VBCC June 2014 Vol 5, No 5

JUNE 2014 VOL 5 NO 5

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com ASCO 2014 Highlights

AVBCC Expert Panel: Impact of Personalized Medicine on Future and Current Therapies

By Wayne Kuznar

Oncologists Cite Lack of Resources and Time as Barriers to Addressing Cost Issues with Patients

Ivy Altomare, MD

By Mark Knight Chicago, IL—Although the majority of oncologists believe that discussing the costs of care with the patient is impor­ tant, many report a lack of resources available to them to inform cost-bene­ fit decisions and a lack of time to dis­ cuss these issues with patients.

Approximately 40% of medical on­

cologists, oncology radiologists, or surgical oncologists responding to a national survey did not report having cost discussions with their patients, and approximately 33% do not even believe it is their role to do so, accord­ ing to new survey results presented by Ivy Altomare, MD, Associate Professor

Continued on page 18

ASCO 2014 Highlights Los Angeles, CA—Increasing complexities in diagnostic science, the devel­ opment of precision medicine, and the use of targeted agents require un­ precedented levels of collaboration between pharmaceutical manufacturers, government agencies, and payers, said oncology experts during a panel discussion on personalized medicine at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Continued on page 12

Enzalutamide Improves Survival After ADT in Patients with Metastatic CRPC

By Robert Osborne Orlando, FL—Treatment with enzalut­ amide (Xtandi) after progression with androgen-deprivation therapy (ADT) led to a significant improvement in sur­ vival for men with metastatic castra­ tion-resistant prostate cancer (mCRPC), according to a new randomized trial reported at the 2014 American Urologi­ cal Association annual meeting.

Patients randomized to placebo had a median radiographic progressionfree survival (PFS; primary end point)

© 2014 Engage Healthcare Communications, LLC

of 3.9 months, whereas the median had not been reached in the enzalut­ amide group, said Christopher P. Evans, MD, Chair, Department of Urology, University of California, Davis, Sacramento.

“In both the intention-to-treat popu­ lation, and in the subgroup of patients with nonvisceral disease, treatment with enzalutamide significantly de­ layed the progression of metastatic disease, reduced the risk of death, and Continued on page 36

Getting to Value in Cancer Care: The Time to Have That Conversation Is Now

By Dana Butler Chicago, IL—The question of value in oncology continues to pose challeng­ es for oncologists and payers alike, as the costs of therapy continue to rise and health plans are wrestling with the need to design insurance coverage

Lee N. Newcomer, MD

that promotes value. The American Society of Clinical Oncology (ASCO) is encouraging oncologists to discuss value and costs with their patients, but oncologists often find them­ selves unwilling or unable to do so.

Continued on page 19

inside FROM THE EDITOR . . . . . . . . . . . . . .

Oncology organizations follow AVBCC’s lead on value

6

NEW FDA APPROVALS . . . . . . . . . . .

Ofatumumab for CLL

6

VALUE PROPOSITIONS . . . . . . . . . .

WellPoint’s value-based insurance

7

4TH CONFERENCE . . . 12 Barriers to actualizing value of personalized medicine OVARIAN CANCER . . . . . . . . . . . . . 17 Veliparib active in recurrent tumors

ASCO 2014 HIGHLIGHTS . . . . . . . . 18 Delaying ADT for PSA-only relapse HEALTH POLICY . . . . . . . . . . . . . . . 31 A call to action on tobacco control ECONOMICS OF CANCER CARE . . 32 Aetna’s value-based accountable care model PROSTATE CANCER . . . . . . . . . . . . 36 PSA analysis may avoid biopsies DRUG UPDATE . . . . . . . . . . . . . . . . 40 Tafinlar/mekinist combination for metastatic melanoma

Now FDA Approved For patients with advanced gastric or gastroesophageal (GE) junction adenocarcinoma who have progressed after prior fluoropyrimidine- or platinum-containing chemotherapy, CYRAMZA is the only FDA-approved antiangiogenic to significantly extend overall survival CYRAMZA as a single agent is indicated for the treatment of patients with advanced or metastatic gastric or GE junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

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, including severe and sometimes fatal hemorrhagic events. In Study 1, which evaluated CYRAMZA as a single agent in advanced gastric cancer, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo.

Patients with gastric cancer receiving nonsteroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs 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%). 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. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. 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 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 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.

CYRAMZA monotherapy significantly extended overall survival (OS)1

CYRAMZA significantly improved progression-free survival (PFS)1 MAJOR OUTCOME MEASURE

OS PROBABILITY

OVERALL SURVIVAL: MEDIAN – MONTHS (95% CI)1 1.0

CYRAMZA

Placebo

0.8

months

months

(4.4, 5.7)

(2.8, 4.7)

5.2

0.6

The phase III REGARD trial evaluated the efficacy and safety of CYRAMZA vs placebo in patients with locally advanced or metastatic gastric or GE junction adenocarcinoma who had progressed on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Major efficacy outcome measure was overall survival. Supportive efficacy outcome measure was progression-free survival. All patients were ECOG PS 0 or 1. Prior to enrollment, 85% of patients had progressed during treatment or within 4 months after the last dose of first-line chemotherapy for metastatic disease, and 15% of patients progressed during treatment or within 6 months after the last dose of adjuvant chemotherapy. Patients were randomized 2:1 to CYRAMZA 8 mg/kg q2w + BSC (n=238) or placebo + BSC (n=117).1

3.8

Hazard Ratio=0.78 (0.60, 0.998); P=0.047

0.4

CYRAMZA Placebo

0.2

0.0 0

1

2

3

238 117

5

6

7

8

9

10 11 12 13

14 15 16 17 18 19

20

26

27

28

0 1

0 0

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk CYRAMZA Placebo

4

154 66

92 34

49 20

17 7

7 4

3 2

37%

• Median PFS with CYRAMZA was 2.1 months (95% CI: 1.5, 2.7) vs 1.3 months (95% CI: 1.3, 1.4) with placebo (hazard ratio 0.48 [95% CI: 0.38, 0.62]; P<0.001)1

CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; PS=performance status; BSC=best supportive care.

INCREASE IN MEDIAN OS

Most Common Adverse Reactions

Use in Specific Populations

• The most commonly reported adverse reactions (all grades) occurring in ≥5% of patients receiving CYRAMZA and ≥2% higher than placebo in Study 1 were hypertension (16% vs 8%), diarrhea (14% vs 9%), headache (9% vs 3%), and hyponatremia (6% vs 2%).

• 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.

• The most common serious adverse events with CYRAMZA in Study 1 were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs 8.7% of patients who received placebo.

• Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% vs 0.9%), epistaxis (4.7% vs 0.9%), rash (4.2% vs 1.7%), intestinal obstruction (2.1% vs 0%), and arterial thromboembolic events (1.7% vs 0%).

• Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In Study 1, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria vs 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

• As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) CYRAMZA-treated patients with post-baseline serum samples tested positive for antiramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting antiramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for anti-ramucirumab antibodies.

Drug Interactions • No formal drug interaction studies have been conducted.

• 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.

Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on next page.

RB HCP ISI 21APR2014 Reference: 1. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

RB89001 05/2014 PRINTED IN USA © Lilly USA, LLC 2014. ALL RIGHTS RESERVED. CYRAMZA™ is a trademark of Eli Lilly and Company.

Visit CYRAMZANowApproved.com

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

WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Permanently discontinue CYRAMZA in patients who experience severe bleeding.

INDICATIONS AND USAGE CYRAMZA as a single-agent is indicated for the treatment of patients with advanced or metastatic, gastric or gastroesophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of 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. Patients with gastric cancer receiving non-steroid anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Study 1; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs 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%). 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.

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.

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.

In Study 1, the most common adverse reactions (all grades) observed in CYRAMZA-treated patients at a rate of ≥10% and ≥2% higher than placebo were hypertension and diarrhea. The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients versus 8.7% of patients who received placebo.

Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 1 CYRAMZA (8 mg/kg) Placebo Adverse Reactions N=236 N=115 (MedDRA)a All Grades Grade 3-4 All Grades Grade 3-4 System Organ Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Gastrointestinal Disorders Diarrhea 14 1 9 2 Metabolism and Nutrition Disorders Hyponatremia 6 3 2 1 Nervous System Disorders Headache 9 0 3 0 Vascular Disorders Hypertension 16 8 8 3 a MedDRA Version 15.0.

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 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 Clinical Trials of CYRAMZA as a single agent did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of the 236 patients who received CYRAMZA in Study 1, 35% were 65 and over, while 9% were 75 and over.

Renal Impairment No dedicated clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab.

Hepatic Impairment No dedicated clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab.

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 Recommended Dose and Schedule The recommended dose of CYRAMZA is 8 mg/kg every 2 weeks administered as an intravenous infusion over 60 minutes.

Continue CYRAMZA until disease progression or unacceptable toxicity. Do not administer CYRAMZA as an intravenous push or bolus.

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 6 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 5 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 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.

Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA-treated patients in Study 1 were: neutropenia (4.7% CYRAMZA versus 0.9% placebo), epistaxis (4.7% CYRAMZA versus 0.9% placebo), rash (4.2% CYRAMZA versus 1.7% placebo), intestinal obstruction (2.1% CYRAMZA versus 0% placebo), and arterial thromboembolic events (1.7% CYRAMZA versus 0% placebo).

Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade ≥3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions.

In Study 1, according to laboratory assessment, 8% of CYRAMZA–treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in Study 1 was 0.8% and the rate of infusion-related reactions was 0.4%.

Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, 33/443 (7.4%) of CYRAMZAtreated patients with post baseline serum samples tested positive for anti-ramucirumab antibodies using an enzyme-linked immunosorbent assay (ELISA). However, this assay has limitations in detecting anti-ramucirumab antibodies in the presence of ramucirumab; therefore, the incidence of antibody development may not have been reliably determined. Neutralizing antibodies were detected in 1 of the 33 patients who tested positive for 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 formal drug interaction studies have been conducted.

TM

CYRAMZA (ramucirumab) injection

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

RB HCP BS 21APR2014

PA000IPAM00 – BS 9.25x13.25

CYRAMZATM (ramucirumab) injection

PA000IPAM00 – BS 9.25x13.25

In This Issue Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris

FROM THE EDITOR

ASCO 2014 HIGHLIGHTS

Oncology organizations follow AVBCC’s lead on value discussions

Getting to value in cancer care Oncologists still avoid cost discussions AZD9291 may overcome EGFR-TKI resistance More…

FDA APPROVALS Ofatumumab approved for CLL More…

HEALTH POLICY A call to action on tobacco control

VALUE PROPOSITIONS WellPoint’s new value-based insurance approach More…

4TH CONFERENCE Worksite pharmacies can enhance cancer management More…

IN THE LITERATURE

Human Resources Jennine Leale

Genetic testing increases survival in lung cancer Panitumumab and cetuximab comparable in metastatic CRC More…

Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Manager Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle

Insurance companies weigh the value of genetic testing IV cancer treatments pricier in the hospital More…

PROSTATE CANCER

Vice President of Finance Andrea Kelly

Associate Director, Content Strategy & Development John Welz

ECONOMICS OF CANCER CARE

Enzalutamide improves survival after ADT in metastatic CRPC More…

DRUG UPDATE Tafinlar/mekinist combination for melanoma

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 President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

Office Coordinator Robert Sorensen

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Executive Administrator Rachael Baranoski Administrative Coordinator Stephanie Ramadan

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 10 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

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

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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

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

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

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA

Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com • Telephone: 732-992-1536 • Fax: 732-992-1881.

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From the Editor

Oncology Organizations Follow the Association for Value-Based Cancer Care’s Lead on Value Discussions

By Craig Deligdish, MD

Managing Director, Oncology Resource Networks, Orlando, FL; Editor-in-Chief, Value-Based Cancer Care

M

ay was a busy month for those who have made a com­ mitment to addressing cost, quality, and value in cancer care. The Association for Value-Based Cancer Care (AVBCC) held its Fourth Annual Conference in Los Angeles, CA. Consistent with previous meetings, the meeting featured much provoc­ ative information and many expert speakers representing different stake­ holders: community oncologists, drug makers, patient advocates, employer groups, hospitals, academic medical centers, specialty pharmacy, technolo­ gy vendors, professional societies, spe­ cialty laboratories, and the investment community. Following in the footsteps of AVBCC, the 2014 American Society of Clinical Oncology (ASCO) annual meeting had sessions on value, pay­ ment reform, and quality.

As was noted by speakers at both conferences, the increasingly unsus­ tainable cost trends have moved the discussion of value, quality, and cost of care to the forefront, despite the as­ sociated complexities and challenges.

Questions remain about whether physicians and other providers should be incentivized or rewarded for pro­ viding value-based care. Regretfully, these discussions often occur in the absence of stakeholders who have con­ tributed to the accelerated costs we are experiencing. Much attention has been given to the high cost of novel chemo­ therapies, biologics, and “drug mar­

gins,” but there are many “elephants in the room,” including increased hos­ pital costs that have resulted from pro­ vider consolidation, increased hospital utilization of 340B drug pricing, the expansion of specialty pharmacy, the costs of other technologies to include radiation therapy, genomic profiling, and the cost of care at the end of life.

The impact of health information technology on oncology practices, and the number of untested and newly rolled out models—including preau­ thorization and prior approval pro­ grams being mandated by payers and administered through companies whose expertise has been radiology benefit management—are also of con­ cern: many of these initiatives may negatively impact the quality of cancer care for patients.

At the AVBCC and ASCO meetings, potential solutions were proposed.

Jeffrey C. Ward, MD, representing the ASCO Clinical Practice Committee Payment Reform Workgroup, dis­ cussed ASCO’s payment reform ini­ tiative. Although much thought has been given to this approach, the real question is whether an episode-based approach out of the gate is realistic, scalable, and reasonable. Its implemen­ tation would be a revolutionary model that would require years of testing and modification before it could be scaled.

More important, however, is wheth­ er it is realistic to expect that payers will shift the historical profits generated by

drug administration and the margins associated with purchasing and billing for drugs to value-based payments to physicians: this point was raised by Barbara L. McAneny, MD, a commu­ nity oncologist with much experience in this area. Historically, significant obstacles were experienced during the implementation of the Medicare Modernization Act of 2003 that creat­ ed the average sales price model. The current problems associated with drug shortages and drugs that the Centers for Medicare & Medicaid Services pays less than the acquisition price for that have resulted from this program sug­ gest that new models should be tested similar to a clinical trial before they are adopted on a large-scale basis.

It is refreshing to see the extent of dialogue regarding the unsustainable cost of cancer treatments, but we need to focus more on the other factors leading to the rising cost trends in oncology. Replacing the current sys­ tem of reimbursement without ade­ quately testing a new system, simply because drugs now cost significantly more than in the past, would be im­ prudent. Yet doing nothing is also not an option.

Reform in healthcare has come slowly: despite disagreement, it is important to have collaboration be­ tween the government, commercial payers, and community and academic professional organizations if a onesize-fits-all solution is to be identified.

Although the commercial health plans have significant interests in addressing the cost of care, the Affordable Care Act has shifted the burden of paying for cancer therapies further toward a government-based payment model.

The real question, in light of the hundreds of drugs in the pipeline (many of which will cost in excess of $10,000/month), is whether the dif­ ferent entities that receive large con­ sulting fees from pharmaceutical com­ panies will be able to move toward a value-based approach. The National Comprehensive Cancer Network (NCCN), which has made a commit­ ment similar to ASCO’s approach, has equal challenges. Other efforts to re­ form the 340B drug pricing program and the incentives for hospitals that abuse this program could further con­ tribute to cost-savings and move to­ ward value-based care.

The US government bears much of the cost of treatment of cancer in the United States; it is time that our elected leaders look at the solutions that other countries have adopted, specifically in Italy, Germany, France, and England: these countries have used negotiation and competitive bidding to reduce the drug acquisition costs by 20% to 30% compared with our country.

As Co-Director of AVBCC, the offi­ cial society of Value-Based Cancer Care, I commend ASCO, the Community Oncology Alliance, and the NCCN for following the lead of AVBCC. n

was progression-free survival (PFS) as assessed by a blinded independent review committee. The median PFS was 22.4 months (95% confidence in­ terval [CI], 19-25.2) in patients receiv­ ing ofatumumab plus chlorambucil compared with 13.1 months (95% CI, 10.6-13.8) in patients receiving chlor­ ambucil alone (hazard ratio, 0.57; 95% CI, 0.45-0.72; P <.001).

The most common adverse reactions (≥5%) reported with ofatumumab plus chlorambucil were infusion reactions, neutropenia, asthenia, headache, leu­ kopenia, herpes simplex, lower respi­ ratory tract infection, arthralgia, and upper abdominal pain. Overall, 67% of the patients who received ofatumu­

mab had ≥1 symptoms of infusion reaction. In addition, 10% of patients had a grade ≥3 infusion reaction. (April 17, 2014)

New FDA Approvals Ofatumumab Approved for Chronic Lymphocytic Leukemia

The US Food and Drug Administra­ tion approved ofatumumab (Arzerra Injection, GlaxoSmithKline) in combi­ nation with chlorambucil, for the treat­ ment of previously untreated patients with chronic lymphocytic leukemia, for whom fludarabine-based therapy is considered inappropriate.

The approval was based on the re­ sults of a multicenter, randomized, open-label trial comparing ofatumu­ mab in combination with chloram­ bucil with chlorambucil alone. The 447 patients included in the study were deemed ineligible for fludar­

6

abine-based therapy because of ad­ vanced age or comorbidities. Overall, 72% of patients had ≥2 comorbidities, and 48% had a creatinine clearance of <70 mL/min.

Infusion of intravenous ofatumu­ mab was administered as 300 mg in cycle 1 on day 1, followed by 1000 mg on day 8 (first arm), or 1000 mg ad­ ministered on day 1 of all subsequent 28-day cycles (second arm). In both arms, chlorambucil was administered at a dose of 10 mg/m2 orally on days 1 to 7 every 28 days. Before each infu­ sion of ofatumumab, patients received premedication with acetaminophen, an antihistamine, and a glucocorticoid.

The primary end point of the trial

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june 2014

Ramucirumab First FDAApproved Drug for Advanced Stomach Cancer after Chemotherapy

The US Food and Drug Adminis­ tration (FDA) approved ramucirumab (Cyramza; Eli Lilly) for the treatment of patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, which mostly af­ fects older adults. Ramucirumab is an angiogenesis inhibitor that blocks the blood supply to tumors and is

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Advance Care Planning

VALUE PROPOSITIONS WellPoint Introduces Value-Based Insurance, Will Pay Oncologists $350/Month per Patient on Pathway

Using value-based insurance to rein in the ever-rising costs of cancer care, WellPoint will begin to pay oncologists $350 monthly this summer for every patient who is being managed according to the company’s clinical pathways.

The program will launch in 6 states and will expand to the entire country by mid-2015, starting with breast, lung, or colorectal cancer, and then applying to other cancers. Other health plans have introduced pathways in oncology as a means to control costs using different payment methods, but this intro­ duces a new approach to reimbursement in oncology.

Brian J. Bolwell, MD, Chairman of Cleveland Clinic’s Taussig Cancer Insti­ tute, said the clinic will participate in the program “where it makes sense.”

He noted that although WellPoint’s clinical recommendations were reason­ able, Cleveland Clinic is developing its own treatment pathways, which may not coincide with every plan’s pathways. “We generally don’t like to practice by insurance company, we practice by patient,” Dr Bolwell said. Indeed, other providers may also find this too intrusive, but the $350 added value for providers will likely go a long way toward acceptance of this approach.

“Oncologist reimbursement at the moment is a broken system,” suggested Richard Schilsky, MD, Chief Medical Officer of the American Society of Clinical Oncology. He noted that WellPoint’s plan provides “many of the important elements you’d like to see” in such a pathways program, but added that although this type of program can make sure that all patients get the same treatment, “precision medicine wants to drive toward everyone getting unique treatment.” However, WellPoint’s pathways may take preci­ sion medicine into account after all.

If fact, the company believes its program will be in line with new develop­ ments in personalized medicine and genetic innovation. It notes that its pathways will apply to only 80% to 90% of patients, and that oncologists will not have any penalties for using treatments that are not on pathway. “There are always going to be unique clinical situations,” said Jennifer Malin, MD, PhD, Medical Director for Oncology Care Management at WellPoint. She said the treatment guidelines will be reviewed at least every 3 months and updated regularly, as needed.

The company estimates that its new program will save approximately 3% or 4% of its cost of cancer treatments, which is approximately $5.4 billion annually. The Wall Street Journal; May 27, 2014

New Approach May Overcome Resistance to Erlotinib Therapy in Lung Cancer

Among patients with lung cancer, as many as 40% do not respond to a targeted therapy with erlotinib (Tarceva), an EGFR inhibitor used for the treatment of patients with non–small-cell lung cancer (NSCLC). The cause for this resistance and how to overcome it have not been known until now.

A new study demonstrates that this resistance is caused by overexpression of the growth protein Cripto-1, which makes lung cancer cells resistant to erlotinib.

Laboratory experiments showed that blocking Cripto-1 signaling trans­ duction overcame the resistance to erlotinib and restored sensitivity to the drug. They used a Src inhibitor, because Cripto-1 activates the oncogenic tyrosine-protein kinase Src. And although the drug used in the study is no longer available, at least 1 other Src inhibitor, dasatinib (Sprycel), has been approved by the US Food and Drug Administration for the treatment of patients with chronic myelogenous leukemia.

“This is a welcome finding because Cripto-1 belongs to a family of pro­ teins that can be targeted by drugs that have already been developed,” said the lead investigator Giuseppe Giaccone, MD, PhD, Associate Director for Clinical Research, Georgetown Lombardi Comprehensive Cancer Center.

Dr Giaccone said that the center is about to be launching a new clinical trial to see if these findings can be duplicated in human patients. The trial will test the combination of erlotinib plus AZD042, an investigational Src inhib­ itor, in patients with NSCLC. The study will include patients with EGFR mutation, because these patients have been shown to be most sensitive to erlotinib.

“There has been very little investigation when a person never responds to an EGFR inhibitor—most research has been done on acquired resistance that occurs after the drug has shown some benefit,” Dr Giaccone said.

“Most patients using erlotinib exhibit either intrinsic or acquired resistance, so we frankly don’t cure anyone with the drug, although we can extend lifespan.”

Dr Giaccone observed, “If we can understand what is limiting the activity of the drug up front, I believe treatment of patients can be vastly improved.”

The study was supported by the National Cancer Institute. Georgetown University Medical Center; June 9, 2014

New FDA Approvals intended to be used in patients with unresectable cancer or with metastatic stomach cancer after receiving chemo­ therapy with a fluoropyrimidine- or a platinum-containing agent. This is the first FDA-approved therapy for pa­ tients with stomach cancer who have already received chemotherapy.

“Although the rates of stomach can­ cer 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,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Re­ search. “Cyramza is a new treatment option that has demonstrated an abil­ ity to extend patients’ lives and slow tumor growth.”

Ramucirumab was approved under the FDA’s priority review program,

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and was also granted an orphan drug status, because it is intended to treat rare conditions.

The safety and efficacy of ramu­ cirumab were demonstrated in a clinical trial of 355 patients with unresectable or metastatic stomach or gastroesoph­ ageal junction cancer. Patients were randomized to ramucirumab (66%) or to placebo (34%). The main end point was overall survival (OS). The median OS was 5.2 months with ramuciru­ mab compared with 3.8 months with placebo (P <.001). Ramucirumab also improved patients’ progression-free survival compared with placebo. A sec­ ond trial comparing ramucirumab plus paclitaxel versus paclitaxel alone also showed an OS improvement with the addition of ramucirumab.

Common adverse events reported with ramucirumab in clinical trials include diarrhea and high blood pres­

sure. The recommended dose of ra­ mucirumab is 8 mg/kg every 2 weeks, administered over 60 minutes until disease progression or unacceptable toxicity. (April 21, 2014)

Palonosetron Receives New Indication for CINV Prevention in Pediatric Patients

Palonosetron HCl (Aloxi; Eisai) in­ jection received a new US Food and Drug Administration (FDA) indication for the prevention of acute chemo­ therapy-induced nausea and vomit­ ing (CINV) associated with initial or repeated courses of emetogenic che­ motherapy in children aged 1 month to <17 years. This is the first FDA approval of a therapy for the preven­ tion of acute CINV in patients aged 1 month to 6 months. The age of peak cancer incidence among children oc­ curs within the first year of life, so this

JUNE 2014

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approval provides an important op­ tion to children, and especially infants, undergoing chemotherapy.

The FDA approval was based on 1 randomized, double-blind, nonin­ feriority pivotal trial comparing palo­ nosetron with ondansetron in pedi­ atric patients. The primary end point was complete response, which was achieved in 59.4% of patients using palonosetron compared with 58.6% of patients receiving ondansetron.

The trial also showed that pediatric patients required a higher dose of palonosetron based on weight than that required by adults; however, the safety profile of the drug in pediatric patients was consistent with its safety profile in adults.

Palonosetron HCl is already ap­ proved for the prevention of CINV in adults aged ≥17 years. (May 28, 2014) n

www.ValueBasedCancerCare.com

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FOR YOUR ONCOLOGY PRACTICE NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer recommendations for abiraterone acetate (ZYTIGA®) plus prednisone1: Category 1* Asymptomatic pre-docetaxel mCRPC Symptomatic post-docetaxel mCRPC

FOR PATIENTS WITH mCRPC WHO HAVE PROGRESSED ON ADT† LOCAL‡

THERAPY

ADT

§

ZYTIGA PLUS PREDNISONE

®

For more information, please visit www.zytigahcp.com.

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.

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.

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.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

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

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.

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,

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

ZYTIGA Next ®

5.2 5 .

2 Months 5.2-month difference in median overall survival vs placebo plus prednisone (median OS: 35.3 months vs 30.1 months, respectively)

57% reduction in risk of radiographic progression or death vs placebo plus prednisone (median rPFS not reached vs 8.28 months, respectively)

Significantly increased median time to initiation of chemotherapy vs placebo plus prednisone (25.2 months vs 16.8 months, respectively)¶

Significantly increased median time to opiate use for prostate cancer pain vs placebo plus prednisone (not reached vs 23.7 months, respectively)¶

Hazard ratio (HR) = 0.792; 95% CI: 0.655, 0.956; P = 0.0151; prespecified value for statistical significance not reached.

HR = 0.425; 95% CI: 0.347, 0.522; P < 0.0001.

HR = 0.580; 95% CI: 0.487, 0.691; P < 0.0001.

HR = 0.686; 95% CI: 0.566, 0.833; P = 0.0001.

*Evidence and consensus level rating. †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 coprimary efficacy endpoints were overall survival and radiographic progression-free survival. ‡Local therapy = radiation and/or surgery. § For many patients with mCRPC, gonadotropin-releasing hormone (GnRH)agonist therapy typically continues throughout the disease course, and is used concomitantly with other mCRPC treatments, including ZYTIGA®. This illustration is not intended to suggest that ZYTIGA® is the only treatment option following androgen-deprivation therapy (ADT).

Primary endpoint. ¶ Secondary endpoint.

Reference: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed August 2, 2013. For the detailed recommendations, view the most recent and complete version of the Guideline on NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 003307-130924

hypercholesterolemia,hyperglycemia,elevatedAST,hypophosphatemia, elevated ALT and hypokalemia.

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 coadministration 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).

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

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 10/13 003686-131001

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

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

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

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

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

Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

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

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

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

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

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 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.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot flush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) All Grades1 Grade 3-4 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

0

7.6

0

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

0

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 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 terms Edema, Edema peripheral, Pitting edema, and Generalized edema all fractures with the exception of pathological fracture 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 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.

4 Includes 5 Includes 6 Includes

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) All Grades Grade 3-4 Laboratory Abnormality (%) (%) Hypertriglyceridemia 62.5 0.4 High AST 30.6 2.1 Hypokalemia 28.3 5.3 Hypophosphatemia 23.8 7.2 High ALT 11.1 1.4 High Total Bilirubin 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases.

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

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 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

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

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.

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].

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.

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.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. 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].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. 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].

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: September 2013 003185-130920

4th Conference

AVBCC Expert Panel: Impact of Personalized Medicine on Future...

Continued from the cover

As with the development and re­ imbursement of orphan drugs, all interested parties need to join forc­ es, said George W. Sledge, Jr, MD, Chief, Medical Oncology, Stanford University Medical Center, CA. “The

“Community oncologists owe it to their patients to be skeptical about what tests are actually helpful to their patients and help them achieve good outcomes.”

ing agents, leaving trial and error as an unsatisfying mechanism to do so.

Big Data and Genomics A technical analysis of genomics tests as used in clinical practice is the duty of the oncologist, said Kevin B. Knopf, MD, MPH, Medical Oncologist, California Pacific Medical Center, San Francisco.

“Oncotype DX is useful sometimes, but I think I order it far less than other community oncologists do, because my research interests are in looking at the economic utility of these tests,” Dr Knopf said. “While everybody’s very excited about big data and genomics, right now we have a lot more noise than signal. I think that the communi­ ty oncologists owe it to their patients to be skeptical about what tests are actually helpful to their patients and help them achieve good outcomes.”

—Kevin B. Knopf, MD, MPH

big challenge in the genomics era is ‘the number needed to study’ ques­ tion,” he said.

Dr Sledge elaborated, “How do we collect rigorous data? It is statistically impossible to do phase 3 studies like we did in the past.” With personalized medicine, many cancers will fit the description of an orphan disease, and the US Food and Drug Administration approaches orphan disease very dif­ ferently, he added.

When asked by panel moderator Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna, how he defines “success” in terms of personalized medicine, Dr Sledge answered, “I want care that is delivered to an individual in a timely fashion and in an effective way that maximally prolongs the life of the patient and minimizes the toxicity, without creating too much financial catastrophe, either for the patient or for the system.”

The era of precision medicine in on­ cology is not quite upon us, Dr Sledge said, noting the uncertainty involved in the treatment of a patient with mul­ tiple driver mutations of a cancer. That uncertainty extends to safely combin­

12

patient define as important, in terms of what we are measuring in cancer care?” Ms Thiboldeaux asked.

“In the perfect world, we would have 1 test that could figure out the different targets, and for each patient, which drug or combination of drugs they should take….

Of 100 people who get trastuzumab as adjuvant therapy, 60 of them wouldn’t have had their disease recur anyway, and 20 still have their disease recur.”

Will Personalized Medicine Offer Cures?

Dr Kolodziej asked whether person­ alized medicine can offer a cure.

“The answer is yes [for a cure], but it’s going to be a lot of one-offs rather than a global solution,” said Dr Sledge.

“Big data attached to a lot of small science is going to solve some of the problems for some of the patients.”

The mechanisms of resistance to epi­ dermal growth factor receptor–target­ ed therapy are different in lung cancer

—Jennifer Malin, MD, PhD

“We need to understand the science and predict early which ones will be the drugs that are really going to make the difference.”

—Christiane Langer, MD

Dr Knopf cited KRAS testing as an example of a genomics test with utili­ ty, because it can identify instances in which cetuximab would not be active, perhaps saving $10,000 monthly in unnecessary treatment costs.

Although there are thousands of potential genetic targets, only approx­ imately 1 dozen have a targeted agent, said Christiane Langer, MD, Associate Group Medical Director in Oncology, Genentech, South San Francisco, CA. “We need to understand the sci­ ence and predict early which ones will be the drugs that are really going to make the difference,” Dr Langer

Value-Based Cancer Care

I

june 2014

said. “That would be a dream.” The most efficient way is to collaborate on clinical trials, and this collaboration should involve the biopharmaceutical manufacturers, medical societies, and the National Cancer Institute, among others. “Otherwise, it will take a long time,” said Dr Langer.

Jennifer Malin, MD, PhD, Medical Director, Oncology and Care Man­ agement, WellPoint, said, “In the per­ fect world, we would have 1 test that could figure out the different targets, and for each patient, which drug or combination of drugs they should take.” Ideally, the combination would cost less than $800 monthly, Dr Malin said, unless it offers a cure, in which case it would have value at a much higher price tag.

The patient’s voice should not be ignored in the determination of value, said Kim Thiboldeaux, President and Chief Executive Officer, Cancer Support Community. “In the develop­ ment of all these great tools and par­ adigms and solutions, in what mean­ ingful way did you involve the patient voice in solutions? How would the patient define value? What would the

“In the development of all these great tools and paradigms and solutions, in what meaningful way did you involve the patient voice in solutions? How would the patient define value?”

—Kim Thiboldeaux

than they are in colorectal cancer and head and neck cancer, “so the idea that we’re going to have a one-size-fits-all, across all diseases, is a joke,” Dr Sledge said. “We already know it’s wrong.”

Louis Jacques, MD, Chief Clinical Officer and Senior Vice President, ADVI, a healthcare advisory services firm, wondered if choosing cancer treat­ ments may someday resemble choosing antibiotics in infectious diseases.

“Is what we’re seeing, in terms not only of heterogeneity but essentially evolution of individual tumors, es­ sentially pointing us to having super cancers that aren’t necessarily going to respond to much of anything, like superbugs in infectious diseases?” Dr Jacques asked.

Continued on page 13

Vol. 5

I

No. 5

4th Conference

Significant Hurdles Must Be Overcome to Actualize the Value of Personalized Medicine

By Wayne Kuznar

Los Angeles, CA—An agenda for per­ sonalized medicine must address qual­ ity control for test performance, billing and coding for molecular tests, and other practical challenges. The most important item in the agenda is the promotion of clinical utility to enhance value, said Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Although the final goal—an im­ provement in value—is universally recognized, there remains a shortage of ideas on how to achieve it, Dr Kolodziej said.

Personalized medicine depends on the ability to pay for diagnostic and therapeutic products. The cost of cancer care is increasing at double to triple the rate of other medical costs. New technologies may have an impact on bending this cost curve, but new technologies will invari­ ably cost more than old technolo­ gies. Therefore, to favorably affect the value equation, quality will have to

“NSCLC is the poster child. We’re cataloging 9000 mutations (in NSCLC), and there are a handful that make a difference….We must agree that we have a long way to go to establish clinical utility” of personalized medicine.

—Michael A. Kolodziej, MD

be improved, said Dr Kolodziej.

The 3 legs of the personalized med­ icine stool are mutation analysis, big data, and targeted therapy. Mutation analysis leads to a therapeutic deci­ sion in an effort to enhance outcome.

Personalized medicine can add to the quality component of the value equa­ tion by improving survival and quali­ ty of life and reducing toxicities.

The 5 hurdles that must be cleared to fully realize the value of personal­ ized medicine include: • The tests • The score-keeping

AVBCC Expert Panel...

—George W. Sledge, Jr, MD Although the past 15 years have supplied adjuvant trastuzumab in breast cancer, rituximab added to the CHOP (cyclophosphamide, doxoru­

Vol. 5

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No. 5

Molecular Tests’ Utility The test must have clinical utili­ ty, which means that the information provided makes a contribution to and improves current optimal manage­ ment of the patient’s disease. The best examples of mutations that predict response to therapy are HER2/neu in breast cancer and non–small-cell lung cancer (NSCLC), RAR-alpha in acute promyelocytic leukemia, and BCR-

Continued from page 12

bicin, vincristine, and prednisone) regimen for the treatment of diffuse large-cell lymphoma, and imatinib in chronic myeloid leukemia as examples of agents that have delivered cures, Dr Knopf sees most of the reward from personalized medicine coming in the form of prolonged survival while maintaining quality of life.

“The big challenge in the genomics era is ‘the number needed to study’ question.

How do we collect rigorous data? It is statistically impossible to do phase 3 studies like we did in the past.”

• The evidence • The doctors • The treatments.

Defining Value of Personalized Medicine Dr Kolodziej asked, “If we accept as a premise that personalized medicine may not affect our ability to interpret a conventional cost-effectiveness anal­ ysis,…should we look at the informa­ tion that we get from personalized medicine through a different lens?”

How should we define the value of personalized medicine in oncology?

Dr Kolodziej pointed out that when using survival benefit, a traditional end point of cost-effectiveness, crizo­ tinib at $5000 monthly does not meet the National Institute for Health and Care Excellence (NICE) definition of cost-effectiveness for the treatment of patients with non–small-cell lung cancer (NSCLC) whose tumors test

positive for ALK gene rearrangement, despite being an effective agent for NSCLC. Different criteria for cost-effective­ ness should be applied to different treatment settings, said Dr Sledge.

Trastuzumab, for example, improves median survival by 5 months in the metastatic setting, but it cures patients in the adjuvant setting, which may unequal different value. In the case of crizotinib, although resistance may eventually develop, it may represent the first step in an effective combi­ nation that may eventually cure the patient.

“To ignore these subtleties by talking about [cost-effectiveness] solely in the context of the first use of the drug, I think is an error,” Dr Sledge said.

One challenge in considering cost-ef­ fectiveness is further precision in se­ lecting patients who will benefit from a given therapy, said Dr Malin. “Of 100 people who get trastuzu­ mab as adjuvant therapy, 60 of them wouldn’t have had their disease recur anyway, and 20 still have their disease recur,” she said. “We’re giving 100 patients treatment to benefit 20.” n

june 2014

I

ABL in chronic myeloid leukemia.

“NSCLC is the poster child. We’re cataloging 9000 mutations (in NSCLC), and there are a handful that make a difference,” Dr Kolodziej said. “EML4ALK of course is actionable [with crizo­ tinib], and there’s good evidence of clinical utility.” Most other mutations have no associated targeted therapy that is approved by the US Food and Drug Administration.

The test must also have clinical valid­ ity, meaning that it relates to the clinical outcome of interest. “We must agree that we have a long way to go to estab­ lish clinical utility,” Dr Kolodziej said.

Analytical validity of molecular tests is problematic without profi­ ciency testing and standards, and im­ proved analytical validity of next-gen­ eration sequencing is needed, said Dr Kolodziej. Targeted next-generation sequencing panels miss a variable amount of content depending on the genes, and exome sequencing misses 5% to 10% of coding sequences. Most doctors do not think about analytical validity when ordering a test.

Coding and information technology challenges with respect to molecular tests also abound. “There are no codes for next-generation sequencing,” Dr Kolodziej noted. The conversion of stack Current Procedural Terminology codes to specific codes will improve the ability to track utilization, enable decision support tools, and enforce coverage policy.

The correct amount of testing to optimize patient outcome is unknown.

The percentage of eligible patients who receive Oncotype testing is <70%.

“How do we get doctors to do it right?” asked Dr Kolodziej. The use of value pathways and statistical proba­ bilities of response according to mu­ tation or combination of mutations are approaches that may represent the future, he said.

The Value Proposition Conundrum Expense, including high copayment, is not the only hurdle to newer treat­ ments, Dr Kolodziej said. Targeted agents have side effects that cause dose interruption or dose reduction within the first month of therapy in up to 33% of patients, and discontinua­ tion in as many as 10%.

The marketing of genetic tests di­ rectly to consumers contributes to the demand for testing, whether evi­ dence-based or not. Aetna documents Continued on page 16

www.ValueBasedCancerCare.com

13

4th Conference

The Value of Personalized Medicine Lies in Evidence Thresholds, Drug Testing, and Pricing Trends

By Wayne Kuznar

Molecular Testing Is Changing The traditional cancer treatment is based on an established test and dis­ ease characteristics, and insurers then work around the lack of specific cod­ ing for the test. For example, United­ Healthcare instituted a program whereby the results of HER2 testing for breast cancer had to be communi­ cated before trastuzumab treatment would be covered.

The payment action on the test was stopped until the test results were known, said Dr Bach. “That matters, and it also matters as we move toward this place where the tests themselves will be expensive. If you put the barri­ cade after the test, then it’s going to have a different effect on utilization than if you do it before.”

The paradigm for cancer drug de­ velopment, US Food and Drug Ad­ ministration (FDA) approval, and la­ beling may eventually change from relaying on site of cancer, cancer stage, and cell type to mutation status or bi­ ologic pathway. “As we move for­ ward, the FDA has been heavy-hand­ ed about saying that we’re going to live in a new age of paired diagnos­ tics,” he said. Crizotinib was the pro­ totype for this model, with the diag­ nostic test codeveloped with the drug manufacturer in the context of a clini­ cal trial.

According to Dr Bach, however, the age of paired diagnostics may already be over, as the number of required

14

“Can we turn the immune system into our ally? Can we shut off critical mechanisms in cancer cell cycles in a way that has limited toxicity? Can we become more precise?”

—Peter B. Bach, MD

tests and tissue samples becomes cumbersome. “We’re going to rapidly need to do too many assays and look for too many different mutations in any particular organ type for us to stick with a paired paradigm,” he said. “I think testing for multiple mu­ tations at the same time in the tumor is where we’re going to end up.”

Value-Based Cancer Care

Building of Evidence A shift in evidence gathering and utilization is taking place around per­ sonalized testing. HER2 testing errors occur in approximately 20% of sam­ ples, resulting in misclassification of patients. There are also many genetic alterations with similar biologic activi­ ty, and there is no gold standard in test development.

There are hundreds of targets and compounds. Tests are becoming a cost issue, often running into the thou­ sands of dollars. “Payers are noticing the costs of these tests, and they’re trying to figure out what the standard should be for them,” said Dr Bach.

The tests are opening up a Pandora’s box in treatment: any mutation found anywhere could justify a trial of treat­ ment. “There is a fear that it’s going to lead to wild experimentation without the capture of data, and I think that’s a legitimate one,” Dr Bach said.

Payers also have operational chal­ lenges, he said. Insurers generally cover tests under fairly simple rules that can be administered, such as ob­ taining a HER2 assay for breast cancer.

But the new multigene tests are com­ plex, as are the clinical scenarios. It is not clear that oncologists will know how to respond to the coming barrage of information.

The appropriate evidence standard remains open, said Dr Bach. Moving

Figure Pricing Trends: Monthly and Median Costs of Cancer Drugs, 1965-2014 50,000

Monthly price of treatment, $ (2013 dollars)

Los Angeles, CA—Although targeted drug development and testing are clearly transforming medicine, resis­ tance to greater uptake of personalized medicine includes a shift in the evi­ dence threshold in personalized test­ ing and drawbacks to the delivery system, including the cost of molecu­ lar tests, said Peter B. Bach, MD, Direc­ tor, Center for Health Policy and Out­ comes, Memorial Sloan Kettering Cancer Center, New York, at the Fourth Annual Conference of the As­ sociation for Value-Based Cancer Care.

There are many obstacles to actualiz­ ing the value of personalized medicine, according to Dr Bach. The question is, how far and how soon could we get there? “Can we target tumors more pre­ cisely?” he asked. “Can we turn the im­ mune system into our ally? Can we shut off critical mechanisms in cancer cell cycles in a way that has limited toxicity?

Can we become more precise?”

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0 1960

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june 2014

2010

from a test result to improved out­ come should be one standard, he ar­ gued. The evidence for off-label uses of agents should go beyond supposi­ tion, but randomized controlled trials are not feasible for every possibility.

“We’re probably headed for a case se­ ries kind of approach,” Dr Bach said.

The FDA now often accelerates drug approval based on single-arm studies with surrogate end points (es­ sentially case series). Imatinib, for ex­ ample, was approved with evidence of cytogenetic changes on sequential case series, and ceritinib was ap­ proved on the basis of response rate in a single-arm trial.

“We’re going to rapidly need to do too many assays and look for too many different mutations….I think testing for multiple mutations at the same time in the tumor is where we’re going to end up.”

—Peter B. Bach, MD

These types of case series or patient registries are open to all patients, he said. “There’s no cherry picking; they enroll all comers.” They capture high-quality data with deep follow-up, with no bias introduced from loss to follow-up or end-point evaluation triggered by clinical events. Outcomes otherwise must be known from histor­ ical data.

Until evidence is built correctly, the default stance will be very conserva­ tive. “We have shown ourselves to be somewhat aggressive about pushing the envelope for using expensive ther­ apies when they are not indicated, so the default is the resistance of 2 oppos­ ing forces,” Dr Bach said.

Drug Pricing Trends Pricing trends are also a problem, with monthly and median costs of can­ cer drugs at the time of FDA approval increasing exponentially over the years (Figure). “Any issue we have with off-label use of drugs that are targeted is going to get worse as the prices go higher,” Dr Bach said. n

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Worksite Health Centers Can Help Employees Manage Cancer Cancer costs employers an estimated $93 billion annually in direct costs, $18.8 billion from lost productivity

By Wayne Kuznar Los Angeles, CA—Worksite health centers can improve the quality and effectiveness of cancer treatment for employees while reducing costs for their employers.

Although they do not have spe­ cific cancer expertise, onsite health centers can support primary and specialty physicians in multiple ways, including navigation through an often fragmented treatment pro­ cess, coordination of procedures, and monitoring, said Larry S. Boress, President and Chief Executive Health Officer, Midwest Business Group on Health, and Executive Director, National Association of Worksite Health Centers, at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

Economic Burden on Employers The impact of cancer on employers in monetary terms is conservatively estimated at $93 billion annually in direct costs and $18.8 billion from lost productivity. Because cancer is one of the most costly medical conditions, employers are looking for ways to im­ prove traditional treatment methods, Mr Boress said.

Cancer treatment can translate into increased employer cost in the form of employee absenteeism, loss of produc­ tivity, and loss of health, and affects caregivers as well, said Mr Boress.

Productivity decreases as much as 25% among employees who are acting as caregivers for family members with cancer.

Onsite Cancer Care Services Mr Boress enumerated the benefits of onsite centers and, more specifical­ ly, how employers are utilizing them in an effort to help manage cancer care. Some employers are utilizing onsite health centers to support em­ ployees with cancer.

“We find that about 30% of com­ panies of all different sizes have some form of onsite health services,” Mr Boress noted. These may be onsite, near-site, or mobile health programs.

Some centers are large enough to serve several thousand employees, although many are much smaller.

The services employers provide vary greatly, ranging from only phar­ macy services to full healthcare fa­ cilities with primary care physicians, nurse practitioners, imaging and in­

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fusion services, physical therapy, and more (Table).

The objectives of onsite health cen­ ters include improving employee health, increasing productivity and re­ ducing absenteeism, offering occupa­ tional health and safety services, and increasing the effectiveness of health promotion efforts. Improving inte­ gration of health management efforts and reducing overall medical costs are other primary aims.

Table Employers Currently Provide an Array of Services to Employees • Treatment of injuries - First aid, acute/urgent care •

•

Occupational health - OSHA exams, drug testing - Physicals/RTW - Travel medicine - Disability management

Worksite wellness programs - Weight management coaching - Fitness programs - Incentive-based activities - Smoking/tobacco cessation - Behavioral health, EAP, lifestyle

• Primary care, care coordination - Health advocacy - Telehealth

• Identification of risks - Health risk assessment, screenings • Prevention of illness - Immunizations • Health and benefits education - “Lunch and Learn,” health fairs - Online health portal • Chronic disease management - Health, disease management coaching

•

Ancillary services - Pharmacy services - Laboratory, x-ray services - Physical therapy - Vision services, dental services - Chiropractic services - Massage therapy - Acupuncture

EAP indicates employee assistance program; OSHA, Occupational Safety and Health Administration; RTW, return to work.

Employers “want to reduce their cost….If you offer these services onsite, the employee can often be back in 30 minutes. It makes a huge difference in productivity and many employers are focusing on that.”

—Larry S. Boress

The ability to coordinate and col­ laborate care management, consoli­ date data, and improve visibility and access to services makes it possible for worksite health centers to achieve these goals. Onsite centers are capa­ ble of integrating worksite programs, providing easy access to services, and improving support for patient self-management.

Companies from highly diverse industries are developing worksite health centers. “They’re doing it, clear­ ly, to improve the health of the popu­ lation,” Mr Boress said. “What many of these employers have done is a reaction to the local health system not meeting their needs in access, quali­ ty, cost, and effectiveness. Also, they

want to reduce their cost.”

Reducing productivity losses is an effective way to reduce costs. When an employee leaves work for a medical service or to visit the pharmacy, the employee is typically gone for 3 to 4 hours. “If you offer these services on­ site, the employee can often be back in 30 minutes. It makes a huge difference in productivity and many employers are focusing on that,” said Mr Boress.

“The whole maze of uncoordinated care and providers causes lost time and productivity and confusion in general.”

—Larry S. Boress

Addressing Fragmented Care A lack of cost and outcomes trans­ parency for cancer treatments and providers makes choosing appropri­ ate options confusing for patients.

According to a 2007 Commonwealth Fund study, many cancer therapies that can increase the chance of survival are not received by patients because of a lack of communication between doctors and patients. “Lack of com­ munication, lack of interaction, lack of

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record-keeping and sharing, lack of a team approach have caused all kinds of problems,” said Mr Boress.

Adding to the confusion is the frag­ mentation of care that occurs with can­ cer treatment. After diagnosis, patients are usually sent to oncologists, un­ dergo various tests, then treatments, return to their doctors for evaluation, and perhaps attend support groups.

This care is often not coordinated.

“The whole maze of uncoordinated care and providers causes lost time and productivity and confusion in general,” said Mr Boress.

Worksite health centers have the capabilities to address these cancerrelated issues. These centers can offer cancer screening and prevention pro­ grams. They can provide support and assist in managing and coordinating care once an employee is diagnosed.

“They can be the navigator to help them understand what lies ahead,” Mr Boress explained.

Worksite health centers can help to streamline the fragmented treatment process, support adherence to thera­ py, and assist with nutritional coun­ seling, fitness, and coping strategies.

Following treatment, centers can assist employees returning to function.

The ability of worksite health cen­ ters to implement these strategies can make cancer therapy more tolerable for employees and more economical for employers. n

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4th Conference

Worksite Pharmacies Can Enhance Overall Drug Management of Patients with Cancer

By Wayne Kuznar

Los Angeles, CA—Worksite pharma­ cies have unique advantages over local pharmacies in caring for employees with cancer.

Bill Raulerson, PharmD, Director, Onsite Pharmacy Operations at Walgreens, described the benefits of onsite pharma­ cies for patients with cancer at the Fourth Annual Conference of the Association for Value-Based Cancer Care.

“Patients filling prescriptions at worksite pharmacies are about 22% less likely to have a gap in therapy.”

—Bill Raulerson, PharmD

“We view the role of our pharma­ cists in the treatment of oncology pa­ tients as an opportunity to leverage that patient relationship,” Dr Rauler­ son said. The advantages are patient access to a trusted clinician, better communication, patient education, and patient advocacy.

Low medication adherence rates are especially common among patients with cancer and may be improved through a worksite pharmacy. “Patients filling prescriptions at worksite phar­ macies are about 22% less likely to have a gap in therapy,” he claimed. Onsite

pharmacies have a 10% higher rate of adherence than local pharmacies.

When a person with concomitant medical conditions, such as diabetes, hypertension, or chronic obstructive pulmonary disease, is diagnosed with cancer, management of comorbidities is essential to keep patients from costly hospital admissions. “Sometimes these other conditions get overlooked,” said Dr Raulerson. “The role we can play is helping them to continue to manage those conditions, because you don’t want that diabetic to end up in the ER [emergency room] or admitted to the hospital and either delay their cancer therapy or lessen it.”

Worksite pharmacists are able to assist patients with cancer with pre­ ventive care and triage, ensuring that high-risk oncology patients receive proper vaccinations. Teaching patients how and when to take their medica­ tions increases adherence, resulting in lower morbidity rates.

Onsite pharmacists can help pa­ tients deal with adverse events, which are common with cancer drugs, and prevent unnecessary use of healthcare resources.

“The role of the onsite pharmacist is leveraging that patient relationship and helping that patient navigate the complexities of oncology treatment,” Dr Raulerson said.

Florencio Calderon, PharmD, BCPS, Clinical Director, Walgreens, ad­ dressed the difficulties employers face in determining how to provide quality cancer treatment for their employees

The implementation of Walgreens Oral Oncology Cycle Management program saved $1374 per patient in reduced waste and hospitalization combined.

—Florencio Calderon, PharmD, BCPS in a cost-effective manner. “I work with our employers in terms of under­ standing where some of the challenges are, and one of the biggest challenges is oncology,” Dr Calderon said.

According to Dr Calderon, employ­ ers must consider the following factors when making employee healthcare decisions: • Evidence-based quality care versus avoidable costs can be difficult • Transparency of outcomes of employ­ ers’ own programs and outcomes available through medical data

Significant Hurdles Must Be Overcome... at a glance ➤ The 3 legs of the personalized medicine stool are mutation analysis, big data, and targeted therapy ➤ The test must have clinical utility and clinical validity ➤ The ultimate question is the value proposition offered by personalized medicine ➤ Our values should guide the approach to creating a better healthcare system, with the goal being better patient outcomes

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that non–evidence-based requests for BRCA testing have increased by 10% annually since a direct-to-consumer campaign in 2004.

The percentage of eligible patients who receive Oncotype testing is <70%. “How do we get doctors to do it right?”

—Michael A. Kolodziej, MD

The ultimate question is the value proposition offered by personalized medicine. Will it improve the qual­ ity, safety, and cost-effectiveness of

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Continued from page 13

delivered healthcare, or will it drive additional medical costs with margin­ al healthcare?

All of these challenges occur in the setting of unsustainable growth in healthcare spending and the near uni­ form agreement that we need to spend our money in a more intelligent, im­ pactful way. Currently, approximate­ ly 30% of health spending is waste, including unnecessary services, pre­ vention failures, fraud, inflated prices, inefficient care delivery, and excess administrative costs, according to the Institute of Medicine.

Our values should guide the ap­ proach to creating a better healthcare system, with the goal being better patient outcomes, Dr Kolodziej said. n

• Site-of-care optimization and medi­ cal benefit management: “Site-ofcare disparity in terms of cost has a significant impact, not only on the employer, but to the patient, be­ cause a lot of the benefit designs have a sharing of the cost” • Alignment of incentives and opti­ mizing benefit design • Ancillary care access, coordination, and management is critical • Create network contracting: “There’s an opportunity to create high-value networks and to have care that exem­ plifies a best-practice approach.”

Oncology care further complicates employers’ healthcare decisions. In 2013, an estimated 1.6 million new cancer cases were reported in the Unit­ ed States. “When we think about the impact to the workforce, the compel­ ling piece is 10% of healthcare costs are attributed to 1.6% of the impact popu­ lation,” Dr Calderon said.

The rising incidence of cancer, cou­ pled with an aging workforce popula­ tion, means that managing this disease will be a growing challenge for em­ ployers. “Just as an ability to have benefits to maintain treatment, these employees will remain in the work­ force. It becomes important in terms of how we manage these patients,” said Dr Calderon.

Oral oncolytics allow patients to be managed as outpatients. “They give them the flexibility to still have a sense of a ‘normal’ life. I say that in quotes, because these drugs do come with tox­ icity,” Dr Calderon explained.

Toxicity leads to nonadherence. “If a patient is not adherent, we’re going to have a disastrous outcome in many ways, not just from a patient perspec­ tive with their disease, but from a cost perspective as well, because that pa­ tient will be hospitalized and will incur higher costs,” Dr Calderon said.

Walgreens Oral Oncology Cycle Management program was created to manage the care of patients taking oral oncolytics. Dr Calderon explained, “This came to fruition because patients are being managed more and more on an outpatient basis, and these drugs have a high toxicity range.” The pro­ gram was created to enhance patient adherence and to identify opportuni­ ties to manage toxicities.

The implementation of this program saved $1374 per patient in reduced waste and hospitalization combined, Dr Calderon said. It also improved the quality of patient care. n

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Ovarian Cancer

Veliparib, a PARP Inhibitor, Active in Recurrent BRCA-Positive Ovarian Cancer

By Charles Bankhead

Tampa, FL—The poly (ADP-ribose) polymerase (PARP) inhibitor veliparib demonstrated activity in relapsed and/or refractory BRCA-mutated ovarian cancer, according to the re­ sults of a phase 2 clinical trial reported at the 2014 Society of Gynecologic Oncology meeting.

Almost 25% of 50 evaluable patients had objective responses, including 2 patients with complete responses. Ap­ proximately 50% of the patients had stable disease lasting ≥16 weeks.

The median progression-free sur­ vival was 8.1 months among patients who had received as many as 3 previ­ ous systemic regimens, reported Rob­ ert L. Coleman, MD, Professor of Gy­ necologic Oncology and Reproductive Medicine, M.D. Anderson Cancer Center, Houston, TX. “Veliparib demonstrated activity in both platinum-sensitive and plati­ num-resistant disease,” said Dr Cole­ man. “A criticism of PARP inhibitors is that they are not active in patients who have developed resistance to other therapies. These results indicate

that veliparib has activity in some of the patients, who generally have few remaining treatment options.”

Laboratory studies suggest that tar­ geting of the DNA-repair defect in BRCA-mutated tumors had potential as a therapeutic strategy. In contrast to some other PARP inhibitors in devel­ opment, veliparib blocks both isomers of the enzyme. This small-molecule inhibitor demonstrated efficacy across several preclinical models of tumors, including ovarian cancer.

This was a nonrandomized, openlabel trial involving patients with ovarian cancers harboring BRCA mutations. Patients had BRCA1/ BRCA2-deficient epithelial ovarian, fallopian tube, or primary peritoneal cancers. The patients had received from 1 to 3 previous regimens and had a performance status of 0 to 2.

All patients received veliparib 400 mg twice daily, and treatment contin­ ued until disease progression, devel­ opment of unacceptable toxicity, or voluntary withdrawal from the study.

The prespecified response rate of

≥25% was necessary for continuing the clinical investigation.

Of the 50 patients included in the safety and efficacy analysis, 8 remain in

“Veliparib demonstrated activity in both platinumsensitive and platinumresistant disease….These results indicate that veliparib has activity in some of the patients, who generally have few remaining treatment options.”

—Robert L. Coleman, MD

the study. More than 80% of the pa­ tients had high-grade serous tumors.

Overall, 14 patients received 1 previous regimen, 18 patients re­ ceived 2 previous regimens, and 18

patients received 3. All but 4 patients had received radiotherapy, all but 3 had exposure to immunotherapy, and only 1 patient had not undergone debulking surgery.

A majority (60%) of the patients had platinum-resistant disease, defined as a platinum-free interval of <6 months.

Three fourths of the patients had BRCA1-mutated tumors, and 12 had founder mutations, which were BRCA1 in 8 patients and BRCA2 in 4.

Hematologic adverse events were generally mild. The most common nonhematologic events were nausea and other gastrointestinal events.

Overall, 11 patients had partial re­ sponses and 2 had complete respons­ es, with an overall response rate of 26%, which met the predefined crite­ ria for continuing the clinical evalua­ tion of veliparib. Response assess­ ment was ongoing in 6 patients, some of whom had unconfirmed respons­ es. A similar proportion of patients with platinum-sensitive or plati­ num-resistant disease derived benefit from veliparib. n

In the Literature Genetic Testing to Select Targeted Therapies Increases Survival in Lung Cancer

The identification of oncogenic driv­ ers has helped transform the care of patients with adenocarcinoma, the most common type of lung cancer diagnosed in 130,000 patients in the United States and 1 million persons worldwide annually. Adenocarcinoma has a >50% estimated frequency of ac­ tionable oncogenic drivers, which are genetic alterations that are critical to the development and maintenance of cancer. In a new study, researchers sought to determine the frequency of oncogenic drivers in patients with lung adenocarcinomas and to use the data to select targeted therapy and to measure survival (Kris MG, et al.

JAMA. 2014;311:1998-2006).

From 2009 through 2012, 14 sites of the Lung Cancer Mutation Consortium enrolled patients with stage IV or re­ current adenocarcinoma of the lung and tested tumors of patients who met certain criteria for 10 oncogenic driv­

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ers. Most of the patients were former smokers, and 34% never smoked. In all, 64% of patients had stage IV dis­ ease at diagnosis.

Among the 1017 patients with con­ firmed adenocarcinoma, tumors from 1007 patients were tested for at least 1 gene; 733 patients had tumors fully genotyped and were tested for 10 genes. Of the 733 patients, an onco­ genic driver was found in 466 (64%) patients. Among these 733 tumors, KRAS mutations were the most fre­ quent (25%), followed by the sensitiz­ ing epidermal growth factor receptor (17%) and anaplastic lymphoma ki­ nase rearrangements (8%).

The results were used to select a targeted therapy or clinical trial in 275 of 1007 (27%) patients. The 260 patients with an oncogenic driver and treatment with a targeted agent had a median survival of 3.5 years compared with 2.4 years in 318 patients with a driver and no targeted therapy, and 2.1 years in 360 patients with no iden­ tified driver.

Multiplexed testing of lung cancer tumors identified genetic alterations that were helpful in physicians se­ lecting targeted treatment. Patients who received matched therapy for lung cancer lived longer than patients who did not receive directed therapy.

Despite lengthened survival, the re­ searchers noted that randomized clin­ ical trials are needed to determine if selected targeted therapies based on oncogenic drivers improve survival.

Panitumumab and Cetuximab Show Comparable Survival Benefit in Patients with Metastatic Colorectal Cancer

Panitumumab (Vectibix) proved noninferior to cetuximab (Erbitux) in overall survival (OS) in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal can­ cer (mCRC), according to the results of ASPECT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab). ASPECT is the first headto-head, open-label, randomized, mul­

JUNE 2014

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ticenter, international, phase 3 study designed to determine if the 2 epider­ mal growth factor receptor (EGFR)targeted monoclonal antibodies pro­ vide a comparable survival benefit in patients with mCRC (Price TJ, et al.

Lancet Oncol. 2014;15:569-579).

From February 2010 to July 2012, researchers enrolled patients aged ≥18 years with chemotherapy-refrac­ tory mCRC, an Eastern Cooperative Oncology Group performance status of ≤2, and wild-type KRAS exon 2 status. Of the 1010 patients enrolled, 999 began study treatment. Patients were randomized 1:1 to receive panitumumab (N = 499; 6 mg/kg in­ travenously once every 2 weeks) or cetuximab (N = 500; 400 mg/m2 in­ travenously followed by 250 mg/m2 weekly).

The primary end point was OS. Noninferiority was determined if panitumu­mab preserved ≥50% of the cetuximab OS effect compared with best supportive care. The median du­ ration of treatments was 14.3 weeks Continued on page 25

www.ValueBasedCancerCare.com

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ASCO 2014 Highlights

Oncologists Cite Lack of Resources and Time... of Medicine, Duke University, Durham, NC, during the 2014 American Society of Clinical Oncology (ASCO) meeting.

Dr Altomare and colleagues sought to determine oncologists’ current atti­ tudes about discussing the costs of treatment with patients as part of the medical decision-making process.

ASCO now advocates that the physi­

cian–patient discussion about cost should be an integral element of high-quality cancer care.

at a glance ➤ In a recent national survey, approximately 40% of oncology providers did not have cost discussions with their patients, and 33% do not believe it is their role to do so ➤ When cost is discussed, 51% of the time the conversations are initiated by patients ➤ Physicians who discuss cost of cancer care with patients are more likely to consider treatments by cost based on their patients’ financial situation

➤ The 2 most common barriers cited were lack of resources to guide these conversations and a lack of time ➤ Because cost is so individualized, real-time, in-office resources are needed to help guide physicians on cost-ofcare discussions

“The majority (60%) say they are frequently or often having cost discussions with their patients. That means that 40% are rarely or never talking about this.”

—Ivy Altomare, MD

The 15-question, self-administered, electronic survey was randomly sent to 2900 ASCO physician members na­ tionally, with a 15% response rate.

“We had a mix of medical oncologists, surgeons, and radiation oncologists,” said Dr Altomare. “Are they discuss­ ing the cost of cancer care with their patients among these different spe­ cialties? And does that affect their

treatment decisions?”

Of the 333 respondents, 67% agreed that doctors should discuss costs of care with patients; 33% disagreed.

“The majority (60%) say they are fre­ quently or often having cost discus­ sions with their patients. That means that 40% are rarely or never talking about this,” Dr Altomare said. When the cost of treatment is discussed, the survey results show that 51% of the time, these conversations are initiated by patients.

The 2 most frequently reported bar­ riers to cost discussions were a lack of resources to guide these conversa­ tions and a lack of time. Cost-of-care discussions are not taking place rou­ tinely, because physicians (58%) do not believe that they have enough in­ formation or knowledge of the subject to enter into a dialogue about it. Of those who reported not discussing costs, 44% indicated that they do not have sufficient time. “If they have the information, that’s still not going to change,” noted Dr Altomare.

A total of 36% of those surveyed contended that it was not their role to explain costs. “The physician went to medical school to treat the patient, de­ cide the therapy; not to think about where healthcare in this country is going,” Dr Altomare said. But even most of the physicians who do not discuss the cost of care agree that the cost to the patient should be consid­ ered when making treatment deci­ sions, he added.

Oncologists who reported frequent

Continued from the cover

discussions are significantly more likely to prioritize treatments in terms of cost, have a sense of patients’ finan­ cial well-being, and assume that their patients are well-informed about cost.

They believe that physicians should explain out-of-pocket expenses and, to a lesser extent, the societal costs of care to their patients. The survey re­ sults suggest that medical oncologists are 3.75 times more likely to have these conversations with patients than radiation or surgical oncologists.

“Cost is so individualized that you need to have a real-time, in-office resource available. I think piloting that type of program is going to be the next step in what we do.”

—Ivy Altomare, MD

Although the majority of oncolo­ gists believe that cost-of-treatment dis­ cussions with their patients are im­ portant to quality care, no protocols or resources exist to guide them.

Dr Altomare said, “Cost is so indi­ vidualized that you need to have a real-time, in-office resource available.

I think piloting that type of program is going to be the next step in what we do.” n

Patients with Cancer Want but Are Not Getting Information on the Cost of Their Therapy

By Wayne Kuznar

Chicago, IL—According to a survey presented at the 2014 American Soci­ ety of Clinical Oncology (ASCO) meet­ ing, the majority of patients with can­ cer want to have cost-of-treatment discussions with their oncologists.

And when they occur, these discus­ sions do not lead to negative feelings in most patients.

However, a separate survey shows that few oncologists feel comfortable discussing costs with patients, accord­ ing to Ronan J. Kelly, MD, MBA, As­ sistant Professor of Oncology, Johns Hopkins Sidney Kimmel Comprehen­ sive Cancer Center, Baltimore, MD.

18

“We have demonstrated that patients do want to know the costs of their treatment, and that these costs are not being routinely discussed in academic medicine.”

—Ronan J. Kelly, MD, MBA

“We have demonstrated that pa­ tients do want to know the costs of their treatment, and that these costs

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are not being routinely discussed in academic medicine,” said Dr Kelly.

Spending on cancer drugs is project­

ed to increase nearly 40% by 2020, as new cancer diagnoses in the United States continue to increase.

In 2007, the ASCO Cost of Cancer Care Task Force recommended that the cost of chemotherapy should be intro­ duced into the patient–physician dis­ cussion from the outset, the investiga­ tors noted.

In their study, Dr Kelly and col­ leagues used the National Compre­ hensive Cancer Network (NCCN) guidelines and the eviti Advisor plat­ form (a digital library of evidencebased standards for cancer care) during the physician–patient consulta­ Continued on page 19

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ASCO 2014 Highlights

Getting to Value in Cancer Care...

Nevertheless, all agree that discuss­ ing value is inevitable and must begin to happen, but how to get there re­ mains a challenge for all stakehold­ ers, including health insurance plans and oncologists, suggested Lee N. Newcomer, MD, Senior Vice President of Oncology, UnitedHealthcare, at the 2014 ASCO annual meeting during a session titled “Can We Find Common Ground? Stakeholder Perspectives on Value in Cancer Care.”

Value-Based Insurance “We have to start having discus­ sions about value, and we are going to have to say that there are certain things that should not be covered,” said Dr Newcomer.

The idea behind copayment or co­ insurance “is for the patient to pause and ask, ‘Is this worth the money?’

Copays were never intended to be large enough to keep people from get­ ting important, high-value care, but to keep them from selecting lower-value care, if they have to pay the first $50 or a percentage,” Dr Newcomer said.

He suggests that it is time to shift the structure of insurance copayment in oncology so that patients will pay less for high-value drugs and services and more for drugs and services with low value, to facilitate value-based care. “A high-value service might have a complete coverage, with no participation from the patient what­ soever, and low-value would have much higher participation, having the

patient pay a third, a half, or even all of it, if it didn’t have true value,” Dr Newcomer emphasized.

“It will be difficult for consumers to understand this for every service they will receive,” he said. Consumers are largely unclear about their bene­

“We have to start having discussions about value, and we are going to have to say that there are certain things that should not be covered.”

—Lee N. Newcomer, MD

fits. “In a value-based program, we are asking consumers to take on an increasingly large amount of infor­ mation that may be even harder to digest,” said Dr Newcomer. It could be overwhelming for “a consumer to

Continued from the cover

sort out a 2-month versus 4-month survival benefit, or grade 5 versus grade 4 toxicities,” he added. “Trying to make this concept easily accessible to consumers, helping them find out the value of a given treatment, is a daunting task and has been a major barrier to getting value based insur­ ance in place.”

The Challenge for Payers Equally overwhelming for payers will be sorting out the different di­ agnoses and treatment regimens and figuring out how to assign coinsur­ ance values to each treatment and service.

“Where do we draw the line, where we say one thing should be free, and another should have 30% participa­ tion?” Dr Newcomer asked. “No mat­ ter where we draw the line, someone will be unhappy.”

In addition, who should decide, and how will it be determined, what will be the patient participation in the care provided? These challeng­ es are daunting, but they have to be addressed. “It’s important for us as payers to have this done exter­ nally, because we will always be perceived as making these decisions from a financial basis only,” said Dr Newcomer.

Once these parameters are deter­ mined, he said, it will be easier for payers to set prices. The more gener­ ous the benefit, the higher the overall price of the premium will be, and this

should help consumers to understand the concept of value.

“The thing that’s the hardest is simply not paying for anything at all,” Dr Newcomer said. ASCO has already recommended that patients with metastatic breast cancer receive only single-agent chemotherapy (ex­ cept under certain circumstances), but if insurance plans restrict payment to only one drug, it would result in strong public reaction in the United States, he predicted.

“A high-value service might have a complete coverage, with no participation from the patient whatsoever, and lowvalue would have much higher participation, having the patient pay a third, a half, or even all of it, if it didn’t have true value.”

—Lee N. Newcomer, MD

“The immediate perception of value-based insurance is that it’s sim­ ply being done to save money,” Dr Newcomer suggested. “Putting these programs in place will have to be a gradual process, accompanied by education.” n

Patients with Cancer Want but Are Not Getting... Continued from page 18 tion to demonstrate treatment options and to display the costs at the time of

at a glance ➤ Patient share of the cost of cancer care quadrupled from 2000 to 2010, and spending on cancer drugs is projected to increase almost 40% by 2020 ➤ Based on a recent survey, most patients with cancer welcome cost-of-treatment discussions, and 81% view them positively ➤ Training providers on cost discussions with their patients is needed

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prescribing to providers and patients with advanced or metastatic lung, co­ lorectal, or breast cancer.

These consultations took place be­ tween February 2013 and October 2013. A total of 18 oncologists were interviewed, and 96 of 107 invited pa­ tients receiving treatment at Johns Hopkins participated in the study.

Of the 96 patients, 78 (81%) re­ sponded that it is “quite important” or “extremely important” for them to know their out-of-pocket costs. More than 66%, however, have never dis­ cussed cost information with their provider.

“Decisional conflict is extremely low by patient report after cost dis­ cussions using the eviti Advisor plat­ form, with 81% of patients reporting no negative feelings arising,” accord­

ing to Dr Kelly.

“For the first time, we show that there are minimal conflicts and no harm to the doctor–patient relation­

“For the first time, we show that there are minimal conflicts and no harm to the doctor–patient relationship when costs are introduced.”

—Ronan J. Kelly, MD, MBA

ship when costs are introduced,” noted Dr Kelly.

“A greater emphasis on the shared decision-making process involving

JUNE 2014

I

up-front cost discussions combined with evidence-based outcomes should empower patients to make better edu­ cated choices and may ultimately help bend the cost curve down­ wards,” Dr Kelly maintained.

Of the 18 oncologists, only 5 (28%) feel comfortable when discussing costs with patients, and only 1 (6%) regular­ ly asks patients about their financial well-being. Despite this lack of com­ fort, 83% of providers believe that the NCCN guidelines should contain cost information.

Between 2000 and 2010, patient re­ sponsibility for the cost of care qua­ drupled to more than $4000 annually.

Dr Kelly suggested that additional training to prepare clinicians for how to discuss costs with their patients is needed. n

www.ValueBasedCancerCare.com

19

ASCO 2014 Highlights

Delaying ADT for PSA-Only Relapse May Be Viable Option for Men with Prostate Cancer and PSA-Only Relapses Chicago, IL—Delaying androgen deprivation therapy (ADT) for at least 2 years did not lead to worse overall survival or prostate cancer–specific survival compared with the initiation of ADT within 3 months of rising pros­ tate-specific antigen (PSA) in men with PSA-only relapse (ie, biochemical re­ lapse) after the primary treatment of prostate cancer with surgery or radia­ tion, according to the results of a large population-based study presented at the 2014 American Society of Clinical Oncology (ASCO) meeting and high­ lighted at a press briefing.

Commenting on the study, ASCO President Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Cen­ ter, New York, said, “This study may provide reassurance about deferring ADT for quality-of-life reasons. We can tell patients that they don’t have to

at a glance ➤ Delaying ADT for ≥2 years did not lead to worse survival outcomes compared with initiating ADT within 3 months of rising PSA ➤ The 5-year survival rate was 85.1% with deferred ADT versus 87.2% with immediate ADT; 10-year survival was 71.6% in each group ➤ These findings should be discussed with patients

Photo by © ASCO/Scott Morgan 2014

By Wayne Kuznar

“This study may provide reassurance about deferring ADT for quality-of-life reasons.

We can tell patients that they don’t have to rush to treatment, and the results provide reassurance for us about withholding ADT.”

The study was based on data for more than 14,000 patients participat­ ing in the prospective Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry based at the University of California, San Fran­ cisco. Overall, 2022 men had a PSAonly relapse (defined as >.02 ng/mL or 3 rising PSA levels, asymptomatic, or no metastasis) after curative sur­ gery or radiation.

Patients with a PSA-only relapse re­ ceived immediate ADT (ie, within 3 months of rising PSA) or deferred

tients had a Gleason score of >7, and 31.8% received radiation as primary treatment.

During follow-up, 176 deaths were reported; 37 of these deaths were from prostate cancer.

The 5-year survival rates were 85.1% for the deferred ADT group and 87.2% for immediate ADT. The 10-year sur­ vival rate was identical in both groups, at 71.6%.

Person-months were used as the unit for analysis (instead of persons); 84,716 person-months were assigned

—Clifford A. Hudis, MD

rush to treatment, and the results pro­ vide reassurance for us about with­ holding ADT.” Lead investigator Xabier Garciade-Albeniz, MD, ScM, Research Asso­ ciate, Harvard University School of Public Health, Boston, said, “Immedi­ ate versus deferred ADT for men with a PSA-only recurrence is a grey area.”

He noted that the National Compre­ hensive Cancer Network guidelines say that the role of ADT in this setting is a “therapeutic dilemma,” noting that “These findings suggest that there may be no need to rush to ADT. Obvi­ ously, this is an observational study with several limitations. A large ongo­ ing randomized phase 3 trial is look­ ing at this question and results of that trial will answer the question and serve as the gold standard.”

“These findings suggest that there may be no need to rush to ADT. Obviously, this is an observational study with several limitations. A large ongoing randomized phase 3 trial is looking at this question and results of that trial will answer the question and serve as the gold standard.”

—Xabier Garcia-de-Albeniz, MD, ScM

ADT (ie, at least 2 years after PSA re­ lapse, or for metastasis, symptoms, or short PSA doubling time).

The median time from primary treatment to PSA relapse was 27 months. The median follow-up after PSA relapse was 41 months. The medi­ an age of the patients was 69 years (range, 63-74 years), 33.8% of the pa­

to deferred ADT, and 13,889 per­ son-months were assigned for the im­ mediate ADT strategy.

Dr Garcia-de-Albeniz and other ex­ perts said that these results could be included in discussions with patients who had a PSA-only relapse who may want to delay ADT because of un­ wanted side effects or other reasons. n

Breakthrough Therapy Designation Program: Reviewing the First-Year Experience

By Alice Goodman

Chicago, IL—The US Food and Drug Administration (FDA) introduced the concept of a breakthrough therapy designation in 2012 to help expedite patient access to new therapies for the treatment of serious or life-threatening diseases. A new study published in association with the 2014 American Society of Clinical Oncology meeting

20

reviewed the first-year experience of the breakthrough therapy program for cancer therapies.

Of the 14 oncology agents that earned the breakthrough therapy designation, 2 are now approved by the FDA, both for hematologic malignancies. These are obinutuzumab (Gazyva), approved in combination with chlorambucil for

Value-Based Cancer Care

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JUNE 2014

the treatment of previously untreated chronic lymphocytic leukemia, and ibrutinib (Imbruvica) for the treatment of mantle-cell lymphoma.

“The breakthrough therapy pro­ gram is still in its early stages, and some of the designations have been granted to drugs in later stages of de­ velopment. These products were not

able to take advantage of all the bene­ fits of BT [breakthrough therapy]. In the future, if BT designations are granted in earlier stages of drug devel­ opment, it is possible that drug devel­ opment and review process could be even further streamlined,” wrote the FDA Office of Media Affairs in an e-mail to Value-Based Cancer Care.

Continued on page 21

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No. 5

ASCO 2014 Highlights

Nationwide Adoption of LDCT Screening Will Detect More Early-Stage Lung Cancer, but at Substantial Economic Cost

By Phoebe Starr

Chicago, IL—The US Preventive Ser­ vices Task Force (USPSTF) recom­ mends annual low-dose computed tomography (LDCT) lung cancer screening for patients at high risk. What would it mean in terms of cost to soci­ ety if those recommendations were im­ plemented in the Medicare population?

A study using budget impact mod­ eling projected that an LDCT lung cancer screening program that adheres to the USPSTF recommendations in a Medicare population would identify approximately 54,900 more cases of lung cancer over a 5-year period, mainly early-stage disease, but at a substantial economic cost, said lead investigator Joshua A. Roth, PhD, MHA, a postdoctoral fellow at Fred Hutchinson Cancer Research Center, Seattle, WA. Dr Roth presented these results at the 2014 American Society of Clinical Oncology meeting, noting that the 5-year cost would be approximately $9 billion in Medicare expenditures.

Medicare is expected to make a deci­ sion on LDCT lung cancer screening coverage in November 2014, and this decision is likely to rely heavily on the

USPSTF recommendations, said Dr Roth. “The take-home message from this presentation is that Medicare should plan for increased expendi­ tures if the USPSTF recommendation is adopted.”

The investigators used a budget im­ pact model to arrive at these calcula­ tions. They selected the Medicare pop­ ulation, because it has the highest rates of lung cancer and a large proportion of members who fit into the high-risk category for annual screening, which includes age 55 to 80 years, a 30-packyear smoking history, current smoker, or quit smoking within the past 15 years, Dr Roth explained.

The USPSTF recommendations are based largely on the findings from the National Lung Screening Trial (NLST), which demonstrated a 20% reduction in lung cancer deaths with LDCT lung cancer screening compared with x-ray screening.

The current model assumed that over a 5-year period, 20% more highrisk patients will be offered screening annually. The investigators examined 3 scenarios: • Expected use based on experience

“The take-home message from this presentation is that Medicare should plan for increased expenditures if the USPSTF recommendation is adopted.”

—Joshua A. Roth, PhD, MHA with mammography (50% of pa­ tients offered screening undergo screening annually) • A low-use scenario (only 25% of patients offered screening follow

through with it) • A high-use scenario (75% of patients offered annual screening take ad­ vantage of it).

The investigators compared LDCT screening with no screening, inputting NLST data along with data from the Surveillance, Epidemiology, and End Results Program and from the peerreviewed literature.

The expected-use scenario would yield 11.2 million more LDCT scans and would result in 54,900 additional lung cancers detected over 5 years ver­ sus no screening. Early diagnoses would rise from 15% to 33%. The total 5-year expenditure for LDCT imaging, diagnostic workup, and lung cancer care would be $9.3 billion. Dr Roth said that this would increase the Medicare premium per member by $3 monthly.

The low-use scenario would cost $5.9 billion, whereas the high-use sce­ nario would cost $12.7 billion (with monthly premium increases per Medi­ care member of $1.90 and $4.10, respectively).

Dr Roth said that the major propor­ tion of the Medicare expenditure would be for the CT scans. n

Breakthrough Therapy Designation Program... Continued from page 20 at a glance ➤ In the 1 year since the program’s inception, the FDA received 50 requests for a breakthrough therapy designation for cancer therapies ➤ In all, 14 requests were granted the designation, 29 were denied, and 7 were withdrawn by their sponsors ➤ Of the 29 requests that were denied, 24 included preliminary clinical evidence showing no substantial improvement compared with existing therapies ➤ Companies receiving initial denial may resubmit their request with more mature data showing substantial improvement on current therapies

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No. 5

“We are delighted now to have an additional tool to help expedite the development and approval of products with the BT designation. We will con­ tinue to use our existing tools and the new BT authority to make our expedit­ ed drug development process even more effective, with the goal of benefit­ ting patients with unmet medical needs,” the e-mail response continued.

The FDA’s Office of Hematology and Oncology Products (OHOP) received 50 requests for a breakthrough therapy designation between the program’s in­ ception on October 30, 2012, and Octo­ ber 31, 2013. OHOP, together with the review division and the Medical Policy Council, completed the assessment of 43 of the 50 requests. In all, 14 requests were granted a breakthrough therapy designation, 29 were denied, and 7 were withdrawn by the sponsors.

Of the 14 granted breakthrough ther­ apy designations, 3 submitted market­ ing applications to the FDA within 3 months of receiving the des­ ignation,

and 2 (obinutuzumab and ibrutinib) received FDA approval approximately 5 to 6 months after submission.

“It is too early to determine the long-term impact of this program on development and approval of oncology products.”

—Yangmin M. Ning, MD, PhD, and colleagues “It is too early to determine the long-term impact of this program on development and approval of oncolo­ gy products,” wrote lead investigator Yangmin M. Ning, MD, PhD, Acting Deputy Director of Safety, FDA’s Divi­ sion of Oncology Products 1, Silver Spring, MD, and colleagues.

Quality of the Evidence Is Key Of the 29 submissions that were de­

JUNE 2014

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nied by the FDA, 24 included prelimi­ nary clinical evidence showing no sub­ stantial improvement compared with existing therapies for their intended use, and 5 had limited clinical data that precluded reliable assessments. Other reasons for denial included reliance on a novel biomarker or a surrogate end point without sufficient evidence of benefit to the patient, and post-hoc analysis of failed trials identifying a subset of patients who may benefit.

The FDA website for expedited re­ view programs states that many of the denials for breakthrough therapy des­ ignation represent “the triumph of hope over evidence.”

In the e-mail, the FDA Office of Media Affairs stated, “Some compa­ nies with denied requests for BT desig­ nation may resubmit more mature data and request the designation again, particularly if the request was submitted prematurely. The denial of a BT designation would not stop the development program for a drug.” n

www.ValueBasedCancerCare.com

21

To learn more, visit us at

www.IMBRUVICA.com CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IMBRUVICATM is indicated for the treatment of patients with CLL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

MANTLE CELL LYMPHOMA (MCL) IMBRUVICATM is indicated for the treatment of patients with MCL who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria).

Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood. IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy.

At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE). Monitor patients for fever and infections and evaluate promptly.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman.

Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS – MCL: The most commonly occurring adverse reactions (≥20%) in the clinical trial were thrombocytopenia*, diarrhea (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%). *Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

IMBRUVICATM: the first-in-class covalent BTK inhibitor

DISCOVERING HOW FAR THERAPY CAN GO Encouraging response rates in previously treated CLL and MCL1 Durable responses1:

Most common adverse reactions (ARs) (≥20%)1:

• Median duration of response (DOR) not reached in CLL —Range: 5.6 to 24.2+ months • 17.5 months median duration of response (95% CI: 15.8, NR) in MCL Phase 2 MCL Trial:

open-label, multi-center, single-arm 1

100

100

80

80

60 40

ORR 58.3%

PR 58.3%

20 0

Response (%)

Response (%)

CLL Trial: open-label, multi-center 1

ORR 65.8%

60 40

PR 48.6%

20

CLL (N=48)

0

CR 17.1% MCL (N=111)

None of the patients achieved a complete response.

CLL: 95% CI (43.2, 72.4) MCL: 95% CI (56.2, 74.5) CR=complete response; ORR=overall response rate; PR=partial response.

ORR and DOR were assessed using a modified version of the International Workshop on CLL (iwCLL) criteria by an Independent Review Committee.

ORR was investigator-assessed according to the revised International Working Group (IWG) non-Hodgkin lymphoma (NHL) criteria.

The most common Grade 3 or 4 nonhematological adverse reactions (≥5%) were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111).

The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%).

© Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 05/14 PRC-00300

• CLL: thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%) • MCL: thrombocytopenia†, diarrhea (51%), neutropenia†, anemia†, fatigue (41%), musculoskeletal pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), constipation (25%), rash (25%), abdominal pain (24%), vomiting (23%), and decreased appetite (21%)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions. † Treatment-emergent decreases (all grades) of platelets (57%), neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

The most common Grade 3 or 4 non-hematological ARs (≥5%) were1:

• CLL: pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients. Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients • MCL: pneumonia (7%), abdominal pain (5%), atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin infections (5%).

Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients. Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111)

*Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 nonhematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), dehydration (6.4%), and musculoskeletal pain (6%). Treatment-emergent Grade 3 or 4 cytopenias were reported in 35% of patients.

Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48).

These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

Adverse reactions leading to dose reduction occurred in 13% of patients.

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

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

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

Reference: 1. IMBRUVICATM (ibrutinib) Prescribing Information. Pharmacyclics, Inc. 2014.

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

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

IMBRUVICATM (ibrutinib) capsules

INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

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

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

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

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

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

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

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

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

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

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

Preferred Term

Gastrointestinal disorders

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

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

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

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

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

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

57

17

Neutrophils Decreased

47

29

Hemoglobin Decreased

41

9

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

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

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

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

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 System Organ Class Preferred Term (%) (%) 4 63 Gastrointestinal disorders Diarrhea 2 23 Constipation 2 21 Nausea 0 21 Stomatitis 2 19 Vomiting 0 15 Abdominal pain 0 13 Dyspepsia Infections and infestations Upper respiratory 2 48 tract infection 6 21 Sinusitis 6 17 Skin infection 8 10 Pneumonia 0 10 Urinary tract infection 4 31 General disorders and administrative Fatigue 2 25 site conditions Pyrexia 0 23 Peripheral edema 4 13 Asthenia 0 13 Chills 2 54 Skin and subcutaneous tissue disorders Bruising 0 27 Rash 0 17 Petechiae 0 19 Respiratory, thoracic and mediastinal Cough 0 15 disorders Oropharyngeal pain 0 10 Dyspnea 6 27 Musculoskeletal and connective tissue Musculoskeletal pain 0 23 disorders Arthralgia 2 19 Muscle spasms 0 21 Nervous system disorders Dizziness 2 19 Headache 0 10 Peripheral neuropathy Metabolism and nutrition disorders Decreased appetite 17 2 Neoplasms benign, malignant, Second 10* 0 unspecified malignancies* Injury, poisoning and procedural Laceration 10 2 complications Psychiatric disorders Anxiety 10 0 Insomnia 10 0 Vascular disorders Hypertension 17 8 *One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

71

10

Neutrophils Decreased

54

27

Hemoglobin Decreased

44

0

* Based on laboratory measurements per IWCLL criteria and adverse reactions Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

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

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

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

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

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

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

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

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

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

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients).

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

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

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

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

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

• Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions].

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

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

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

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

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

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

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

Active ingredient made in China.

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044

In the Literature Panitumumab and Cetuximab Show Comparable Survival Benefit... Continued from page 17

for panitumumab and 14.1 weeks for cetuximab.

At a median follow-up of >9 months, the findings showed that panitu­ mumab was noninferior to cetuximab. The median OS was 10.4 months with panitumumab and 10 months with cetuximab (hazard ratio [HR], 0.97, 95% confidence interval [CI], 0.84-1.11; P = .007). The Z score was −3.19, meeting the criteria of noninferiority of less than −1.96. Median progression-free survival was also similar between panitumumab and cetuximab (4.1 months and 4.4 months, respectively; HR, 1; 95% CI, 0.88-1.14).

The incidence of adverse events of any grade was consistent across treatment groups. Serious adverse events were reported in 30% of the panitumumab group and 34% of the cetuximab group, with 35% and 36%, respectively, need­ ing dose reductions because of adverse events. Grade 3 or 4 skin toxicity was more common with panitumumab than with cetuximab (13% vs 10%, respec­ tively), as was hypomagnesemia (7% vs 3%, respectively). However, infusion reactions were more common with cetuximab than with panitumumab (2% vs <0.5%, respectively).

Considering the consistency of efficacy and toxicity that was observed, small but meaningful differences in the rate of grade 3 or 4 infusion reactions and the differences in dose scheduling can guide clinician choice of anti-EGFR therapy for this patient population, concluded the researchers.

Study Identifies Troubling Trends in NSCLC Trials

Changes in the design and interpretation of phase 3 trials for advanced non–small-cell lung cancer (NSCLC) have begun to emerge regarding statis­ tical power, sample size, and the primary end points used. In a new study, researchers explored how the design and interpretation of these trials has changed over the past 3 decades. The findings point to a disquieting shift in NSCLC trials (Sacher AG, et al. J Clin Oncol. 2014;32:1407-1411).

Using PubMed to conduct a literature search of all phase 3, randomized, placebo-controlled clinical trials evaluating systemic treatment for advanced NSCLC between 1980 and 2010, the researchers identified 245 trials, 203 of which met the inclusion criteria. Review of the included trials revealed several notable trends.

The number of NSCLC phase 3 trials increased dramatically over time, from 32 trials conducted in the 1980s to 53 studies in the 1990s, to 118 trials from 2001 to 2010. The sample size also increased from a median of 152 patients in the 1980s, to 184 patients in the 1990s, to 413 patients between 2001 and 2010.

The distribution of treatments has also shifted from multiagent triplet chemotherapy in the 1980s to predominately doublet therapy in the 1990s, and then to a sizable increase in targeted therapies in the most recent decade.

The researchers also found a significant shift in the primary study end point.

In most of the studies conducted before 2000, the primary end point was overall survival (OS), with 97% of trials reporting median OS in the 1980s and 96% in the 1990s. Significantly fewer trials used OS as the primary end point between 2001 and 2010 (81%; P <.002).

Instead, progression-free survival was the primary end point in 13% of trials conducted during this period. Although the percentage of trials with statisti­ cally significant improvement in the primary outcome has remained stable over time, the percentage of trials reporting positive outcomes without achiev­ ing that end point increased from 31% in 1980 to 1990 to 53% in 2001 to 2010.

In 60 of the trials reporting a statistically significant improvement in surviv­ al, there was a decreasing trend for an improved median net survival benefit over time (3.9 months in 1981-1990 compared with 2.4 months in 1991-2000 and 2.5 months from 2001-2010). When all trials deemed positive were as­ sessed, this changed from 3.9 months in 1980 to 1990 to 2 months from 1991 to 2000 and 0.9 months from 2001 to 2010. Despite the declining net survival, the findings showed that average median survival across trials in each decade increased from 6.7 months in 1980 to 1990, to 7.9 months from 1991 to 2000, to 9.5 months from 2001 to 2010.

The researchers concluded that important changes in the design and in­ terpretation of phase 3 clinical trials in patients with advanced NSCLC have occurred over the past 30 years. Although the size of the trials has increased significantly, they have less clinically meaningful end points and are less effec­ tive in identifying the clinical benefit of new therapies for the management of patients with cancer. n

Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 PRC-00339

Issued: February 2014

JUNE 2014

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ASCO 2014 Highlights

Obesity Ups Death Risk in Premenopausal Patients with ER-Positive, but Not ER-Negative, Breast Cancer

By Phoebe Starr

Unit, University of Oxford, United Kingdom, at a press briefing.

The results of the study surprised Dr Pan and his colleagues, who ex­ pected to see an increased mortality risk in patients with pre- and post­

obesity as a complicating factor in can­ cer care. ASCO is working to support physicians and patients who need to lose weight. New strategies are need­ ed to address this challenge,” stated ASCO President Clifford A. Hudis,

“With some two-thirds of adults in the United States now obese or overweight, there is no avoiding obesity as a complicating factor in cancer care….New strategies are needed to address this challenge.”

Photo by © ASCO/Scott Morgan 2014

Chicago, IL—Obesity increased the risk for breast cancer–associated death in premenopausal patients with estro­ gen receptor (ER)-positive breast can­ cer, had little effect in postmenopausal women with ER-positive disease, and had no effect in patients with ER-neg­ ative disease, according to results of a large study of 80,000 women with early breast cancer that were reported at the 2014 American Society of Clini­ cal Oncology (ASCO) meeting.

In premenopausal patients with ER-positive breast cancer, obesity in­ creased the risk of death by 34%. Sur­ prisingly, this was not the case in postmenopausal women.

Obesity is a well-known public health problem and is associated with an increased risk for breast cancer, as well as a long list of other potential adverse effects on health.

“It has been shown that obesity in­ creases the risk of developing cancer, and this study says it increases the risk of poor outcome once you have cancer if you are premenopausal and have ER-positive breast cancer,” said lead investigator Hongchao Pan, PhD, Medical Research Council Senior Re­ search Fellow, Clinical Trial Service Unit and Epidemiological Studies

—Clifford A. Hudis, MD

menopausal ER-positive breast cancer.

“These paradoxical findings show that we have an incomplete understanding of the mechanisms associated with obesity and breast cancer prognosis,” Dr Pan noted.

“Obesity is a major challenge, and trends suggest that it will replace to­ bacco as our leading public health problem. With some two-thirds of adults in the United States now obese or overweight, there is no avoiding

MD, Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, at a press briefing.

Study Details The study was conducted by the Early Breast Cancer Trialists’ Collabo­ rative Group and was based on the records of 80,000 women enrolled in 70 clinical trials. Obesity was defined as a body mass index (BMI) of ≥30 kg/

m2, overweight as a BMI of 25 kg/m2 to 30 kg/m2, and normal weight as 20 kg/m2 to 25 kg/m2.

Data were collected on ER status, menopausal status, and cancer recur­ rence, and the findings were adjusted for tumor characteristics, including size and nodal status, and for any dif­ ferences in treatment.

A Cox regression analysis that was undertaken to compare the effects of obesity on breast cancer mortality in obese versus normal-weight women showed that obesity was a significant and independent factor associated with breast cancer death in 20,000 pre­ menopausal ER-positive women (rela­ tive risk [RR], 1.34 [95% confidence interval (CI), 1.22-1.47]; 2-sided P value <.001).

Little effect of obesity was observed in the 40,000 postmenopausal women with ER-positive disease (RR, 1.06; 95% CI, 0.99-1.14), and no effect was found in the 20,000 women with ER-negative disease (RR, 1; 95% CI, 0.93-1.08).

At 10 years, the breast cancer–relat­ ed mortality rate was 21.5% in obese women and 16.6% in normal-weight women, a difference of approximate­ ly 5%. n

AZD9291, a Novel Mutation-Selective EGFR Inhibitor, May Overcome EGFR-TKI Resistance Designated as breakthrough therapy by FDA Chicago, IL—AZD9291, a novel muta­ tion-selective tyrosine kinase inhibitor (TKI), may become a treatment option for patients with advanced, EGFRmutated non–small-cell lung cancer (NSCLC) that has progressed with standard EGFR inhibitors, according to results of a phase 1 study presented at the 2014 American Society of Clinical Oncology (ASCO) meeting and high­ lighted at a press briefing.

These results demonstrated excel­ lent safety and promising efficacy in patients with NSCLC and acquired resistance to EGFR-targeted TKIs in patients with the T790M mutation.

So far, no dose-limiting toxicity and no maximum-tolerated dose have been identified.

The US Food and Drug Admin­

26

“The greater precision appears to have reduced the toxicity rendered to normal tissues that presumably do not express this mutation.”

—Peter P. Yu, MD

istration has granted AZD9291 a break­ through therapy designation for the treatment of patients with EGFRpositive NSCLC that has progressed

Value-Based Cancer Care

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with currently available EGFR-targeted TKI therapy.

ASCO President-Elect Peter P. Yu, MD, Director, Cancer Research, Palo Alto Medical Foundation, CA, said that the issue of drug resistance is im­ portant to understand for all cancers, but it is difficult to overcome resis­ tance. Dr Yu was particularly pleased that the knowledge about the mecha­ nism of drug resistance (ie, the pres­ ence of the T790M mutation) led to designing a TKI to overcome that resistance.

Targeted TKIs for EGFR-Mutated NSCLC “The greater precision [of AZD9291] appears to have reduced the toxicity rendered to normal tissues that pre­

sumably do not express this muta­ tion,” Dr Yu commented.

EGFR mutations were the first bio­ marker for lung cancer that led to the development of EGFR-targeted thera­ pies. Currently, the TKIs erlotinib (Tarceva), gefitinib (Iressa), and afati­ nib (Gilotrif) are approved for the treatment of patients with EGFRmutated NSCLC. Patients will respond to these drugs, but most will acquire resistance to EGFR-targeted TKIs within 10 to 14 months. Approximately 60% of pa­ tients who become resistant to one of these TKIs have a secondary EGFR mutation known as T790M. The exciting finding from this phase 1 study is that AZD9291 appears to be effective in patients with the T790M Continued on page 27

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ASCO 2014 Highlights

Cetuximab versus Bevacizumab: Comparable Benefit as First-Line Therapy for Metastatic Colorectal Cancer

By Phoebe Starr

“These 2 distinctly different biologic treatments did not impart differences in outcomes. Either is appropriate in the first-line metastatic setting.”

—Alan P. Venook, MD

amendments and 11 interim analyses, reflecting the rapidly evolving treat­ ment landscape of colorectal cancer in the past 15 years, Dr Venook noted.

“The question was, which was the optimal first-line treatment?” he asked.

“The assumption at the start was that maybe one was better.”

High Survival Rates in Both Arms The CALGB/SWOG 80405 random­ ized 1137 previously untreated pa­ tients with KRAS wild-type (codons 12, 13) to chemotherapy (by physi­ cian’s choice) plus bevacizumab or cetuximab. Of these patients, 75% of patients received FOLFOX (5-fluo­ rouracil [5-FU]/leucovorin/oxalipla­ tin [Eloxatin]), and 25% received FOLFIRI (5-FU/leucovorin/irinotecan [Camptosar]).

At a median follow-up of 24 months, no significant differences were seen between the 2 groups in OS, which was 29 months with bevacizumab (plus chemotherapy) and 29.9 months with cetuximab (plus chemotherapy).

The PFS was 10.8 months and 10.4 months, respectively.

With the exception of 1 small study, the median OS of >29 months is the longest yet recorded in a trial of pa­ tients with mCRC. In the late 1980s, the median survival was just 8 months, according to Dr Venook, who called this OS benefit “unprecedented.”

No new toxicities emerged in this study, Dr Venook noted.

“Our findings clearly show that the 2 antibodies—with either FOLFOX or FOLFIRI—are both acceptable and similarly effective. First-line therapy

AZD9291, a Novel Mutation-Selective... Continued from page 26 mutation, and it is much less toxic than the currently approved TKIs, ex­ plained lead investigator Pasi A. Jänne, MD, PhD, Director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston.

Study Details In the open-label, multicenter, phase 1 AZD9291 First Time in Patients Ascending Dose Study (AURA), pa­ tients were assigned to 1 of 5 dosing cohorts at doses ranging from 20 mg daily to 240 mg daily. These cohorts were not preselected according to T790M status.

A total of 5 expansion cohorts were preselected according to T790M status.

As of January 2014, 199 patients were enrolled. No dose-limiting toxicity was identified at doses of 20 mg to 240

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No. 5

The exciting finding from the phase 1 study is that AZD9291 appears to be effective in patients with the T790M mutation, and it is less toxic than the currently approved TKIs. —Pasi A. Jänne, MD, PhD mg daily, and no maximum-tolerated dose was defined.

Adverse events included grade 1

diarrhea (30%), rash (24%), and nau­ sea (17%). Grade 3 or 4 adverse events occurred in 16% of patients; 6 patients (3%) required dose reductions, and 7 patients discontinued treatment as a result of adverse events. There were 5 reports of interstitial lung disease that responded to treatment, and investi­ gators are exploring this side effect further.

The overall response rate in all evaluable patients was 51%. The over­ all response rate was higher in can­ cers with the T790M mutation: 64% in mutation-positive patients versus 23% in mutation-negative patients.

Overall disease control was 96% in mutation-positive patients (85 of 89 patients). The longest duration of re­ sponse was 8 months, and responses were seen across all dose levels.—PS n

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should reflect the patient’s preference or concern for potential side effects.”

The findings of the current study are different from those of the European FIRE-3 trial reported last year, in which cetuximab improved OS.

Photo by © ASCO/Phil McCarten 2014

they had different toxicity profiles, their relative efficacy was unknown.

CALGB/SWOG 80405 underwent 14

Photo by © ASCO/Silas Crews 2014

Chicago, IL—A head-to-head compar­ ison of 2 monoclonal antibodies for metastatic colorectal cancer (mCRC) has shown no difference in their bene­ fit when paired with chemotherapy in the first-line setting.

The results of the phase 3, federally funded CALGB/SWOG 80405 trial were presented at a 2014 American Society of Clinical Oncology (ASCO) meeting plenary session by Alan P. Venook, MD, Madden Family Distin­ guished Professor of Medical Oncolo­ gy and Translational Research, Uni­ versity of California, San Francisco.

The optimal monoclonal antibody to pair with chemotherapy in the first-line treatment of mCRC has been unclear.

US oncologists tend to use bevacizu­ mab (Avastin) more than ce­ tuximab (Erbitux), but the recent European FIRE-3 study showed that cetuximab had an overall survival (OS) benefit, although, puzzlingly, no benefit in pro­ gression-free survival (PFS).

“In CALGB/SWOG 80405, we did not show a meaningful difference be­ tween cetuximab and bevacizumab.

These 2 distinctly different biologic treatments did not impart differences in outcomes. Either is appropriate in the first-line metastatic setting,” said Dr Venook.

In 2004, when the study was de­ signed, bevacizumab and cetuximab had just been approved, and although

“The really important thing is that this sets a new standard and a new high bar for clinical trials in advanced colorectal cancer.”

—Clifford A. Hudis, MD

The Value of Federally Funded Trials “These patients are doing a little better, and I believe this represents a less biased approach. This is what co­ operative groups do: treat patients in studies for which companies are not paying the bill,” Dr Venook said in a press briefing.

He did not predict that the compara­ bility between the arms would lead to more prescriptions for cetuximab, however, “since patients don’t like skin rash.” Expanded RAS testing and other molecular and clinical analyses may identify subsets of patients who get more or less benefit from the spe­ cific regimens.

ASCO President Clifford A. Hudis, MD, Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center, New York, who mod­ erated the press briefing, commented, “The really impor­ tant thing is that this sets a new standard and a new high bar for clinical trials in advanced colorectal cancer. It also highlights the reason that we will continue to need significant investment. With each incremental benefit, the size of trials will need to get larger to see differences.” n

www.ValueBasedCancerCare.com

27

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

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.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival 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 overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ 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 on the next page of this advertisement.

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

Reference: 1. Mateos M-V, 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. *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.

S:10.187”

Brief Summary 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.

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.

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 previouslytreated 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 Please see full Prescribing Information for VELCADE at of VELCADE administered intravenously in combination with VELCADEHCP.com. 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%), VELCADE, MILLENNIUM and are registered trademarks of Millennium vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Pharmaceuticals, Inc., Cambridge, MA 02139 vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia Millennium Copyright © 2013, Millennium Pharmaceuticals, Inc. V-12-0306a (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), All rights reserved. Printed in USA

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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.

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 postimplantation loss and a decreased number of live fetuses.

Health Policy

Smoking Still a Major Cause of Cancer Death: A Call to Action on Tobacco Control Responsible for 130,000 cancer deaths annually in the United States

By Charles Bankhead San Diego, CA—Tobacco researchers and regulators lauded progress in to­ bacco control, but they emphasized that the health burden of tobacco use contin­ ues, reflecting the expanding list of dis­ eases caused or exacerbated by tobacco.

At the 2014 American Association for Cancer Research (AACR) meeting, speakers continually pointed to tobacco control efforts that have led to a 60% reduction in smoking prevalence since the 1964 Surgeon General’s report on the health consequences of smoking.

Even so, 480,000 Americans contin­ ue to die annually from causes related to tobacco use, including 130,000 can­ cer deaths.

“Smoking prevalence has decreased from 42% of adults in 1964 to 18% today,” said Roy S. Herbst, MD, PhD, MS, Chief, Medical Oncology, Yale Cancer Center, New Haven, CT, and Chair of the AACR tobacco control council. “In that time, an estimated 8 million lives have been saved.”

Main Cause of Preventable Death “But we still have a long way to go.

Tobacco remains the largest prevent­ able cause of death in the United States. It contributes to 18 different types of cancer and up to 30% of all cancer-related deaths. Eliminating the scourge of tobacco is one of the most effective things we can do in the area of cancer control,” Dr Herbst said.

The AACR recently published a col­ lection of articles that have played a role in reducing smoking and other forms of tobacco use. Titled 50 Years of Tobacco Control, the publication in­ cludes reprints of articles that original­ ly appeared in the AACR’s 7 peerreviewed journals.

Since 1964, a “remarkable denor­ malization of smoking has occurred,” marked by “stunning progress” in to­ bacco control. The 1964 Surgeon Gen­ eral’s report was “a critical building block in reducing the death and dis­ ease toll from tobacco,” said Mitchell Zeller, JD, Director, US Food and Drug Administration (FDA)’s Center for Tobacco Products, Rockville, MD. Jonathan M. Samet, MD, MS, Direc­ tor, Institute for Global Health, Uni­ versity of Southern California, Los Angeles, and Senior Editor of 50 Years of Tobacco Control noted that 31 reports from the Surgeon General have fol­ lowed the 1964 publication.

The 2014 report further lengthens

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the list of diseases caused by smoking, said Dr Samet. Notable additions in­ clude liver and colon cancers. The re­ port “drives home the need for action, citing this large burden of smokingattributable death and morbidity. The burden has not decreased, although we are making progress in some areas,” said Dr Samet.

The report ends with a call for more action and more collaboration among various stakeholders to bring about change more rapidly, “to end this epi­ demic as quickly as possible,” said Dr Samet.

“The report did not say what should be done; it simply said the problem was big enough that something should be done,” said Dr Samet. “The reports are about what the scientific evidence shows. It provides a framework for decision making.”

The report “drives home the need for action, citing this large burden of smokingattributable death and morbidity. The burden has not decreased, although we are making progress in some areas.”

—Jonathan M. Samet, MD, MS

“Tobacco remains the largest preventable cause of death in the United States. It contributes to 18 different types of cancer and up to 30% of all cancer-related deaths.”

—Roy S. Herbst, MD, PhD, MS Smoking has remained a major pub­ lic health problem, said Robert T. Croyle, PhD, Director, Division of Cancer Control and Population Scienc­ es, National Cancer Institute (NCI), Bethesda, MD. “We’re in a bizarre situation where we have a legal product on the market which is responsible for about a half a million deaths each year. In any other circumstance, without this long, strange history, there would be a lot more en­ gagement by the scientific community,

by clinicians, and organizations, really marshaling every effort to address the problem,” Dr Croyle stated.

One of the key challenges to in­ creased control of tobacco use involves finding ways to engage with today’s “typical” smoker.

“The subpopulations which are the highest users are often those of lower income, lower levels of education, and in some regions of the country,” said Dr Croyle. “If you are a college-educat­ ed, wealthy individual living in the state of California, you may assume or believe that the smoking problem is one of the past. Clearly, for many of us, we see that, across the United States, this is an overwhelming problem.”

The FDA and e-Cigarettes The AACR meeting concluded only a couple of weeks before the FDA an­ nounced proposed rules to bring e-cig­ arettes under its regulatory authority, which was hinted to by Mr Zeller during the meeting.

After the FDA tried to ban the im­ portation of e-cigarettes, an importer sued the agency, claiming it had no regulatory authority because e-ciga­ rettes do not contain tobacco. The ar­ gument held up in federal district and appellate courts.

Mr Zeller pointed out that the 2009

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Family Smoking Prevention and To­ bacco Control Act gave the FDA “au­ thority and unprecedented opportuni­ ty to reduce the death and disease toll through use of science-based product regulation.”

“For the first time, the federal gov­ ernment is able to regulate the manu­ facturing, marketing, and distribution of tobacco products,” Mr Zeller said.

“Until now, it was the tobacco indus­ try that decided which products reached the market and which ones did not, which claims and descriptors appeared in labeling and advertising.

FDA now plays a vital gate-keeping role in protecting the public by review­ ing products and health-related claims for tobacco products we regulate.”

That apparently will include e-ciga­ rettes. The 2009 legislation included a so-called deeming provision, allowing the FDA to extend its regulatory reach to products the agency deems to meet the statutory definition of tobacco products.

“FDA now plays a vital gatekeeping role in protecting the public by reviewing products and health-related claims for tobacco products we regulate.”

—Mitchell Zeller, JD

“The statutory definition of tobacco product includes anything ‘made or derived from tobacco,’” said Mr Zeller.

“The nicotine in e-cigarettes is derived from tobacco.”

Aside from exercising its regulatory authority over tobacco products, the FDA has made youth tobacco use a priority. The NCI plans to ramp up efforts to address tobacco-related health problems at a global level, said Dr Croyle.

As the United States has become more restrictive toward tobacco use, the tobacco industry has shifted more of its focus on global markets. Several institutes with the National Institutes of Health have planned a collaborative research program, some of which may be funded by the FDA, which can fund research as part of its expanded au­ thority over tobacco products. n

www.ValueBasedCancerCare.com

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Economics of Cancer Care

Aetna’s Model of Value-Based, Financially Viable Accountable Care Improves Health Outcomes Interview with Charles Kennedy, MD

By Rosemary Frei

C

harles Kennedy, MD, Chief Executive Officer of Aetna’s Accountable Care Solutions, is responsible for leading Aetna’s ac­ countable care partnerships with healthcare providers. Dr Kennedy also serves as the health insurance industry representative on the Health IT Policy Committee, a federal advisory com­ mittee that makes recommendations to the National Coordinator for Health IT on a policy framework for the de­ velopment and adoption of a nation­ wide health information infrastruc­ ture. Value-Based Cancer Care (VBCC) interviewed Dr Kennedy in connec­ tion with his discussion of accountable care organizations (ACOs) at the 2014 Medical Informatics World meeting.

VBCC: How many ACOs does Aetna have, and what is the driving force behind them?

Dr Kennedy: We have signed 35 accountable care agreements with var­ ious health systems and provider or­ ganizations across the country. As of the end of 2013, Aetna had 550,000 members in these accountable care ar­ rangements, and we project that we will have 850,000 by the end of 2014.

Value-based, patient-centered care models, including ACOs, are an im­ portant component of Aetna’s vision for a more connected and effective healthcare system.

“Keeping the patient within the ACO network affects the physician’s ability to proactively and effectively manage that patient’s care, health outcomes, and costs.”

—Charles Kennedy, MD

VBCC: Can you describe the “smart approach to patient steerage” to a narrow network of providers?

Dr Kennedy: Narrow networks that are centered on the ACO can play an important role in creating accountabil­ ity for creating financial and quality outcomes for members in our ACOs. By improving the quality of patient care and the cost of that care, the ACO becomes more efficient with its care delivery. When linked to our gain-

32

share contracts, ACO-based services can create savings that benefit every­ one—the ACO, the insurance compa­ ny, and, ultimately, the purchaser of healthcare services, the patient.

In our ACO-based arrangements, members are still able to choose pro­ viders from Aetna’s broad network, but they receive a higher level of bene­ fits when they seek care from provid­ ers who are part of the ACO. VBCC: How does the strong emphasis on patient loyalty fit into Aetna’s model of ACO? Dr Kennedy: The ACO and the phy­ sicians participating in it must focus more than ever on patient loyalty and patient satisfaction. Keeping the pa­ tient within the ACO network affects the physician’s ability to proactively and effectively manage that patient’s care, health outcomes, and costs.

There are many ways to enhance patient loyalty. Care management, wellness programs, patient outreach, expanded hours, and web-based and mobile technology all play roles. These programs improve loyalty by improv­ ing the experience and increasing convenience.

Furthermore, we need to ensure that members understand the benefits of participating in an accountable care model. For example, because doctors want to ensure care, you have access to them when you need them, rather than going to the emergency depart­ ment, and they may offer extended hours. When you see a specialist in the accountable care network, this physi­ cian may have more information about your health history because of the data-sharing tools that we work with the ACO to implement. As a result, providers can make better decisions about care, can order fewer redundant tests, and can require fewer forms for patients to complete.

If patients suffer from a chronic con­ dition such as diabetes or asthma, they may receive additional education and support from their care team to help manage their health condition. Physi­ cians are encouraged and are financial­ ly compensated by Aetna to work to­ gether and to focus on preventive care, because it can reduce the development or progression of chronic disease.

VBCC: How does Accountable Care Solutions plan to migrate to a model

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of upside and downside risk?

Dr Kennedy: Aetna’s goal is to pro­ vide a financially viable, multiyear strategy to help the health delivery systems move from a volume-based approach (where they are paid based on number of services, admissions) to a value-based approach (where their revenues are derived from their ability to deliver better healthcare value).

We work with these systems or ACOs to assess the level of risk they are able to assume, and we meet them where they are.

“Aetna’s goal is to provide a financially viable, multiyear strategy to help the delivery systems move from a volumebased approach…to a valuebased approach.”

—Charles Kennedy, MD

VBCC: How does Accountable Care Solutions use federal programs as a part of these strategies?

Dr Kennedy: We frequently use federal programs as part of the strate­ gy when working with a care delivery system, because commercial spending in healthcare is a mere fraction of the spending within Medicare. For exam­ ple, if Aetna’s commercial business represents 10% to 15% of the patients they see, it would be difficult for a delivery system to see the return on investment it needs to fully transform its model. Aligning our programs with federal programs, such as the Multipurpose Senior Services Pro­ gram, or Medicare Advantage, offers the patient share and volume to be

able to justify the reengineering, the new programs, and the new technolo­ gies that need to be put in place to be successful. Therefore, federal pro­ grams are critical to our overall strate­ gy for success.

VBCC: What are some of the services Accountable Care Solutions uses to achieve these goals?

Dr Kennedy: Aetna offers a wide range of consulting services, products, and technologies to support account­ able care models. For example, we help ACOs grow their patient base through jointly marketed insurance services in the marketplace—directly and through public and private exchanges.

We offer enablement solutions and advisory services to support the trans­ formation to value-based care. This could include next-generation, datadriven electronic medical records; health information exchange solutions from our Medicity subsidiary to en­ able the exchange of patient clinical information across different sites of service; personal health records cus­ tomized for patient use; and care man­ agement platforms integrated with physician and patient tools.

Our health plan experience and ana­ lytics can help providers keep patients in their ACO network, streamline op­ erations, and improve care delivery for populations. For example, we can pro­ vide analytics to show the ACO which of their patients are receiving care outside the ACO network. We then work with them on a wide range of strategies to keep more of those pa­ tients in their network where it is ap­ propriate. Aetna’s iTriage is a useful solution in these cases. It is easy to use and can help patients identify in-net­ work healthcare options for particular symptoms, and make appointments from the convenience of their smart­ phone or the Internet.

Health plans have extensive experi­ ence managing populations of pa­ tients. We work collaboratively with them on care management programs and technology to better manage highrisk populations and to improve out­ comes at the individual and popula­ tion level.

Finally, we offer solutions, such as iTriage, to engage patients and help guide them to the right level of care at the right time. n

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Now enrolling: MURANO study Investigating the Selective BCL-2 Inhibitor GDC-0199/ABT-199 in Chronic Lymphocytic Leukemia GDC-0199/ABT-199 is an investigational agent that has not been approved by regulatory agencies.

A Phase III Study of GDC-0199/ABT-199 Plus Rituximab Compared With Bendamustine Plus Rituximab in Patients With Relapsed or Resistant Chronic Lymphocytic Leukemia (CLL)

GDC-0199/ABT-199 + rituximab

Phase III Relapsed or resistant CLL (N=370)

GDC-0199/ABT-199 continued for 2 years or until disease progression

Bendamustine + rituximab Randomize Primary Endpoint

Secondary Endpoints

• Investigator-assessed progression-free survival, defined as time from randomization until disease progression or death from any cause

• Overall response rate • Incidence of adverse events

Key Inclusion Criteria

Key Exclusion Criteria

• Adult patients ≥18 years of age • Diagnosis of CLL per diagnostic criteria and relapsed or refractory CLL per the iwCLL guidelines • Previously treated with 1-3 lines of therapy (eg, completed ≥2 treatment cycles per therapy), including ≥1 standard chemotherapy-containing regimen • Previously treated with bendamustine, only if duration of response was ≥24 months • ECOG performance status of 0-1 • Adequate bone marrow function • Adequate renal and hepatic function

• Transformation of CLL to aggressive non-Hodgkin lymphoma or CNS involvement by CLL • Undergone an allogenic stem-cell transplant • A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease • Hepatitis B, hepatitis C, or known HIV-positive • Receiving warfarin treatment • Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug • Received any anticancer or investigational therapy within 14 days prior to the first dose of study drug or has not recovered from previous therapy • Received CYP3A4 inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamezapine, phenytoin, St John’s Wort) within 7 days prior to the first dose of GDC-0199/ABT-199 • Prior GDC-0199/ABT-199 treatment

To learn more about this study, please visit www.ClinicalTrials.gov (NCT02005471, GO28667) or call the Trial Information Support Line at 1-888-662-6728.

GDC-0199/ABT-199 is being codeveloped by AbbVie and Genentech, a member of the Roche Group.

© 2014 Genentech USA, Inc. All rights reserved. BIO0002506000 Printed in USA.

Reference: ClinicalTrials.gov, as of 5/2014.

A2396579

Economics of Cancer Care

Insurance Coverage for Genetic Testing and Personalized Medicine: Which Way Is the Wind Blowing?

By Alice Goodman

Tampa, FL—Genetic testing and tar­ geted medicines, the key players in personalized medicine, are seen as the waves of the future for managing pa­ tients with cancer, but getting there remains a challenge when it comes to insurance coverage for these expen­ sive tests and therapies. Little is known about the current coverage, payers’ attitudes about future expansion of coverage, and the determinants of that coverage.

“The majority of payers are interested in expanding coverage for these services, but need more pharmacoeconomic data to demonstrate costeffectiveness.”

—Nisreen Shamseddine, MS

A recent survey presented at the 2014 Academy of Managed Care Phar­ macy meeting elicited some answers to these questions. The majority of payers currently cover at least some genetic testing and targeted therapies, and plan to evaluate the need for ex­ panded coverage of these services, according to the survey results.

One of the most important findings from this study is that payers need more pharmacoeconomic data show­ ing the value of genetic testing as it relates to the selection of therapy and patient outcomes to make coverage decisions.

“Many of the new medications are specialty pharmaceuticals, and many have genetic tests to go along with them. We wanted to see if payers are onboard with advances in pharma­ cogenomics. The majority of payers are interested in expanding coverage for these services, but need more

34

pharmacoeconomic data to demon­ strate cost-effectiveness,” lead investi­ gator Nisreen Shamseddine, MS, of Xcenda, Palm Harbor, FL, told ValueBased Cancer Care.

“Of the 100s of genetic tests listed in the National Comprehensive Can­ cer Network Biomarker Compendi­ um, decision makers do not know which ones have value. The takehome message of our study is that, overall, genetic testing is important to decision makers, but they are current­ ly operating without full information.

They need more information, with pharmacoeconomic data being one of those missing pieces,” noted coinves­ tigator Melissa S. Denno, PharmD, MS, Manager, Global Health Econom­ ics and Outcomes Research, Xcenda.

The study was based on a dou­ ble-blind online survey conducted be­ tween July 18 and August 4, 2013. The survey consisted of 28 questions about current and future coverage decisions regarding genetic testing and person­ alized medicine, including health eco­ nomic questions.

The 60 respondents included phar­ macy and medical directors repre­ senting coverage of 107 million lives.

Regional plans (60%) and national plans (38%; 2% unspecified) repre­ senting commercial, Medicare, and/ or Medicaid plans were included. The types of plans included managed care organizations, integrated health de­ livery systems, preferred provider

“Of the 100s of genetic tests listed in the National Comprehensive Cancer Network Biomarker Compendium, decision makers do not know which ones have value.”

—Melissa S. Denno, PharmD, MS

organizations, and pharmacy benefit managers.

Coverage Trends in Oncology Overall, 90% of respondents said they currently covered some form of genetic testing, with approximately 40% of plans covering between 76% and 100% of the cost. Slightly more than 83% of the respondents noted that requests for genetic testing from

physicians and patients have increased over the past 5 years.

In all, 68% of respondents plan to increase coverage for genetic testing over the next 5 years compared with 5% who want to decrease coverage, approximately 17% who want to main­ tain the same coverage, and 10% who are unsure.

The majority (98.3%) of respondents identified cancer as the disease state in which genetic testing was likely to have the most significant impact on patient outcomes.

When asked which available bio­ markers were currently covered by plans, the 2 most frequently covered were HER2 for breast cancer (95% of plans) and KRAS mutation testing for metastatic colorectal cancer (91.7%).

Respondents said that literature was scarce about the cost-effective­ ness of genetic testing and personal­ ized medicine; 45.7% of respondents believed that personalized medicine would increase the cost of care for their plans.

A large majority (83.4%) of plans believed that genetic testing would dictate decisions about treatment se­ lection. When asked what factors were clinically important for personalized medicine, the 3 most frequently named factors were: • Predicting response to an agent • Getting the most effective therapy the first time • More efficient management of cost. n

Dabrafenib-Trametinib Combination Projected to Improve Survival at Increased Cost versus Other First-Line Therapies in Metastatic Melanoma Tampa, FL—Combining dabrafenib (Tafinlar) with trametinib (Mekinist) as upfront treatment for patients diag­ nosed with BRAF V600 mutation–pos­ itive metastatic melanoma should lead to improved survival, but it increases the direct costs of treatment compared with other first-line therapies. Dabraf­ enib plus trametinib may be a costeffective option from a payer perspec­ tive, depending on the threshold value

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used to determine cost-effectiveness.

These were the findings of a study presented at the 2014 Academy of Managed Care Pharmacy meeting.

The study assessed the cost-effec­ tiveness of the combination of dabraf­ enib plus trametinib compared with other common therapies (dabrafenib, trametinib, vemurafenib [Zelboraf], dacarbazine [DTIC], but not ipilimu­ mab [Yervoy] or interleukin-2) for the

first-line treatment of BRAF V600/E/K mutation–positive unresectable or metastatic melanoma.

The direct medical costs associated with the treatment of metastatic mela­ noma over a 30-year period were con­ sidered from treatment initiation to approximate a lifetime projection. The future costs, life-years, and quality-ad­ justed life-years (QALYs) were dis­ counted at 3% annually.

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Economics of Cancer Care

Intravenous Cancer Treatments Pricier in Hospital than in Community Office Setting

By Kate O’Rourke

Tampa, FL—Intravenous (IV) cancer therapies are more costly, by approxi­ mately 10%, when patients receive them in a hospital outpatient setting rather than in a community-based physician office, according to a study presented at the 2014 Academy of Managed Care Pharmacy meeting.

Barbara L. McAneny, MD, Chief Executive Officer and Managing Part­ ner, New Mexico Cancer Center, Albu­ querque, and one of the study investi­ gators, said that the research adds to the growing evidence that care is more costly in the hospital setting. “As we switch to more high-deductible health plans, out-of-pocket costs per patient go up considerably, which makes can­ cer care increasingly difficult for pa­ tients to afford,” Dr McAneny told Value-Based Cancer Care. “The current trend of acquisition of practices by hospitals is exactly the wrong direc­ tion for the country to be going in at a time when healthcare costs are spiral­ ing out of control.”

This retrospective analysis was based on pharmacy and medical claims from a database with approxi­ mately 32 million covered members in the United States. Adult patients were included if they received IV cancer treatment with a chemotherapy or a biologic agent between 2006 and Au­ gust 31, 2012, and had ≥2 medical claims, at least 30 days apart for a can­ cer, no secondary cancer, and at least 6 months of preindex and postindex

kemia (11.9%), metastatic lung cancer (10.1%), and colorectal cancer (8.4%).

During a 12-month period, the mean total healthcare costs were significant­ ly higher for patients who received treatment in the outpatient setting than in the community setting— $122,473 versus $82,773.

Patients seen in the outpatient set­ ting also had 415 days treatment dura­ tion versus 300 days in the office setting, higher 6-month treatment costs—$103,460 versus $68,792, re­

whelming evidence that cancer care costs taxpayers and patients more in hospital outpatient departments.

“This is disconcerting, because hospi­ tals are rapidly acquiring community cancer clinics. This flies in the face of healthcare reform designed to lower costs. If the consolidation of cancer care into hospitals continues, we will drive cancer care costs to unsustain­ able levels,” Mr Okon told Value-Based Cancer Care. “It took close to 50 years to evolve the world’s best cancer care

The estimates of projected median progression-free survival were ap­ proximately twice as long for the da­ brafenib-trametinib combination com­ pared with the comparators: 10.36 months for dabrafenib-trametinib ver­ sus 5.98 months, 5.52 months, 5.98 months, and 3.91 months for dabraf­ enib, trametinib, vemurafenib, and DTIC, respectively.

The overall survival was projected to be from 7 months to approximately 15 months longer with the combina­ tion—25.55 months for dabrafenib plus trametinib versus 15.19 months, 18.18 months, 15.19 months, and 9.67 months for dabrafenib, trametinib, vem­urafenib, and DTIC, respectively.

The threshold value for cost-effec­

tiveness may be as high as $200,000 per QALY, according to a 2003 study

by Ubel and colleagues; this estimate was based on a review of several fre­ quently used clinical examples with cost-effectiveness ratios that exceeded conventional limits.

The expected costs were higher for the combination of dabrafenib plus trametinib than for comparators in more than 99% of simulations. QALYs are higher for dabrafenib plus trame­ tinib in 75.9% of the simulations ver­ sus trametinib and in 97.1% of the simulations versus DTIC. The combi­ nation of dabrafenib plus trametinib is projected to have higher costs and lower QALYs in 2.9% of the simula­ tions versus DTIC to 22.9% of the

simulations versus trametinib.

Using a threshold for cost-effective­

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health plan eligibility.

A total of 18,740 patients were as­ signed to a community physician of­ fice cohort or to a hospital outpatient cohort, depending on where they re­ ceived at least 95% of their IV treat­ ment. The 5 cancer types included early breast cancer (47.5%), metastatic breast cancer (22.1%), non-Hodgkin lymphoma/chronic lymphocytic leu­

spectively, and higher 12-month treat­ ment costs of $143,206 versus $98,071 (all P <.001). After adjusting for base­ line characteristics, the average annual costs for patients seen in community offices were 8% lower than for patients seen in a hospital outpatient setting.

According to Ted Okon, Executive Director, Community Oncology Alli­ ance, Washington, DC, there is over­

“The current trend of acquisition of practices by hospitals is exactly the wrong direction for the country to be going in at a time when healthcare costs are spiraling out of control.”

—Barbara L. McAneny, MD

The dabrafenib-trametinib combination is more likely to be the preferred therapy if the threshold value for cost-effectiveness is approximately $180,000 per QALY or greater.

ness of $200,000 per QALY gained, the probability that the combination of

JUNE 2014

I

“This is disconcerting, because hospitals are rapidly acquiring community cancer clinics. This flies in the face of healthcare reform designed to lower costs. If the consolidation of cancer care into hospitals continues, we will drive cancer care costs to unsustainable levels.”

—Ted Okon

delivery system to provide quality, affordable, accessible cancer care in communities across the country. In close to 5 years, we are dismantling that system. Every American should be alarmed at this.” n

dabrafenib plus trametinib and its com­ parators are cost-effective is 41% for dabrafenib plus trametinib, 20.6% for dabrafenib, 36.1% for trametinib, 0% for vemurafenib, and 2.3% for DTIC. The dabrafenib-trametinib combi­ nation is more likely to be preferred compared with the other therapies if the threshold value for cost-effective­ ness is approximately $180,000 per QALY or greater, according to the researchers.

The investigators stated that the cost-effectiveness of the dabraf­enibtrametinib combination should con­ tinue to be evaluated as survival data continue to mature and as data from large phase 3 studies become available.—AG n

www.ValueBasedCancerCare.com

35

Prostate Cancer

Enzalutamide Improves Survival After ADT... delayed the time to initiation of cyto­ toxic chemotherapy,” said Dr Evans.

“Consistent benefits also were seen in the visceral-disease group.”

“Enzalutamide added to andro­ gen-deprivation therapy at progres­ sion provides meaningful clinical benefit to men with metastatic castra­ tion-resistant prostate cancer,” he added.

Enzalutamide disrupts androgen signaling by affecting 3 activities in­ volving the androgen receptor: the drug inhibits binding of androgens to the androgen receptor, inhibits andro­ gen receptor nuclear translocation, and inhibits androgen receptor–medi­ ated DNA binding. In the post­ docetaxel setting, enzalutamide treat­ ment resulted in improved survival and radiographic PFS (Scher HI, et al.

N Engl J Med. 2012;367:1187-1197).

Phase 3 Clinical Trial: PREVAIL The data came from the multicenter international phase 3 clinical trial PREVAIL involving 1717 patients with mCRPC who had progressed with ADT but who had not yet received chemotherapy. The inclusion criteria limited enrollment to patients who were asymptomatic or who had only mild symptoms. Patients continued ADT and were randomized to enzalut­

“Treatment with enzalutamide significantly delayed the progression of metastatic disease, reduced the risk of death, and delayed the time to initiation of cytotoxic chemotherapy.

Enzalutamide added to androgen-deprivation therapy at progression provides meaningful clinical benefit.”

—Christopher P. Evans, MD

amide 160 mg daily or to placebo. The coprimary end points were radio­ graphic PFS and overall survival (OS).

A final OS analysis was planned to take place after 765 events had oc­ curred, but the trial ended premature­ ly after a planned interim analysis demonstrated significant advantages in the coprimary end points in favor of enzalutamide.

The total patient population includ­ ed 204 patients with visceral involve­ ment. The median age was approxi­ mately 71 years, and approximately 50% of patients had a Gleason score of ≥8 at diagnosis; almost 90% had previ­ ous antiandrogen exposures, and ap­ proximately 25% had undergone radi­ cal prostatectomy.

Overall, approximately 80% of the patients had bone metastases, and more than 50% had soft-tissue disease.

The median treatment duration was almost 17 months in the enzalut­ amide arm versus 4.7 months in the placebo group (P = .001), and the magnitude of benefit was similar in patients with and without visceral involvement. Treatment duration in the subgroup with visceral disease was 14 months with enzalutamide and 3.7 months with placebo. Almost 70% of patients in the enzalutamide arm completed at least 12 months of

Continued from the cover

treatment, said Dr Evans.

At the interim analysis, the median OS was 32.4 months (upper confi­ dence interval not yet reached) with enzalutamide and 30.2 months with placebo, representing a 30% reduc­ tion in the hazard ratio (HR; P <.001).

Patients without visceral disease also had significant improvement in OS (not yet reached vs 30.2 months with placebo; HR, 0.692; P = .001). In the patients with visceral involvement, OS at the interim analysis favored enzalutamide (27.8 vs 22.8 months), but the upper limit of the confidence intervals had yet to be reached in either treatment arm.

Enzalutamide more than doubled the time to chemotherapy versus pla­ cebo (28 vs 10.8 months, respectively; HR, 0.349; P <.001), although that anal­ ysis is ongoing.

Enzalutamide was associated with slightly more adverse events (AEs), including serious events (31.6% vs 26.2%, respectively) and grade ≥3 (42.3% vs 37.3%, respectively). The time to a first grade ≥3 AE was prolonged in the enzalutamide arm versus placebo (22.7 vs 13.7 months, respectively), and discontinuation related to AEs and fatal AEs occurred in a similar proportion of patients in each group. n

PSA Trend Analysis May Help Avoid Unnecessary Biopsies

By Robert Osborne

Orlando, FL—Delaying a prostate-spe­ cific antigen (PSA)-triggered prostate biopsy to allow for additional PSA as­ sessments might have avoided more than 70% of subsequent biopsies, ac­ cording to a study of negative biopsies for >28,000 men reported at the 2014 American Urological Association an­ nual meeting.

This analysis based on the deceler­ ation of PSA growth rate suggested that 80% of negative biopsies might have been avoided. A decline to a level below the prebiopsy PSA growth rate might have eliminated 72% of the biopsies. “This analysis of the diverse Veterans Affairs population suggests that a delay in a biopsy to allow for additional PSA testing may help avoid the biopsy,” Thomas E. Neville, PhD, Founder and Chief Executive Officer, Soar BioDynamics, Incline Village, NV, and colleagues noted in a

36

poster presentation.

“In many cases, subsequent PSA trends showed a decrease that could have reduced unnecessary biopsies by 72%. The fastest growth in PSA per year was also the most likely to de­ crease, with a 93% potential reduction in biopsies.”

Aggressive, potentially lethal pros­ tate cancers exhibit a faster PSA growth rate compared with low-risk, indolent cancers. Most lethal prostate cancers produce smooth exponential growth in PSA above a no-cancer base­ line, according to Dr Neville. As the PSA growth rate increases, so does the lethal status of the prostate cancer.

Benign conditions can also spark an increase in PSA growth rate, but unlike aggressive cancers, the increase is often followed by a decline, which provides strong justification to delay a biopsy, Dr Neville noted.

Value-Based Cancer Care

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JUNE 2014

The data came from the Veterans Affairs Health System database, which

“A delay in a biopsy to allow for additional PSA testing may help avoid the biopsy.

In many cases, subsequent PSA trends showed a decrease that could have reduced unnecessary biopsies by 72%.”

—Thomas E. Neville, PhD, and colleagues

comprises 33 million PSA test results for 14 million men. A total of 28,314 men (aged 50-75 years) who had nega­

tive prostate biopsies from 2001 to 2012 and at least 3 PSA measurements in the 2 years before biopsy plus at least 1 PSA measurement after the bi­ opsy were included in the study.

The investigators calculated esti­ mates for 4 PSA-based parameters: the baseline cutoff value associated with no cancer, the PSA values associated with cancer, trends in cancer-associated PSA values over time, and the annual can­ cer-associated PSA growth rate.

Dr Neville and colleagues identified men who had decreases in PSA after a prostate biopsy that had been associat­ ed with an increasing PSA trend. The men were grouped according to PSA growth rate and calculated the propor­ tion of men who had postbiopsy de­ clines in PSA for each PSA growth rate category.

The results suggested that the pro­ portion of biopsies that could have Continued on page 38

Vol. 5

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No. 5

5

FIFTH ANNUAL

Y E AR A N N I V E R S A RY

Navigation and 5 Survivorship Conference YEAR

A N N I V E R S A RY

September 18-21, 2014 Walt Disney World Dolphin Hotel • Orlando, Florida

TO DATE, THE CONFERENCE HAS HAD MORE THAN:

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Abstracts

Thank you again for a wonderful conference on the conference to my administration each year to help me get funding for the following year and so far...so good. I attend various national conferences throughout the year and stand amazed at your ability to continue

Expert Speakers

55

60 Abstracts Submitted

(only missed your first year). I submit a report

to provide new and motivating presentations.

– 2013 Conference Attendee

93%

108

93% of 2013 conference attendees said they intended to change their practice as a result of participating in the AONN+ Conference

50 40 30 20

20 10 0

23

9 2010

2011

2012

2013

Year of Submission

“WOW! I am so impressed with the growth of AONN. Lillie, Sharon, and their team are awesome. The speakers were knowledgeable about their subject matter and all the presentations were relevant to my practice. I will use the pearls of wisdom shared by the speakers to my team at

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97% of 2013 conference attendees rated the AONN+ Conference as Above Average or Excellent when compared with other continuing education activities

home. I arrived feeling we have a pretty good program and I am leaving with ideas to share to make it even better!”

– Donna Moore Wilson, BSN, RN, CBCN Oncology Nurse Navigator Bon Secours Cancer Institute Richmond, Virginia

AONN+ K-SIZE_22414

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Breast Cancer

ASCO Guidelines Target Advanced HER2-Positive Breast Cancer

By Eileen Koutnik-Fotopoulos

A

pproximately 15% to 20% of patients with breast cancer have HER2-positive disease.

The American Society of Clinical On­ cology (ASCO) released new clinical practice guidelines for the treatment of women with advanced HER2-positive breast cancer, focusing on systemic therapies (Giordano SH, et al. J Clin Oncol. 2014 May 5. Epub ahead of print). The guideline recommendations are summarized in the Table.

The treatment of HER2-positive breast cancer has evolved, with HER2-targeted therapies demonstrat­ ing improved survival for patients with early-stage or metastatic disease.

“The rationale for this guideline is that

several new agents have been ap­ proved by the US Food and Drug Ad­ ministration [FDA] for the treatment of metastatic HER2-positive breast cancer since the approval of trastuzumab,” noted Sharon H. Giordano, MD, M.D. Anderson Cancer Center, Houston, and colleagues.

Since the approval of trastuzumab in 1998, lapatinib (Tykerb), pertuzumab (Perjeta), and ado-trastuzumab emtan­ sine (T-DM1; Kadcyla) have also re­ ceived FDA approval.

ASCO convened a panel of experts to conduct a systematic literature review from 2009 to 2012 that addressed overall survival (OS), progression-free survival (PFS), and adverse events. A total of 16

“The rationale for this guideline is that several new agents have been approved by the US Food and Drug Administration for the treatment of metastatic HER2-positive breast cancer since the approval of trastuzumab.”

—Sharon H. Giordano, MD, and colleagues

trials met the inclusion criteria. Among the studies considered were the CLEO­ PATRA trial, an international, multi­ center, randomized, double-blind, pla­

Table Targeted Therapy for Patients with Advanced HER2-Positive Breast Cancer • HER2-targeted therapy is recommended for most patients • Patients with congestive heart failure or compromised left-ventricular ejection fraction should be evaluated for HER2-targeted therapy on an individual basis • Recommend standard first-line therapy, or, for select patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone for patients with HER2positive and estrogen receptor (ER)-positive/progesterone receptor (PR)-positive breast cancer • A combination of trastuzumab, pertuzumab, and a taxane is recommended for first-line treatment for those who can take taxanes • Patients who have progressed during or after first-line HER2-targeted therapy should receive second-line HER2-targeted therapy • Patients who have progressed during or after second-line or greater HER2-targeted therapy should receive thirdline or greater HER2-targeted therapy • Patients who have progressed during or after first-line or greater HER2-targeted therapy should receive second-line HER2-targeted therapy with T-DM1

• Patients who have progressed during or after second-line or greater HER2-targeted therapy and have not taken T-DM1 or pertuzumab should be offered 1 of these treatments • Patients who have progressed during or after second-line or greater HER2-targeted therapy, and already received pertuzumab and T-DM1, should be offered third-line or greater HER2-targeted therapy (eg, lapatinib plus capecitabine), as well as other combinations of chemotherapy and trastuzumab; lapatinib and trastuzumab; or hormonal therapy (in patients with ER-positive and/or PR-positive disease) • The optimal duration of chemotherapy is 4 to 6 months or until maximum response, depending on toxicity and the absence of progression; when chemotherapy is stopped, targeted therapy can continue until disease progression or unacceptable toxicity • Use first-line HER2-targeted therapy in patients who have completed trastuz­umab-based adjuvant treatment for >12 months before recurrence • Use second-line HER2-targeted therapy in patients who have completed tras­tuzumab-based adjuvant treatment for ≤12 months before recurrence

T-DM1 indicates ado-trastuzumab emtansine.

PSA Trend Analysis May Help Avoid... been avoided increased with the base­ line PSA growth rate. For example, 52% of biopsies could have been avoided for men with the slowest PSA growth rates of 0% to 5%. The estimat­ ed biopsy avoidance rate reached 93% for men whose PSA growth rates ex­ ceeded 100%.

The investigators then calculated the PSA levels associated with an 80% probability of finding cancer on biopsy across the categories of PSA growth

38

rate. The calculations suggested that a PSA level of 5.2 ng/dL would be the 80% threshold value for men who had PSA growth rates of 15% to 30%. By contrast, a PSA level of 2.5 ng/dL would be the threshold for 80% cancer probability among men with PSA growth rates of >100%.

Long-term PSA monitoring can help distinguish the nature of a PSA eleva­ tion, such as an initial increase fol­ lowed by a decrease, frequently ob­

Value-Based Cancer Care

I

june 2014

cebo-controlled, phase 3 trial comparing the combination of pertuzumab, trastu­ zumab, and docetaxel with the combi­ nation of trastuzumab and docetaxel as first-line treatment for patients with previously untreated HER2-positive metastatic breast cancer. They also as­ sessed the phase 3 EMILIA trial, an open-label study comparing T-DM1 versus capecitabine plus lapatinib in patients with HER2-positive locally ad­ vanced or metastatic breast cancer.

The CLEOPATRA trial found OS and PFS benefits with docetaxel, tras­ tuzumab, and pertuzumab in first-line treatment. The EMILIA trial found sur­ vival and PFS benefits for T-DM1 in second-line treatment and PFS benefits in third-line treatment.

Three trials also evaluated endocrine therapy for patients with HER2-posi­ tive advanced breast cancer. “Approxi­ mately half of all HER2-positive breast cancers are also hormone receptor pos­ itive,” noted the researchers. “The de­ pendency of HER2-positive, hormone receptor–positive tumors on estrogen signaling is only partially understood.”

The guideline therefore addressed the use of endocrine therapy in this subset of patients. n

Continued from page 36

served in association with benign prostate conditions, Dr Neville and colleagues noted in their presentation.

The results suggest several screen­ ing strategies to take advantage of the information provided by PSA trend analysis. PSA testing, beginning when men are in their 40s, could be used to establish a baseline for long-term trend analysis.

Dynamic trend analysis could help inform PSA testing intervals and could

lead to earlier identification of lethal prostate cancers. Multivariable algo­ rithms could be developed to individ­ ualize decision-making regarding prostate biopsies.

“These new screening methods have the potential to identify early the men at greatest risk of life-threatening dis­ ease, while reducing unnecessary bi­ opsies and overdiagnosis, treatment, and side effects,” the investigators concluded.—RO n

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A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to discuss the most recent available data concerning improvements in cost of care, safety profiles, and patient preferences as they pertain to the use of emerging agents used in the treatment of patients with MM. IN MULTIPLE MYELOMA

Value-BasedCare

™

November 2013 u 8th IN A SERIES

Cost-Effective Use of Imaging Modalities for Diagnosis and Monitoring in Multiple Myeloma

Topics include: • Effective Treatment of Newly

Diagnosed and Relapsed/ Refractory Patients with MM: Utilizing Optimal Dosing Regimens • Appropriate Duration of Therapy

for MM in a Value-Based Care Plan • Improving the Standard of Care

in MM: Interpreting Overall Survival Data and Assessing the Cost of a Complete Response • Establishing a Value-Based

Paradigm for the Management of Patients with MM: A Pharmacoeconomic Analysis of Treatment Options

Introduction Identification, characterization, and management of osteolytic bone lesions are key aspects of care in multiple myeloma (MM).1 A comprehensive, chart-based study from the Mayo Clinic, published in 2003, revealed that 84% of patients with myeloma developed skeletal lesions at some time during the course of their disease.2 Based on conventional radiography at the time of diagnosis, 79% of patients presented with at least one type of skeletal abnormality (Figure 1).2 In the decade since the publication of this influential study, these high estimates of skeletal-related events have held constant.1 What has changed, however, are the options available to clinicians for imaging the skeleton. Although radiographic skeletal survey remains the fundamental imaging study at both the initial workup and follow-up of the patient with MM, additional newer technologies can be utilized. These include magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET) scan, which may be combined with CT scan (PET-CT). Bone densitometry is another imaging technology with application in the disease.3 These technologies may provide helpful diagnostic and follow-up information on the patient, but despite evidence-based guidelines on imaging in MM, there is currently no standard for their appropriate clinical use.3-7 Individual providers, institutions, and payers are tasked with the decision to deploy or to forego MRI, CT, and PET on a case-by-case basis. The choice to utilize these sophisticated imaging methods ultimately affects the value of myeloma care: overuse or inappropriate use of such technologies results in unnecessary utilization costs; failure to use the technologies when prudent may result in a lower quality of care.

This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients.

These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

The most recent of the guidelines, from the National Comprehensive Cancer Network (NCCN), recommends radiographic skeletal survey for all patients at initial workup and for the follow-up of every patient annually or when symptoms are present.3 The NCCN makes provisional recommendations for MRI, CT, and PET scans, which are described as “useful under some circumstances” in initial workup and may be used “as clinically indicated” for follow-up surveillance.3 When is additional testing “useful” and “indicated”? Different organizations and experts have given various answers to this question. According to the NCCN, PET-CT scanning and MRI scans provide greater sensitivity than did conventional radiography.3 Therefore, during an initial workup in a patient who presents with bone pain, weakness, or other symptoms in

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care.

Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

STAKEHOLDER’S PERSPECTIVE Assessing the Optimal Use of Imaging Modalities in Patients with Myeloma ...........................5

Imaging Options in MM: Evidence-Based Guidelines and Expert Consensus Since 2007, 5 different sets of clinical practice guidelines have been issued on the use of imaging technologies in MM (Table).3-7 These guidelines provide a good starting point for individual providers, institutions, and payers seeking to evaluate these modalities.

This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

James R. Berenson, MD Institute for Myeloma & Bone Cancer Research West Hollywood, CA

An official publication of

11/15/13 9:58 AM

VIEW THE SERIES ONLINE AT:

www.ValueBasedCancer.com/myeloma VBCMM_AVBCC127_Ksize13114

Drug Update

Tafinlar (Dabrafenib)/Mekinist (Trametinib) Combination Therapy Received Accelerated FDA Approval for the Treatment of Patients with Metastatic Melanoma

By Loretta Fala, Medical Writer

C

utaneous melanoma, an aggres­ sive form of skin cancer that develops in the melanocytes of the skin, is becoming increasingly prevalent in the United States.1 Ac­ cording to the American Cancer Soci­ ety, an estimated 76,100 new cases of melanoma will be diagnosed in 2014, and approximately 9710 patients are expected to die from this cancer.2 In fact, melanoma causes more deaths than any other skin disease.3 As of 2011, there were an estimated 960,231 patients living with melanoma of the skin in the United States.4 How­ ever, the actual prevalence of melano­ ma may be underestimated because of underreporting of superficial and in situ melanomas treated in the outpa­ tient setting.5 The risk factors for melanoma in­ clude family history of the disease; history of melanoma; more than 1 clini­ cally atypical mole or dysplastic nevus; and, in rare cases, genetic mutations.6 In addition, exposure to ultraviolet radia­ tion from the sun or from tanning beds and lamps is a major risk factor for most melanomas and having fair skin that burns easily also increases the risk for developing melanoma.6 However, melanoma can develop in individuals of any ethnic background and can occur anywhere on the body, including areas of the body not exposed to sun or ultra­ violet light.1 Data from the Surveillance, Epide­ miology, and End Results Program indicated that between 2004 and 2010, approximately 91.3% of patients with melanoma survived 5 years or more.4 Melanoma outcomes are linked direct­ ly to the stage at presentation.7 An es­ timated 82% to 85% of patients present with localized disease, 10% to 13% present with regional disease, and 2% to 5% present with distant metastases.7 The 5-year survival rates for stage III disease range from 20% to 70%, de­ pending on the nodal tumor burden.

In patients with distant metastases, long-term survival is <10%.7 Melanoma—metastatic disease in particular—is associated with substan­ tial healthcare costs.8,9 The estimated annual cost of melanoma in 1991-1996

was $249 million; this figure increased to $390 million in the population aged ≥65 years.8 According to a Medicare claims data analysis (1991-2005), pa­ tients with metastatic melanoma had a monthly average of more than $11,000 in total healthcare costs; the majority of these costs were related to inpatient hospital costs.9 In addition, productiv­ ity from melanoma mortalities ac­ counted for $3.5 billion per year in 2000-2006 in the United States.10 Prevention and early detection of melanoma may improve outcomes and reduce the economic burden.10 Treatment for early-stage disease in­ cludes surgery to remove the melano­ ma.11 Therapeutic options for meta­ static melanoma include surgery to remove the affected lymph nodes, chemotherapy, radiation therapy, im­ munotherapy (ie, interleukin-2, ipilim­ umab), and signal transduction inhib­ itors (BRAF inhibitors, MEK inhibitors, multikinase inhibitors, and KIT inhib­ itors).11-13 The recent development of agents that inhibit the mitogen-activated pro­ tein (MAP) kinase pathway represents an important advance in treating met­ astatic melanoma.14 These include da­ brafenib (Tafinlar) and vemurafenib (Zelboraf), which block MAP kinase signaling in patients with melanoma and with the BRAF V600E mutation; as well as trametinib (Mekinist), which inhibits MAP kinase (that is down­ stream of BRAF in the MAP kinase pathway) in patients with melanoma with BRAF V600E or BRAF V600K mutation.14 The First Combination Treatment Option for Metastatic Melanoma On January 10, 2014, the combina­ tion of dabrafenib plus trametinib (both manufactured by GlaxoSmith­ Kline) was granted accelerated US Food and Drug Administration (FDA) approval for the treatment of patients with unresectable melanoma or meta­ static melanoma with BRAF V600E or BRAF V600K mutation as detected by an FDA-approved test.15 Dabrafenib and trametinib were pre­ viously approved by the FDA inde­

Copyright © 2014 American Health & Drug Benefits. All rights reserved.

40

Value-Based Cancer Care

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june 2014

pendently as single agents in May 2013 for the treatment of patients with met­ astatic or unresectable melanoma.16 Discussing the recent approval of the new combination, Richard Pazdur, MD, Director of the Office of Hematol­ ogy and Oncology Products at the FDA’s Center for Drug Evaluation and Research, said, “Mekinist and Tafinlar are the first drugs approved for combi­ nation treatment of melanoma. Their development for combination use is based on the strong understanding of the biological pathways of the disease.

This approval illustrates the value of continuing to study drugs in combina­ tion for clinical development.”15

ERK pathway. This overactive BRAF signaling stimulates proliferation of malignant melanoma cells and results in resistance to cell apoptosis.19,20 Dabrafenib and trametinib target 2 different tyrosine kinases in the RAS/ RAF/MEK/ERK pathway.17,18 Da­ brafenib inhibits some mutations of BRAF kinases.17 Trametinib reversibly inhibits MEK1 and MEK2 activation as well as MEK1 and MEK2 kinase activ­ ity.18 The combination of dabrafenib and trametinib resulted in greater growth inhibition of BRAF V600 muta­ tion–positive melanoma cell lines in vitro and prolonged the inhibition of tumor growth in BRAF V600 muta­ tion–positive melanoma xenografts compared with either drug alone.17,18

“Mekinist and Tafinlar are the first drugs approved for combination treatment of melanoma.

Their development for combination use is based on the strong understanding of the biological pathways of the disease.”

Dosing and Administration Before initiating treatment with the dabrafenib/trametinib combination, the presence of BRAF V600E or BRAF V600K mutation in tumor specimens must be confirmed. The FDA-ap­ proved THxID BRAF companion diag­ nostic assay (bioMérieux, Inc) is used to detect these mutations, and should be administered before the use of the combination therapy.17,18 The recommended dose of the com­ bination therapy is dabrafenib 150 mg orally twice daily plus trametinib 2 mg orally once daily.17,18 Dabrafenib/tra­ metinib is administered at least 1 hour before or at least 2 hours after a meal.17,18 Dabrafenib is available as a 50-mg or a 75-mg capsule.17 Trame­ tinib is available in 3 tablet strengths: 0.5 mg, 1 mg, and 2 mg.18

—Richard Pazdur, MD

Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma.17 Trametinib (as a single agent) is not indicated for the treatment of patients who have received previous BRAF inhibitor therapy.18 After its FDA approval, the combi­ nation of dabrafenib and trametinib was added to the list of preferred sys­ temic therapy options for metastatic melanoma by the National Compre­ hensive Cancer Network.7 Mechanism of Action The RAS/RAF/MEK/ERK and PI3K/PTEN/AKT signaling has an im­ portant role in transmitting signals that regulate gene expression and prevent programmed cell death.19 BRAF muta­ tions, which are frequently present in various cancers, lead to overexpressed BRAF signaling and deregulated downstream signaling via the MEK/

Efficacy: Phase 1/2 Clinical Trial The FDA approval of dabrafenib/ trametinib combination therapy was based on demonstration of its durable objective responses in a multicenter, open-label, randomized, dose-ranging phase 1/2 clinical trial that also com­ pared dabrafenib/tremetinib with dabrafenib as a single agent in select patients.14,17 In this trial, patients were random­ ized (1:1:1 ratio) to trametinib (at 2 different doses) in combination with dabrafenib compared with dabrafenib as a single agent, in 162 patients with BRAF V600E or BRAF V600K muta­ Continued on page 41

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Drug Update

Tafinlar (Dabrafenib)/Mekinist (Trametinib)... tion–positive, unresectable or meta­ static melanoma. Eligible patients were permitted to have had 1 previous chemotherapy regimen and previous aldesleukin; patients with previous exposure to BRAF or MEK inhibitors were not eligible for the study.14,17,18 Patients randomized to receive da­ brafenib as a single agent were offered trametinib 2 mg orally once daily with dabrafenib 150 mg orally twice daily at the time of investigator-assessed dis­ ease progression.14,17,18 The primary ef­ ficacy outcome measure was investi­ gator-assessed overall response rate (ORR). Additional efficacy outcome measures were investigator-assessed duration response, independent ra­ diology review committee (IRRC)-as­ sessed ORR, and IRRC-assessed dura­ tion of response.14,17,18 The majority of patients had not re­ ceived previous anticancer therapy for unresectable or metastatic disease.14,17,18 All patients had tumor-containing BRAF V600E or BRAF V600K mutation as determined by local laboratory or centralized testing; 85% had the BRAF V600E mutation, and 15% had the BRAF V600K mutation.14,17,18 The medi­ an follow-up duration was 14 months.

Efficacy outcomes for the group re­ ceiving dabrafenib in combination with trametinib 2 mg daily and the group receiving dabrafenib as a single agent are shown in Table 1.14,17,18 Similar ORR results were achieved in subgroups defined by the BRAF mutation subtype. The ORR results were also similar to the intent-to-treat analysis, based on exploratory sub­ group analyses of patients with retro­ spectively confirmed BRAF V600E or BRAF V600K mutation–positive mela­ noma using the THxID BRAF compan­ ion diagnostic assay.14,17,18 Safety The most common adverse reac­ tions (≥20%) associated with da­ brafenib/trametinib combination ther­ apy are pyrexia, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, head­ ache, arthralgia, night sweats, de­ creased appetite, constipation, and myalgia.17,18 The distribution of these adverse events by grade is listed in Table 2.

Warnings and Precautions There are no contraindications for the use of dabrafenib/trametinib com­ bination therapy.

Drug interactions. Coadministra­ tion of trametinib 2 mg once daily and dabrafenib 150 mg twice daily is not

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associated with clinically relevant drug interactions. Concurrent admin­ istration of strong inhibitors or strong inducers of cytochrome (CY) P3A4 or CYP2C8 with dabrafenib should be avoided. Concomitant use of da­ brafenib with sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in the loss of efficacy of these agents.17,18 A complete list of the warnings and precautions for dabrafenib and trame­ tinib, alone and in combination, is outlined in Table 3.17,18 Use in Specific Populations Pregnancy. Dabrafenib and trame­ tinib can cause fetal harm when ad­ ministered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be counseled about the potential hazard to the fetus.17,18 Nursing mothers. Because of the potential for serious adverse reactions from dabrafenib and trametinib in nursing infants, 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.17,18 Females and males of reproductive potential. Female patients of repro­ ductive potential should be advised to use highly effective contraception during treatment with dabrafenib/tra­ metinib combination therapy. When the combination therapy is used, pa­ tients should be advised to use a non­ hormonal method of contraception because dabrafenib can render hor­ monal contraceptives ineffective. Pa­ tients should be advised to contact their healthcare provider if they be­ come pregnant, or if pregnancy is sus­ pected, while taking the dabrafenib/ trametinib combination therapy.17,18 Pediatric use. The safety and effec­ tiveness of dabrafenib and trametinib as single agents or in combination have not been established in pediatric patients.17,18 Geriatric use. Across all clinical tri­ als of dabrafenib/trametinib combina­ tion therapy, there was an insufficient number of patients aged ≥65 years to determine whether they respond dif­ ferently from younger patients.17,18 Hepatic impairment. Dose adjust­ ments for dabrafenib and trametinib are not recommended for patients with mild hepatic impairment. The appropriate doses of dabrafenib and trametinib have not been established in patients with moderate or severe hepatic impairment.17,18

Renal impairment. Dose adjust­ ments for dabrafenib and trametinib are not recommended for patients with mild or moderate renal impair­ ment. The appropriate doses of da­ brafenib and trametinib have not been

Continued from page 40 established in patients with severe renal impairment.17,18 Conclusion A new treatment option became available for patients with advanced

Table 1 Phase 2 Clinical Trial: Dabrafenib/Trametinib Combination versus

Dabrafenib Alone Dabrafenib + trametinib Dabrafenib End points (N = 54) (N = 54) Investigator assessment Overall response rate, N (%) Complete response, % Partial response, %

41 (76) (95% CI, 62%-87%)

29 (54) (95% CI, 40%-67%)

9

4

67

50

10.5

5.6

(95% CI, 7-15)

(95% CI, 5-7)

Duration of response Median, mo

Independent radiology review committee assessment Overall response rate, N (%) Complete response, % Partial response, %

31 (57)

25 (46)

(95% CI, 43%-71%)

(95% CI, 33%-60%)

9

7

48

39

7.6 (95% CI, 7-not reported)

7.6 (95% CI, 6-not reported)

Duration of response Median, mo

CI indicates confidence interval.

Sources: Tafinlar (dabrafenib) capsules prescribing information; January 2014; and Mekinist (trametinib) tablets prescribing information; January 2014.

Table 2 Most Common Adverse Reactions Associated with Dabrafenib/Trametinib

Combination Therapy Dabrafenib plus Dabrafenib plus trametinib 2 mg trametinib 1 mg (N = 55) (N = 54) All grades, Grades 3 All grades, Grades 3 Adverse reactions % and 4, % % and 4, % Pyrexia

71

5

69

9

Chills

58

2

50

2

Fatigue

53

4

57

2

Rash

45

0

43

2

Nausea

44

2

46

6

Vomiting

40

2

43

4

Diarrhea

36

2

26

0

Abdominal pain

33

2

24

2

Peripheral edema

31

0

28

0

Cough

29

0

11

0

Headache

29

0

37

2

Arthralgia

27

0

44

0

Night sweats

24

0

15

0

Decreased appetite

22

0

30

0

Constipation

22

0

17

2

Myalgia

22

2

24

0 Continued on page 42

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Drug Update

Tafinlar (Dabrafenib)/Mekinist (Trametinib)...

References

Table 3 Warnings and Precautions for Dabrafenib and Trametinib Alone and in Combination Warnings and precautions

Dabrafenib

Trametinib

Dabrafenib/trametinib combination

New primary malignancies Cutaneous/noncutaneous malignancies can occur with dabrafenib/ trametinib; monitor patients for new malignancies before, during, and after discontinuing therapy

√

√

Tumor promotion in BRAF wild-type melanoma Increased cell proliferation can occur with BRAF inhibitorsa

√

√

Hemorrhage Major hemorrhagic events can occur with dabrafenib/trametinib; monitor patients for bleeding

√

Venous thromboembolism Deep-vein thrombosis, pulmonary embolism can occur with dabrafenib/ trametinib

√

Cardiomyopathy Assess left-ventricular ejection fraction before and 1 month after treatment, then every 2-3 months thereafter Ocular toxicities Evaluate for any visual problemsb

√b

Interstitial lung disease Withhold trametinib for new or progressive unexplained pulmonary symptomsc Serious febrile reactions Can occur in patients receiving dabrafenib/trametinibd

√

√

√b

√b

√c

√c

√d

Serious skin toxicity Monitor patients for skin toxicities and for secondary infectionse,f

√d √f

√e,f

Hyperglycemia Monitor serum glucose levels in patients with preexisting diabetes or hyperglycemia

√

√

Glucose-6-phosphate dehydrogenase deficiency Closely monitor patients for hemolytic anemia

√

√

Embryofetal toxicity Can cause fetal harm; advise female patients of reproductive potential about the potential risk to the fetusg

√g

√

√

Dabrafenib is not indicated for the treatment of patients with wild-type BRAF melanoma.

Retinal pigment epithelial detachments can occur when dabrafenib is used in combination with trametinib. For retinal vein occlusion, permanently discontinue trametinib. Uveitis and iritis can occur when dabrafenib is used as a single agent or in combination with trametinib. c For treatment-related interstitial lung disease or pneumonitis, permanently discontinue trametinib. If trametinib is used in combination with dabrafenib, the dose of dabrafenib should not be modified. d The incidence and severity of pyrexia are increased when dabrafenib is combined with trametinib. e For intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of dabrafenib, treatment with dabrafenib should be discontinued. f For intolerable Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of trametinib, treatment with trametinib should be discontinued. g Dabrafenib may render hormonal contraceptives less effective and an alternative method of contraception should be used.

Sources: Tafinlar (dabrafenib) capsules prescribing information; January 2014; and Mekinist (trametinib) tablets prescribing information; January 2014. a

b

melanoma with BRAF V600E or BRAF V600K mutation with the recent FDA accelerated approval of dabrafenib/ trametinib combination therapy. This is the first combination therapy to re­ ceive FDA approval for use in patients with metastatic melanoma. Using

42

these 2 agents together may improve patient outcomes by providing addi­ tional benefits that are not available with a single agent.

In the clinical trial that demonstrat­ ed the safety and clinical activity of dabrafenib/trametinib combination

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Continued from page 41

therapy, significantly more patients receiving the combination therapy had a cancer shrinkage or disappearance, which lasted 10.5 months, compared with patients receiving dabrafenib alone and whose response lasted only 5.6 months. n

1. American Cancer Society. Melanoma skin can­ cers. Updated October 29, 2013. www.cancer.org/ cancer/skincancer-melanoma/detailedguide/melano ma-skin-cancer-what-is-melanoma. Accessed May 12, 2014.

2. American Cancer Society. What are the key statistics about melanoma skin cancer? Updated January 9, 2014. www.cancer.org/cancer/skincancer-melanoma/ detailedguide/melanoma-skin-cancer-key-statistics.

Accessed May 12, 2014.

3. American Cancer Society. What is melanoma skin cancer? Updated March 19, 2014. www.cancer.org/ cancer/cancercauses/sunanduvexposure/skin-cancerfacts. Accessed May 12, 2014.

4. National Cancer Institute. SEER stat fact sheets: mel­ anoma of the skin. http://seer.cancer.gov/statfacts/ html/melan.html. Accessed April 14, 2014.

5. Cockburn M, Swetter SM, Peng D, et al. Melanoma underreporting: why does it happen, how big is the problem, and how do we fix it? J Am Acad Dermatol.

2008;59:1081-1085.

6. American Cancer Society. What are the risk fac­ tors for melanoma skin cancer? Updated October 29, 2013. www.cancer.org/cancer/skincancer-melanoma/ detailedguide/melanoma-skin-cancer-risk-factors.

Accessed May 12, 2014.

7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): melanoma. Version 4.2014. April 22, 2014. www.nccn.org/professionals/physician_gls/pdf/ melanoma.pdf. Accessed May 14, 2014.

8. Seidler AM, Pennie ML, Veledar E, et al. Economic burden of melanoma in the elderly population: popula­ tion-based analysis of the Surveillance, Epidemiology, and End Results (SEER)–Medicare data. Arch Dermatol.

2010;146:249-256.

9. Davis KL, Mitra D, Kotapati S, et al. Direct economic burden of high-risk and metastatic melanoma in the elderly: evidence from the SEER-Medicare linked data­ base. Appl Health Econ Health Policy. 2009;7:31-41.

10. Ekwueme DU, Guy GP Jr, Li C, et al. The health burden and economic costs of cutaneous melanoma mortality by race/ethnicity-United States, 2000 to 2006.

J Am Acad Dermatol. 2011;65:S133-S143.

11. American Cancer Society. How is melanoma skin cancer treated? Updated October 29, 2013. www.can cer.org/cancer/skincancer-melanoma/detailedguide/ melanoma-skin-cancer-treating-general-info. Accessed May 12, 2014.

12. American Cancer Society. Immunotherapy for mel­ anoma skin cancer. Updated October 29, 2013. www. cancer.org/cancer/skincancer-melanoma/detailed­ guide/melanoma-skin-cancer-treating-immunothera py. Accessed May 12, 2014.

13. American Cancer Society. Targeted therapy for melanoma skin cancer. Updated January 1, 2014. www. cancer.org/cancer/skincancer-melanoma/detailed­ guide/melanoma-skin-cancer-treating-targeted-thera py. Accessed May 12, 2014.

14. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367:1694-1703.

15. US Food and Drug Administration. FDA approves Mekinist in combination with Tafinlar for advanced melanoma. Press release. January 10, 2014. Up­dated January 15, 2014. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ucm381159.htm.

Accessed April 8, 2014.

16. US Food and Drug Administration. FDA approves two drugs, companion diagnostic test for advanced skin cancer. Press release. May 29, 2013. Updated June 3, 2013. www.fda.gov/newsevents/newsroom/ pressannouncements/ucm354199.htm. Accessed May 13, 2014.

17. Tafinlar (dabrafenib) capsules [prescribing informa­ tion]. Research Triangle Park, NC: GlaxoSmithKline; January 2014.

18. Mekinist (trametinib) tablets [prescribing informa­ tion]. Research Triangle Park, NC: GlaxoSmithKline; January 2014.

19. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT path­ ways in malignant transformation and drug resistance.

Adv Enzyme Regul. 2006;46:249-279.

20. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway.

Recent Pat Anticancer Drug Discov. 2009;4:28-35.

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