diminishes its importance.

Tyrosine kinase inhibitors may not be as effective as chemotherapy in the adjuvant treatment of solid tumors. This study supports my current practice of not using these drugs in the adjuvant setting.

”

—CHARLES RYAN, MD

performance status, and risk for disease recurrence.

Patients were randomized in a 1:1:1 ratio to receive sorafenib, sunitinib, or placebo for 1 year. After 1322 patients were accrued, the starting doses of the active drugs were lowered and titrated according to the side effects, which reduced the rates of discontinuation in the experimental arms from approximately 26% for patients starting with full doses to 14% for those starting with reduced doses.

Dr Haas said that the dosing adjustments could have relevance for reducing discontinuation of these drugs in other settings.

Interim analysis revealed similar rates (approximately 40%) of recurrence in all 3 groups and similar rates (5.6-5.7 years) of DFS, the primary end point of the trial.

The 5-year recurrence-free survival rates were 53.8% with sunitinib and 52.8% with sorafenib, which was similar to the 55.8% in the placebo arm. Overall survival was not significantly different between arms, ranging from 77% ­­to 81%.

Based on these interim findings, the Data Safety and Monitoring Committee recommended release of the results.

The most common side effects with the 2 active drugs included grade ≥3 hypertension (16% each for sorafenib and sunitinib vs 4% for placebo), handfoot reaction (sorafenib, 33%; sunitinib, 14%; placebo, 1%), rash (15%, 2%, and 1%, respectively), and fatigue (7%, 17%, and 3%, respectively).

Final analysis of disease recurrence and survival will be presented in the future.

“The findings suggest that patients with locally advanced kidney cancer treated with surgery should not receive adjuvant sorafenib or sunitinib,” Dr Haas said.

All patients in the trial exceeded the 4.6-year DFS projected in the null hypothesis when the trial was designed, she added.

At a question and answer session after Dr Haas’ presentation for the press, Charles Ryan, MD, of the University of California, San Francisco, who moderated the discussion, noted that some oncologists are using adjuvant VEGF therapy with no supportive evidence. In his view, the interim results of ASSURE provide convincing evidence against this practice.

“The fact that this is a negative trial no way diminishes its importance. Tyrosine kinase inhibitors [VEGF inhibitors] may not be as effective as chemotherapy in the adjuvant treatment of solid tumors,” Dr Ryan stated. “This study supports my current practice of not using these drugs in the adjuvant setting.”

Other Adjuvant Trials

Other adjuvant trials are ongoing in kidney cancer. These include a study of the tyrosine kinase/VEGF inhibitor axitinib (Inlyta), and a study of the mTOR inhibitor everolimus (Afinitor); both trials are currently accruing patients.

Adjuvant trials of immunotherapy and other targeted approaches are being considered. n

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

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

the additional value of choice of administration.

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

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

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

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

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

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

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

Please see Brief Summary for VELCADE adjacent to this advertisement.

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

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

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

FDA News Palbociclib Approved for Metastatic... Continued from page 5

each treatment cycle, and on day 14 of the first 2 cycles. (February 3, 2015)

FDA Expedites Approval of Lenvatinib for Refractory Differentiated Thyroid Cancer

The FDA approved lenvatinib (Lenvima; Eisai), a multitargeted tyrosine

kinase inhibitor (TKI), for the treatment of patients with progressive, differentiated thyroid cancer that is refractory to therapy with radioactive iodine (also known as 131I), a common treatment used for patients with advanced thyroid cancer. The FDA expedited its review of lenvatinib under its priority review program, based on data suggesting that lenvatinib provides significant improvement in safety or efficacy in

terms of the treatment of differentiated thyroid cancer, the most common type of thyroid cancer.

The National Cancer Institute estimates that 62,980 Americans were diagnosed with thyroid cancer in 2014, and more than 1800 patients died from the disease. Lenvatinib is the fourth TKI approved by the FDA in the past decade for the treatment of patients with refractory thyroid cancer.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Monitor patients closely and take appropriate precautions.

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

“The development of new therapies to assist patients with refractory disease is of high importance to the FDA,” said Richard Pazdur, MD, Director of the FDA’s Office of Hematology and Oncology Products. “Today’s approval gives patients and healthcare professionals a new therapy to help slow the progression of DTC [differentiated thyroid cancer].”

Lenvatinib also received orphan drug designation, because thyroid cancer is considered a relatively rare disease.

The FDA’s approval of lenvatinib was based on a phase 3 clinical trial with 392 patients with progressive, radioactive iodine therapy–refractory differentiated thyroid cancer who were randomized to lenvatinib or to placebo.

The median progression-free survival (PFS) was 18.3 months in the lenvatinib arm compared with a median PFS of 3.6 months in the placebo arm. In addition, 65% of patients receiving lenvatinib had a reduction in their tumor size compared with only 2% in patients in the placebo arm. The majority of the patients in the placebo arm were switched to lenvatinib therapy upon disease progression (for complete study details, see page 17).

The most common side effects of lenvatinib were hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria, swelling and pain in the palms, palmar-­ plantar erythrodysesthesia syndrome, and dysphonia.

Lenvatinib is associated with serious side effects, including cardiac failure, arterial thromboembolic events, hepatotoxicity, renal failure and impairment, gastrointestinal perforation or fistula formation, QT interval prolongation, hypocalcemia, reversible posterior leukoencephalopathy syndrome, hemorrhage, risks to an unborn child, and impaired suppression of thyroid-­stimulating hormone production. (Feb­­ruary 13, 2015)

Lenalidomide Combined with Dexamethasone Receives Expanded Indication for Patients with Newly Diagnosed Myeloma

The FDA approved an expanded i­ndication for lenalidomide (Revlimid; Celgene Corporation) in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. This combination was previously approved for the treatment of patients with multiple myeloma who had received ≥1 therapies before.

“The approval of Revlimid as an option for use in all patients with multiple myeloma represents a new paradigm in the management of this disease,” said Kenneth Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber/Brigham and Women’s Continued on page 22

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Genitourinary Cancers Symposium

Caution: Active Surveillance Ill Advised in Men with Intermediate-Risk Prostate Cancer

By Phoebe Starr

“

Orlando, FL—Active surveillance is sometimes used as management strategy in patients with intermediate-risk prostate cancer, especially in older, sicker men with short life expectancy. A new study validates the use of active surveillance for men with low-risk prostate cancer but provides sobering data regarding this type of management for those with intermediate-risk prostate cancer.

The study results were presented at the 2015 Genitourinary Cancers Symposium.

Surveillance Can Increase Mortality

The study findings showed that intermediate-risk patients had almost a 4-fold higher risk for dying from prostate cancer compared with patients with lowrisk prostate cancer when managed by active surveillance.

“This is the first study to analyze longterm outcomes of intermediate-risk patients managed by active surveillance.

This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death in the intermediate-risk patients assigned to active surveillance,” stated senior investigator, D. Andrew Loblaw, MD, MSc, of the Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.

This is the first study to analyze long-term outcomes of intermediaterisk patients managed by active surveillance. This study validates active surveillance for low-risk patients with prostate cancer. We were surprised by the greater risk of prostate cancer death.

”

—D. ANDREW LOBLAW, MD, MSC

Lead investigator Hima Bindu Musunuru, MD, of the Sunnybrook Health Sciences Centre, said, “Extreme caution should be exercised if active surveillance were to be implemented for intermediate-risk patients.”

Dr Loblaw said that further study is needed to define favorable versus unfavorable intermediate-risk patients. “We think there may be a subgroup of intermediate-risk patients out there who may be safely managed by active surveillance,” he stated.

Study Details

The prospective study included 945 patients with prostate cancer who were managed with active surveillance be-

tween 1995 and 2013 at Sunnybrook Health Sciences Centre; 237 (23.9%) patients had intermediate-risk disease and a median follow-up of 6.9 years, and 708 patients had low-risk prostate cancer and a median follow-up of 6.4 years. The median treatment-free interval for intermediate-risk patients was 12.3 years.

Patients with progressive disease, as reflected by a prostate-specific antigen doubling time of <3 years, were offered radiation or surgery; 86 patients with intermediate-risk prostate cancer received treatment.

For patients with intermediate-risk prostate cancer, the 10- and 15-year overall survival rates were 68.4% and 50.3%, respectively, versus 83.6% and 68.8%, re-

spectively, for low-risk patients (P <.001).

The 10- and 15-year cancer-specific survival was 95.5% and 88.5%, respectively, for the intermediate-risk group, and 98.2% and 96.3%, respectively, for the low-risk patients (P = .006).

Just under 66% of the intermediate-risk patients were aged >70 years. In the study, active surveillance was offered to men with shorter life expectancy and comorbidities, which is in line with the current National Comprehensive Cancer Network guidelines.

The risk for dying from any cause was twice as high for intermediate-risk patients compared with low-risk patients.

Moreover, the risk for prostate cancer– specific death at 15 years was 3.75 times higher for intermediate-risk patients compared with low-risk patients at the same time point (11.5% vs 3.7%, respectively).

Future Research

The field of molecular and biological markers for intermediate-risk prostate cancer is an active area of investigation, according to Dr Loblaw and Am­erican Society of Clinical Oncology Expert and 2015 Genitourinary Can­cers Symposium News Planning Committee team member Charles Ryan, MD, of the University of California,­San Francisco. n

History of Testicular Cancer Increases Risk for Aggressive Prostate Cancer Later on Orlando, FL—Previous studies have shown that a history of testicular cancer increases the risk for developing prostate cancer. A new study presented at the 2015 Genitourinary Cancers Symposium shows, for the first time ever, a link between a history of testicular cancer and an increased likelihood of intermediateand high-risk prostate cancer sometime in the future.

This case-control study included approximately 180,000 men from the Surveillance, Epidemiology, and End Results registry, of whom 32,435 men had a history of testicular cancer and 147,044 had a history of melanoma. Melanoma was selected as a control cancer, because it has no known link to prostate cancer.

First Evidence for a New Biologic Link

By age 80 years, 12.6% of men with a history of testicular cancer developed

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prostate cancer compared with only 2.8% of those with no such history, an almost 10% increase in risk. The incidence of intermediate- or high-risk prostate cancer was 5.8% in those with a history of testicular cancer versus 1.1% in those with no such history. Overall, a history of testicular cancer was associated with a 4.7-fold increased risk for prostate cancer and a 5.2-fold increased risk for intermediateor high-risk disease.

“This study should alert men with a history of testicular cancer to be more proactive about discussing screening for prostate cancer risk with their doctors,” said senior study investigator Mohummad Minhaj Siddiqui, MD, of the University of Maryland School of Medicine, and Director of Urologic Robotic Surgery, University of Maryland Marlene and Stewart Greenebaum Cancer Center, Baltimore.

After controlling for other risk factors

“

This study should alert men with a history of testicular cancer to be more proactive about discussing screening for prostate cancer risk with their doctors.

”

—MOHUMMAD MINHAJ SIDDIQUI, MD

for prostate cancer, including age, race, and previous radiotherapy, there was still an increased risk for prostate cancer and intermediate- and high-risk prostate cancer in men with a history of testicular cancer. However, the absolute risk for developing intermediate- or high-risk cancer was relatively low, Dr Siddiqui pointed out—approximately 5.8%.

“Ninety-five percent of men who have had testicular cancer will not develop MARCH 2015

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aggressive prostate cancer,” he said. Nevertheless, the results should encourage close follow-up of men who have had testicular cancer, he noted.

“This study is suggestive, and we need further validation studies to establish this association with certainty,” Dr Siddiqui said. He emphasized his hopes that these findings will prompt further research on the biologic link between these 2 diseases.—PS n

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Genitourinary Cancers Symposium

Debate on PSA Prostate Cancer Screening Redux First post-2011 USPSTF findings raise new questions

By Phoebe Starr Orlando, FL—A new retrospective study of 87,562 men diagnosed with prostate cancer between January 2005 and June 2013 show that the incidence of prostate cancer and men with prostate-specific antigen (PSA) >10 decreased gradually between 2005 and 2011. However, the incidence of high-risk prostate cancer at diagnosis increased annually by 3% between 2011 and 2013, totaling 6%. This increase could lead to an additional 1400 prostate cancer deaths 10 years later.

These findings were presented at the 2015 Genitourinary Cancers Symposium, resuscitating the debate about PSA screening.

What happened between 2011 and 2013 to account for this increase in higher-risk prostate cancer?

In 2011, the US Preventive Services Task Force (USPSTF) issued a new recommendation against routine PSA screening for all men in the general population. The previous, 2005 USPSTF recommendation was against PSA screening only in older men aged ≥75 years.

The new study findings suggest, but do not prove, that adoption of the new USPSTF recommendations could lead to more aggressive cancers at diagnosis, and

“

Our study is the first to measure changes in prostate cancer presentation in the period following the USPSTF PSA screening recommendations….Men who are at increased risk for prostate cancer, especially those with a family history of prostate cancer, should consider talking with their doctor about PSA screening.

”

—TIMOTHY E. SCHULTHEISS, PHD

subsequently more prostate cancer–related deaths. More research is needed to validate these findings, say the investigators.

“Our study is the first to measure changes in prostate cancer presentation in the period following the USPSTF PSA screening recommendations,” said lead investigator Timothy E. Schultheiss, PhD, Director and Professor, Radiation Physics, City of Hope, Duarte, CA. “Given the findings of our analysis in this time frame, men who are at increased risk for prostate cancer, especially those

with a family history of prostate cancer, should consider talking with their doctor about PSA screening,” he said.

“We can only speculate about whether the USPSTF recommendations are responsible” for the increase in higher-risk cases being diagnosed, “but we believe that the USPSTF might reconsider their recommendation,” Dr Schultheiss added.

Need to Reconsider Current Guidelines?

The study included men diagnosed

with intermediate- or high-risk prostate cancer based on their blood PSA level >10 ng/mL who were included in the National Oncology Data Alliance (NODA), a database that captures cancer cases at more than 150 US hospitals.

NODA is similar to the National Cancer Institute’s Surveillance, Epidemiology, and End Results database, but includes more recent data for the years 2011-2013.

This was not a screening study per se, Dr Schultheiss emphasized. It just included men who presented to the clinic and were diagnosed with prostate cancer based on their PSA level, but the reasons why they presented to the clinic were not available for analysis.

Commenting on the study, American Society of Clinical Oncology Expert and 2015 Genitourinary Cancers Symposium News Planning Committee team member Charles Ryan, MD, of the University of California, San Francisco, said, “It is far too early to say this is cause and effect. This study adds to the ongoing debate about PSA screening and underscores the importance of reconsidering guidelines.” n

Localized Renal Cancer Surgery Associated with Substantial Costs from Lost Productivity Orlando, FL—The total costs of renal surgery are not limited to hospitalization but accrue long after discharge. According to data presented at the 2015 Genitourinary Cancers Symposium, most patients took more than 30 days off work after radical or partial nephrectomy, with the average estimated wages lost to unpaid time exceeding $10,000.

“Despite advances in minimally invasive surgery,” said the study’s lead investigator, Peter Chang, MD, MPH, Urologic Oncology, Beth Israel Deaconess Medical Center, Boston, MA, “more than 50% of patients take over 1 month off from work after localized renal cancer surgery. The mean estimated wages lost from surgery-related time off work, assuming unpaid leave, was $10,371.”

Hospital-related direct and indirect costs of radical and partial nephrectomy have been previously evaluated, Dr Chang said. However, costs associated with time off work and potential lost wages or caretaker assistance have not been documented after renal cancer surgery.

14

“

Despite advances in minimally invasive surgery, more than 50% of patients take over 1 month off from work after localized renal cancer surgery.

The mean estimated wages lost from surgery-related time off work, assuming unpaid leave, was $10,371.

”

—PETER CHANG, MD, MPH

“Loss of productivity related to time taken off work hasn’t been well-characterized before, so that’s what we wanted to examine in greater detail with this study,” he said.

The initial cohort consisted of 315 men and women with localized renal cancer undergoing radical and partial nephrectomy enrolled in a prospective quality-of-life study at an academic medical center. The patients responded to a questionnaire asking them about

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time off work, job physicality, income by tax bracket, and need for caretaker assistance.

“We asked the patients…how many people were required to take care of them while they were at home, because that’s additional people who might be required to take off work,” Dr Chang said.

The analytic cohort consisted of 69 patients who were employed at the time of surgery. (Patients who underwent cytoreductive nephrectomy or were ­

u­ nemployed at the time of surgery were excluded from analysis.)

Dr Chang and his colleagues obtained the outcome of potential lost wages as a result of time off work by multiplying the average income in the reported tax bracket by the time taken off work divided by 365 days. Of the patients, 33% had at least 1 caretaker take time off work during convalescence.

With this study, Dr Chang also sought to identify predictors of taking time off work for more than 30 days.

“The cost of lost productivity and wages is substantial,” Dr Chang affirmed, “and it hasn’t really been quantified before. We believe it should at least be taken into account when considering economic costs of cancer care….Incorporating these societal costs should allow for more comprehensive cost-­ effectiveness analysis.”

Future directions include assessing time off work and other societal costs prospectively in a larger, more diverse cohort.—PS n

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Personalized Medicine

AR-V7 Predicts Chemotherapy Sensitivity in Metastatic Prostate...

Continued from the cover

help in treatment selection for patients with metastatic castration-resistant prostate can­­cer (CRPC).

The study showed that the presence of AR-V7 in circulating tumor cells was predictive of sensitivity to chemotherapy with the taxanes docetaxel (Taxotere) and cabazitaxel (Jevtana) in men with metastatic CRPC. A previous study by the same team of researchers showed that patients whose circulating tumor cells harbored AR-V7 had primary resistance to AR-directed therapy with enzalutamide (Xtandi) and abiraterone (Zytiga); the study was published late last year (Antonarakis ES, et al. N Engl J Med. 2014;371:1028-1038).

dated in a prospective multicenter trial.

No commercial test for AR-V7 is currently available. These researchers and

“

AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future….

Taxanes may be more efficacious than AR-directed therapy in AR-V7–positive men.

”

—EMMANUEL S. ANTONARAKIS, MBBCH

In Search of Biomarkers

Taken together, the studies suggest that patients who are AR-V7–positive should be offered chemotherapy with one of the taxanes instead of enzalutamide or abiraterone, whereas patients who are AR-V7–negative can be offered either type of therapy safely.

Lead investigator Emmanuel S. Antonarakis, MBBCh, Assistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, said, “We urgently need markers that predict which therapies are going to be effective, and which will not, in individual patients with prostate cancer. AR-V7 testing may be extremely valuable in guiding treatment decisions for men with hormone-resistant disease in the near future.”

Dr Antonarakis noted that the findings related to AR-V7 need to be vali-

were found to be AR-V7–positive. In general, at least 33% of patients with CRPC are AR-V7–positive.

other investigators are working on developing a CLIA (Clinical Laboratory Improvement Amendments)-approved test for AR-V7, Dr Antonarakis said.

“Taxanes may be more efficacious than AR-directed therapy in AR-V7– positive men,” Dr Antonarakis stated.

“We need to prospectively validate this marker for therapy selection. The utility of the test will be greater in positive patients, if confirmed, whereas the utility in AR-V7–negative patients is not so great.”

Study Details

The present study included 37 men with metastatic CRPC who were initiating chemotherapy with docetaxel or enzalutamide; 17 of 37 (46%) patients

The primary end point of the study was the associations between AR-V7 status and prostate-specific antigen (PSA) response rates; a ≥50% reduction in PSA from baseline was considered to be a positive PSA response to therapy. Other end points were progression-free survival (PFS) as measured by PSA levels and by clinical or radiographic progression.

PSA responses were achieved in 41% of AR-V7–positive and 65% of AR-V7– negative patients. The median PSAbased PFS rates were comparable between these 2 groups—4.5 months versus 6.2 months, respectively; the median PFS was also comparable: 5.1 months versus 6.9 months, respectively.

When the investigators incorporated

data from their previous study of 62 men who received abiraterone or enzalutamide, clinical outcomes were superior in AR-V7–positive men who received taxanes versus abiraterone or enzalutamide, whereas outcomes were not significantly different for AR-V7– negative men who received either type of therapy.

A striking difference in PSA response was observed between the 2 types of therapy in AR-V7–positive men; 41% of patients showed positive response with the taxanes versus 0% (P <.001) with enzalutamide or abiraterone.

The median PSA-based PFS and the median PFS were significantly longer in AR-V7–positive men who ­ received taxanes (P = .001 and P = .003, respectively).

“The AR-V7 biomarker is better at separating patients requiring AR-directed therapy versus chemotherapy. If a patient is AR-V7–positive, he has a greater chance of progression on enzalutamide or abiraterone compared with taxanes. In fact, he has a 79% lower chance of progression on a taxane and a 4.8-fold greater increase in risk of progression on enzalutamide or abir­ aterone,” Dr Antonarakis commented.

“In AR-V7–negative patients, there is no difference in PFS between taxanes or AR-directed therapy.”

According to these results, the presence of AR-V7 in circulating tumor cells is not associated with primary re­ sistance to the taxanes; it is, however, associated with primary resistance to ­ AR-directed therapy. n

Quality Care

Foreign-Trained Physicians Less Likely to Screen for Cancer, Especially Among Immigrant Populations

By Rosemary Frei, MSc

S

creening for cancer is suboptimal among some immigrant populations, especially those whose primary care physicians are trained in foreign countries, according to results of a new study of primary care practices in Canada; specifically, women from South Asia whose family physicians were trained in South Asia were less likely to be screened for cervical cancer than nonimmigrant women whose physicians

were not immigrants (Lofters AK, et al.

Cancer Med. 2015;4:212-223.

Overall, South Asian patients are less likely to be screened for cervical, breast, or colorectal cancer than immigrants from other countries, regardless of their doctors’ country of origin.

Although the study was conducted in Canada, the results likely apply to ethnic populations in the United States, both primary care physicians and their

physicians, suggested lead investigator Aisha K. Lofters, MD, PhD, a family physician at St. M ­ ichael’s Hospital and Adjunct Scientist, Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada.

“Our findings may reflect differences in what’s emphasized in medical school curriculums around the world,” Dr Lofters said. “These findings also suggest that there’s a particular gap with South

Asian–trained doctors being less likely to perform Pap tests on South Asian women.”

Study Details

Using 2008-2010 data from several Canadian administrative databases, Dr Lofters and her team analyzed information on 6303 doctors in urban centers serving 1,156,627 women eligible for breast cancer screening, 2,730,380 Continued on page 16

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Health Policy

High-Quality Cancer Care Focus of ASCO’s Medicaid Reform...

Continued from the cover

ing we want more money to take care of Medicaid patients; we say we are ready to completely rethink the entire way this program is run,” said Blase N. Polite, MD, MPP, Chair of ASCO’s Government Relations Committee, and Assistant Professor of Medicine, University of Chicago, in a news conference in January 2015.

“And increased resources in conjunction with us providing better care, and showing value, are really the key driving points of our recommendations.”

ASCO President Peter P. Yu, MD, FACP, Director of Cancer Research, Palo Alto Medical Foundation, CA, agreed that the statement stems from concern for the quality of and access to cancer care.

“We…believe that no individual diagnosed with cancer should be without insurance that guarantees access to high-quality cancer care delivered by a cancer specialist. Therefore, patients with cancer who have Medicaid should receive the same timely and high-quality care as patients with private insurance,” said Dr Yu during the news conference.

“For these and other reasons, ASCO strongly believes that the society should­­… make concrete, constructive recommendations for strengthening this program to ensure that our most vulnerable citizens receive needed healthcare,” Dr Yu said.

Quality Cancer Care, Removing Barriers

Dr Polite outlined the 5 central points in the recommendations: 1. Every state should expand its Medicaid program to cover individuals with incomes below the federal poverty level or use another method to ensure that bene­

pation in approved clinical trials, and should allow patients to cross state lines to participate in such trials.

Accountability

“

We are ready to completely rethink the entire way this program is run. And increased resources in conjunction with us providing better care, and showing value, are really the key driving points.

”

—BLASE N. POLITE, MD, MPP

ficiaries have access to comprehensive, subsidized, high-quality cancer care, as measured by cancer-specific quality metrics and delivered by cancer specialists 2. Medicaid reimbursement levels should be increased to those of Medicare, and oncologists should take the lead in the creation of cancer-related quality measures and payment reforms 3. State flexibility in running the Medicaid program should be tied to meeting quality metrics

“

No individual diagnosed with cancer should be without insurance that guarantees access to high-quality cancer care delivered by a cancer specialist.

”

—PETER P. YU, MD, FACP

4. Medicaid should eliminate barriers between current Medicaid enrollees and those who are eligible for Medicaid under the expansion of the program with the Affordable Care Act; it should cover all genetic testing (not just testing for BRCA mutations) without deductibles or copays for all established cancer-related syndromes; and cover risk-reducing therapies, including surgeries and medications, in patients with inherited cancer risk syndromes 5. Medicaid should cover routine patient care costs associated with partici-

“In exchange for greater flexibility and increased resources, we as physicians are ready to be held accountable for the quality of care we provide our patients,” Dr Polite emphasized. “We believe that states should be willing to do the same in exchange for the flexibility they want to administer the Medicaid program.”

Other recommendations include: • Out-of-pocket expenses associated with oral cancer medications should be equal to those for intravenous or injected oncology medications or, alternatively, intravenous and oral therapies and supportive care drugs should be exempt services with respect to cost-sharing • The 340B program should be changed to fit its original intent of ensuring care for uninsured and underinsured patients with Medicaid across care settings • Medical home designations should be applied to the spectrum of care facilities and providers needed by patients with cancer, including care coordination and patient education by cancer specialists.

“Over the next year, ASCO will work closely with federal and state policymakers to identify viable approaches and ways to meet the needs of patients whose healthcare depends on Medicaid,” said Dr Yu at the conclusion of the news conference. n

Foreign-Trained Physicians Less Likely to... women eligible for cervical cancer screening, and 2,260,569 men and women eligible for colorectal cancer screening.

Overall, physicians trained in Canada were the most likely to screen their patients for cancer. A multivariable analysis revealed that family doctors who studied medicine in the Caribbean/Latin America, the Middle East/North Africa, South Asia, and Western Europe were less likely to screen patients for cancer than those who studied medicine in Canada.

Furthermore, physicians who were trained in South Asia were the least likely to screen for cervical cancer. The odds ratio of physicians trained in South Asia

16

screening South Asain women for cervical cancer was 0.56 compared with physicians trained in the United States, Australia, or New Zealand screening women from these countries for cervical cancer.

People from the Caribbean/Latin America were the only ethnic group that did not have lower probabilities versus nonimmigrants of being screened for cervical, breast, or colorectal cancer.

Overall, ethnic patients with higher income and those who had a female physician were more likely to be screened for cancer than other groups.

“The study highlights certain physician characteristics that are associated with cancer screening for eligible pa-

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tients, including immigrant patients, and that should be considered when designing physician-targeted interventions. We have also highlighted an ethnic community, South Asians, which requires particular attention, both among its patients and its primary care providers,” Dr Lofters and colleagues wrote.

New Screening Programs

These findings add urgency to programs aimed at boosting cancer screening in other subpopulations, Dr Lofters told Value-Based Cancer Care.

She said that she was launching a pilot project that uses the “Plan-Do-Study-

Continued from page 15

Act” approach for improving cancer screening among South Asian patients.

“The main tools are patient education, patient reminders, and small media—brochures and pamphlets. And the way the doctors will deliver them will be adapted based on how well it’s working,” said Dr Lofters.

She was also involved in the design of the Screening Saves Lives program. In that program, South Asian community leaders are educated about the importance of cancer screening, and they, in turn, educate their peers about this.

Dr Lofters suggested that these types of programs could also be helpful in the United States. n

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In the Literature Anti-CD19 CAR T-Cells Show Promise in B-Cell Cancer

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cies. The researchers recommended further development of this approach for advanced B-cell malignancies.

Lenvatinib Prolongs Progression-Free Survival in Advanced Thyroid Cancer

Lenvatinib (Lenvima) is a novel oral multitargeted tyrosine B:7.625 in kinase inhibitor (TKI) that inhibits vascular endotheliT:7.375 in al growth factor receptors 1, 2, and 3;

fibroblast growth factor receptors 1 to 4; platelet-derived growth factor receptor alpha; RET; and KIT-signaling networks. In a phase 2 study of patients with radioactive iodine therapy–refractory differentiated thyroid cancer, lenvatinib demonstrated clinical benefit.

Based on these results, researchers conducted a phase 3 study to assess progression-free survival (PFS) among patients who received lenvatinib compared with Continued on page 18

In mCRPC therapy…

Is there more to the story?

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

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

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

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

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

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

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

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

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

Please see additional Important Safety Information on the next page.

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

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Patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) have limited treatment options and a median survival of only a few months. Although recent advances have improved the treatment of B-cell malignancies, new treatments for chemotherapy-refractory cases are needed.

Previous reports showed that a single infusion of autologous T-cells that express anti-CD19 chimeric antigen receptor (CAR) in patients with indolent B-cell malignancies led to lengthy remissions. In what is believed to be the first study of its kind, researchers evaluated the safety and efficacy of autologous anti-CD19 CAR T-cells in patients with advanced CD19-positive B-cell malignancies (Kochenderfer JN, et al. J Clin Oncol. 2015;33:540-549).

The study included 15 patients with advanced B-cell malignancies. Of these, 9 patients had DLBCL, with 3 different subtypes: 4 patients had primary mediastinal B-cell lymphoma, 4 patients had DLBCL not otherwise specified, and 1 patient had DLBCL transformed from chronic lymphocytic leukemia (CLL).

In addition, 2 patients had indolent lymphomas, and 4 had CLL. All patients received an initial conditioning chemotherapy regimen consisting of cyclophosphamide at a total dose of 120 mg/kg to 60 mg/kg followed by 5 daily infusions of fludarabine 25 mg/m2. A day later, patients received a single infusion of anti-CD19 CAR T-cells.

Of the 15 patients, 8 achieved complete remission, 4 achieved partial remission, 1 had stable disease, and 2 were not evaluable for response. In the subgroup of 9 patients with DLBCL, 4 of 7 evaluable patients with chemotherapy-refractory DLBCL had complete remission; 3 of these 4 patients are in ongoing complete remission, with durations ranging from 9 to 22 months.

Of the patients with DLBCL, 2 achieved partial response, and 1 achieved stable disease. In the subgroup of 6 patients with indolent B-cell malignancies, all patients achieved a complete remission or partial remission; 3 of 4 patients with CLL are in ongoing complete remission ranging from 14 to 23 months.

The peak level of CAR-positive blood cells varied among patients from 9 to 777 CAR-positive cells/µL. These levels peaked between 7 and 17 days after infusion. Grade 3 and 4 acute toxicities included fever, hypotension, delirium, and other neurologic toxicities; these toxicities were transient and resolved within 3 weeks after cell infusion.

This is the first study to show a successful treatment of DLBCL with ­ anti-­CD19 CAR T-cells. The majority

of patients with chemotherapy-refractory DLBCL and indolent B-cell malignancies achieved complete remission; these findings demonstrate the feasibility and effectiveness of treating this patient population with anti-CD19 CAR T-cells.

Infusion with anti-CD19 CAR T-cells may offer a powerful new treatment option for patients with chemotherapy-refractory B-cell malignan-

In the Literature Lenvatinib Prolongs Progression... Continued from page 17

placebo (Schlumberger M, et al. N Engl J Med. 2015;372:621-630).

The SELECT study was a randomized, double-blind, placebo-controlled, multicenter, phase 3 study involving 392 patients with progressive differentiated thyroid cancer that was refractory to radioactive iodine therapy. Patients were randomized in a 2:1 ratio to lenvatinib 24

mg daily in 28-day cycles (N = 262) or to placebo (N = 131). Pretreatment with 1 previous TKI regimen was permitted. At disease progression, patients in the placebo group could receive open-label lenvatinib. The median duration of treatment was 13.8 months for the lenvatinib group and 3.9 months for the placebo group.

The primary end point was PFS, and the secondary end points were response rate, overall survival, and safety.

The median PFS was 18.3 months among the patients who received lenvatinib compared with 3.6 months with placebo, a 14.7-month PFS extension with active treatment (hazard ratio for disease progression or death, 0.21; 99% confidence interval, 0.14-0.31; P <.001). This is the longest improvement in PFS observed in studiesB:7.625 comparing active drug in therapy and placebo T:7.375in in patients with differentiated thyroid cancer.

The PFS benefit associated with lenvatinib was observed in all prespecified groups. Lenvatinib was associated also with a significantly greater patient response rate compared with placebo­­ —­­64.8% versus 1.5%, respectively. Furthermore, more complete and partial responses were observed with lenvatinib than with placebo (4 and 165 vs 0 and 2, respectively). The median overall survival was not reached in either group.

For men with mCRPC who progressed on ADT

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

More than 1,000 days.

And every day tells a story.

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

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

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

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

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

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

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

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

ADT=androgen-deprivation therapy.

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In the Literature Adverse events of any grade, which occurred in >40% of patients in the lenvatinib group, included hypertension (67.8%), diarrhea (59.4%), fatigue or asthenia (59.0%), decreased appetite (50.2%), decreased weight (46.4%), and nausea (41.0%). The most frequently reported grade ≥3 adverse events reported in the len­ ­ vatinib group included hypertension (41.8%), proteinuria (10.0%), decreased

weight (9.6%), fatigue (9.2%), and diarrhea (8.0%).

A total of 37 patients in the lenvatinib group and 3 patients in the placebo group discontinued treatment because of adverse events.

The 10-year survival rate for patients with differentiated thyroid cancer refractory to radioactive B:7.625 iniodine therapy is 10% from time ofT:7.375 metastasis.

Lenvatinib in was associated with significant improve-

ment in PFS and response rate among patients with progressive, radioactive iodine–refractory, differentiated thyroid cancer, which offers a new treatment option for this patient population. Although the toxic effects of lenvatinib therapy were considerable, most toxic effects were managed with dose modification and medical therapy. Based on these results, in February 2015, the FDA approved lenvatinib for the treatment of

patients with differentiated thyroid cancer that is refractory to radioactive iodine therapy (see article on page 10).

Ruxolitinib More Effective Than Standard Therapy in the Treatment of Polycythemia Vera

Polycythemia vera, a myeloproliferative neoplasm characterized by elevated red blood cell levels, poses an increased Continued on page 20

B:10 in

T:9.75 in

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

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

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

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In the Literature Ruxolitinib More Effective Than... Continued from page 19

risk for thrombotic and cardiovascular events and a significant clinical burden.

If untreated, polycythemia vera can transform to myelo­fibrosis or to acute myeloid leukemia. Based on earlier results of a phase 2 study, researchers conducted a new phase 3 clinical study to evaluate the clinical benefit of ruxolitinib (Jakafi), a Janus kinase (JAK) 1

and 2 inhibitor, versus standard therapy in patients with polycythemia vera that was resistant to standard therapy with hydroxyurea (Vannucchi AM, et al. N Engl J Med. 2015;372:426-435).

The study included 222 patients with polycythemia vera requiring phlebotomy for hematocrit control, a spleen volume of ≥450 cm3, and no previous treatment with a JAK inhibitor participating in the RESPONSE trial. The RE-

SPONSE study was an international, randomized, open-label, multicenter, phase 3 clinical trial that randomized phlebotomy-dependent pa­­tients with splenomegaly in a 1:1 ratio to a 10-mg twice-daily dose of ruxolitinib (N = 110) or to standard therapy (N = 112) selected by the investigator.

The primary end point was hematocrit control through week 32 and at least a 35% reduction in spleen volume at

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress.

Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

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

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week 32. The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) was used to evaluate symptom outcomes.

The median exposure time to therapy was 81 weeks in the ruxolitinib group and 34 weeks in the standard therapy group. Significantly more patients receiving ruxolitinib achieved the primary end point versus the standard therapy group (20.9% vs 0.9%, respectively).

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

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

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

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

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

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

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

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

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

Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract 11.5 infection 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0

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In the Literature Furthermore, ruxolitinib was associated with a higher rate (60%) of hematocrit control through week 32 compared with standard therapy (19.6%). In addition, 38.2% and 0.9% of patients in the 2 groups, respectively, had at least a 35% reduction in spleen volume. Ruxolitinib was also associated with a significantly higher rate of complete hematologic response compared with standard therapy (23.6% vs 8.9%, respectively).

Overall, 49% of patients in the ruxolitinib group had at least a 50% reduction in the MPN-SAF total symptom score at week 32 versus 5% in the standard therapy group. The ruxolitinib group also maintained their primary response at week 32 through week 48 compared with the standard therapy group (19.1% vs 0.9%, respectively).

In terms of safety, ruxolitinib was associated with a greater incidence of

grade 3 or 4 anemia and thrombocytopenia (2% and 5%, respectively) compared with standard therapy (0% and 4%, respectively). Grade 1 and 2 herpes zoster infection occurred in 6% of patients receiving ruxolitinib versus no patients in the standard therapy group.

However, through week 32, more patients (N = 6) in the standard therapy group had thromboembolic events compared with the ruxolitinib group (N = 1).

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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

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

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

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

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

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

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

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

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

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

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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2

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Overall, the RESPONSE trial showed that ruxolitinib was well-tolerated and significantly more effective than standard therapies in controlling hematocrit, reducing spleen volume, and improving polycythemia vera–related symptoms in patients who had an inadequate response to or had unacceptable side effects from hydroxyurea. The FDA approved ruxolitinib for the treatment of patients with polycythemia vera in December 2014. n

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FDA News Lenalidomide Combined with Dexamethasone Receives Expanded... Continued from page 12

Cancer Center. “We now have clinical evidence demonstrating that starting and keeping newly diagnosed multiple myeloma patients on Revlimid significantly improves progression-free survival.”

The approval was based on the results of several phase 3 clinical trials, including the FIRST trial. This trial

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evaluated the continuous use of a regimen of lenalidomide plus dexamethasone (Rd) until disease progression compared with the regimen of melphalan, prednisone, and thalidomide (MPT) for 18 months as the primary analysis; a secondary analysis evaluated the use of Rd at a fixed duration of 18 cycles in 1623 patients with newly diagnosed myeloma who were not candidates for stem-­­cell transplant.

The primary end point in this randomized, open-label, 3-arm trial was median progression-free survival (PFS). The PFS was significantly longer among patients who received the continuous Rd regimen (25.5 months) than among patients who received the MPT regimen (21.2 months; hazard ratio [HR], 0.72; P ­­ = .001).

Based on an interim overall survival (OS) analysis, the median OS was 58.9 months with continuous Rd and 48.5

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%.

Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose.

ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n=8) or moderate (n=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information.

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus.

Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA. Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: May 2014 015924-140528

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months with the MPT regimen (HR, 0.75; 95% confidence interval, 0.620.90). Furthermore, patients in the continuous Rd arm had a 25% reduction in mortality risk compared with patients in the MPT arm.

The most common grade 3 or 4 events reported in the continuous Rd arm (until disease progression) included neutropenia (27.8%), anemia (18.2%), thrombocytopenia (8.3%), pneumonia (11.3%), asthenia (7.7%), fatigue (7.3%), back pain (7%), hypokalemia (6.6%), rash (7.3%), cataract (5.8%), dyspnea (5.6%), deep-vein thrombosis (5.6%), and hyperglycemia (5.3%). (February 18, 2015)

Nivolumab First Immuno­ therapy to Get FDA Approval for Metastatic Lung Cancer

The FDA approved a new indication for the immunotherapy nivolumab (Opdivo; Bristol-Myers Squibb) for the treatment of patients with metastatic squamous non–small-cell lung cancer (NSCLC) whose disease progressed during or after platinum-based chemotherapy. Nivolumab is the first immunotherapy to receive FDA approval for patients with lung cancer. It was initially approved late last year for the treatment of patients with unresectable or metastatic melanoma.

Nivolumab is a monoclonal antibody that binds to the PD-1 receptor; it blocks the interaction of PD-1 with its ligands 1 and 2, which inhibits an antitumor immune response.

This new indication is based on results from an open-label, multicenter, multinational randomized trial in patients with metastatic squamous NSCLC with disease progression during or after chemotherapy with a platinum-based regimen. Patients were randomized to nivolumab (N = 135) 3 mg/kg intravenously every 2 weeks or to docetaxel ­­(N = 137) 75 mg/m2 intravenously every 3 weeks. The major efficacy outcome was overall survival (OS).

The OS was 9.2 months with niv­ol­ umab compared with 7.3 months with docetaxel, a significant improvement (P = .002).

Additional efficacy support was provided from a single-arm, multinational, multicenter trial in 117 patients with metastatic squamous NSCLC whose ­disease progressed after platinum-based chemotherapy and ≥1 additional systemic regimens. Objective response rate, the major efficacy outcome, was 15%.

At the time of analysis, the response duration was ≥6 months in 59% of the responding patients.

Adverse events were similar to previous trials with nivolumab. Immune-­ mediated adverse reactions included pneumonitis, colitis, hepatitis, nephritis/ renal dysfunction, hypothyroidism, and hyperthyroidism. (March 4, 2015) n

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Leukemia

Blinatumomab Immunotherapy Attacks Minimal Residual Disease in ALL, Leads to High Rates of Complete Response

By Wayne Kuznar

at a glance ➤ Assessment of MRD is increasingly used to evaluate response to treatment ➤ In a recent study of patients with ALL, 78% of patients who received at least 1 dose of blinatumomab had a complete MRD response ➤ Of these responses, 98% occurred within the first cycle of receiving blinatumomab

with elevated MRD have a high relapse risk after stem-cell transplantation.

© American Society of Hematology. All rights reserved.

San Francisco, CA—In patients with acute lymphoblastic leukemia (ALL), assessment of minimal residual disease (MRD) is increasingly used to evaluate response to treatment. An antibody that recruits the body’s T-cells to attack MRD in patients with ALL whose disease is in remission can prevent full relapse.

In a recent phase 2 clinical trial of patients with ALL, no MRD was detected in 78% of the patients who received blinatumomab (Blincyto), a bispecific T-cell engager antibody construct; of these, nearly all complete responses occurred in the first cycle of treatment.

The results of the trial were presented at the recent annual meeting of the American Society of Hematology.

Nearly all patients with ALL and persistent or recurrent MRD relapse despite continued chemotherapy, and patients

Therefore, alternate treatment approaches to improve outcomes in patients with persistent or recurrent MRD are needed.

Blinatumomab directs cytotoxic T-cells to CD19-positive cells, resulting in serial lysis. “CD19 is a highly specific B-cell marker that is expressed throughout B-cell development and in more than 90% of B-cell lineage cancers,” said Nicola Gökbuget, MD, Hematologic Oncologist, Goethe University Hospital, Frankfurt, Germany. In a previous small pilot trial of 20 patients, blinatumomab produced an 80% MRD response.

In December, the FDA approved blin­ ­atumomab for the treatment of patients with Philadelphia chromosome–negative relapsed or refractory B-cell precursor ALL, “but the difference in this trial

is that we treat the patients before the relapse,” Dr Gökbuget said.

The FDA approved blinatumomab for the treatment of patients with Philadelphia chromosome– negative relapsed or refractory B-cell precursor ALL. The difference in this trial is that we treat the patients before the relapse.

“

”

—NICOLA GÖKBUGET, MD

Complete Response with Blinatumomab

In addition to evaluating blinatumomab in ALL, Dr Gökbuget’s study utilized a new, more sensitive method to detect MRD, using a polymerase chain reaction–based method of individual gene rearrangement to measure MRD. The open-label confirmatory enrolled 116 patients with MRD-positive B-cell precursor ALL, defined as a level ≥10–3 in an assay with a minimum sensitivity of 10–4, which is close to full relapse, said Dr Gökbuget.

Of the 116 patients, 112 were evaluable for complete MRD response, the primary end point. Blinatumomab was given by continuous intravenous infu-

sion 15 µg/m2 daily for 28 days per cycle, followed by 2 weeks off, for up to a maximum of 4 cycles (each cycle followed by 2 weeks off). Hematopoietic stem-cell transplantation was offered to eligible patients at any time after the first cycle.

Of patients who received at least 1 dose of blinatumomab, 78% had a complete MRD response; 98% of the complete responses occurred within the first cycle. Among 103 patients who received at least 1 dose of blinatumomab and had an MRD ≥10–3 at screening, 80% achieved a complete MRD response after cycle 1.

The 2 types of adverse events reported include events related to cytokine release (ie, fever, chills, fatigue) and neurologic events. “The most commonly occurring adverse events were flu-like symptoms associated with T-cell activation,” Dr Gökbuget said.

Pyrexia was the most common adverse event, which occurred in 90% of patients. Other events related to cytokine release were chills (28%) and fatigue (24%). The most common gastrointestinal adverse events were nausea (22%), vomiting (22%), and diarrhea (20%). Grade ≥3 adverse events included neutropenia (16%), pyrexia (7%), and tremor (5%).

The most frequent neurologic adverse events were tremor (29%) and aphasia (13%). Dr Gökbuget noted that most adverse events were grade 1 or 2, but that they are clinically relevant, because they can lead to treatment interruption. n

Vosaroxin, a Quinolone Derivative, Extends Survival in Older Patients with Acute Myeloid Leukemia

A

n investigational first-in-class ­anticancer quinolone derivative, vosaroxin, extended median over­ ­all survival (OS) when used with cytar­­ abine (Cytosar-U) in a phase 3 clinical trial of patients with relapsed or refrac­­ tory acute myeloid leukemia (AML), although the difference was not significant.

The benefit was more pronounced in older patients aged >60 years, a group in which the favorable effect of vosaroxin VOL. 6

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did achieve significance, according to Farhad Ravandi, MD, Professor of Medicine, Department of Leukemia, M.D. Anderson Cancer Center, Houston.

Vosaroxin intercalates DNA and inhibits topoisomerase II, resulting in replication-dependent, site-specific DNA damage, G2 arrest, and apoptosis. The FDA has granted orphan drug status to vosaroxin for AML, and a fast track designation for the potential treatment of

relapsed or refractory AML in combination with cytarabine.

Dr Ravandi discussed data from a 124site international randomized trial of 711 patients with relapsed or unresponsive AML. All patients received intravenous cytarabine 1 g/m2 on days 1 to 5, and were randomized to the addition of placebo or intravenous vosaroxin 90 mg/ m2 on days 1 and 4 for induction and 70 mg/m2 for subsequent cycles.

MARCH 2015

I

The median OS times were 7.5 months in the vosaroxin arm and 6.1 months in the placebo arm, with a hazard ratio (HR) of 0.865 (P = .06). A predefined analysis of OS censoring for stem-cell transplantation showed that patients randomized to the vosaroxin arm had a median OS of 6.7 months compared with 5.3 months in the placebo arm (HR, 0.809; P = .02). The secondary end point of complete remission rate of vosaContinued on page 24

www.ValueBasedCancerCare.com

23

Leukemia

Monitoring Response to TKI Therapy by PCR Improves Outcomes in Chronic Myeloid Leukemia

By Wayne Kuznar

D

isease progression is slower and overall survival (OS) is greater in patients with chronic myeloid leukemia (CML) who are being monitored for their response to tyrosine kinase inhibitor (TKI) therapy and show good adherence. However, few clinicians monitor response and adherence to oral TKI treatment in patients with CML. Data from 245 patients with newly diagnosed chronic-phase CML cared for ­­in the Southern California Permanente Medical Group show that although most patients start TKI therapy within 90 days of diagnosis, only approximately 66% show high adherence to therapy, and using polymerase chain reaction (PCR) monitoring to evaluate response to treatment can improve outcomes.

“We found that patients who had any monitoring by PCR had better outcomes than those who did not undergo monitoring, and this was independent of their insurance level,” said Reina Haque, PhD, MPH, Cancer Epidemiologist and Research Scientist II, Kaiser Permanente, Pasadena, CA. “To avoid bad outcomes, patients must be monitored.”

Dr Haque and colleagues collected data from electronic health records and chart reviews, including TKI use and adherence, healthcare utilization, and clinical outcomes.

Adherence to TKI therapy was mea-

sured by medication possession ratio (MPR), the number of days a medication is supplied divided by the number of days between the first and last drug dispensing date. Patients were classified into good adherence (MPR ≥90%) and poor adherence (MPR <90%). The mean MPR for TKI use was 88%.

More than 90% of the cohort started TKI therapy within 3 months of diagnosis. Virtually all patients (96%) began therapy with imatinib (Gleevec). Despite full pharmacy coverage, only 63% of patients showed good adherence. The reasons for first-line treatment discontinuation included: ➤A dverse effects: 41 patients ➤ I ncomplete cytogenetic or molecular response: 38 patients ➤D rug nonresponse, provider recommendation, or nonadherence: 21 patients ➤B one marrow/stem-cell transplant: 7 patients.

Disease progression and OS were evaluated in patients diagnosed in 2001-2006 who received imatinib.

With a mean follow-up of 5.1 years (maximum, 13 years), the rate of chronic-phase CML progression to accelerated phase or blast crisis phase was lower in patients with good adherence (10.0 per 1000 person-years) than in those with poor adherence (14.2 per 1000 person-years).

Patients with high adherence had a lower mortality rate than those with low adherence (25.9 per 1000 vs 39.2 per 1000 person-years). OS was better in patients with high adherence, although the difference did not achieve significance.

PCR Monitoring and Outcomes

The key to outcomes, however, was PCR monitoring. “We found that patients who underwent PCR monitoring had a significantly reduced risk of a composite outcome of progression, bone

“

Patients who had any monitoring by PCR had better outcomes than those who did not undergo monitoring.…To avoid bad outcomes, patients must be monitored.

”

—REINA HAQUE, PHD, MPH

marrow or stem-cell transplant, or mortality, regardless of their TKI adherence status, whereas MPR was not associated with the outcomes,” said Dr Haque.

Specifically, the hazard ratio for the composite outcome was 0.6 with PCR monitoring in patients with MPR ≥90% and 0.10 in patients with MPR <90%.

Education Intervention Persuades Clinicians

In a separate study, an educational intervention was successful in persuading healthcare professionals to discuss the impact of nonadherence to TKI on CML outcomes.

Sara R. Fagerlie, PhD, Director of Scientific Services at Educational Concepts Group in Atlanta, measured the impact of 1-hour educational interventions that addressed frontline treatment and treatment for relapse of CML. The programs educated 631 providers in the community setting. Participants were asked about communication and follow-up with patients with CML before and after the intervention.

Before the education, “more than half were not evaluating adherence for a CML patient who missed major response milestones,” said Dr Fagerlie, and only 60% reported always discussing the impact of TKI nonadherence on clinical outcomes in CML. “With just the 1-hour intervention, practitioners were recognizing when they needed to evaluate adherence, and 86% were planning to discuss the impact of adherence with their patients,” Dr Fagerlie said. Education also resulted in a 13% increase in providers incorporating technology, such as texting, e-mail, or cell phone application as a patient adherence tool. n

Vosaroxin, a Quinolone Derivative, Extends Survival in Older Patients with Acute Myeloid...

Continued from page 23

24

“

These data provide support that the vosaroxin/cytarabine combination is the most effective approach to date for the treatment of older patients with this challenging condition.

© American Society of Hematology. All rights reserved.

roxin versus placebo was 30.1% versus 16.3%, respectively (P <.001).

The trial also stratified patients by age ≥60 years and <60 years. Within a predefined analysis of patients aged <60 years, the combination of vosaroxin and cytarabine had a median OS of 9.1 months compared with 7.9 months for placebo plus cytarabine, a nonsignificant difference.

In patients aged ≥60 years, the median OS was 7.1 months in the vosaroxin arm compared with 5.0 months in the placebo arm (HR, 0.755; P = .006).

“Although it is clear that we still have a long way to go to improve outcomes for such patients, these data provide support that the vosaroxin/cytarabine combination is the most effective ap-

”

—FARHAD RAVANDI, MD

proach to date for treatment of older patients with this challenging condition,” said Dr Ravandi.

David P. Steensma, MD, a hematolo-

VALUE-BASED CANCER CARE

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MARCH 2015

gist/oncologist at Dana-Farber Cancer Institute, Boston, called these results “underwhelming” and “not a great leap forward.” Dr Steensma noted, “AML is a

really difficult population, no question about it, but there’s also no question that 7.5 months is pretty crummy, and we need to do better than that.”

Dr Ravandi countered that 1-month and 2-month improvements in survival are exciting in the treatment of solid tumors, “and I don’t see why we shouldn’t be excited in AML as well,” he said. “In my opinion, these data support the use of this therapy in older patients with AML.” As expected, the vosaroxin arm had greater toxicity, “because if you use 2 cytotoxic agents, you are going to see more myelosuppression,” Dr Ravandi said. The toxicity with vosaroxin was mainly related to myelosuppression, with no increase in organ toxicity.—WK n

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Breast Cancer

Lowering Dietary Fat Increases Long-Term Survival in Women with Hormone-Negative Breast Cancer

By Alice Goodman in death rate in women with estrogen receptor (ER)-negative breast cancer who lowered their dietary fat intake.

Photo by © SABCS/Todd Buchanan 2014

San Antonio, TX—Results of a new nutrition study show that women who reduced their intake of dietary fat for 5 years after being diagnosed with early breast cancer had significantly lower rates of death from all causes compared with controls, at 15 years of follow-up; this reduction was seen specifically in women with hormone receptor (HR)-­ negative breast cancer. No long-term effect of dietary fat reduction on mortality was observed in women with HR-positive breast cancer. The results of the study, called Women’s Intervention Nutrition Study (WINS), were presented at the 2014 San Antonio Breast Cancer Symposium.

“These findings with respect to longterm influence of dietary lifestyle intervention on overall survival are mixed, but of potential importance,” said lead investigator Rowan T. Chlebowski, MD, PhD, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA. At 15 years, the overall death rate was lower in the dietary intervention group than in the control group—13.6% versus 17%, respectively—in the overall analysis, but this difference did not reach statistical significance. An exploratory analysis showed a 36% reduction

The WINS Details

The WINS trial enrolled 2437 women with early breast cancer who were treated at 39 centers in the United States with standard of care; the patients’ ages at enrollment ranged from 48 to 79 years.

Of this group, 1597 patients had ER-positive breast cancer, 478 had ER-negative breast cancer, and 362 had

Women with HR-negative breast cancer who reduced their intake of dietary fat for 5 years had extended survival rates by 15 years of These findings follow-up. with respect to long-term influence of dietary lifestyle intervention on overall survival are…of potential importance.

“

”

—ROWAN T. CHLEBOWSKI, MD, PHD

ER-negative/progesterone receptor (PR)-negative breast cancer. Within the first 6 months after diagnosis, women were randomized to a dietary fat intervention or to the control group.

The dietary intervention group had 975 patients; of these, 205 women had

ER-negative, and 147 had ER-negative and PR-negative (ie, double-negative) breast cancer. The control group included 1462 women; of these, 273 had ER-negative, and 215 had ER-negative/ PR-negative breast cancer.

In the intervention group, centrally trained dietitians counseled women for 8 biweekly individual sessions on how to implement a low-fat diet, and then the women were contacted by the ­dietitians every 3 months for 5 years.

Women assigned to the dietary intervention group kept diaries of their fat intake (noted in grams).

At 5 years, fat calories were 9.2% lower in the intervention group, and these women lost approximately 6 pounds on average compared with the control group.

Dr Chlebowski noted that although HER2 status was not assessed at the time of the study, he suggested that women with triple-negative breast cancer (ER-­ negative, PR-negative, and HER2-negative status) might also benefit from dietary fat reduction based on these results. He added that lowering dietary fat is a good strategy for overall health, but this study highlights specific benefits in this patient population. n

More Bad News for Erythropoiesis-Stimulating Agents in Chemotherapy-Induced Anemia

By Charles Bankhead

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“ Photo by © SABCS/Todd Buchanan 2014

San Antonio, TX—Adding an erythropoiesis-stimulating agent (ESA) to best supportive care failed to demonstrate noninferiority for progression-free survival (PFS) compared with best supportive care alone in patients with metastatic breast cancer, in a clinical trial known as EPO-ANE-3010 that was requested by the FDA. Standard care alone or in combination with epoetin alfa (Epogen; Procrit) resulted in a median PFS of 7.4 months, as defined by investigator-assessed progressive disease. A separate analysis based on independent review showed identical PFS of 7.6 months in the 2 treatment groups. Moreover, investigator-determined time to progression showed a troubling increase in the risk for disease progression in patients who received the ESA.

The findings bring to full circle the use of ESAs for the treatment of che-

For the management of anemia in the firstor second-line chemotherapy treatment of metastatic breast cancer, transfusion would be the preferred approach. If epoetin alfa is to be used in the more advanced settings...this­should be done very cautiously.

”

—BRIAN LEYLAND-JONES, MD, PHD

motherapy-induced anemia, which has gone from enthusiastic support to disMARCH 2015

I

appointment, said Brian Leyland-Jones, MD, PhD, a medical oncologist at the Avera Cancer Institute, Sioux Falls, SD, who presented the trial results at the 2014 San Antonio Breast Cancer Symposium.

“For the management of anemia in the first- or second-line chemotherapy treatment of metastatic breast cancer, transfusion would be the preferred approach,” said Dr Leyland-Jones. “If epoetin alfa is to be used in the more advanced settings of metastatic breast cancer, this should be done very cautiously, in limited circumstances, only after a careful assessment of risks and benefits for epoetin alfa and alternative treatments—transfusion, interruption or cessation of chemotherapy—and with the patient fully involved in the decision-making process.”

Continued on page 26

www.ValueBasedCancerCare.com

25

Cancer Rehabilitation

A Conversation with Alberta Hickman, a Lung Cancer Survivor Who Benefited from Cancer Prehabilitation

By Julie K. Silver, MD Associate Professor, Harvard Medical School, Department of Physical Medicine and Rehabilitation, and founder of Oncology Rehab Partners www.OncologyRehabPartners.com status before the operation.1 Moreover, she had a shorter-than-usual hospital length of stay for this type of surgery.

This is Alberta’s perspective about cancer prehabilitation in her own words.

Q Why do you think Dr Sherwood

T

imothy Sherwood, MD, the thoracic surgeon who was featured in Part 2 of this series, referred Alberta Hickman for prehabilitation before operating on her after she was diagnosed with lung cancer. Alberta received her care at Mary Washington Hospital in Fredericksburg, VA, which recently adopted the STAR Program, a best practices cancer rehabilitation model of care.

The medical team published Alberta’s story as a case report, because she did so well and her physical function improved after surgery compared with her baseline Editor’s Note: This is a 3-part series on cancer prehabilitation.

Part 1 was a cancer prehabilitation researcher’s perspective; Part 2 was an oncology surgeon’s perspective; and Part 3 is a patient’s perspective.

recommended prehabilitation for you?

Alberta Hickman: I was 75 years old at the time, and I was diagnosed in the emergency department with pneumonia. They found 2 spots: one was cancer, and one was pneumonia. Five months earlier, I had had back surgery, which was my fourth back surgery. Dr Sherwood said, “You are not in good shape,” and I agreed with him, because I just had a big surgery with a lot of metal in my back.

Q What convinced you to go to pre­­ habilitation?

Ms Hickman: Dr Sherwood told me that I might have to go to a nursing home after the surgery. I just wanted to stay out of that nursing home. Dr Sherwood picked the right words to motivate me!

Q Were you worried that your surgery

was going to be delayed?

Ms Hickman: I wasn’t too worried. I have a strong faith in God. I have the best doctor, and with my faith, I was not afraid. And, with the STAR Program, I relied on them getting me in shape, which they did. So, I really wasn’t afraid.

Q You went to physical therapy to

improve your strength and endurance.

How did that help you?

Ms Hickman: Before the surgery, Dr Sherwood made me go up and down a lot of steps. I had trouble with them.

The physical therapists would have me walk halls and go up and down steps. I went to the STAR Program before and after surgery. I felt better after I had been to the STAR Program than before I had surgery. I noticed this because grocery shopping is now easier. I push the cart, and I get a lot of exercise by going to the grocery store. I don’t use the carts you ride around in. I make it a point to walk all over the store. I go several times a week.

Q Were you discouraged or distressed?

Ms Hickman: There was an opportunity that I could have gotten down on myself and just gone downhill, but I don’t want that for my life. It was real comforting to me to know that I was doing something to help myself, and I sure did do it. I did everything they said. I like being independent. I don’t want to be a burden on anybody.

Q What happened when you were in

the hospital after surgery?

Ms Hickman: After my surgery, Dr Sherwood came into my room and said, “You’re a super star!” All of the conditioning paid off, and he and I could both tell. That made me really

happy, because that’s what I wanted.

Dr Sherwood had told me that he thought I would have to spend 3 to 5 nights in the hospital. After the second night, he said, “Would you like to go home?” Of course I said yes. I was happy about that.

Q What did your family think about

your cancer prehabilitation?

Ms Hickman: My son was really proud of me doing the STAR Program, and my daughter was too. Everybody has learned from me doing this, that you can have cancer, go to the STAR Program, and get better. They’ve seen it.

It’s awareness that just because you have cancer, it doesn’t have to be bad.

Q What do you want to share with

healthcare professionals who are read­ ing this article about your experience?

Ms Hickman: I am definitely better off now. I am just thankful that I had all of this. I feel stronger. I try to stay away from any mention of nursing homes. I know if I get cancer again, I’ll just do what the doctors tell me, I’ll go to the STAR Program, and I will get better. I feel very blessed that I had this available to me. n

Reference

1. Hunt E, VanderWijst K, Stokes B, et al. Prehabilitation improves the physical functioning of a newly diagnosed lung cancer patient before and after surgery to allow for a safe surgical resection and decreased hospital length of stay: a case report. J Oncol Navig Surviv.

2014;5:34-35.

More Bad News for Erythropoiesis-Stimulating Agents in Chemotherapy-Induced...

Continued from page 25

An ongoing randomized, phase 3 clinical trial of darbepoetin alpha (Aransep) versus best supportive care for anemia in platinum-treated non– small-cell lung cancer is expected to provide additional information about the benefit-risk profile of ESAs, Dr Leyland-­Jones added.

For more than a decade, concern has surrounded the use of ESAs in chemotherapy-­ related anemia. Two earlier studies of ESAs in metastatic

26

breast cancer showed higher on-study mortality, no difference in time to progression, and a higher incidence of thrombotic events in patients who received ESAs. In 2004, the FDA requested a trial to confirm findings from the EPO-INT-76 trial, which showed a 37% increased risk for on-study mortality in patients with metastatic breast cancer who received epoetin alfa but no difference in time to progression.

A principal investigator in the EPO-

VALUE-BASED CANCER CARE

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MARCH 2015

INT-76 trial, Dr Leyland-Jones presented the results from the new EPOANE-3010 trial, which was conducted at sites in 19 countries and enrolled 2098 patients receiving first- or second-line chemotherapy for metastatic breast cancer and a hemoglobin level of ≤11 g/dL. The patients’ median age was 52 years; 25% of the patients had a body mass index of ≥30; 55% were postmenopausal; and the median hemoglobin level was 10.4 to 10.5 g/dL. Patients re-

ceived a median of 8 doses of epoetin alfa, and the median weekly dose was 32,316.7 IU. The overall survival was 17.2 months with epoetin alfa and 17.4 months with standard of care, a difference that did not meet criteria for noninferiority. The adverse event profiles were similar in the 2 treatment groups.

These results further question the use of ESAs in the treatment of anemia associated with chemotherapy. n

VOL. 6

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NO. 2

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

*

TH

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

Drug Update

Cyramza (Ramucirumab) Approved for the Treatment of Advanced Gastric Cancer and Metastatic Non–Small-Cell Lung Cancer

By Loretta Fala, Medical Writer

G

astric cancer and lung cancer impose a substantial burden on patients. In light of the high mortality rate and quality-of-life issues associated with these 2 types of cancer, there is a marked need for additional therapeutic options to improve outcomes for patients with gastric or lung cancer.

survival rate was 43%, and the 5-year relative survival rate was 17%.7 Lung cancer is the third costliest cancer in the United States, after breast cancer and colorectal cancer, with a total estimated annual cost of $10.3 billion.8

Gastric Cancer

Angiogenesis, the formation of new capillaries and blood vessels, is a process involved in tumor growth.9 Vascular endothelial growth factor (VEGF) is a primary mediator of angiogenesis in normal physiology and in certain diseases.9 VEGF and VEGF receptor-2–mediated

The prevalence of gastric cancer has been on the decline in the United States in the past 80 years.1 Gastric cancer is most common in older people aged >65 years, affecting 6 in 10 people in this agegroup. It is estimated that 24,590 new cases of gastric cancer will be diagnosed in the United States in 2015.1 The gastroesophageal junction (GEJ) is the area just beneath the diaphragm, where the esophagus joins the stomach.

GEJ adenocarcinoma (or stomach cancer) is a cancer that affects this region of the gastric tract.2 As with other types of cancer, early detection and advances in treatment have improved the outlook for patients with gastric cancer. However, most gastric cancers are diagnosed at advanced stages rather than at early stages, resulting in a low survival rate.3 Overall, the 5-year relative survival rate of all patients with gastric cancer in the United States is approximately 29%.3 The total US expenditures for stomach cancer were estimated to be $1.8 billion in 2010.4 Lung Cancer

Lung cancer is the second most common cancer in men and in women in the United States, with an estimated 221,200 new cases projected for 2015.5 Non– small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer.6 Overall, lung cancer claims more lives than any other type of cancer—more than that of colon, breast, and prostate cancers combined—accounting for approximately 27% of all cancer deaths in the United States.5 Although the 5-year survival rate for localized lung cancer is 54%, only 15% of lung cancers are diagnosed at this stage.7 For all lung cancer cases diagnosed between 2003 and 2009, the 1-year relative Copyright © 2015 American Health & Drug Benefits. Used with permission.

All rights reserved.

28

The Vascular Endothelial Growth Factor Pathway

“

Patients require new treatment options, particularly when they no longer respond to other therapies. Cyramza is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.

”

—RICHARD PAZDUR, MD

signaling and angiogenesis may play a key role in the pathogenesis of gastric cancer and lung cancer.10-12 The blockade of VEGF receptor-2 signaling inhibits angiogenesis (ie, blood supply) to ­tumors.12 A number of small molecule inhibitors and antibody-based agents that target the VEGF pathway have been studied across various cancer types.9 In clinical studies, targeting the VEGF receptor-2 pathway has shown promise as a second-line treatment for patients with gastric or lung cancer.10-12 Ramucirumab Receives Several FDA Approvals in 2014 A New Option for Advanced Stomach Cancer

On April 21, 2014, ramucirumab (Cyramza; Eli Lilly), a human VEGF receptor-2 antagonist, was approved by the US Food and Drug Administration (FDA) as a single agent for the treatment of patients with advanced stomach cancer or GEJ adenocarcinoma that has progressed with or after fluoropyrimidine- or platinum-containing chemo-

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therapy.13 Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody, also referred to as an angiogenesis inhibitor (ie, blocking the blood supply to tumors).13 The FDA granted ramucirumab a priority review based on its potential to provide a significant improvement in safety or effectiveness in the treatment of advanced gastric cancer or GEJ adenocarcinoma. The FDA also designated ramucirumab as an orphan drug because it is approved for a rare disease.13 According to Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, “Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies. Cyramza is a new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.” 13 Expanded Indication

On November 5, 2014, the FDA expanded the initial indication of ramucirumab to be used alone or with paclitaxel for the treatment of patients with advanced stomach cancer that has progressed with or after previous fluoropyrimidine- or platinum-containing chemotherapy.14

A New Option for Non–Small-Cell Lung Cancer

On December 12, 2014, the FDA approved ramucirumab to be used in combination with docetaxel for the treatment of patients with metastatic NSCLC that has progressed with or after platinum-based chemotherapy.15 In patients with lung cancer and the EGFR or ALK genetic mutations, ramucirumab should only be used after their disease has progressed while using FDA-approved therapies for these mutations.16 Dr Pazdur commented, “Today’s approval is the third indication that Cyramza has received in 2014.” 15 He further stated, “The commitment to study Cyramza in a variety of malignancies provides important treatment options to patients.” 15

Mechanism of Action

Ramucirumab is a VEGF receptor-2 antagonist that specifically binds VEGF

receptor-2 and blocks the binding of VEGF receptor ligands, VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand-stimulated activation of VEGF receptor-2, thereby inhibiting ligand-induced proliferation and migration of human endothelial cells.16 Dosing and Administration

Ramucirumab is administered as an intravenous (IV) infusion only. It should not be administered as an IV push or bolus.16 For patients with advanced gastric cancer, the recommended dose of ramucirumab, either as a single agent or in combination with weekly paclitaxel, is ­8 mg/kg every 2 weeks.16 For patients with metastatic NSCLC, the recommended dose of ramucirumab is 10 mg/kg, administered intravenously on day 1 of a 21-day cycle, before the infusion of docetaxel.16 Ramucirumab is available as an injection in single-dose vials in a 100-mg/10mL (10 mg per mL) solution and in a 500-mg/50-mL (10 mg per mL) solution.16 Clinical Studies The REGARD Trial: Gastric Cancer

The REGARD trial was a multinational, randomized, double-blind study that evaluated the efficacy of ramuciru­ mab plus best supportive care compared with placebo plus best supportive care and randomized (in a 2:1 ratio) 355 patients with locally advanced or metastatic gastric cancer, including GEJ adenocarcinoma.10,16 The patients (median age, 60 years) received either an IV infusion of ramucirumab 8 mg/kg or placebo every 2 weeks. The primary efficacy end point was overall survival (OS), and the supportive outcome measure was progression-free survival (PFS).10,16 The efficacy results from the REGARD trial are shown in Table 1. Patients randomized to receive ramuciru­ mab had significant improvements in OS and PFS compared with patients randomized to placebo.10,16 The median OS was 5.2 months in the ramucirumab group compared with 3.8 months in the placebo group.10,16 Moreover, treatment with ramucirumab was associated with a 52% reduction in the risk for disease progression or death from any cause compared with placebo.10 According to the REGARD study

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Drug Update investigators, ramucirumab is the first biologic agent given as a monotherapy to demonstrate survival benefits in patients with advanced gastric cancer or GEJ adenocarcinoma that had progressed after first-line chemotherapy.10 The investigators stated that these findings reinforce the importance of targeting the VEGF receptor-2 pathway when treating patients with advanced gastric cancer.10

containing chemotherapy.11,16 The patients (median age, 61 years) were randomized to receive either ramucirumab 8 mg/kg or placebo as an IV infusion on days 1, 8, and 15 of each 28-day cycle. The primary efficacy outcome measure was OS, and the supportive outcome measures were PFS and objective response rate.11,16 As shown in Table 2, treatment with ramucirumab plus paclitaxel showed a significantly longer OS compared with The RAINBOW Trial: placebo plus paclitaxel (9.6 months vs Gastric Cancer 7.4 months, respectively).11,16 Moreover, The RAINBOW trial, a multina- ramucirumab plus paclitaxel demonstrattional, randomized, double-blind study ed significant improvements in PFS and of ramucirumab plus paclitaxel versus objective response rate compared with placebo plus paclitaxel, included 665 placebo plus paclitaxel.11,16 The RAINBOW study’s investigators patients (randomized in a 1:1 ratio) with locally advanced or metastatic suggested that ramucirumab plus pacligastric cancer (including GEJ adeno- taxel could be considered a standard carcinoma) who received platinum-­ second-line treatment option for pacontaining and fluoropyrimidine-­ tients with advanced gastric cancer.11 Table 1 T he REGARD Trial: Ramucirumab versus Placebo in Gastric Cancer

Efficacy measure

Ramucirumab + best supportive therapy (N = 238)

Placebo + best supportive therapy (N = 117)

Overall survival Deaths, N (%) Median, mo Hazard ratio

179 (75)

99 (85)

5.2 (95% CI, 4.4-5.7)

3.8 (95% CI, 2.8-4.7)

0.78 (95% CI, 0.60-0.998)

Stratified log-rank P value

.047

Progression-free survival Events, N (%) Median, mo Hazard ratio

199 (84)

108 (92)

2.1 (95% CI, 1.5-2.7)

1.3 (95% CI, 1.3-1.4)

0.48 (95% CI, 0.38-0.62)

Stratified log-rank P value

<.001

CI indicates confidence interval.

Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

Table 2 T he RAINBOW Trial: Ramucirumab plus Paclitaxel versus Placebo plus Paclitaxel in Gastric Cancer Efficacy measure

Ramucirumab + paclitaxel (N = 330)

Placebo + paclitaxel (N = 335)

Overall survival Deaths, N (%) Median, mo Hazard ratio

256 (78)

260 (78)

9.6 (95% CI, 8.5-10.8)

7.4 (95% CI, 6.3-8.4)

Hazard ratio

296 (88)

4.4 (95% CI, 4.2-5.3)

2.9 (95% CI, 2.8-3.0)

0.64 (95% CI, 0.54-0.75) <.001

28 (95% CI, 23-33)

Efficacy measure

Hazard ratio

CI indicates confidence interval; CMH, Cochran-Mantel-Haenszel.

Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

Warnings and Precautions

Boxed warning. Ramucirumab was approved with a boxed warning about the increased risk for hemorrhage, including severe and sometimes fatal hemorrhagic events. Ramucirumab should be discontinued in patients who have severe bleeding.16 Arterial thromboembolic events. Serious, sometimes fatal, arterial thromboembolic events occurred in clinical trials. Ramucirumab should be permanently discontinued in patients who experience a severe arterial thromboembolic event.16 Hypertension. An increased incidence of severe hypertension occurred in patients receiving ramucirumab as a single agent and in patients receiving ramucirumab combined with paclitaxel and combined with docetaxel. Hypertension should be controlled before initiating treatment with ramucirumab.

Blood pressure should be monitored every 2 weeks or more frequently as indicated during treatment.16 Infusion-related reactions. Patients should be monitored for the signs and symptoms of infusion-related reactions during the infusion of ramucirumab.16 Gastrointestinal perforation. As an antiangiogenic therapy, ramucirumab can increase the risk for gastrointestinal perforation, which can be fatal. Ramucirumab should be permanently discon-

Placebo + docetaxel (N = 625)

428 (68)

456 (73)

10.5 (95% CI, 9.5-11.2)

9.1 (95% CI, 8.4-10.0)

Stratified log-rank P value

.024

Progression-free survival Median, mo

<.001

No pharmacokinetic interactions were observed between ramucirumab and pac­ litaxel or between ramucirumab and docetaxel.16

0.86 (95% CI, 0.75-0.98)

Events, N (%) 16 (95% CI, 13-20)

Drug Interactions

Ramucirumab + docetaxel (N = 628)

Median, mo 279 (85)

≥30% and ≥2% higher than placebo plus docetaxel were neutropenia (55%), fatigue/asthenia (55%), and stomatitis/ mucosal inflammation (37%).16 There are no contraindications associated with ramucirumab.16

Table 3 T he REVEL Trial: Ramucirumab plus Docetaxel versus Placebo plus Docetaxel in Non–Small-Cell Lung Cancer

Deaths, N (%)

Objective response rate (complete response plus partial response) Stratified CMH P value

The most common adverse reactions observed in patients treated with single-agent ramucirumab at a rate of ≥10% and ≥2% higher than placebo were hypertension (16%) and diarrhea (14%).16 In patients treated with ramucirumab plus paclitaxel, the most common adverse reactions observed at a rate of ≥30% and ≥2% higher than placebo plus paclitaxel were fatigue/asthenia (57%), neutropenia (54%), diarrhea (32%), and epistaxis (31%).16 In patients receiving ramucirumab plus docetaxel, the most common adverse reactions observed at a rate of

.017

Stratified log-rank P value Rate, %

Safety and Adverse Events

Overall survival

Progression-free survival Median, mo

The REVEL trial was a multinational, randomized, double-blind study in patients with NSCLC that had progressed while receiving or after receiving 1 platinum-based therapy regimen for locally advanced or metastatic NSCLC.12,16 Patients (median age, 62 years) received either ramucirumab 10 mg/m2 intravenously plus docetaxel 75 mg/m2 intravenously every 21 days or placebo plus docetaxel 75 mg/m2 intravenously every 21 days. The primary end point was OS, and the supportive outcome measures were PFS and objective response rate.12,16 Efficacy results from the REVEL trial are shown in Table 3. Patients in the ramucirumab plus docetaxel group had statistically significant improvements in OS and PFS compared with patients in the placebo plus docetaxel group. Moreover, the objective response rate (complete response or partial response) for patients receiving ramucirumab plus docetaxel was 23% (95% confidence interval, 20-26) compared with 14% (95% confidence interval, 11-17) for patients receiving placebo plus docetaxel (P <.001).16

0.81 (95% CI, 0.68-0.96)

Stratified log-rank P value Events, N (%)

The REVEL Trial: Non–Small-Cell Lung Cancer

Hazard ratio

558 (89)

583 (93)

4.5 (95% CI, 4.2-5.4)

3.0 (95% CI, 2.8-3.9)

0.76 (95% CI, 0.68-0.86)

Stratified log-rank P value

<.001

CI indicates confidence interval.

Source: Cyramza (ramucirumab) injection prescribing information; December 2014.

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Cyramza (Ramucirumab) Approved for the Treatment of Advanced Gastric Cancer and Metastatic...

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tinued in patients with a gastrointestinal perforation.16 Impaired wound healing. Ramucirumab has not been studied in patients with serious or nonhealing wounds. As an antiangiogenic therapy, ramucirumab has the potential to adversely affect wound healing. Ramucirumab should be withheld before surgery and resumed after surgery based on adequate wound healing. If wound-healing complications develop during treatment, ramucirumab should be discontinued until the wound is fully healed.16 Clinical deterioration of cirrhosis.

New-onset or worsening encephalopathy, ascites, or hepatorenal syndrome can occur in patients with Child-Pugh class B or C cirrhosis. Ramucirumab should be only used in patients with Child-Pugh class B or C cirrhosis if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.16 Reversible posterior leukoencepha­ lopathy syndrome. This syndrome has been reported in clinical studies with ramucirumab. If the diagnosis of reversible leukoencephalopathy is confirmed with magnetic resonance imaging, ramucirumab should be discontinued.16

pregnant while taking the drug, assess the potential hazard to the fetus.16 Nursing mothers. It is not known whether ramucirumab is excreted in human milk. Whether the patient should discontinue nursing or discontinue the drug is dependent on the importance of the drug to the mother.16 Pediatric use. The safety and effectiveness of ramucirumab in pediatric patients have not been established.16 Geriatric use. Among patients receiving ramucirumab in the 2 gastric cancer clinical trials, no overall differences in safety or efficacy were observed between patients aged ≥65 years and younger patients.16 Renal impairment. No dose adjustment is recommended for patients with renal impairment.16 Hepatic impairment. No dose adjustment is recommended for patients with mild hepatic impairment.16 Reproductive potential. Ramuciru­ mab may impair fertility. Females of reproductive potential should be advised to avoid getting pregnant while receiving ramucirumab and for at least 3 months after the last dose.16

Use in Specific Populations

In 2014, ramucirumab received FDA approval for 3 indications—as a single agent or in combination with paclitaxel for advanced gastric cancer, and in combination with docetaxel for metastatic

Pregnancy. Based on its mechanism of action, ramucirumab may cause fetal harm. If ramucirumab is used during pregnancy, or if the patient becomes

Conclusion

NSCLC. These FDA approvals mark the availability of an additional second-line treatment option for 2 types of advanced cancer.

In patients with advanced stomach cancer or GEJ adenocarcinoma, ramucirumab as a single agent and in combination with paclitaxel demonstrated significant improvements in OS and PFS compared with placebo, and compared with placebo in combination with paclitaxel, based on findings from the REGARD and the RAINBOW clinical trials.

In patients with metastatic NSCLC, ramucirumab plus docetaxel showed significant improvements in OS and PFS compared with placebo plus docetaxel, as was demonstrated in the REVEL study. n References

1. American Cancer Society. What are the key statistics about stomach cancer? Revised January 9, 2015. www. cancer.org/cancer/stomachcancer/detailedguide/stomach-­ cancer-key-statistics. Accessed February 9, 2015.

2. American Cancer Society. What is stomach cancer?

Revised January 9, 2015. www.cancer.org/cancer/stomach cancer/detailedguide/stomach-cancer-what-is-stomachcancer. Accessed February 9, 2015.

3. American Cancer Society. Survival rates for stomach cancer, by stage. Revised January 9, 2015. www.cancer. org/cancer/stomachcancer/detailedguide/stomach-cancersurvival-rates. Accessed February 8, 2015.

4. National Cancer Institute. Costs of cancer care. In: Cancer Trends Progress Report—2011/2012 Update.

August 2012. http://progressreport.cancer.gov/doc_detail.­ asp?pid=1&did=2007&chid=75&coid=726. Accessed February 9, 2015.

5. American Cancer Society. What are the key statistics about lung cancer? Revised January 20, 2015. www.can cer.org/cancer/lungcancer-non-smallcell/detailedguide/ non-small-cell-lung-cancer-key-statistics. Accessed Feb-

ruary 9, 2015.

6. American Cancer Society. Non-small cell lung cancer. www.cancer.org/cancer/lungcancer-non-smallcell/.

Accessed February 10, 2015.

7. American Cancer Society. Cancer facts & figures 2014.

2014. www.cancer.org/acs/groups/content/@research/ documents/webcontent/acspc-042151.pdf. Accessed February 10, 2015.

8. Hardison BL. The financial burden of cancer. NCI Benchmarks. April 23, 2010. http://benchmarks.cancer. gov/2010/04/the-financial-burden-of-cancer/. Accessed February 9, 2015.

9. Sullivan LA, Brekken RA. The VEGF family in cancer and antibody-based strategies for their inhibition.

MAbs. 2010;2:165-175.

10. Fuchs CS, Tomasek J, Yong CJ, et al; for the REGARD Trial Investigators. Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2014;383:31-39.

11. Wilke H, Muro K, Van Cutsem E, et al; for the RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224-1235.

12. Garon EB, Ciuleanu TE, 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;384:665-673.

13. US Food and Drug Administration. FDA approves Cyramza for stomach cancer. Press release. April 21, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnounce ments/ucm394107.htm. Accessed February 9, 2015.

14. Eli Lilly and Company. Lilly’s Cyramza (ramuciru­ mab) in combination with paclitaxel granted FDA approval for advanced gastric cancer after prior chemotherapy. Press release. November 5, 2014. https://investor. lilly.com/releasedetail.cfm?releaseid=880745. Accessed February 6, 2015.

15. US Food and Drug Administration. FDA expands approved use of Cyramza to treat aggressive non-small cell lung cancer. Press release. December 12, 2014. www. fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm426720.htm. Accessed February 9, 2015.

16. Cyramza (ramucirumab) injection [prescribing information]. Indianapolis, IN: Eli Lilly and Company; December 2014.

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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

*

TH

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

*

TH

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