VBCC May 2015 | Vol 6 | No 4 by Value-Based Cancer Care

MAY 2015 VOL 6 NO 4

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

AVBCC 5th Conference: Continuing Challenges for Optimizing Value in Oncology By Wayne Kuznar

Pembrolizumab Scores Big Over Ipilimumab in Advanced Melanoma

May soon be a new standard of care for this patient population By Phoebe Starr Philadelphia, PA—As new immunotherapies become available for the treatment of melanoma and other cancers, head-to-head trials of these agents shed more light on how best to use them. In the phase 3 KEYNOTE-006 trial, pem-

brolizumab (Keytruda) outperformed ipilimumab (Yervoy)—a current standard of care—as upfront treatment for patients with unresectable advanced melanoma. The data were presented at the 2015 American Association for Cancer Continued on page 8

Washington, DC—The Fifth Annual Conference of the Association for Value-Based Cancer Care (AVBCC), held May 3-6, 2015, launched 3 days of presentations by US oncology stakeholders, including physicians, pharma-

cists, nurses, payers, policymakers, and drug/diagnostics manufacturers. Co-Chairs Burt Zweigenhaft, BS, President and Chief Executive Officer of Onco360, Louisville, KY, and Gary M. Owens, MD, President of Gary Continued on page 19

NCCN 2015 UPDATES

Promising Therapies in Multiple Drug Classes Being Explored for B-Cell Lymphomas But only few patients enter clinical trials, slowing drug development By Wayne Kuznar Hollywood, FL—Targeted therapy in B-cell lymphoma is rapidly expanding beyond anti-CD20 antibodies. Some of the emerging therapies are conjugated antibodies, treatments that target signaling pathways or apoptosis, immunomodulatory drugs (IMiDs), and immune checkpoint inhibitors, said Andrew D. Zelenetz, MD,

PhD, Vice Chair, Medical Informatics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, at the 2015 National Comprehensive Cancer Network conference. The major challenge in the development of new therapeutics—both CD20- directed and non–CD20-directed—in Continued on page 14

Value of Cancer Care for Most Tumors Lower in United States than in Western Europe By Rosemary Frei, MSc

reevaluation of the value of cancer care between 1982 and 2010 in the United States versus Western Europe (Soneji S, Yang JW. Health Aff [Millwood]. 2015;34:390-397) paints an entirely different picture from a similar analysis published in 2012

(Philipson T, et Samir Soneji, al. Health Aff PhD, MA [Millwood]. 2012; 31:667-675). The earlier study found significant improvements in breast and prostate cancer survival in the United States relative to Western Europe, Continued on page 24

INSIDE VALUE PROPOSITIONS . . . . . . . . . . New genetic test for breast cancer on the horizon AACR MEETING HIGHLIGHTS . . . . . 2 immunotherapies better than 1 in advanced melanoma Pembrolizumab shows promise in lung cancer

7 8

NCCN 2015 UPDATES . . . . . . . . . . . 14 Many drugs in development for multiple myeloma Assess response to first-line TKI at 3 months in CML LUNG CANCER . . . . . . . . . . . . . . . . 17 1 in 4 patients not tested for EGFR mutations

5th CONFERENCE . . . . 19 Pathways have the potential to deliver personalized medicine ECONOMICS OF CANCER CARE . . 24 US oncologists favor establishment of NICE-like body Repeal of Medicare SGR welcomed by oncologists SURVIVORSHIP . . . . . . . . . . . . . . . . . Revised survivorship plan reduces time, resources

DRUG UPDATE . . . . . . . . . . . . . . . . 36 Akynzeo approved for CINV prevention

Introducing the first and FDA-approved treatment

patients with polycythemia vera an inadequate response to or are In a phase 3 trial of Jakafi® (ruxolitinib) vs best available therapy: 21% of patients receiving Jakafi achieved the primary composite end point of hematocrit (Hct) control and spleen volume reduction compared with <1% of patients on best available therapy at week 32 (P < 0.0001)*

Indications and Usage Jakafi is indicated for treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.

Important Safety Information Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi Severe neutropenia (ANC <0.5 X 109/L) was generally reversible by withholding Jakafi until recovery Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly

Tuberculosis (TB) infection has been reported. Observe patients taking Jakafi for signs and symptoms of active TB and manage promptly. Prior to initiating Jakafi, evaluate patients for TB risk factors and test those at higher risk for latent infection. Consult a physician with expertise in the treatment of TB before starting Jakafi in patients with evidence of active or latent TB. Continuation of Jakafi during treatment of active TB should be based on the overall risk‐benefit determination Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate Advise patients about early signs and symptoms of herpes zoster and to seek early treatment When discontinuing Jakafi, myeloproliferative neoplasm-related symptoms may return within one week. After discontinuation, some patients with myelofibrosis have experienced fever, respiratory distress, hypotension, DIC, or multi‐organ failure. If any of these occur after discontinuation or while tapering Jakafi, evaluate and treat any intercurrent

only for

who have had intolerant of hydroxyurea

Visit www.jakafi.com/HCP illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi without consulting their physician. When discontinuing or interrupting Jakafi for reasons other than thrombocytopenia or neutropenia, consider gradual tapering rather than abrupt discontinuation Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred. Perform periodic skin examinations The three most frequent non‐hematologic adverse reactions (incidence >10%) were bruising, dizziness and headache A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or fluconazole or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

to see Full Prescribing Information and learn more about Jakafi for use in PV

* A randomized, open-label, active-controlled phase 3 trial comparing Jakafi with best available therapy in 222 patients. Best available therapy included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%). The primary end point was the proportion of subjects achieving a response at week 32, with response defined as having achieved both Hct control (the absence of phlebotomy eligibility beginning at the week 8 visit and continuing through week 32) and spleen volume reduction (a ≥35% reduction from baseline in spleen volume at week 32). Phlebotomy eligibility was defined as Hct >45% that is ≥3 percentage points higher than baseline or Hct >48% (lower value). Reference: 1. Jakafi Prescribing Information. Wilmington, DE: Incyte Corporation.

FDA News Venetoclax Receives FDA Breakthrough Therapy Designation for Relapsed or Refractory CLL and 17p Deletion

The FDA granted venetoclax (RG7601, GDC-0199/ABT-199; Roche/ AbbVie) a breakthrough therapy designation for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and the

17p deletion genetic abnormality. Venetoclax, an investigational small- molecule inhibitor of the BCL-2 protein, an apoptosis regulator, is being investigated for several hematologic cancers in addition to CLL. A breakthrough therapy designation allows the drug manufacturer to accelerate the development of the drug, as well as guarantees the acceleration of the FDA review process for medica-

tions that are intended to treat life- threatening diseases, when the evidence shows that the specific medication may provide a substantial improvement to patients compared with currently available therapies on the market. “People who have relapsed or refractory CLL with a 17p deletion typically have a poor prognosis, and do not respond to many currently available treatment options,” said Sandra Horning,

BRIEF SUMMARY: For Full Prescribing Information, see package insert. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Jakafi until recovery [see Adverse Reactions (6.1)]. Perform a pre-treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions (6.1)]. Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in patients treated with Jakafi. Perform periodic skin examinations. ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1)] • Risk of Infection [see Warnings and Precautions (5.2)] • Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and Precautions (5.3)] • Non-Melanoma Skin Cancer [see Warnings and Precautions (5.4)]. 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. Clinical Trials Experience in Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebocontrolled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment. Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse Reactions

a b

c d

e f

All Gradesa Grade 3 (%) (%)

VALUE-BASED CANCER CARE

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebocontrolled study. Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya Jakafi (N=155) Laboratory Parameter

All Gradesb (%)

Grade 3 (%)

Placebo (N=151) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Thrombocytopenia

Anemia

Neutropenia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label, active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse events, regardless of causality, was observed in 4% of patients treated with Jakafi. Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in ≥ 6% of Patients on Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment Jakafi (N=110) Adverse Events

Grade 4 (%)

Best Available Therapy (N=111)

All Gradesa (%)

Grade 3-4 (%)

All Grades (%)

Headache

Abdominal Painb

Diarrhea

Dizzinessc

Fatigue

Pruritus

Dyspnead

Muscle Spasms

Nasopharyngitis

Constipation

Cough

Grade 3-4 (%)

Bruisingb

Edemae

Dizzinessc

Arthralgia

Headache

Asthenia

Urinary Tract Infectionsd

Epistaxis

Weight Gaine

Herpes Zosterf

Flatulence

Nausea

Herpes Zosterf

a b

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 includes abdominal pain, abdominal pain lower, and abdominal pain upper includes dizziness and vertigo includes dyspnea and dyspnea exertional includes edema and peripheral edema includes herpes zoster and post-herpetic neuralgia

National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 c includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site d hematoma, increased tendency to bruise, petechiae, purpura e includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis f includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, Other clinically important treatment emergent adverse events observed in less than 6% of patients bacteria urine identified, nitrite urine present treated with Jakafi were: Weight gain, hypertension, and urinary tract infections includes weight increased, abnormal weight gain Clinically relevant laboratory abnormalities are shown in Table 4. includes herpes zoster and post-herpetic neuralgia

30051_incjak_fa3_pv_ahdbppo.indd 3

Grade 4 All Grades Grade 3 (%) (%) (%)

MD, Chief Medical Officer and Head of Global Clinical Development at Roche. “We are pleased that the FDA has granted venetoclax Breakthrough Therapy designation and hope this regulatory pathway will help us bring venetoclax to people with this difficult-to-treat disease soon,” she explained. Approximately 30% to 50% of patients with relapsed or refractory CLL have the 17p deletion; these patients

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FDA News have poor results with conventional chemotherapy, with a median life expectancy of <3 years. (May 7, 2015)

FDA Grants Orphan Drug Status to Cantrixil, an Investigational Chemotherapy for Ovarian Cancer

The FDA has granted orphan drug

designation to Cantrixil (Novogen/ CanTx) for the treatment of patients with ovarian cancer. Cantrixil is a cyclodextrin envelope that contains the active ingredient TRXE-002. Cantrixil is designed as an intracavity chemotherapy intended for injection into the peritoneal and pleural cavities, without any local irritation or toxicity. The goal of using this construct is to reach high drug levels in the area

Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatmenta Jakafi (N=110) Laboratory Parameter

All Gradesb Grade 3 (%) (%)

Best Available Therapy (N=111) Grade 4 (%)

All Grades (%)

Grade 3 (%)

Grade 4 (%)

Hematology Anemia

Thrombocytopenia

Neutropenia

where cancer cells spread. The FDA granted this designation to cantrixil after reviewing preliminary preclinical data from the drug manufacturer. Graham Kelly, PhD, Novogen and CanTx Chief Executive Officer, said, “Receiving this designation is one more step in our objective of bringing Cantrixil to market as a drug that we hope will provide meaningful clinical

count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic impairment [see Dosage and Administration (2.4) in Full Prescribing Information]. OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib. Jakafi is a registered trademark of Incyte. All rights reserved. U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013 © 2011-2014 Incyte Corporation. All rights reserved. Issued: December 2014 RUX-1428

Chemistry Hypercholesterolemia

Elevated ALT

Elevated AST

Hypertriglyceridemia

a b

Presented values are worst Grade values regardless of baseline National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4 and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics (12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however, monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics (12.3) in Full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Jakafi, a decision should be made 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 Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 52% were 65 years of age and older. No overall differences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of hepatic impairment and with a platelet

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benefit to patients with ovarian cancer and deliver that long-sought breakthrough for patients with a cancer that has shown only slight improvement in 5-year survival rates over the last 30 years.” Dr Kelly added, “CanTx came out of a belief by Yale University and some long-term ovarian cancer researchers in the Yale Medical School that Cantrixil represented a potential breakthrough in the treatment of ovarian cancer.” (CanTx is a venture company that was established by researchers at Yale University.) Orphan drug designation for an investigational drug is intended to promote drug development for rare diseases with small patient populations. This designation can provide the drug manufacturer several incentives to encourage and to support the development of drugs with low incidence rates, including financial subsidies for clinical research, tax incentives, extended regulatory patent protection, and enhanced marketing rights upon approval of the drug. Preclinical data for Cantrixil were presented by the Yale researchers at the recent 2015 Annual Conference of the American Association for Cancer Research. That data represented the key criteria that the researchers had set for Cantrixil to justify its transition to clinical trials. The data indicate that Cantrixil in patients with late-stage chemoresistant ovarian cancer can effect a very significant (>95%) tumor reduction. Cantrixil is expected to be available for use in Australia (Novogen is an Australian company) in late 2015 or early 2016 for patients with malignant ascites, a terminal condition associated with ovarian cancer and other types of cancer for which no other therapy is available; this is being recognized as the first step before the regulatory approval of this agent for ovarian cancer in the United States or in Australia. Researchers will ultimately seek a primary indication for Cantrixil as first-line therapy for early-stage cancers of the abdominal cavity, such as ovarian, uterine, colo rectal, and gastric carcinomas. Approximately 85% of advanced cases of ovarian cancer respond to first-line chemotherapy, but the majority of these cases relapse within several years. (April 21, 2015) n

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www.ValueBasedCancerCare.com

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

FDA NEWS

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

Venetoclax gets breakthrough therapy designation for CLL and 17p deletion More…

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

VALUE PROPOSITIONS

PUBLISHING STAFF

Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com

New genetic test for breast cancer on the horizon More…

Publisher Cristopher Pires cpires@the-lynx-group.com

AACR MEETING HIGHLIGHTS

Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale

5TH CONFERENCE

Continuing challenges in optimizing value in oncology Pathways have the potential to deliver personalized medicine

IN THE LITERATURE

Patient-reported outcomes needed in clinical trials for accurate evaluation of drug safety More…

2 immunotherapies better than 1 in advanced melanoma Pembrolizumab shows promise in lung cancer More…

ECONOMICS OF CANCER CARE

Comparing value of cancer care in the US and in Western Europe US oncologists favor establishment of NICE-like body More…

NCCN CONFERENCE UPDATES

Promising therapies for B-cell lymphomas In CML, assess response to first-line TKI at 3 months More…

SURVIVORSHIP

Revised survivorship plan reduces time, resources

LUNG CANCER

1 in 4 patients not tested for EGFR mutations

DRUG UPDATE

Akynzeo, a dual-acting oral drug, approved for CINV prevention

Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino

VBCC Editorial Board

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Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 11 times a year by Engage Healthcare Communica tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2015 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, Anthem, Inc John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

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

Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd Albuquerque, NM

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

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

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, FASHP Pharmacy, Oncology, Healthcare, and School Health Consulting, Tampa, FL

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

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

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

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com

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

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com. Address all editorial queries to: editorial@valuebasedcancercare.com, Telephone: 732-992-1891, Fax: 732-992-1881. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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VALUE PROPOSITIONS

Advance Care Planning

New Genetic Tests for Breast Cancer on the Horizon, May Challenge Current Screening Strategy Several genetic tests and new methods for assessing the risk for breast cancer associated with genetic mutations, which increase the risk for the disease, show promise and may soon change the way genetic screening is done for breast cancer. Color Genomics, a biotechnology company, is developing an inexpensive genetic test for breast and ovarian cancer using a simple saliva sample. In addition, the 2 major laboratories, Quest Diagnostics and LabCorp, are collaborating with French researchers to combine their data in an effort to enhance how BRCA1 and BRCA2 mutations are diagnosed; other companies and laboratories have been invited to join this venture, called “BRCA Share.” Genetic screening has recently received much publicity by Angelina Jolie’s well-advertised decision to undergo a double mastectomy and recently also have her ovaries and fallopian tubes removed to reduce her risk for the disease because of her BRCA1-positive status. Nevertheless, who should have genetic testing remains controversial. Color Genomics Chief Executive, Elad Gil, PhD, said he wanted to “democratize access to genetic testing,” a statement that has generated concern among some experts. The company plans to charge $249 for its saliva test for BRCA1 and BRCA2 mutations, as well as 17 other genetic mutations. This price is a fraction of the cost of many other genetic tests currently provided by other companies. Dr Gil said his company’s test would be inexpensive enough for women to pay out of pocket to circumvent the need for insurance companies’ approval. He said the company was starting a program to provide free testing to women who cannot afford this test. One of Color Genomics’s unpaid advisers is Mary-Claire King, PhD, the genetics expert from the University of Washington who was involved in the discovery of the BRCA gene. Last year, Dr King issued a call to offer genetic breast cancer testing to all US women aged ≥30 years. Other experts argue that the cost of genetic testing does not justify testing in the general population. “We have to be careful that we are not just increasing this group of worried-well who have incomplete information,” said Kenneth Offit, MD, Chief of Clinical Genetics Service, Memorial Sloan Kettering Cancer Center. Furthermore, some experts question whether the saliva testing can be so inexpensive, considering that genetic sequencing is not the only cost involved; the expert interpretation of the results may increase the overall costs. Other companies charge ≥$1500 for a complete multigene genetic analysis of the BRCA genes. As for BRCA Share, Quest Diagnostics will provide money to improve the database and the interpretation process. “We are going to help them make it better,” said Charles M. Strom, MD, PhD, Vice President for Genomics and Genetics at Quest Diagnostics. Companies will pay for access to the data in the BRCA Share database based on their size, and some companies will have access without paying, if appropriate. The New York Times; April 21, 2015

Turbo-Charging the Immune System Potential Game-Changer in Killing Cancer A protein that “turbo-charges” the immune system to enable it to fight off any cancer or virus has been discovered by researchers at the Imperial College

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in London, United Kingdom. This recent breakthrough has been described as a “game-changer” for the treatment of cancer, representing a new molecule that boosts the body’s ability to fight off chronic diseases, including cancer. “This is exciting because we have found a completely different way to use the immune system to fight cancer,” said Professor Philip Ashton-Rickardt, Chair, Section of Immunobiology, Department of Medicine, Imperial College, who led the study that discovered that protein. He and his colleagues are now developing a gene therapy based on this protein, and hope to begin human trials in 3 years. “It could be a game-changer for treating a number of different cancers and viruses,” Dr Ashton-Rickardt said. “This is a completely unknown protein. Nobody had ever seen it before or was even aware that it existed. It looks and acts like no other protein.” The novel protein is called lymphocyte expansion molecule (LEM); it promotes the spread of cancer-killing T-cells by generating large amounts of energy not found in other proteins. When the immune system detects cancer cells, it normally overacts in the attempt to kill the cancer, which quickly depletes it of energy, and the process stops. The LEM protein, however, provides a significant energy boost that generates a huge number of T-cells in quantities that the cancer cells are unable to destroy. The protein also increases the immune memory cells, which can recognize tumors and viruses they have encountered before, making it less likely that the cancer will recur. The hope is to create a new type of immune therapy that will enhance the T-cells of patients with cancer with the protein, which will then be injected back into the body. If successful, this could revolutionize the approach to cancer therapy. The London Telegraph; April 16, 2015

New Immuno-oncology Collaboration to Promote CAR T-Cell Therapies MaxCyte, a next-generation technology company dedicated to developing cell therapies using high-performance cell-transfection systems, announced the launch of its new strategic research collaboration with Johns Hopkins University to develop chimeric antigen receptor (CAR) T-cell therapies that harness patients’ immune systems to kill cancer cells. MaxCyte’s approach to CAR-cell therapy targets solid tumors by enabling control over the on-target off-tumor toxicity that limits other CAR therapies to hematologic cancers. This is done by introducing the CAR construct as a transiently expressing mRNA that enables the control of the duration of expression and toxicity against target antigens in normal tissue. This unique approach also avoids the cell expansion step required for standard approaches, dramatically reducing manufacturing time and expense for CAR therapies from days or weeks to only hours. The preclinical work by MaxCyte in collaboration with Johns Hopkins University will file an Investigational New Drug application for a CAR T-cell therapy that targets a broad range of solid tumors. “We are truly excited to be collaborating with Johns Hopkins, one of the leading hospitals in the world, in the development of this next-generation CAR therapy,” said Doug Doerfler, MaxCyte’s President and Chief Executive Officer. “The combination of Johns Hopkins’ world renowned research and clinical development capabilities and MaxCyte’s unique product development capabilities will enable the rapidly advancing area of CAR therapies to move into the clinic in solid tumors in a platform that provides rapid cost-effective manufacture of Cellular Therapeutics.” MaxCyte press release; April 21, 2015 n

MAY 2015

www.ValueBasedCancerCare.com

AACR Meeting Highlights

Pembrolizumab Scores Big Over Ipilimumab in Advanced... Continued from the cover

Research annual meeting. Pembrolizumab significantly improved overall survival (OS), progression-free survival (PFS), and overall response rate compared with ipilimumab, and was associated with fewer adverse events, including high-grade adverse events. The study was just published in the New England Journal of Medicine (Robert C, et al. 2015 April 19. Epub ahead of print) to coincide with the presentation at the meeting. “This is a paradigm shift. In the past we would be able to cure maybe 1 in 10 patients with melanoma, and with the newer therapies we can cure 1 in 3. The data from KEYNOTE-006 should change the standard of care for advanced melanoma,” stated senior investigator of the study, Antoni Ribas, MD, PhD, Director, Tumor Immunology Pro-

at a glance ➤ Pembrolizumab significantly improved overall survival in this patient population and is associated with fewer adverse events than ipilimumab ➤ Grade 3 and 4 toxicities were 19% with ipilimumab versus 10%-13% with pembrolizumab ➤ Ipilimumab will continue to be used as the standard of care for patients with melanoma, but upfront treatment with pembrolizumab may be a new treatment option soon

gram Area, Jonsson Comprehensive Cancer Center, University of California, Los Angeles.

previous systemic therapy was allowed. Previous therapy with CTLA-4, PD-1, or PD-1 ligand 1 inhibitors was not allowed.

“

This is a paradigm shift. In the past we would be able to cure maybe 1 in 10 patients with melanoma, and with the newer therapies we can cure 1 in 3. The data from KEYNOTE-006 should change the standard of care for advanced melanoma.

”

—ANTONI RIBAS, MD, PHD

Ipilimumab is an anti–CTLA-4 therapy, and pembrolizumab is an anti–PD-1 antibody. These drugs take the “brakes” off of the immune system by different mechanisms of action, enabling the immune system to attack the cancer. Both immune checkpoint inhibitors are approved by the FDA. Ipilimumab is approved as first-line therapy for advanced melanoma. Pembrolizumab and nivolumab, another anti–PD-1 antibody, are FDA-approved for disease progression after ipilimumab therapy, and if BRAF V600 mutation– positive, a BRAF inhibitor. Study Details

The global KEYNOTE-006 trial enrolled 834 patients from 83 sites. All the patients had unresectable stage III or IV advanced melanoma, and no more than 1

Patients were randomized in a 1:1:1 manner to pembrolizumab 10 mg/kg every 2 weeks (N = 279), to pembroliz umab 10 mg/kg every 3 weeks (N = 277), or to 4 cycles of ipilimumab 3 mg/ kg every 3 weeks (N = 278). At a median follow-up of 7.9 months, the median PFS was 5.5 months for the 2-week pembrolizumab dose, 4.1 months for the 3-week group, and 2.8 months for ipilimumab, showing a 42% relative reduction in risk for disease progression favoring pembrolizumab (P <.001). The estimated 6-month PFS rates for the 3 treatment arms were 47.3%, 46.4%, and 26.5%, respectively. The median follow-up was 13.8 months. The 1-year OS rates were 74.1% and 68.4% for the 2-week and 3-week pembrolizumab groups, respectively, compared with 58.2% for ipilimumab.

The 37% improvement in survival with pembrolizumab was statistically significant compared with ipilimumab (P = .005 and P = .003, respectively). The objective response rates were 33% in the pembrolizumab arms versus 11.9% in the ipilimumab arm. The complete response rates were 5%, 6.1%, and 1.4%, respectively. Responses were ongoing in 89.4% of the 2-week pembroliz umab group, 96.7% of the 3-week pembrolizumab group, and 87.9% of the ipilimumab group. No difference in safety and efficacy was observed between the 2 dose levels of pembrolizumab studied in the trial. Adverse Events

Toxicity results favored pembrolizu mab as well. Grade 3 or 4 adverse events occurred in 19% of the patients who received ipilimumab and in 10% to 13% of the patients in the pembrolizumab arm. Pembrolizumab-related autoimmuneor immune-related adverse events included hypothyroidism (10.1% for the 2-week group, 8.7% for the 3-week group) and hyperthyroidism (6.5% and 2.5%, respectively). Colitis was reported in 8.2% of the patients who received ipilimumab.

On the Horizon

Dr Ribas anticipates that upfront treatment with pembrolizumab will be added to its labeling, but noted that ipilimumab will still continue to be used for the treatment of melanoma, because it achieves durable responses. Studies of combinations of anti–PD-1 agents with ipilimumab are ongoing, and these combinations are expected to be superior to either drug alone. n

Two Immunotherapies Are Better Than One in Advanced Melanoma Ipilimumab plus nivolumab combination improves outcomes By Phoebe Starr Philadelphia, PA—Combination immunotherapy with ipilimumab (Yervoy) plus nivolumab (Opdivo) was superior to ipilimumab monotherapy in previously untreated patients with advanced melanoma in a phase 2 randomized clinical trial, according to lead investigator F. Stephen Hodi, MD, Director of the Melanoma Center, Dana-Farber Cancer Institute,

Boston, MA, who presented the study at the 2015 American Association for Cancer Research (AACR) annual meeting. The study was published online in the New England Journal of Medicine (Postow MA, et al. 2015 April 20. Epub ahead of print) simultaneously with the presentation at the meeting. “The combination of ipilimumab and

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nivolumab achieved durable responses and a substantially higher response rate, longer progression-free survival [PFS], and higher rates of complete response than ipilimumab monotherapy in patients with both wild-type BRAF and BRAF mutation–positive tumors,” Dr Hodi said. Based on favorable phase 1 experience

with the combination, the randomized phase 2 study was initiated to evaluate the combination of ipilimumab plus nivolumab versus ipilimumab alone (the standard of care) in previously untreated patients with advanced melanoma. Study Details

A total of 142 patients were random-

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AACR Meeting Highlights

Liquid Biopsy Detects KRAS Mutations in Plasma DNA in Nonresectable Pancreatic Cancer, Can Predict Patient Outcomes By Phoebe Starr Philadelphia, PA—High levels of KRAS mutations in plasma circulating tumor DNA (ctDNA) predict worse overall survival (OS), whereas low levels of KRAS mutations in plasma ctDNA indicate improved OS in patients with advanced pancreatic cancer. Because the majority of pancreatic tumors harbor KRAS mutations, analyzing plasma ctDNA levels of these mutations can help to predict patient outcomes, according to results of a prospective-retrospective study presented at the 2015 American Association for Cancer Research annual meeting. The study also showed that combining baseline KRAS levels in plasma with KRAS levels after 2 cycles of chemotherapy improved the predictive ability of the liquid biopsy analysis compared with baseline KRAS alone. “Monitoring KRAS levels in plasma and then combining baseline levels with longitudinal levels is a powerful predictor of overall survival,” stated coinvestigator Vlada Melnikova, MD, PhD, Vice President, Research and Development, Trovagene, San Diego, CA.

(Lead investigator Julia S. Johansen, MD, DMSc, Clinical Professor, University of Copenhagen, Denmark, did not attend the meeting.)

“

Monitoring KRAS levels in plasma and then combining baseline levels with longitudinal levels is a powerful predictor of overall survival.

”

—VLADA MELNIKOVA, MD, PHD

Liquid biopsies, such as the plasma biopsy, have several advantages over tissue biopsies. Liquid biopsies are easier to obtain and are less costly, because they do not involve invasive procedures. In addition, tissue biopsies can degrade, and repeated biopsy is required in some cases, and the tissue may not be available for biopsy. Furthermore, biopsies can be required at different stages as a cancer progresses,

and it would be more attractive to physicians, patients, and payers to be able to use serial liquid biopsies rather than tissue biopsies. The prospectively collected samples were retrospectively analyzed and were from patients participating in the Danish BIOPAC study, Dr Melnikova explained. The study was based on archived plasma samples from 182 patients (85 females and 97 males) with advanced or metastatic pancreatic cancer who were treated with gemcitabine or with FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin), the standard of care when the study was initiated. The assay used to assess the 640 plasma samples from the 182 patients at baseline and after 2 cycles of chemotherapy was developed by Trovagene, and is highly sensitive for the detection of KRAS mutations in plasma ctDNA. Of 182 patients, 176 had evaluable plasma samples and baseline. Predicting Survival

Using a cutoff point of 5.5 copies per 100,000 for low and high KRAS

at a glance ➤ High KRAS levels can predict improved survival in patients with advanced pancreatic cancer ➤ Combining baseline KRAS and longitudinal KRAS data after 2 cycles of chemotherapy was a better predictor of survival than baseline KRAS alone ➤ The plasma test is expected to cost approximately $1300 ➤ It is not known whether Medicare will provide reimbursement for this test

levels in plasma ctDNA, a statistically significant negative association was found between KRAS levels and OS (P <.001). Among the patients who received gemcitabine, a median survival of 296 days for those with low baseline KRAS levels compared with Continued on page 10

Two Immunotherapies Are Better Than One in... ized in a 2 to 1 manner to receive ipilim umab every 3 weeks for 4 cycles followed by nivolumab alone every 2 weeks versus ipilimumab monotherapy followed by placebo, and treated until disease progression or unacceptable toxicity. At randomization, patients were stratified

at a glance ➤ The combination of ipilimumab plus nivolumab achieved durable responses, higher response rate, longer PFS, and higher complete response rates than ipilimumab alone ➤ ORR in BRAF mutation– positive patients was 52% for the combination group with a 22% complete response rate, which was similar to that in patients with BRAF wildtype tumors ➤ Adverse events occurred in 91% of the combination therapy arm and in 93% of the ipilimumab monotherapy arm

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according to BRAF mutation status (wild-type or mutation-positive).

the ORR was 52% for the combination group, with a 22% complete response

“

The combination of ipilimumab and nivolumab achieved durable responses and a substantially higher response rate, longer progression-free survival, and higher rates of complete response than ipilimumab monotherapy in patients with both wild-type BRAF and BRAF mutation–positive tumors.

”

The objective response rate (ORR) was 61% for the combination versus 11% for ipilimumab in patients with BRAF wild-type tumors (P <.001). Among these patients, the median duration of response was not reached in either treatment arm, with an ongoing response in 82% of the combination group and 75% of the ipilimumab monotherapy group. In patients with the BRAF mutation,

—F. STEPHEN HODI, MD

rate, which was similar to that in patients with BRAF wild-type tumors, versus 0% for ipilimumab alone. More than 66% of the patients in the combination arm who discontinued therapy remained in complete response or partial response. The median PFS was not reached in the BRAF wild-type group with the combination and was 4.4 months with ipilimumab monotherapy (P <.001). MAY 2015

Continued from page 8

Among patients with the BRAF mutation, the median PFS was 8.5 months with the combination and 2.7 months with ipilimumab monotherapy. In patients discontinuing treatment as a result of toxicity, the ORR was 68% in the combination arm versus 10% in the ipilimumab monotherapy arm. Adverse Events

Treatment-related adverse events occurred in 91% of the combination therapy arm and in 93% of the patients who received ipilimumab monotherapy. Treatment-related events leading to discontinuation of therapy were observed in 47% of the combination arm and 17% of the ipilimumab-alone arm. The rate of grade 3 or 4 adverse events in the combination arm was 54% versus 24% in the ipilimumab-alone arm. The most common grade 3 or 4 drug-related events associated with combination immunotherapy included colitis (17%), diarrhea (11%), and an elevated alanine aminotransferase level (11%). For ipilimumab, the most frequently reported grade 3 or 4 adverse events were diarrhea (11%) and colitis (7%). Steroids were used to manage the side effects, and most resolved. n

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AACR Meeting Highlights

Projections for 2030: Increase in ER-Positive, Decrease in ER-Negative Breast Cancer By Phoebe Starr

Philadelphia, PA—Over the next 15 years, up to a 50% increase is projected in the number of breast cancer cases, according to a study from the National Cancer Institute (NCI). The incidence of estrogen receptor (ER)-positive breast cancers, diagnosed mostly by mammography, is projected to increase, whereas cases of ER-negative cancers, the moredifficult-to-treat cancers, are projected to decrease. ER-positive in situ cancers are expected to increase by approximately 50% and ER-negative cancers are expected to decrease by approximately 50% by 2030. This analysis predicts that women will be older at breast cancer diagnosis, with a projected increase from 24% of all cases of breast cancer to 35% in the group of women aged 70 to 84 years. These projections can help with resource allocation for management. “How do we plan for a better future? Our data suggest some clues about what we would like to know about moving forward,” said Philip S. Rosenberg, PhD, Senior Investigator at the NCI. “Knowing more about how to manage the clinical burden, especially among women aged 70 to 84, would be helpful. Also, we need to know more about the natural history of these in situ lesions. It would be useful to clarify all of the reasons for the decline in ER-negative tumors, because there may be a hidden prevention clue in that. Finally, it would be useful to make future estimates for each racial or ethnic group, which we plan to do,” Dr Rosenberg added.

Key Projections

The estimates for this study used statistical modeling, incorporating more

effect (ie, during the years after she announced that she had breast cancer, more breast cancers were diagnosed).

decline in ER-positive tumors in the 50to 69-year age-group as a result of a decline in the use of hormone therapy. The main 15-year projections of the current study included: • Change in total cases of breast cancer from 283,000 in 2011 to 441,000 in 2030, a 50% increase • Older age at diagnosis—age 70 to 84 years accounting for 35% of all cases, up from 24% in 2014 • An increase in ER-positive in situ tumors from 19% to 29% • A decrease in ER-negative tumors from 17% to 9%.

“

Future Opportunities

We need to know more about the natural history of these in situ lesions. It would be useful to clarify all of the reasons for the decline in ER-negative tumors, because there may be a hidden prevention clue in that.

”

—PHILIP S. ROSENBERG, PHD

than 500,000 cases of breast cancer included in the SEER (Surveillance, Epidemiology, and End Results) registry through 2010. The modeling accounted for age at diagnosis on a year-by-year basis, and adjusted for the “Betty Ford”

There appears to be a greater increase in rates of ER-positive and in situ breast cancer than previously appreciated. This modeling study does not tell us causes, but it suggests opportunities for research….The data will also help us in apportioning research dollars.

”

—LOUIS M. WEINER, MD

An earlier study by the same group of investigators projected cancer burden through 2016. That study predicted a

“These are powerful and important data for the future. It is important to understand where the disease burden will be as we move forward with an aging and diverse population. What we would like to see is a reduced incidence of breast cancer,” said press conference moderator Louis M. Weiner, MD, Director of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC. “There appears to be a greater increase in rates of ER-positive and in situ breast cancer than previously appreciated. This modeling study does not tell us causes, but it suggests opportunities for research. For example, it would be great to identify the factors responsible for the decline in ER-negative tumors. The data will also help us in apportioning research dollars. These massive data sets point out areas where we need more research,” Dr Weiner said. n

Liquid Biopsy Detects KRAS Mutations in Plasma DNA in Nonresectable Pancreatic Cancer...

Continued from page 9

148 days for those with high baseline KRAS levels. Among the patients who received FOLFIRINOX, the median survival was 499 days for those with low baseline KRAS levels and 210 days for those with high baseline KRAS levels. The investigators analyzed KRAS mutational load in 176 patients with serially collected plasma samples during treatment, and a similar association was observed. High KRAS counts during treatment were significantly associated with lower OS (P <.001). The strength of this association was greater for post-

baseline KRAS counts than for the baseline KRAS counts. Combining baseline KRAS and longitudinal KRAS data after 2 cycles of chemotherapy was an even better predictor of survival than baseline KRAS alone. The patients were divided into 4 groups—low baseline KRAS and low longitudinal KRAS (responders), low baseline KRAS and high longitudinal KRAS (nonresponders), high baseline KRAS and high longitudinal KRAS (nonresponders), and high baseline KRAS and low longitudinal KRAS (responders). Based on combining KRAS levels in

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plasma ctDNA at baseline and after 2 cycles of chemotherapy, the median survival for each of the 4 groups was 336 days, 252 days, 224 days, and 134 days, respectively. Commercializing the Test

The company is in the process of introducing the plasma test, but there is no indication yet whether Medicare will reimburse for this test under the not otherwise specified code. The test will be priced at approximately $1300, but insurers may pay less for it. Other companies are planning to

market or are already marketing plasma tests (ie, “liquid biopsies”) to identify genetic mutations. The company is also rolling out an assay to detect KRAS mutations in urine. A pilot study also presented at the meeting showed that the urinary and plasma assays to detect KRAS mutations in ctDNA were concordant with tissue biopsies of patients with metastatic colorectal cancer, and thus can detect minimal residual disease. The next step will be to study whether liquid biopsies are prognostic for survival in this group of patients. n

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

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

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

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

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

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

AACR Meeting Highlights

Metformin May Not Improve Survival in Patients with Pancreatic Cancer By Christine Erickson

Philadelphia, PA—Several retrospective studies have shown that metformin is associated with longer survival in patients

with cancer, including pancreatic cancer. However, in a new study led by Roongruedee Chaiteerakij, MD, PhD, Division

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

VALUE-BASED CANCER CARE

MAY 2015

of Gastroenterology and Hepatology, Mayo Clinic Cancer Center, Rochester, MN, metformin did not improve survival

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

for patients with pancreatic ductal adenocarcinoma (PDAC). The results were presented at the 2015 American Association for Cancer Research meeting. Chaiteerakij and colleagues used data from the Mayo Clinic Specialized Programs of Research Excellence pancreatic cancer database. The study included 1360 patients (59% male; mean age, 67 years) with PDAC who have been taking metformin; overall survival was the primary outcome. Patients were categorized into 5 groups based on the use of metformin: A. Never used (N = 908) B. Metformin started >1 year before PDAC diagnosis (N = 84) C. Metformin started within 1 year before PDAC diagnosis (N = 212) D. Metformin started <30 days after PDAC diagnosis (N = 104) E. Metformin started >30 days after PDAC diagnosis (N = 34). “The diabetes drug metformin is being used in some cancer treatment trials based on epidemiologic studies that have reported that use of metformin reduces the risk of death from cancer,” Dr Chaiteerakij stated. Because retrospective studies of cancer survival may have unintended biases related to the complexity of diabetes management, this study addressed these inherent biases. “This study highlights the importance of appropriate design of retrospective studies and the necessity of conducting prospective studies with solid rationale for determining the effect of diabetes drugs on cancer risk or death,” Dr Chaiteerakij said. The median survival of patients who used metformin was 292 days compared with 308 days for nonusers, a nonsignificant difference. However, among the 413 patients with resectable cancer, those who used metformin survived longer than nonusers—782 versus 612 days (P = .07). This analysis suggests that metformin does not improve survival for most patients with PDAC, but those with resectable cancer who started metformin after PDAC diagnosis benefited from this medication. The researchers noted that there is an inherent survival bias in these patients. “Studies of medication exposure and cancer survival warrant very careful and detailed data collection, which is not always possible in a retrospective study design,” Dr Chaiteerakij said. “Researchers should exercise caution when initiating clinical trials based on retrospective epidemiologic studies.” n

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AACR Meeting Highlights

Olaparib-Carboplatin Combination Shows Promise for Patients with Ovarian or Triple-Negative Breast Cancer By Dana Taylor

Philadelphia, PA—The use of the poly (ADP-ribose) polymerase (PARP) inhibitor, olaparib (Lynparza), plus carboplatin chemotherapy shows promising activity in patients with recurrent breast or ovarian cancer; furthermore, the order of administration of these therapies did not affect the occurrence of side effects, according to new data from a phase 1 clinical trial presented at the 2015 American Association for Cancer Research (AACR) meeting. In December 2014, olaparib was approved by the FDA for the treatment of women with ovarian cancer and BRCA mutations. “Studies to identify treatment combinations that might increase the number of patients benefiting from olaparib are important,” said Victoria L. Chiou, MD, a Medical Oncology Fellow at the National Cancer Institute. The goal of the study, Dr Chiou noted, was to investigate “the best way to deliver combination therapy using olaparib and carboplatin to maximize DNA damage, which likely correlates with antitumor effects, and minimize clinical toxicities.”

The results, she said, showed that “the overall sequence of treatments did not significantly impact the side effects that patients felt. Moreover, we identified a safe drug treatment schedule that also had preliminary activity, known as tumor shrinkage, in women with breast cancer and ovarian cancer.” Overall, the women with ovarian cancer and BRCA mutation had a 60% overall response rate (ORR) with the combination of the PARP inhibitor plus chemotherapy, compared with the approximately 30% ORR reported for olaparib alone in heavily pretreated patients with ovarian cancer and BRCA mutation.

The patients were randomized to 1 of 2 groups; group 1 received olaparib before carboplatin in cycle 1 and carboplatin before olaparib in cycle 2; group 2 re-

“

The overall sequence of treatments did not significantly impact the side effects that patients felt. Moreover, we identified a safe drug treatment schedule that also had preliminary activity, known as tumor shrinkage, in women with breast cancer and ovarian cancer.

Study Details

Overall, 59 women with recurrent breast or ovarian cancer were included in the study. Of these, 47 women had ovarian cancer, 10 had triple-negative breast cancer, 1 had a uterine carcinosarcoma, and 1 had endometrial cancer. In all, 26 women with ovarian cancer and 4 women with triple-negative breast cancer had a BRCA mutation.

”

—VICTORIA L. CHIOU, MD

ceived carboplatin before olaparib in cycle 1 and olaparib before carboplatin in cycle 2. Starting with cycle 3, all patients

received the same treatment regimen. Toxicity analysis showed no significant difference in the frequency of grade 3 or 4 adverse events. The most common grade 3 or 4 events were neutropenia and anemia. Furthermore, updated results showed that olaparib, used for 7 days, plus carboplatin, given once every 21 days, had preliminary clinical activity in heavily pretreated patients with breast or ovarian cancer. Of the 54 patients in this analysis, 1 woman with triple-negative breast cancer had a complete response lasting 23 months; of the 24 partial responses, 20 were in women with ovarian cancer and 4 were in women with triple-negative breast cancer. Dr Chiou noted that 2 patients are still on study. “One woman has had a partial response that has persisted more than 19 months, and another woman who had stable disease documented at the initial time of abstract submission has since achieved a partial response and has been on the study for more than 12 months,” she said. n

New Hope for Patients with Advanced Lung Cancer? Immunotherapy with pembrolizumab shows impressive results By Phoebe Starr Philadelphia, PA—Immunotherapy with pembrolizumab (Keytruda) was safe and effective in the treatment of patients with previously treated as well as treatment-naïve patients with advanced non–small-cell lung cancer (NSCLC), according to results of the KEYNOTE-001 trial, said Edward B. Garon, MD, Assistant Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Santa Monica, who presented these data at the 2015 American Association for Cancer Research (AACR) meeting. The overall response rates (ORRs) and progression-free survival (PFS) correlated with high levels of PD-1 ligand 1 (PD-L1) expression in tumor tissue, which may turn out to be a biomarker

“

With these data, we can confidently say, in previously treated patients with NSCLC and PD-L1 expression in at least 50% of tumor cells…pembrolizumab is associated with superior outcomes compared to what can be expected with cytotoxic chemotherapy.

”

—EDWARD B. GARON, MD

for response to pembrolizumab. No significant differences in safety and efficacy were observed at the different dose levels of pembrolizumab used in this study. Studies of other anti–PD-1 therapies have been disappointing with regard to use of PD-L1 expression as a biomarker. The Merck assay developed specifically for pembrolizumab used staining in ≥50% of tumor cells as a cutoff point for high PD-L1 expression. Other companies developing anti–PD-1 therapies have their own assay, using different cutoff points and different techniques. “With these data, we can confidently say, in previously treated patients with NSCLC and PD-L1 expression in at least 50% of tumor cells, that pembro lizumab is associated with superior outContinued on page 14

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www.ValueBasedCancerCare.com

NCCN 2015 Updates

Promising Therapies in Multiple Drug Classes Being Explored for B-Cell... Continued from the cover

lymphoma is that few patients enter into clinical studies. “We have too many drugs to test and not enough patients to test them in,” Dr Zelenetz said. The CD20-directed cytolytic antibodies that have already been approved by the FDA include rituximab (Rituxan), ofatumumab (Arzerra), and obinutuzu mab (Gazyva); the latter 2 are approved for the treatment of patients with chronic lymphocytic leukemia (CLL). A head-to-head phase 2 clinical trial in patients with relapsed indolent non- Hodgkin lymphoma (NHL) showed a trend toward higher overall response rates (ORRs) and complete remissions with obinutuzumab compared with ri tuximab, with comparable safety and progression-free survival (PFS) seen at this early time point, said Dr Zelenetz. Monoclonal Antibodies

Blinatumomab (Blincyto) is a T-cell– engaging bispecific monoclonal antibody that received accelerated FDA approval in December 2014 for the

treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Blinatumomab “brings the T-cell in juxtaposition to the B-cell, so that you can get signaling through the T-cell, to induce cytotoxic cell death,” Dr Zelenetz said. In indolent lymphomas with a variety of histologies, the response rates to blin atumomab have been 70% to 80%. In a phase 1 study of patients with indolent lymphoma, blinatumomab monotherapy used for only 4 to 8 weeks produced durable responses. Antibody Drug Conjugates

Antibody drug conjugates are meant to deliver miniscule amounts of drugs, which normally have a narrow therapeutic index when given systemically, specifically to the tumor. Several antibody drug conjugates are in development for B-cell lymphoma and have shown “exciting clinical activity,” said Dr Zelenetz. Pinatuzumab vedotin is a monoclonal

antibody drug conjugate that targets CD22; polatuzumab vedotin is an antibody drug conjugate that targets CD79b.

The major challenge in the development of new therapeutics in lymphoma is that few patients enter into clinical studies. We have too many drugs to test, and not enough patients to test them in.

”

“

—ANDREW D. ZELENETZ, MD, PHD

In the phase 2 ROMULUS study in patients with relapsed or refractory NHL, the median PFS was 5.4 months with pinatuzumab plus rituximab and 5.2 months with polatuzumab plus rituximab in the subset of patients with heav-

ily pretreated diffuse large B-cell lymphoma (DLBCL). “I would argue that picking the winner is really a matter of flipping a coin,” Dr Zelenetz said. “The PFS in this study is quite remarkably similar.” In relapsed or refractory follicular lymphoma, however, polatuzumab had greater clinical activity than pinatuzu mab, as evidenced by 40% versus 10%, respectively, of complete responses. Targeting Critical Signaling Pathways

Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor and other key signaling pathways. Ibrutinib (Imbruvica), which targets BTK, has already been approved for the treatment of patients with CLL or mantle-cell lymphoma (MCL). In relapsed or refractory activated B-cell–like subtype DLBCL, responses were observed with ibrutinib, and were stronger in patients with CD79B and MYD88 L265P mutations. Ibrutinib has

AACR Meeting Highlights

New Hope for Patients with Advanced... comes compared to what can be expected with cytotoxic chemotherapy,” Dr Garon stated. The study was published online in the New England Journal of Medicine (Garon EB, et al. 2015 April 19. Epub ahead of print) to coincide with his presentation. The phase 1b KEYNOTE-001 study included 495 treatment-naïve and previously treated patients with NSCLC to 2 different dose levels of pembrolizumab (2 mg every 3 weeks or 10 mg/kg every 2 weeks); the patients were assigned to a training group (N = 182) or a validation group (N = 313). PD-L1 expression was assessed in all tumor samples. The overall results showed that the ORR was 19.4%, with no clear difference in response, regardless of previous treatment, dose of pembrolizumab, or histology. Among the patients who responded, the median duration of response was 12.5 months. The median duration of PFS was 3.7 months, and the median duration of overall survival (OS) was 12 months. Pembrolizumab was generally well- tolerated. The most common treatment-related adverse events were fatigue, pruritus, and decreased appetite,

“

The results are impressive in this difficult-to-treat patient population. We don’t expect to see improvements in survival in this population.

”

—SUZANNE L. TOPALIAN, MD

and these effects were similar at all dose levels. In the training set, a proportion score of 50% (≥50% of cells that stained positive for PD-L1) was found to be highly posi-

VALUE-BASED CANCER CARE

MAY 2015

tive. In the validation set, patients were categorized for PD-L1 expression as follows: a proportion score <1% was considered low; a score of 1% to 49%, intermediate; and a score ≥50%, high. The validation set included 313 patients (223 previously treated, and 90 treatment- naïve to systemic therapy for NSCLC). PD-L1 staining correlated with response, with no difference in previously treated or treatment-naïve patients. In the highest expressers, those with a proportion score ≥50%, the ORR was 42.5%, the median PFS was 6.3 months, and the median OS had not yet been reached. The ORR was significantly better in the group with a proportion score ≥50% than in patients with a score from 1% to 49%, or <1% (P <.001 and P = .01, respectively). Pooled data from the training and validation set showed that PFS correlated with high PD-L1 expression. (The median PFS was 6.3 months for the group with a proportion score >50% versus 3.3 months for a score from 1% to 49%, and 2.3 months for a score <1%.) At a median follow-up of 10.9 months, the median OS was not yet reached in the group with a score ≥50% in previ-

Continued from page 13

ously treated and treatment-naïve patients. In the previously treated patients, the median OS was 7.3 months for those with a score from 1% to 49% and 8.6 months for those with a score <1%. In treatment-naïve patients, the median OS was 16.2 months for those with a proportion score from 1% to 49% and 10.4 months for the proportion score <1% group. Dr Garon emphasized that PD-L1 is an imperfect biomarker, because a proportion of patients with a proportion score <1% respond to pembrolizumab, as did some of those in the proportion score 1% to 49% group. It would be important not to exclude those with low or intermediate PD-L1 expression who failed with other treatments from being considered for pembrolizumab treatment at this point. “The results are impressive in this difficult-to-treat patient population. We don’t expect to see improvements in survival in this population,” stated Suzanne L. Topalian, MD, Professor of Surgery and Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University. Dr Topalian moderated a press conference where these data were discussed. n

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NCCN 2015 Updates

Promising Therapies in Multiple Drug Classes Being... demonstrated relatively modest activity in relapsed or refractory follicular lymphoma, with an ORR of 28%. The PI3K enzyme is involved in several signaling pathways. The prototypical drug for the inhibition of PI3K delta is idelalisib (Zydelig), which is already approved for use in relapsed CLL, relapsed follicular lymphoma, and small lymphocytic lymphoma. In double refractory indolent NHL, the response rate to idelalisib was 57% in a phase 2 study, with an 11-month PFS. “The major question for both of these pathway inhibitors is, ‘How do we integrate them earlier in the treatment in a way that fundamentally changes the natural history of the lymphomas we’re treating?’” said Dr Zelenetz.

fludarabine and patients with p53 mutations. In early data of patients with MCL, the ORR to ABT-199 was 70% to 80%. The use of ABT-199 warrants fur-

the treatment of indolent follicular lymphoma, with an ORR of 98% and a complete response rate of 87%, “and this has translated to durable responses in a

“

The major question for both of these pathway inhibitors [ibrutinib and idelalisib] is, ‘How do we integrate them earlier in the treatment in a way that fundamentally changes the natural history of the lymphomas we’re treating?’

”

—ANDREW D. ZELENETZ, MD, PHD

Targeting Apoptosis

ABT-199 is a potent and selective second-generation BCL-2 inhibitor. In relapsed or refractory CLL, the ORR to ABT-199 monotherapy is nearly 80%, with a complete response rate of 23%. ABT-199 has shown good activity in patients whose disease is refractory to

ther clinical study in multiple NHL histologies, said Dr Zelenetz. Immunotherapies

The IMiD lenalidomide (Revlimid) has been combined with rituximab for

variety of subtypes of indolent lymphoma,” Dr Zelenetz said. In DLBCL, the response to lenalidomide is substantially different by the cell of origin, with “a pretty impressive 53% response rate among the non–ger-

Continued from page 14

minal center tumors,” he noted. This is surprising, given the substantial activity in follicular lymphoma, a germinal center tumor. The addition of lenalidomide to the R-CHOP (rituximab, cyclophosphamide [Cytoxan], doxorubicin [Adriamycin], vincristine [Oncovin], and prednisone) regimen overcomes the adverse impact of a non–germinal center cell of origin. Immune checkpoint blockade has a rationale for use in patients with lymphoma based on the tumor microenvironment. There are a number of important checkpoints in the regulation of the immune response that are active in lymphomas, including PD-1 and PD-1 ligand 1 (PD-L1) or 2. The preliminary results with nivolu mab (Opdivo) and pidilizumab suggest antitumor activity, which “seems to be based on modulation of the tumor microenvironment given low-level PD-L1 expression on tumor cells,” Dr Zelenetz said. Combining these agents with rituximab shows potential for improving response. n

Many Targeted Drugs in Development for Multiple Myeloma: Monoclonal Antibodies Close to Approval By Wayne Kuznar Hollywood, FL—New targeted agents in multiple myeloma will turn it into a chronic illness, with sustained complete response possible in a significant fraction of patients, predicted Kenneth C. Anderson, MD, Director, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, at his presentation at the 2015 National Comprehensive Cancer Network (NCCN) conference. New monoclonal antibodies and proteasome inhibitors are in development for the treatment of patients with multiple myeloma, as well as agents that target protein degradation, in addition to novel classes of targeted therapies, Dr Anderson said. Monoclonal Antibodies

“Monoclonal antibodies have been elusive in myeloma…but I think we are going to find some this year, not 1 but 2,” said Dr Anderson. Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7, formerly known as CS1). It activates natural killer cells directly and via a CD16-mediated pathway. When used in combination with lena-

lidomide (Revlimid) and dexamethasone (Decadron) in a phase 2 trial in patients with relapsed multiple myeloma, elotuz umab was associated with a 92% response rate at the 10-mg/kg dosage and a progression-free survival of 32.5 months.

myeloma cells in vitro when used with lenalidomide, this antibody has gone forward into the clinic. The complete resolution of monoclonal proteins has been achieved with the combination of daratumumab, lenalidomide, and dexa-

“

Monoclonal antibodies have been elusive in myeloma…but I think we are going to find some this year, not 1 but 2….I do think they will confer additional benefit.

”

—KENNETH C. ANDERSON, MD

“These responses can last almost 3 years, even in high-risk myeloma,” Dr Anderson said. “I do think that this particular antibody is highly likely to be FDA-approved by the end of the year.” The target for the human monoclonal antibody daratumumab is CD38. After showing enhanced killing of multiple

observed in patients with relapsed or refractory multiple myeloma. These antibodies have been associated with responses in some patients who have disease that is refractory to all currently FDA-approved drugs included in the current NCCN guideline. “I do think they will confer additional benefit,” Dr Anderson said, “especially in patients who have refractory disease.” “Immunotherapies are coming to a clinic near you in myeloma,” he said. A potent antibody-drug conjugate directed at CD138, which is highly expressed on all multiple myeloma cells, is indatuximab ravtansine (BT062). The overall response rate was 83% in 35 evaluable patients who received indatuximab ravtan sine, lenalidomide, and dexamethasone. HDAC and Proteasome Inhibitors

methasone, “and my prediction is…this particular antibody will likely be FDA-approved by the end of 2015,” said Dr Anderson. The other CD38-targeting antibody is SAR650984. When combined with lenalidomide and dexamethasone, response rates as high as 67% have been

Histone deacetylase (HDAC) inhibitors block the shuttling of ubiquitinated protein to the aggresome for its degradation. Vorinostat (Zolinza), used for the purpose of blocking the aggresomal degradation pathway, together with bor tezomib (Velcade), which blocks the proteasome degradation pathway, sig nificantly improved the response rate Continued on page 16

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NCCN 2015 Updates

In CML, Assess Response to First-Line TKI at 3 Months By Wayne Kuznar

Hollywood, FL—Switching therapy in patients with chronic myelogenous leukemia (CML) should be considered in those who have a suboptimal response to a first-line tyrosine kinase inhibitor (TKI) at 3 months, said Jerald P. Radich, MD, Director of the Molecular Oncology Laboratory, Fred Hutchinson Cancer Research Center, Seattle, WA, and Vice Chair of the National Comprehensive Cancer Network (NCCN) guideline panel on CML. He discussed the management of patients with CML at the 2015 NCCN conference. In patients with CML, response to therapy should be assessed at 3 months, and if a molecular response is not achieved, first consider poor adherence. “The NCCN recommends evaluating compliance whenever a milestone is not achieved,” said Dr Radich. In the Adherence Assessment with Glivec: Indicators and Outcomes (ADAGIO) study, the adherence of patients with CML to imatinib as prescribed was only 14.2% as assessed by pill count, with 71% of patients taking less than the prescribed dose. Dr Radich noted that the likelihood of achieving a major molecular response (MMR) or maintaining a complete cytogenetic response (CCyR) hinges on adherence of more than 90%. After ruling out nonadherence, if patients still have more than 10% of BCRABL1 transcripts, or have not had a partial cytogenetic response at 3 months after the initiation of imatinib (Gleevec) or nilotinib (Tasigna), the NCCN guidelines recommend evaluating for drug–drug interactions and considering mutational analysis, with a switch to a different primary TKI if necessary.

Early Molecular Response Is Important

Achieving an early molecular response is important, because it predicts a higher probability of achieving an MMR, which is associated with a long er duration of CCyR and higher rates of event-free survival and progression- free survival.

If a patient is having a poor response at 3 months, “it should set off a bell that this may be a patient who’s going to need something more than a TKI in the future,” Dr Radich said. Consideration of human leukocyte antigen typing for a potential stem-cell transplant in the future may be prudent at this point.

“”

The NCCN recommends evaluating compliance whenever a milestone is not achieved. If a patient is having a poor response at 3 months, it should set off a bell that this may be a patient who’s going to need something more than a TKI in the future.

“

”

—JERALD P. RADICH, MD

An early MMR “is a good place to get to,” said Dr Radich. Not achieving, or losing, MMR is associated with shortened progression-free survival. The rationale to switch therapy when the patient’s BCR-ABL1 transcript level is >10% at 3 months comes from a study in which patients with <9.8% of BCRABL transcripts after 3 months of im atinib had an 8-year overall survival rate of 93.3% compared with 57% for patients with >9.8% of BCR-ABL transcripts. The same effect is true for second- line therapy.

Data to support that an early change in therapy improves prognosis in poor responders are lacking. The TIDEL II trial in Australia and New Zealand “suggests that maybe you can salvage some people” by switching from imatinib to nilotinib, said Dr Radich. In addition, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST)cmr study suggests that switching from imatinib to a second-generation TKI if BCR-ABL is detectable after 2 years of treatment “may push your molecular response further,” he said.

When to Consider Mutation Analysis

The analysis of mutations status may provide additional information in patients with CML who have inadequate response. “For chronic-phase patients upfront, there’s really no need to do it, because the sensitivity of the molecular assays we have for sequencing aren’t there,” Dr Radich said. “If people do not reach their milestones, or if they reach their milestones and lost those milestones, that’s when you test.” Once patients progress with therapy, switching to a second-generation TKI is associated with CCyR in 20% to 50% of patients, at which point, a transplant search should be started. “A really good toggle point in looking for response to second-generation drugs is really at 3 months,” Dr Radich said. “If they haven’t had a major cytogenetic response at 3 months with new therapy, then it’s clear their disease-free survival is really poor.” In the setting of chronic-phase CML that progresses after treatment with any single approved TKI, ponatinib (Iclusig) is a “remarkably effective drug,” said Dr Radich. Approximately 50% to 70% of heavily pretreated patients will get a CCyR with ponatinib. The key in treatment is keeping patients from going into accelerated-phase or blast-crisis phase disease, Dr Radich said. The median survival once patients progress to accelerated-phase or blast-crisis phase disease is only 10 months. Most accelerated-phase or blast-crisis phase disease progression occurs early, usually in the first year of treatment with firstline imatinib. n

Many Targeted Drugs in Development for... compared with bortezomib alone in a phase 3 trial in patients with relapsed or refractory multiple myeloma. However, diarrhea, fatigue, and thrombocytopenia limited tolerability. The broad-acting type 2 HDAC inhibitor panobinostat (Farydak) was approved by the FDA in February 2015 for the treatment of patients with relapsed or refractory multiple myeloma based on data from the PANORAMA 1 study, in which patients who received panobino stat, bortezomib, and dexamethasone

had an improvement in median progression-free survival of >4 months compared with bortezomib plus dexamethasone alone. Panobinostat was approved with a boxed warning alerting patients and physicians that severe diarrhea and severe and fatal cardiac events, arrhythmias, and electrocardiographic changes have occurred with this drug in clinical trials. ACY-1215 is a selective HDAC inhibitor with a much more favorable

VALUE-BASED CANCER CARE

MAY 2015

side-effect profile. The response rates with ACY-1215 have been approximately 45%, including 33% of patients who have bortezomib-refractory multiple myeloma, said Dr Anderson. “I think we will need to have an open mind as to whether we can use an HDAC inhibitor…in a way that’s tolerated to appreciate its benefit,” he said. At higher doses of ACY-1215, the full resolution of the myeloma protein is realized, even in patients with lenalidomide-refractory disease.

Continued from page 15

Additional Targets

Additional agents in development for multiple myeloma are Bruton’s tyrosine kinase inhibitors and kinesin spindle protein (KSP) inhibitors. The KSP inhibitor filanesib (ARRY520) blocks mitosis, and is being tested primarily with bortezomib in patients with low serum levels of a binding protein known as AAG. Protein kinase B (AKT) inhibitors may also be useful, because proteasome inhibitors activate AKT. n

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NO. 4

Lung Cancer

Approximately 1 in 4 Patients with Lung Cancer Are Not Tested for EGFR Mutations By Alice Goodman

Geneva, Switzerland—A study with real-world data showed that almost 1 in 4 (24%) patients with advanced lung cancer are not receiving appropriate testing for EGFR mutations, even though guidelines recommend this genetic test to guide the selection of the most appropriate therapy. This important finding was reported at the 2015 European Lung Cancer Conference by James Spicer, MBBS, PhD, Reader in Experimental Oncology, King’s College London, United Kingdom. Dr Spicer said that in Europe and in North America, almost 25% of patients are not tested for EGFR mutations, and up to 20% of patients are tested, but the results are not available at the time the treatment decision is made. Failure to test patients for this mutation has the potential to lead to suboptimal outcomes, he continued, because targeted therapy with an EGFR inhibitor is more effective for cancers that carry the EGFR mutation. Current Guidelines, EGFR Inhibitors Require Testing

“The arrival of a new group of EGFR inhibitors for the treatment of lung cancer driven by mutations in the EGFR gene has brought with it a new requirement for diagnostic laboratories to implement genetic testing. For many institutions, this has represented a significant departure from traditional pathology, which has previously focused only on microscopic examination of tumor tissue,” Dr Spicer commented in the news release. The ability to test for molecular alterations has taken time to percolate down

to clinical practice. Dr Spicer and colleagues had anecdotal evidence to suggest that in the real world, mutational testing was falling through the cracks for some patients.

Reasons for Lack of Testing Adherence

The reasons cited by survey respondents for not ordering testing and not following guidelines related to test re-

testing or failure to incorporate results in treatment selection. Dr Novello stated that it was interesting that the investigators were able to show that EGFR mutation testing

“

The arrival of a new group of EGFR inhibitors for the treatment of lung cancer driven by mutations in the EGFR gene has brought with it a new requirement...to implement genetic testing. For many institutions, this has represented a significant departure from traditional pathology.

”

To get a better idea of the uptake of EGFR testing, he and his colleagues conducted an online survey of 562 oncologists in 10 countries between December 2014 and January 2015. The 10 countries included Canada, France, Germany, Italy, Japan, South Korea, Spain, Taiwan, the United Kingdom, and the United States. The investigators found that in Europe and North America, 24% of patients with advanced lung cancer were not tested for EGFR mutations. Moreover, even in some situations where patients were tested, the test results were not considered when deciding between first-line therapy with an EGFR inhibitor or chemotherapy.

—JAMES SPICER, MBBS, PHD

sults included the lack of sufficient tissue, a long turnaround time for testing, and patients’ poor performance status. Silvia Novello, MD, PhD, Associate Professor, Department of Oncology, University of Turin, Italy, commented on the study, noting, “The first 2 reasons are partially related to an incomplete integration of multidisciplinary oncology teams, while the third one can be attributed to an imperfect knowledge of data regarding the use of EGFR inhibitors.” EGFR inhibitors are associated with a survival benefit in advanced lung cancer, and these results suggest that many patients are denied access to the best treatment because of a lack of EGFR

“

The first 2 reasons are partially related to an incomplete integration of multidisciplinary oncology teams, while the third one can be attributed to an imperfect knowledge of data regarding the use of EGFR inhibitors.

”

—SILVIA NOVELLO, MD, PHD

was requested before first-line therapy in 81% of patients with stage IIIb/IV non–small-cell lung cancer cases. She said it was also interesting that results were demonstrated to be available before administration of treatment in 77% of cases. n

DNA Blood Testing May Be an Alternative to Tumor Sampling for Identifying EGFR Mutations Geneva, Switzerland—Circulating DNA (ctDNA) in the blood of patients with cancer appears to detect lung cancer mutations, providing similar information to tumor tissue sampling, according to a study presented at the 2015 European Lung Cancer Conference. This makes blood testing for ctDNA an attractive option when tumor tissue sampling is not accessible. These results have important implications for the selection of targeted

“

We were asking is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumor is not accessible for bronchoscopy or CT-guided biopsy?

”

—MARTIN RECK, MD, PHD

therapies aimed at specific tumor mutations, said Martin Reck, MD, PhD, Department of Thoracic Oncology, LungenClinic, Grosshansdorf, Germany, who presented the study results at the European Society for Medical Oncology. Studies suggest that plasma ctDNA from the tumor can identify tumor mutations. To test this assumption, the large international ASSESS trial compared the ability of blood testing versus Continued on page 18

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Multiple Myeloma

Value of MRI in Smoldering Myeloma Stressed by the International Myeloma Working Group By Charles Bankhead

A New Gold Standard

Characterizing MRI as the “gold standard” for detecting bone marrow involvement in myeloma, the new recommendations update the previous suggestion from the IMWG that whole-body x-ray should remain the standard for the evaluation of myeloma-related bone disease. “In its previous recommendations, the IMWG supported the use of MRI in the

Meletios A. Dimopoulos, MD

New data highlight the value of MRI in this setting, suggesting that the current practice should be changed accordingly.

Updated MRI Recommendations

absence of osteolytic lesions on wholebody x-ray,” stated Meletios A. Dimopoulos, MD, Chair of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece, and colleagues. However, the group did not suggest the use of MRI for symptomatic myeloma. Therefore, a patient with focal lesions

DNA Blood Testing May Be... standard tumor tissue testing to detect EGFR mutations. “We were really asking a question on behalf of patients: is there a valid test that can identify an EGFR mutation and give me the opportunity for superior treatment, even if my lung tumor is not accessible for bronchoscopy or CT [computed tomography]-guided biopsy? And, are the results of this blood test in agreement with the results of the ‘gold-standard’ tissue test?” Dr Reck stated. The investigators assessed 1162 matched tumor tissue and blood samples for the presence of an EGFR mutation in patients with lung cancer. There was an 89% agreement found between the 2 types of tests. Plasma testing identified approximately 50% of the patients with EGFR mutations compared with tumor tissue sampling, for a sensitivity of 46%. Dr Reck pointed out that these tests were performed in local laboratories used in routine clinical practice, not in a laboratory selected for a clinical trial. This makes the results more reflective

on MRI but with no lytic lesions on whole-body x-ray and with no other criteria of hypercalcemia, renal failure, anemia, and bone disease (CRAB) is “considered to have smoldering or asymptomatic myeloma, and follow-up with no treatment is recommended,” the team noted. Now new data highlight the value of MRI in this setting, suggesting that the current practice should be changed accordingly. The panel analyzed evi dence for various types of MRI, and the role of MRI in symptomatic, as well as asymptomatic myeloma, smoldering myeloma, and MGUS.

ll patients with smoldering or asymptomatic multiple myeloma should undergo whole-body magnetic resonance imaging (MRI), or pelvic and spinal MRI if whole body is unavailable, according to recommendations from the International Myeloma Working Group (IMWG). The presence of >1 focal lesions >5 mm should be considered diagnostic for symptomatic myeloma requiring therapy. MRI is not recommended as part of the routine workup in patients with monoclonal gammopathy of undetermined significance (MGUS), unless specific clinical characteristics increase the level of suspicion, according to new recommendations from the IMWG (Dimopoulos MA, et al. J Clin Oncol. 2015;33:657-664).

“

For symptomatic myeloma, the panel affirmed that MRI is the gold standard approach to detecting bone marrow involvement in patients with multiple myeloma, but emphasized that MRI only detects bone marrow involvement, not bone destruction in the disease. Although whole-body MRI is the preferred imaging technique, MRI of the spine and pelvis can detect approximately 90% of focal lesions in myeloma, making it an acceptable alternative when whole-body MRI is not available.

Continued from page 17

Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually found through tumor tissue testing.

of the “clinical reality and not a ‘virtual’ trial reality,” he said. The study showed that the presence of EGFR mutations in ctDNA from plasma or serum can be detected with the testing techniques used in this study in approximately 50% of patients. Commenting on this study, Rafael Rosell, MD, PhD, Catalan Institute of Oncology, Barcelona, Spain, noted that since the trial was conducted, refinements in blood tests for ctDNA have improved the sensitivity of these tests. Therefore, in the future, using ctDNA should be possi-

VALUE-BASED CANCER CARE

MAY 2015

”

—RAFAEL ROSELL, MD, PHD

ble to do a better job at finding EGFR and other genetic mutations. “Cell-free DNA detected in the bloodstream of cancer patients represents an excellent tool to examine genetic alterations that are usually found through tumor tissue testing. This represents one of the most astonishing phenomena in biology,” Dr Rosell stated. “This work paves the way for further studies and expands the routine use of examining mutations, such as EGFR mutations, as part of cancer patient care,” he added.—AG n

MRI is the “procedure of choice” for evaluating painful skeletal lesions and for detecting spinal cord compression. MRI is particularly useful for evaluating collapsed vertebrae when myeloma is not active. The panel concluded that the presence of >7 focal lesions on MRI in combination with a diffuse pattern correlate with inferior survival. Whether these patients require a different approach to treatment is a question that requires a clinical trial to resolve. As for the question of following patients for response to therapy, the panel found MRI associated with a high false- positive rate and, in the absence of clinical indications, “is not recommended.” The evidence showed that: ➤M RI reveals abnormal marrow in as many as 50% of patients who have no osteolytic lesions on whole-body x-ray ➤M RI is useful for the evaluation of symptomatic patients who are at high risk for disease ➤ I dentifying patients with multiple myeloma who are at risk for progression from asymptomatic to symptomatic disease remains a major unresolved issue ➤M RI improved the identification of such patients better than the CRAB criteria. Finally, the evidence for the use of MRI to identify a single-bone plasmacytoma (SBP) shows that “MRI should be part of the staging procedures in patients with SBP to better assess the extent of the local tumor and reveal occult lesions elsewhere,” according to the expert panel. Based on this new analysis, the expert panel now recommends that: ➤P atients with >1 unequivocal focal lesion that is >5 mm on MRI be considered symptomatic and require therapy ➤P atients with equivocal focal lesions should have a repeated MRI after 3 to 6 months, and evidence of progression should be considered symptomatic disease that is in need of therapy. The data were less compelling for the role of MRI in MGUS. The panel concluded that whole-body MRI “identifies patients with MGUS with focal lesions that possibly reflect infiltration by monoclonal plasma cells in the bone marrow. These patients seem to have increased risk of progression to myeloma.” In keeping with the evidence, the panel said that “MRI is not recommended as part of the routine workup for patients with MGUS unless there are clinical features that increase suspicion.” n

VOL. 6

NO. 4

5th Conference

AVBCC 5th Conference: Continuing Challenges for Optimizing Value in...

Continued from the cover

Owens Associates, Ocean View, DE, introduced the current trends and challenges in optimizing value in cancer care. The goal of the conference was to articulate challenges and potential multistakeholder solutions to the barriers associated with cost, quality, and access to care. Cost pressures and payment models continue to dominate the conversation, said Mr Zweigenhaft. From the perspective of the medical oncologist, infused drugs remain the largest portion of drug utilization spending. Drug margins no longer drive practice incomes, he said. Oncology drug margin compression continues following the 2013 budget sequester, which reduced providers’ reimbursement by almost 30%. The large drug margins have given way to smaller margins and to larger administration fees, resulting in higher overall practice costs. Some consequences of the fiscal unsustainability in oncology are more common prior authorizations, higher deductibles, tiered formularies, bundled payments, and new pathways. The increased complexity that these measures create, along with declining margins, have “made it really tough for most of these practices to find fiscal sustainability,” Mr Zweigenhaft said. A shortage of oncologists will also transform care. Most of the 11,000 oncologists who are treating patients with cancer are aging. The number of oncologists aged ≥65 years now exceeds those aged ≤40 years, and older physicians carry a heavier clinical workload, according to the 2015 report, The State of Cancer Care in America, from the American Society of Clinical Oncology. Oncology pharmacists and nurse navigators will have to step up to fill the need, Mr Zweigenhaft said, helping patients to reconcile their treatment goals

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and manage their toxicities, including financial toxicity. The challenges with new payment models in oncology also include the

The 340B Drug Pricing Program has created a perverse financial incentive for hospitals that qualify for 340B to buy physician practices, generating more

“”

“

Genetics will move us from upwards of 600 diagnoses to 1200 individual diagnoses of cancer. —BURT ZWEIGENHAFT, BS

question of the affordability of personalized medicine. “Genetics will move us from upwards of 600 diagnoses to 1200 individual diagnoses of cancer,” said Mr Zweigenhaft. The significant growth in molecular diagnostics, including the FDA’s approval of companion diagnostics, creates an enhanced role for information technology, as health systems and payers attempt to tackle the abundance of new information in cancer care.

All of us who are in healthcare financing have a fiduciary duty, whether you’re an employer, payer, a provider, or a drug developer.

”

—GARY M. OWENS, MD

revenue per patient. Patient engagement is needed to improve patient adherence as a way to enhance economic and clinical outcomes. Citing the example of imatinib (Gleevec) in the treatment of chronic myelogenous leukemia, adherence to therapy improved outcomes for all stakeholders, including the patient. “Low-compliance patients represent a higher global spending,” Mr Zweigenhaft noted.

MAY 2015

Defining Value in Cancer Care

Dr Owens summarized the discussion of the Steering Committee, which attempted to define issues in value-based care in oncology. He listed 8 key points, including issues relevant in the formula for value. These issues included the need for patient-reported outcomes. He questioned, “What happens in the real world after these drugs get in common use?” Other concerns included the failure to tackle the total cost of care and toxicity in cost to multiple stakeholders, including to patients and their families. As one of the solutions, the assumption of risk across various stakeholders (eg, hospitals, payers, providers, drug manufacturers) “may eventually help us manage these financial toxicity issues,” Dr Owens suggested. “All of us who are in healthcare financing have a fiduciary duty, whether you’re an employer, payer, a provider, or a drug developer. Everybody has a clear understanding of what their fiduciary roles are and in defining those fiduciary roles.” As the use of electronic medical rec ords and large databases in the insurance world grows, it is from these sources that information will be developed. “It’s a huge step in translating those data into information, and I think we’re still taking the baby steps right now,” noted Dr Owens. “The more you can know about a disease process and the more you can know about the different interventions and what the outcomes are, hopefully the better you can manage it.” He also advised that a common language is needed to align incentives. Finally, Dr Owens pointed out that the failure to provide timely care, provide state-of-the-art care, or to advise patients of the potential downsides of treatments can result in litigation risk. n

www.ValueBasedCancerCare.com

5th Conference

Pathways Have the Potential to Deliver Personalized Medicine By Wayne Kuznar Washington, DC—The institution of cancer treatment pathways is not incompatible with personalized medicine, but rather it has the potential to offer access to a rapid learning system that can promote personalized therapy, said Michael Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna, at the Fifth Annual Conference of the Association for Value-Based Cancer Care.

sider to be indicative of a positive response, ultimately had a different impact on the patient,” said Dr Kolodziej. There are numerous EGFR variants, including more than 250 point mutations, and each mutation is clinically distinct and responds differently to afatinib or to

erlotinib (Tarceva), or does not respond at all in the case of point mutations. Unless the clinician can know the specific variant, rational treatment selection is not possible. “We need a construct by which we actually learn something,” he said, pointing to the American Society of Clin-

ical Oncology’s CancerLinQ (Figure). In CancerLinQ, patients undergoing genomic profiling and receiving treatment based on the results are entered into a national registry and their outcomes are being tracked. “We need to think about expression

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We need to think about expression assays, we need to think about proteomics, we need to think about immunological markers.

”

—MICHAEL KOLODZIEJ, MD

Pathways can enable personalized care, going beyond just the genome. A patient with lung cancer who is aged 70 years is different from a patient with lung cancer who is aged 40 years, irrespective of their mutational structure. The view of cancer as a linear disease, in which treatment is chosen based on a known mutation, does not necessarily lead to improved patient outcomes, he argued. One example is the use of EGFR mutation status to select treatment for patients with NSCLC. Patients with an EGFR mutation—deletion 19 or substitution—have better progression-free survival than patients without an EGFR mutation. A retrospective data analysis showed greater overall survival associated with afatinib (Gilotrif) treatment than with chemotherapy in patients with deletion 19, but with a hint that overall survival is worse in patients with a point mutation receiving afatinib. “The 2 mutations that we would con-

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Visit LENVIMAinfo.com

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Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension.

Hemo The in freque hemor hemor LENVI dose o LENVI

Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction.

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Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months.

LENVI poten treatm

4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure.

Advise

Adver

The m respec (62% v stomat erythro

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

Please

MAY 2015 I78618ha_b.indd 1-2

VOL. 6

NO. 4

5th Conference Figure A SCO’s CancerLinQ Platform

Provide services Point of care

Intake data

Trend analysis Correlation analysis

Hypothesis generation

Transform data

Analyze data Aggregate data

Peer review and feedback

assays, we need to think about proteomics, we need to think about immunological markers,” he said. “If it were really an N of 1, we would be paralyzed by indecision. What we need is the ability to sort a population into just the right size…put in molecular markers, and we make an intervention and measure what happens,” Dr Kolodziej said. “We need to be able to take the population and identify appropriate subpopulations that allow us

to predict in a probabilistic fashion the likelihood that that next patient who is similar will respond, and identify what the clinically different elements are that predict a lack of response.” Pathways have the potential to promote personalized therapy, Dr Kolodziej said. “The answer might be in the cloud, but it doesn’t make decisions at the bedside, and that’s why we need pathways to actually deliver personalized medicine.” n

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

6% of e after hold de 2.

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

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3 or tudied

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

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

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

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MAY 2015

www.ValueBasedCancerCare.com

2/23/15 4:50 PM

In the Literature Patient-Reported Outcomes Needed in Clinical Trials of Cancer Therapies for Accurate Drug Safety Evaluations

Accurately reporting the occurrence and severity of drug-related adverse events in clinical trials is important for determining the drug’s true risk–benefit ratio. Currently, however, toxicity profiles are based on clinician assessment

rather than on patient assessment, and the underreporting of toxicities by physicians could affect the drug’s absolute estimates of toxicity. A recent study evaluated the concordance between the patients’ and physicians’ reporting of toxicities during anticancer treatments and the potential underreporting of toxicities by physicians (Di Maio M, et al. J Clin Oncol. 2015;33:910-915). The study used toxicity responses from

1090 patients with cancer who enrolled in 3 clinical trials—1 clinical trial for patients with breast cancer, ELDA (Elderly Breast Cancer—Docetaxel Adjuvant), and 2 clinical trials for patients with advanced non–small-cell lung cancer, GECO (Gemcitabine–Coxib) and TORCH (Tarceva or Chemotherapy). The patients’ responses were collected at the end of each treatment cycle using the European Organisation for

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

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

Modification

Adjusted Doseb

First occurrence

Interrupt until resolved to Grade 0-1 or baseline

20 mg (two 10 mg capsules) orally once daily

Second occurrencec

Interrupt until resolved to Grade 0-1 or baseline

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

Third occurrencec

Interrupt until resolved to Grade 0-1 or baseline

10 mg (one 10 mg capsule) orally once daily

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

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Research and Treatment of Cancer quality-of-life questionnaires. The physicians’ responses were collected using case report forms; any toxicity grade of >0 was considered “toxicity reported by the physician.” Overall, 6 drug-related adverse events were evaluated, including nausea, vomiting, hair loss, anorexia, constipation, and diarrhea. The results revealed that for all 6T:14.625” toxicities, the Cohen’s κ ranged between S:14.375”

resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. 5.5 Proteinuria In Study 1, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome. 5.6 Renal Failure and Impairment In Study 1, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group. The primary risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. 5.7 Gastrointestinal Perforation and Fistula Formation In Study 1, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. 5.8 QT Interval Prolongation In Study 1, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of Grade 3 or greater was 2% in LENVIMA-treated patients compared to no reports in the placebo group. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of Grade 3 or greater QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. 5.9 Hypocalcemia In Study 1, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. 5.10 Reversible Posterior Leukoencephalopathy Syndrome Across clinical studies in which 1108 patients received LENVIMA, there were 3 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. 5.11 Hemorrhagic Events In Study 1, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. Across clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of fatal intracranial hemorrhage among 16 patients who received lenvatinib and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. 5.12 Impairment of Thyroid Stimulating Hormone Suppression LENVIMA impairs exogenous thyroid suppression. In Study 1, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC. 5.13 Embryofetal Toxicity Based on its mechanism of action and data from animal reproduction studies, LENVIMA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. 6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label. Please see the Warnings and Precautions sections in the full prescribing information. • Hypertension • Cardiac Dysfunction • Arterial Thromboembolic Events • Hepatotoxicity • Proteinuria • Renal Failure and Impairment • Gastrointestinal Perforation and Fistula Formation • QT Interval Prolongation • Hypocalcemia • Reversible Posterior Leukoencephalopathy Syndrome • Hemorrhagic Events • Impairment of Thyroid Stimulating Hormone Suppression 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Safety data obtained in 1108 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize risks of serious adverse drug reactions. The median age was 60 years (range 21-89 years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in the entire population was 5.5 months. The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodinerefractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131). The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity. In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension (3%), and dehydration (3%). Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%). Table 2 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMAtreated patients than patients receiving placebo in the double-blind phase of the DTC study.

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Table 2

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

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Table 3

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In the Literature 0.15 and 0.45, indicating poor-to-moderate agreement between physician and patient reporting of adverse events. In addition, the percentages of toxicities reported by the patients were always higher than the percentages that were reported by the physicians. For example, anorexia was reported in 62.3% of patients, 60.0% reported nausea, 26.0% of patients reported T:14.625” vomiting, 51.0% reported constipation, S:14.375” Table 2

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

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

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

44 2

16 2

4 0

9 2 5 2 2 0.4 1 0.4 0.4

17 25 8 15 11 15 2 8 4

0 1 0 0 1 1 0 0 0

11 0.4

35 8

4 0

13 7 2

15 18 2

1 1 1

3 0 0.4

11 3 9

1 0 0

3 0.4 0 0

1 3 5 2

0 0 0 0

1 0 0

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0 0 0

1 1

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

Table 3

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

Laboratory Abnormality

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

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

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

3 4 5 9 6 4

0 0 0 2 1 1

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

constipation, 50.8% for diarrhea, and 65.2% for hair loss. The researchers attributed physician underreporting to several factors, including less attention paid to adverse events that do not require treatment modifications, judgment of adverse events as not related to treatment, and not reporting adverse events that are expected with the given treatment. According to the investigators, the

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

results from this study underline the importance of patient-reported toxicity information in clinical trials of cancer medications, especially because of the high risk for physician underreporting of treatment-related adverse events. Integrating patient-reported outcomes into drug safety evaluation can ensure that patients’ preferences are at the forefront of anticancer treatment decision-making.

Ibrutinib Highly Active in Patients with Waldenström’s Macroglobulinemia

In a recently reported phase 2 study of 63 patients with Waldenström’s macroglobulinemia and/or MYD88 and CXCR4 mutations who had received at least 1 previous treatment, ibrutinib (Imbruvica) was highly active, safe, and associated with durable responses (Treon SP, et al. N Engl J Med. 2015;372:1430-1440). This study led to the expedited FDA approval of ibrutinib on January 29, 2015, for the treatment of patients with Waldenström’s macroglobulinemia; ibru tinib is the first FDA-approved therapy for this indication. Waldenström’s macroglobulinemia is a B-cell lymphoma associated with a buildup of clonal lymphoplasmacytic cells and monoclonal immunoglobulin (Ig) M secretion. In this study, the investigators assessed the effect of MYD88 and CXCR4 mutations on outcomes in 63 previously treated patients with Waldenström’s macroglobulinemia who received a daily dose of ibrutinib. The study’s primary objective was the overall response rate (≥25% reduction in IgM levels), partial response rate (≥50% reduction), very good partial response rate (≥90% reduction), complete response rate (100%), and major response rate (complete response or major response). The secondary objectives included progression-free survival and drug safety. The study results indicated that MYD88L265P was present in 56 patients and CXCR4WHIM was present in 21 patients; all patients with wild-type MYD88 had wild-type CXCR4 (CXCR4WT). After receiving ibrutinib, the median serum IgM levels decreased from 3520 mg/dL to 880 mg/dL, and the median hemoglobin levels increased from 10.5 g/dL to 13.8 g/dL. Furthermore, bone marrow involvement decreased from 60% to 25%. The overall and major response rates were 90.5% and 73%, respectively; a very good partial response was reported in 10 patients, a partial response in 36 patients, and a minor response in 11 patients. The overall and major response rates were highest in patients with the MYD88L265PCXCR4WT genotype, followed by the MYD88L265P CXCR4WHIM and MYD88WTCXCR4WT genotypes. The median times to at least minor and partial responses were 4 weeks

T:10” S:9.5”

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50.8% reported hair loss, and 35.7% reported diarrhea. Conversely, 18.5% of physicians reported anorexia in their patients, nausea in 44.8%, vomiting in 23.5%, constipation in 18.6%, hair loss in 19.1%, and diarrhea in 22.8%. Furthermore, any physician report of grade 0 was considered underreporting and included 74.4% for anorexia, 40.7% for nausea, 47.3% for vomiting, 69.3% for

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Economics of Cancer Care

Value of Cancer Care for Most Tumors Lower in United States than in Western... Continued from the cover

concluding that the high costs in the United States were worth it. However, the new analysis shows that Americans are getting far less value for their money than Western Europeans are for several tumor types, including prostate cancer. The new study further highlights significant flaws in the earlier study, such as miscalculating the rates of stomach cancer deaths, not including lung cancer in the analysis, and not considering the stage at cancer diagnosis.

Soneji noted that survival data can provide inaccurate results if they do not account for cancer stage at diagnosis. Survival times can often be inflated because of earlier diagnosis and overdiagnosis, he said. These do not necessarily affect disease course and mortality, and are more common in the United States, he added. Furthermore, the earlier study also looked at 10 countries, whereas the new analysis expanded to 20 countries, in-

at a glance ➤ Americans pay more for cancer treatment than Western Europeans, but often do not achieve improved survival ➤ US prostate cancer costs are significantly higher, because more aggressive treatment is more costly ➤ Stomach and colorectal cancers had the highest number of life-years saved in the United States compared with Western Europe

Dr Soneji’s analysis showed that in contrast to what was reported in the previous analysis, 78% fewer cases of breast cancer deaths were averted and 60% fewer prostate cancer deaths were averted in the United States. Overall, compared with Western Europe: • 621,820 stomach cancer deaths were averted in the United States, resulting in 13,705,501 US life-years saved

“

Reassessing Value in Cancer Care

Samir Soneji, PhD, MA, Assistant Professor of Health Policy, Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, NH, told Value-Based Cancer Care (VBCC) that some of the conclusions of Dr Philipson and his colleagues are implausible. “For example, they calculated that there were 224,212 excess stomach cancer deaths in the US compared with Western Europe between 1982 and 2005. But the United States had lower stomach cancer mortality rates than Western Europe throughout the entire period, so the United States could have only averted stomach cancer deaths, not experienced excess deaths,” said Dr Soneji. “And in fact, the greatest number of deaths averted occurred in cancers for which decreasing mortality rates were more likely to be the result of successful prevention and screening than from advancements in treatment.” Dr Soneji and his colleague analyzed information from the World Health Organization Cancer Mortality Database. The 2012 analysis used survival data from large national cancer registries in the United States and Europe. Dr

New Evidence for Number of US Deaths Averted

The United States spends substantially more in cancer care costs relative to the number of quality-adjusted life-years saved….While the cost of prostate cancer treatment is much higher in the United States, the United States doesn’t experience many more lives saved. The cost is higher because of more aggressive treatment.

”

—SAMIR SONEJI, PHD, MA

cluding countries with higher healthcare spending and similar life expec tancy increases and population-wide screening as the United States. In addition, the 2012 analysis focused on 13 cancer types—breast, prostate, colorectal, testicular, soft-tissue, thyroid, stomach, uterine, melanoma, Hodgkin lymphoma, non-Hodgkin lymphoma, acute myeloid leukemia, and chronic myeloid leukemia. The new analysis included all these cancer types (except soft-tissue and uterine) and added cervical and lung cancers. Both studies calculated excess and averted deaths in the United States versus Western Europe; that is, the surfeit of deaths and the reduction in deaths, respectively, taking into account differences across age-groups in population size, sex proportions, and mortality rates. Dr Soneji and his colleague also tried to replicate the results of Dr Philipson’s team by looking at the same set of cancer types in the same European countries during the study period of 1982 to 2005. The number of deaths averted and the overall results “varied substantially by cancer type,” they wrote.

VALUE-BASED CANCER CARE

MAY 2015

• 4354 cervical cancer deaths were averted, resulting in –41,090 US lifeyears saved • 69,389 breast cancer deaths were averted after 1986 and 2592 excess breast cancer deaths occurred in 19821986 and 1990, resulting in overall 66,797 deaths averted • 264,632 colorectal cancer deaths were averted • 11,759 excess prostate cancer deaths occurred in 1982-1995, and 71,641 prostate cancer deaths were averted after 1995 • –1,119,599 excess lung cancer deaths, resulting in –28,311,995 US life-years saved. Dr Soneji told VBCC that the small number of averted breast cancer deaths “is likely due to advancements in breast cancer treatment that were common in both the US and Europe—transatlantic use of similar chemotherapy drugs and surgery.” However, he noted, the ratio of incremental cost to quality-adjusted life-years (QALYs) saved is high, “because the United States spends substantially more in cancer care costs relative to the number of quality-adjusted life-years saved”;

that is, not too many more lives are saved in the United States than in Europe. Similarly, Dr Soneji said, “While the cost of prostate cancer treatment is much higher in the United States, the United States doesn’t experience many more lives saved. The cost is higher because of more aggressive treatment,” which is costly. Lives Saved

Stomach and colorectal cancers had the highest numbers of life-years saved in the United States compared with Western Europe, but the cost was significantly higher for colorectal cancer. This is because although there are longstanding and vigorous screening programs in the United States for both types of cancers, the most effective stomach cancer prevention method is to minimize intake of salted or smoked meats (because they contain nitrosamines), which is more widely done in the United States and has a minimal cost to the healthcare system. Lung and Cervical Cancers

The lopsided results for lung cancer reflect the historically higher lung cancer mortality rates in the United States and the fact that “half of lung cancers are diagnosed at stage 4, so these are very advanced cancers that require extensive, aggressive treatment,” said Dr Soneji. He and Mr Yang predicted that the death differential will fall in the coming years, in sync with declining smoking rates in the United States. Cervical cancer had, by far, the lowest ratio of incremental cost to QALYs saved. The explanation, Dr Soneji noted, is that “both sets of countries achieved progress against cervical cancer mortality; this progress has been about equal (so the difference is very small). Yet, cervical cancer care in the United States is more expensive for a variety of reasons—more expensive chemotherapy, more expensive surgery, and more expensive radiation therapy.” The ACA’s Potential Impact on Cancer

“If greater access to wellness visits and preventive services translates to greater use of these types of medical care, the ACA [Affordable Care Act] may lead to more cancer deaths being averted,” Dr Soneji and Mr Yang wrote. This can be done because the ACA mandates full coverage of annual wellness visits for the elderly, for example, and it may do so in a cost-effective manner. n

VOL. 6

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Economics of Cancer Care

US Oncologists Favor Establishment of NICE-Like Body to Determine Medicare Cancer Drugs Reimbursement By Rosemary Frei, MSc

ccording to a recent study, 63.6% of oncologists surveyed favor the establishment of an independent panel of health experts to decide which treatments Medicare will pay for based on a cost-benefit analysis (Gogineni K, et al. J Clin Oncol. 2015; 33:846-853). Less than 50% of patients and members of the general public think this is a good idea. The United Kingdom’s National Institute for Health and Care Excellence (NICE) is one model for such a panel. Despite oncologists’ support, “I think the culture in the US is such that the fear of fewer choices (even if we can safely say that more choices does not necessarily mean better care) will make it very difficult to institute a body like NICE,” lead investigator Keerthi Gogineni, MD, MSHP, Assistant Pro-

at a glance ➤ A new survey shows 63.6% of US oncologists favor the establishment of a NICE-like panel to decide Medicare reimbursement based on costbenefit analyses ➤ Overall, 70.3% of oncologists believe that unnecessary tests and treatments add a moderate/large amount to Medicare costs

fessor of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, told Value-Based Cancer Care. “I would hope that one way around this would be to require new drug/technology applications to include an incremental cost-effectiveness analysis as part of the approval process, so that at least we begin generating the data we need to be able to delineate what has value,” she said. In addition, “having clinical guidelines that have to be met, especially in oncology, in order to get reimbursed would be one way to ensure that high-quality care is being delivered,” Dr Gogineni added. Study Details

A total of 326 patients with cancer with appointments at the University of Pennsylvania’s Abramson Cancer Center, as well as 250 oncologists and hematologists and 891 members of the general public completed the survey. The majority of the respondents said they feel Medicare spending is a moderate or “big” problem facing the United States, and that cuts can be made without denying healthcare to anyone who really needs it. Furthermore, in response to a menu of 6 potential factors that increase Medicare spending, drug company pricing and insurance company profits were rated as the top 2 contributors to the problem. Physicians and hospitals also share the blame, however, according to survey respondents—70.3% of oncologists thought unnecessary tests and treat-

Despite oncologists’ support, the culture in the US is such that the fear of fewer choices…will make it very difficult to institute a body like NICE.

“

”

—KEERTHI GOGINENI, MD, MSHP

ments add a moderate or a large amount to Medicare costs, as did 69.1% of patients with cancer and 80.9% of the general public respondents. In addition, 66.9% of patients with cancer and 79.4% of the public responded in the affirmative that hospitals or doctors committing “fraud by submitting bills for services not provided” contributes significantly to high Medicare costs. Only 19.2% of oncologists thought this to be true. The multivariable analysis revealed that African Americans, Hispanic Americans, and Americans aged ≥55 years were most likely to believe that provider fraud contributes to high Medicare costs. Oncologists Concern with High Cost of Patient Care

The researchers suggested that these results indicate that “health care providers are no longer impervious to criticism as a major contributor of high costs.” This

corroborates “physicians’ apprehension about Centers for Medicare and Medicaid Services’ disclosure of provider utilization and payment data,” they wrote. The survey also included 4 proposed solutions to high Medicare costs. In response to the first solution, “Refuse to pay when a less expensive test or treatment has been shown to work just as well”—more than 75% of patients, oncologists, and the public supported that proposal. Means testing, in which patients with more financial resources pay a larger portion of their costs, was supported by small majorities of the 3 groups. Means testing was most highly favored by members of the public who were male or Democrats. Creating an annual ceiling for the amount that Medicare would spend on any 1 person was far less popular, garnering only 12.9% of patients’ support, 16.8% of oncologists’, and 28.3% of the general public’s. n

Medicare’s Sustainable Growth Rate Repeal Met with Relief By Laura Morgan

he April 14, 2015, repeal of the sustainable growth rate (SGR) formula for physician payments under Medicare is being welcomed by the healthcare community, including the American Society of Clinical Oncology (ASCO). The 392 to 37 vote to pass H.R. 2, called the Medicare Access and Children’s Health Insurance Program Reauthorization Act of 2015, came just in time to avoid the 21% cut in Medicare fees that would have come into effect after the most recent SGR patch expired on March 31, 2015.

Alternative Payment Models

Among the provisions of the SGR repeal legislation is a continued emphasis on alternative payment models. Specialists are among those being encouraged to use this approach, with oncologists first in line. Shortly before the SGR repeal, the US Department of Health & Human Services (HHS) Secretary Sylvia M. Burwell wrote that, “Our target is to have 30% of Medicare payments tied to quality or value through alternative payment models by the end of 2016, and 50% of payments by

the end of 2018….We plan to develop and test new payment models for specialty care, starting with oncology care” (Burwell SM. N Engl J Med. 2015;372:897-899). “We think this is a vast improvement over where we’ve been over the last 5 years. And we’re really appreciative of the way Congress worked closely with the physician community over this,” A SCO’s Government Relations Committee Chair, Blase N. Polite, MD, MPH, Assistant Professor of Medicine, University of Chicago, told Value-Based Cancer Care (VBCC) in an interview. “Congress’s in-

tent, we believe, is to allow flexibility— we think there will be 3 or 4 different models for alternative payment models in oncology. You don’t want everybody to go to the same model; you want HHS to establish the ground rules, and then let innovation come from physicians.” Merit-Based Incentive Payment System

The new bill also states that healthcare “professionals who receive a significant share of their revenues through an alternative payment model(s)” and meet Continued on page 26

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www.ValueBasedCancerCare.com

Economics of Cancer Care

Substantial Costs Associated with Systemic Therapy After Ipilimumab in Patients with Advanced Melanoma By Laura Morgan

San Diego, CA—The healthcare costs of patients with advanced melanoma after ipilimumab (Yervoy) therapy are significant, according to recent study findings presented at the 2015 Academy of Managed Care Pharmacy annual meeting. According to Elisabetta Malangone-Monaco, MS, Truven Health Analytics, Bethesda, MD, and colleagues, “While IPI [ipilimumab], an anti– CTLA-4 immunotherapy indicated for unresectable advanced MEL [melanoma], has been a mainstay of first-line treatment, there is currently no established standard of care following its progression.” The study evaluated the use of systemic therapies after first-line ipilimumab, and the healthcare costs associated with systemic therapies after first-line therapy in patients with advanced melanoma. This retrospective, observational cohort study was conducted using US administrative claims data between 2011

“

While IPI [ipilimumab], an anti–CTLA-4 immunotherapy indicated for unresectable advanced MEL [melanoma], has been a mainstay of first-line treatment, there is currently no established standard of care following its progression.

”

—ELISABETTA MALANGONEMONACO, MS, AND COLLEAGUES

and 2013, which comprised inpatient medical data, outpatient medical data, and outpatient prescription drug data for patients with employer-sponsored primary insurance or with Medicare sup-

plemental insurance. The patients included in the study received systemic therapy after the use of ipilimumab, including chemotherapy, targeted therapy, or immunotherapy. The researchers measured the per-patient per-month all-cause total healthcare costs from the date of first treatment after ipilimumab therapy; these healthcare costs comprised melanoma systemic therapy drugs costs, medical claims with a diagnosis of melanoma, and other nonspecified utilization. The study’s results demonstrated that of the 111 patients who received systemic therapy after the completion of ipi limumab therapy, 77.5% used a single agent, 18.9% used 2 agents, and 3.6% used 3 or more agents. The per-patient per-month all-cause total healthcare cost amounted to $20,383, of which 24% was attributed to office- and pharmacy-administered drugs, 29% was related to medical claims with a diagnosis of melanoma, and 48% was attributed to

Medicare’s Sustainable Growth Rate... several criteria will not be subject to the merit-based incentive payment system. Merit-based incentive payment systems will come into effect in 2019 and will unify the onerous requirements of the Physician Quality Reporting System, the value-based payment modifier, and

the meaningful use of electronic health records. This provides another incentive to move to alternative payment models, said Dr Polite.

“

We think there will be 3 or 4 different models for alternative payment models in oncology. You don’t want everybody to go to the same model; you want HHS to establish the ground rules, and then let innovation come from physicians.

at a glance ➤ The vote to repeal the SGR formula for physician payments under Medicare has had a positive impact on the healthcare community ➤ Oncologists are encouraged to use alternative payment models so more Medicare payments can be tied to quality or value-based care ➤ The bill further incentivizes physicians to use alternative payment models so they are not subject to merit-based incentive payment systems

providing a strong incentive to do that in several ways, one of which is to join an alternative payment model and avoid all the requirements associated with

”

—BLASE N. POLITE, MD, MPH

“What they [HHS] want you to do is move completely away from fee-for-service reimbursement and to value-based reimbursement—they’re asking us to blow up the current system and start doing things differently. And they’re

VALUE-BASED CANCER CARE

MAY 2015

merit-based incentive payment systems,” Dr Polite told VBCC. Providers who avoid merit-based incentive payment systems by participating in an alternative payment model will receive a 5% bonus annually from 2019

other nonspecified utilization. During the follow-up period, the researchers reported that of the 4 most frequently used systemic therapies in this study––temozolomide (Temodar), vemurafenib (Zelboraf), paclitaxel (Abraxane), and carboplatin (Paraplatin)––the melanoma drug costs were lowest for paclitaxel and carboplatin, but the nonspecified utilization costs were highest for these agents. Furthermore, the proportion of per- patient per-month all-cause total healthcare costs attributed to nonspecified utilization ranged from 36% for patients receiving vemurafenib to 74% for patients receiving carboplatin. The researchers concluded that many physicians continue to use traditional chemotherapies for advanced melanoma despite the approval of new therapies for this indication; in addition, the cost of these conventional chemotherapies after the use of ipilimumab is substantial. n

Continued from page 25

to 2024. Then, starting in 2026, providers who participate in alternative payment models and meet various criteria will receive an annual 0.75% payment increase, whereas those still participating in other payment systems will only receive increases of 0.25% annually. Future of the Sustainable Growth Rate

The future still remains uncertain, however, noted Robert Steinbrook, MD, Adjunct Professor of General Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, in an article about the SGR repeal (Steinbrook R. JAMA. 2015 April 17. Epub ahead of print). “At some point, the cumulative effect of the new payment updates will not keep up with physician costs, unless the volume and cost of services substantially decrease, which is the same underlying issue as with the old payment updates,” Dr Steinbrook pointed out. “The SGR formula lasted 18 years. Within the decade, its replacement is likely to be under scrutiny as well.” n

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Economics of Cancer Care

Real-World Treatment Patterns of Axitinib for Advanced Renal-Cell Carcinoma By Laura Morgan

San Diego, CA—Approved in 2012 by the FDA, axitinib (Inlyta) is indicated for the treatment of patients with advanced renal-cell carcinoma (RCC) whose disease had failed 1 previous systemic therapy. The approval of axitinib was based on the safety and efficacy data from clinical trials, which are often limited in their patient population and short-term analysis. Therefore, Elizabeth MacLean, PhD, Pfizer Global Health and Value, New York, NY, and colleagues sought to assess real-world patient experience with axitinib to help optimize therapy for patients with advanced RCC. The study was presented at the 2015 Academy of Managed Care Pharmacy annual meeting. In this retrospective, observational study, researchers analyzed data from 1175 patients with advanced RCC who received axitinib as subsequent therapy. The patient data from 22 specialty pharmacies were matched with patient data from longitudinal medical and

pharmacy databases (between April 2009 and February 2014). The researchers focused their assessment on the duration of axitinib therapy, dose modifications of axitinib, and axitinib- related patient out-of-pocket costs. Overall, 56% of patients received axitinib as second-line therapy, 28% as third-line therapy, and 16% as fourthline or later therapy. The 3 most common therapies that patients received before starting axitinib included sunitinib (Sutent; 38%), everolimus (Afinitor; 22%), and pazopanib (Votrient; 21%). The mean duration of second- and third-line axitinib therapy was 172.3 days and 169.2 days, respectively. The researchers identified various patient characteristics that affected the duration of subsequent axitinib therapy, including sex, location, baseline hypothyroidism treatment, and previous therapy for RCC. Longer treatment duration was reported in male patients versus female patients, patients in the Northeast versus the Midwest or the West, and pa-

tients with treatment for baseline hypothyroidism. Previous treatment with

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Results from this analysis provide insight into routine clinical use of axitinib as subsequent RCC therapy in the United States in the period following FDA approval, and allows for comparison of axitinib dosing patterns in the realworld versus in a clinical trial setting.

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—ELIZABETH MACLEAN, PHD, AND COLLEAGUES

bevacizumab (Avastin) and temsirolimus (Torisel) was associated with shorter

treatment duration compared with previous sunitinib therapy. Of the patients who started subsequent therapy with axitinib, 87% received the standard 5-mg dose, and of these patients, 70% did not undergo dose adjustment. Conversely, 14% of patients decreased the axitinib dose, 10% increased the axitinib dose, and 6% increased then decreased the dose of axitinib. The copayments for axitinib therapy ranged from $0 to $85 for 52% of the patients, and the mean copay was $294 for all patients: $153 for patients with commercial insuranc0e, $699 for patients with Medicare, and $16 for patients with Medicaid. “Results from this analysis provide in sight into routine clinical use of axitinib as subsequent RCC therapy in the United States in the period following FDA approval, and allows for comparison of axitinib dosing patterns in the real-world versus in a clinical trial setting,” the researchers said. n

Health Plan Cost-Savings with Netupitant/ Palonosetron for the Prevention of CINV San Diego, CA—According to the National Comprehensive Cancer Network guidelines for the prevention of chemotherapy-induced nausea and vomiting (CINV), highly and moderately emetogenic chemotherapy should be managed with a 5-HT3 receptor antagonist, an NK1 receptor antagonist, and dexamethasone (Decadron). A recent study by Russell L. Knoth, PharmD, Eisai, Woodcliff Lake, NJ, and colleagues sought to quantify the cost impact of adopting the 5-HT3/NK1 combination netupitant plus palonosetron (Akynzeo) in a US health plan for the prevention of CINV. The study results were presented at the 2015 Academy of Managed Care Pharmacy annual meeting. Using a decision analytic model, researchers compared the costs of antiemetic prophylaxis during a 3-year period before and after netupitant plus palonosetron became a treatment option in a US health plan. This analysis was based on the annual VOL. 6

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plan costs, per-member per-month costs, and the costs per utilizing member. The calculated treatment costs were derived using standard prescribing dosages and current US medication prices.

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Results of the model indicate that adoption of NEPA [netupitant/ palonosetron] for the prevention of CINV will have a relatively neutral impact on a U.S. health plan budget.

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—RUSSELL L. KNOTH, PHARMD, AND COLLEAGUES

The researchers identified 1383 patients who were eligible to receive netupitant plus palonosetron for moderately or highly emetogenic chemotherapy. The study’s results revealed

that before the adoption of netupitant plus palonosetron, the cost of preventing CINV totaled nearly $4 million (ie, $3,997,255). After a 3-year period, however, netupitant plus palonosetron reduced the annual cost by $51,227. In addition, the reduced per-member per-month cost for netupitant plus palonosetron resulted in an annual cost-savings of $0.002 in year 1, $0.003 in year 2, and $0.004 in year 3. Finally, a review of the per–utilizing member cost showed that there were only 2 other antiemetic regimens that were less expensive than netupitant plus palonosetron. Several study limitations may impact the interpretation of these results. For example, the treatment costs were based on current medication prices, which are likely to change. In addition, the researchers did not account for the costs of patients who may have switched therapy during their chemotherapy cycles. “Results of the model indicate that MAY 2015

at a glance ➤ Using netupitant plus palonosetron reduces the annual costs for CINV prevention ➤ A new strategy using this combination may reduce the incidence of CINV and should have a neutral impact on US health plan costs

adoption of NEPA [netupitant/palonosetron] for the prevention of CINV will have a relatively neutral impact on a U.S. health plan budget,” the researchers concluded. Nevertheless, this study focused on medication costs alone and did not consider the combination’s established efficacy of reducing the incidence of CINV, which may further confer cost-savings benefits on health plans.—LM n

www.ValueBasedCancerCare.com

Survivorship

Revised Survivorship Care Plan Template Reduces Time and Resource Commitments Implementing such programs in oncology practice is now easier By Charles Bankhead

revised survivorship care plan template addresses obstacles that have limited the use of survivorship plans in clinical practice, suggested an American Society of Clinical Oncology (ASCO) expert panel headed by Deborah K. Mayer, PhD, MSN, RN, Professor of Nursing and Director of Survivorship Care, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. “For the most part, we think the revised template addresses the major barriers that have limited use of survivorship care plans in oncology practice,” Dr Mayer told Value-Based Cancer Care (VBCC). “We’re encouraged by the feedback we received from the study participants, and we plan to monitor use of the template and possibly make other modifications that we might identify.” In its 2005 report, “From Cancer Patient to Cancer Survivor: Lost in Transition,” the Institute of Medicine (IOM) outlined the key components of survivorship care in the United States. The IOM also called for the development and routine use of a survivorship plan as part of cancer care, consisting of a treatment summary and a plan for follow-up care. The revised plan was evaluated in a pilot study of oncology experts who reviewed the template and provided feedback to the expert panel. A summary of the revised template and the responses from pilot participants was recently published (Mayer DK, et al. J Oncol Pract. 2014;10:345-351). The pilot study considered the utility of implementing a survivorship care plan at 11 sites, which included a total of 45 plans. On average, the revised template required approximately 30

minutes to implement a survivorship plan in a clinical setting. The study participants gave the new template high marks for incorporating information that is easy to obtain, while covering the essentials of a survivorship plan.

7. Ongoing toxicity or adverse effects of all treatments and likely course of recovery 8. Genetic or hereditary risk factors, predisposing conditions, and genetic testing results.

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For the most part, we think the revised template addresses the major barriers that have limited use of survivorship care plans in oncology practice.

”

—DEBORAH K. MAYER, PHD, MSN, RN

Essentials of a Survivorship Care Plan

The survivorship care plan includes 2 parts, a treatment summary and a care plan, which promote communication between the patient, cancer providers, primary care providers, and any other potential provider. The expert panel outlined the essential components of a survivorship treatment plan, which include: 1. Contact information for institutions and providers 2. Specific diagnosis, including relevant subtypes 3. S tage of disease 4. Date of surgery, surgical procedure, and location on the body 5. Names of chemotherapy agents administered and end date of treatment 6. Area treated with radiation and end date of treatment

In addition, the panel incorporated the key elements of a follow-up care plan, which is meant to help monitor the care of cancer survivors on an ongoing basis. These key elements include: 1. Contact information for oncology team and treatment facility 2. Name, duration, and potential adverse effects of adjuvant therapy 3. Schedule of follow-up visits 4. Tests for recurrence 5. Early detection screening if different from the general population 6. Other tests and examinations 7. Possible symptoms of cancer recurrence 8. List of long-term effects based on treatment 9. General health promotion. The oncology expert panel concluded that limiting the template to these essential elements would reduce the time and resource commitments, thereby in-

directly addressing the lack of reimbursement for the development and preparation of such a plan. The panel members also agreed that the essential elements are insufficient, but could be supplemented with resource tool kits for survivors, such as ones developed by ASCO and other organizations. Care Coordination

The appropriate coordination between oncology and primary care providers will require systemwide commitment and buy-in, the authors noted. Systems and processes must be put in place to handle relevant data from the multiple providers who are involved in the care of patients with cancer. Those responsible for the survivorship care plan must be clearly defined. The education of primary care providers is essential to their acceptance of these plans. In addition, programs for patients with cancer should establish relationships with primary care providers to refer patients who do not have primary care providers.

Reimbursement

The panel did not specifically address reimbursement, but attempted to address the other barriers in its review of the treatment summary and follow-up care plan. “By focusing on essential elements and reducing the time burden, the lack of reimbursement for the services may be addressed indirectly,” Dr Mayer told VBCC. “We also have been encouraged by electronic health record vendors’ efforts to facilitate the survivorship care plan process, and we’re hopeful that the functionality will continue to increase.” n

Highlights from the 2015 ASCO Conference!

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COMING SOON!

A Focus on Non–Small-Cell Lung Cancer an e-newsletter brought to you by the publishers of Value-Based Cancer Care ®

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VALUE-BASED CANCER CARE

MAY 2015

VOL. 6

NO. 4

Big Data in Oncology

CancerLinQ Moves to Its Patient Data-Gathering Clinical Phase By Rosemary Frei, MSc

Southcoast Centers for Cancer Care, New Bedford, MA, is among the first oncology practices across the United

States to adopt CancerLinQ, representB:7.625 in ing a total of approximately 500,000 T:7.375 in patients. Another 7 large cancer cen-

ters have lined up to sign up next, according to ASCO President Peter Paul Yu, MD, Director of Cancer Research, Continued on page 30

In mCRPC therapy…

Is there more to the story?

Photo courtesy of ASCO.

he American Society of Clinical Oncology (ASCO) and a German company called SAP are launching the clinical phase of ASCO’s big-data initiative—CancerLinQ. This clinical phase is focused on gathering and analyzing data from the 97% of US patients with cancer who do not participate in clinical trials. In a recent conference, representatives from ASCO and SAP, as well as a community oncologist discussed the putative potential of CancerLinQ to improve cancer care, from the implementation of personalized medicine to helping payers set care quality and efficiency benchmarks.

”

—CLIFFORD A. HUDIS, MD

Patients “will be reassured that no matter where they are receiving care, they’re getting the highest possible quality, evidence-based care,” said Clifford A. Hudis, MD, ASCO Immediate Past President, and Chief, Breast Medicine Service, Memorial Sloan Kettering Cancer Center, NY. “And the physicians will be…reassured that they’re provided personalized guidance on their treatment decisions, by matching what they are planning for their patients against national quality standards,” he added. “And finally, for the private and public payers and other healthcare organizations, this will bring them metrics and tools that will allow them to support the further development of high-quality and ever-more-efficient care,” Dr Hudis said. VOL. 6

INDICATION ZYTIGA® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant. Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia. Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations. Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

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Physicians will be… reassured that they’re provided personalized guidance on their treatment decisions, by matching what they are planning for their patients against national quality standards.

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

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

NO. 4

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Date: 03/16/15

www.ValueBasedCancerCare.com

Customer Code: 029979-150220

Group 360 Job #: 725462

Big Data in Oncology

CancerLinQ Moves to Its Patient Data-Gathering... Palo Alto Medical Foundation, CA. “We’ll be able to query the database regarding toxicity and tolerance of various chemotherapeutic regimens from the database of thousands of like patients. We’ll have access to real-time data as to our processes and our outcomes, to improve the care we deliver to

patients,” said Therese M. Mulvey, MD, PhD, Physician-in-Chief, Southcoast Centers for Cancer Care. “We’ll also be able to use molecular markers in diseases where clinical trials may be lacking. Many patients have molecular markers performed on their tumors, and this data is locked away and

unavailable for comparison,” Dr Mulvey said. Participating in CancerLinQ, she said, will help us “to improve personalized medicine for patients.” Value-Based Cancer Care talked with Anne-Marie Meyer, PhD, Faculty DiB:7.625 in rector, Integrated Cancer Information T:7.375 in and Surveillance System (ICISS) pro-

Continued from page 29

gram, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, about the challenges of collecting big data in oncology. Dr Meyer was involved in developing North Carolina’s 5.5-million- patient ICISS program. One of the challenges is the different working styles and needs of the many groups involved

For men with mCRPC who progressed on ADT

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

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

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

compared with placebo plus prednisone.

Co-primary end point—overall survival: hazard ratio (HR)=0.792; 95% CI: 0.655, 0.956; P=0.0151; prespecified value for statistical significance not reached. Co-primary end point—radiographic progression-free survival: median not reached for ZYTIGA® plus prednisone vs a median of 8.28 months for placebo plus prednisone. HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

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

VALUE-BASED CANCER CARE

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

MAY 2015

Date: 03/16/15

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Customer Code: 029979-150220

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Group 360 Job #: 725462

Big Data in Oncology Creating systems such as CancerLinQ is a herculean task, because the data going into these systems are as complex as the people they represent.

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—ANNE-MARIE B:7.625 in MEYER, PHD T:7.375 in

in such undertakings, said Dr Meyer, including clinicians, computer scientists/ engineers, andpopulation scientists. “It’s like sitting down a person from Italy with a person from Switzerland— they speak different languages and they use different tools,” she said. But that has to be overcome and “you’ve got to build these intense and close interdisciplinary partnerships,” said Dr Meyer. “It’s a herculean task, because the data

going into these systems are as complex as the people they represent.” She said it is similar to living in a building that is under construction. “If the construction is planned well and the materials are ready, timelines met, expectations clearly communicated, etcetera, life goes on comfortably and efficiently. But if it is not planned well, it can be expensive and painful.” n

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Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®. Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). †At a prespecified interim analysis for OS, 37% (200/546) of patients treated with ZYTIGA® plus prednisone compared with 43% (234/542) of patients treated with placebo plus prednisone had died. ‡Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

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In the Literature Ibrutinib Highly Active in Patients with Waldenström’s... Continued from page 21

and 8 weeks, respectively, and the me dian duration of treatment was 19.1 months. The estimated 2-year progression-free survival rate was 69.1%, and the overall survival rate was 95.2%. The data revealed that grade ≥2 adverse events included neutropenia (22%), thrombocytopenia (14%), post-

procedural bleeding (3%), epistaxis (3%), and atrial fibrillation (5%). Neutropenia and thrombocytopenia were especially common in heavily pretreated patients, and fish oil supplement contributed to grade 2 epistaxis. In addition, all atrial fibrillation events occurred in patients with a history of arrhythmia. The researchers concluded that ibrutinib is safe and effective in patients with

cancer and its role in determining response to breast cancer therapy. In a recent study, the investigators assessed whether mutations in the PI3K catalytPIK3CA Mutations ic subunit (PIK3CA) correlated with Associated with Poor response to neoadjuvant HER2-targetResponse to HER2-Targeted ed therapies in patients with breast Breast Cancer Therapies cancer (Majewski IJ, et al. J Clin Oncol. There is limited information about 2015;33:1334-1339). the effects of phosphatidylinositol 3- The researchers used HER2-positive kinase (PI3K) on the biology of breast breast tissue biopsies from 355 patients

Waldenström’s macroglobulinemia, and that MYD88 and CXCR4 mutation status affects responses to ibrutinib.

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information. INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer. CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions]. Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information]. The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown. Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

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ZYTIGA® (abiraterone acetate) Tablets ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions]. • Adrenocortical Insufficiency [see Warnings and Precautions]. • Hepatotoxicity [see Warnings and Precautions]. • Increased ZYTIGA Exposures with Food [see Warnings and Precautions]. Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients. The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion. The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia. Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 XULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months. Table 1: Adverse Reactions due to ZYTIGA in Study 1 ZYTIGA with Placebo with Prednisone (N=791) Prednisone (N=394) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/ discomfort2 29.5 4.2 23.4 4.1 Muscle discomfort3 26.2 3.0 23.1 2.3 General disorders Edema4 26.7 1.9 18.3 0.8 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia6 7.2 1.1 4.6 1.0 Chest pain or chest discomfort7 3.8 0.5 2.8 0 Cardiac failure8 2.3 1.9 1.0 0.3

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In the Literature who had been recruited to the Neo ALTTO clinical trial, where the patients received neoadjuvant lapatinib and/or trastuzumab (Herceptin). The therapy response was measured by pathologic complete response, as defined by no invasive cancer in the breast and no pathologic involvement in the axillary nodes; event-free survival; and overall survival. The study results showed that PIK3CA mutations were found in 23% of HER2-

positive breast tumors. For each treatment arm, the pathologic complete response rate was lower in patients with PIK3CA mutations compared with patients without PIK3CA mutations. The difference was especially evident in patients who received the combination of trastuzumab and lapatinib; in this treatment arm, patients with PIK3CA mutations had a pathologic complete response rate of 28.6% com-

pared with 53.1% in patients without these mutations. PIK3CA mutations did not affect event-free survival or overall survival in patients who received trastuzumab and/or lapatinib. The researchers concluded that in HER2-positive tumors, PIK3CA mutations confer a lower clinical benefit from trastuzumab, lapatinib, and the combination of trastuzumab plus lapatinib than tumors without a PIK3CA

mutation. According to the investigators, these findings support further research of HER2 therapies and PIK3CA mutations in the clinic.

Better Outcomes with Nivolumab plus Ipilimumab than with Ipilimumab Monotherapy for Untreated Melanoma

In a recent double-blind, randomized, Continued on page 34

ZYTIGA® (abiraterone acetate) Tablets

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia,

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 (continued) ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) 1 System/Organ Class All Grades Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Musculoskeletal discomfort, and Musculoskeletal stiffness terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 4 Includes

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm. Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) Placebo (N=394) Laboratory All Grades Grade 3-4 All Grades Grade 3-4 Abnormality (%) (%) (%) (%) Hypertriglyceridemia 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Hypokalemia 28.3 5.3 19.8 1.0 Hypophosphatemia 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 Study 2: Metastatic CRPC Prior to Chemotherapy: Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0

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Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm. Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N=542) Placebo (N=540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based on non-fasting blood draws Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group. In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms. Post Marketing Experience The following additional adverse reactions have been identified during post approval use of ZYTIGA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis DRUG INTERACTIONS Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

MAY 2015

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In the Literature Better Outcomes with Nivolumab plus Ipilimumab than with Ipilimumab Monotherapy for Untreated... Continued from page 33

phase 2 study of patients with untreated metastatic melanoma, the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) resulted in a significantly greater objective response rate (ORR) and progression-free survival compared with

ipilimumab monotherapy (Postow MA, et al. N Engl J Med. 2015 Apr 20. Epub ahead of print). A total of 142 patients with untreated metastatic melanoma were randomly assigned in a 2:1 ratio to receive ipilimumab and nivolumab or ipilimumab alone. The study’s primary end point was the rate of investigator-assessed objective response in patients with BRAF V600 wild-type tumors; the sec-

ondary end points included investigator-assessed progression-free survival in patients with BRAF wild-type tumors, the ORR and progression-free survival among patients with BRAF V600 mutation–positive tumors, and safety. The study results demonstrated that among the 72 patients with BRAF wild-type tumors who received niv olumab plus ipilimumab, the objective response was 61% (95% confi-

ZYTIGA® (abiraterone acetate) Tablets

Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information]. In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients. Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established. Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function. In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3)] in full Prescribing Information. Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information]. OVERDOSAGE Human experience of overdose with ZYTIGA is limited. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function. Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations]. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician. • Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone. • Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions. • Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions. • Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician. • Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests. • Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

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dence interval [CI], 49-72) compared with 11% (95% CI, 3-25) in the 37 patients who received ipilimumab monotherapy; a complete response was reported in 22% of patients who re ceived the combination therapy versus in none of the patients who received ipilimumab monotherapy. Furthermore, the median change in the tumor volume was a 68.1% decrease in patients who received the combination therapy compared with a 5.5% increase in patients who received ipilim umab monotherapy. Overall, the median duration of response was not reached in either group, and the ongoing response was 82% in the combination group versus 75% in the ipilimumab monotherapy group. In addition, the median progression-free survival was 4.4 months in the combination group, but was not reached in patients who received the combination therapy. Among patients with BRAF-mutated tumors, the ORR was 52% (95% CI, 31-73) in the combination group versus 10% in the ipilimumab monotherapy group (95% CI, 0-45). Furthermore, the progression-free survival was 8.5 months in the combination group versus 2.7 months in the ipilimumab monotherapy group. The study’s safety analysis showed that the rate of treatment-related adverse events was 91% in the combination group compared with 93% in the ipilimumab monotherapy group. Grade 3 or 4 drug-related adverse events, such as colitis, diarrhea, and elevated alanine aminotransferase levels, were reported more frequently with combination therapy than with ipilimumab monotherapy (54% vs 24%, respectively); however, the majority of these events were manageable. According to the investigators, the combination of nivolumab plus ipilimumab was superior to ipilimumab monotherapy in terms of ORR, progression-free survival, and complete response in patients with BRAF wildtype advanced melanoma and in patients with BRAF-mutated advanced melanoma. n

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

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Akynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of Chemotherapy-Induced Nausea and Vomiting By Loretta Fala, Medical Writer

ne of the most fear-inducing side effects of chemotherapy is nausea and vomiting.1 Without appropriate antiemetic prophylaxis, 70% to 80% of all patients with cancer who receive chemotherapy experience nausea and/or vomiting.2 Consequently, pre venting and managing chemotherapy- induced nausea and vomiting (CINV) is a crucial part of care planning for patients with cancer. In addition to being a distressing side effect of cancer treatment, CINV has multiple clinical consequences for patients, their families, and the healthcare system, including2-4: • Nonadherence to chemotherapy treatment • Early treatment discontinuation • Problems with appetite and eating, which can lead to nutritional deficits • Impaired daily functioning • Performance status decline3 • Impaired health-related quality of life, as assessed by the Functional Living Index–Emesis • More frequent office visits and emergency department admissions, and higher direct and indirect costs of care compared with patients without CINV. The economic costs associated with CINV are significant. In a study of working-aged adults who were receiving highly or moderately emetogenic chemotherapy, uncontrolled CINV was associated with higher costs; that is, the monthly medical costs for patients with uncontrolled CINV were $1300 higher than the costs for patients without uncontrolled CINV. In addition, the monthly indirect costs, such as lost work time, were $400 higher for patients with uncontrolled CINV than for patients without uncontrolled CINV.4 Given the many potential negative effects of CINV, the use of effective antiemetic therapy is an essential part of treatment planning for patients undergoing chemotherapy and should be initiated at the start of cancer treatment.5 Several factors influence the incidence and severity of CINV. The primary risk

factor for CINV is the chemotherapy regimen, including the type of chemotherapy agent, the route of administration, and the treatment dosage. Patient-related factors that influence CINV include sex and age. For example, women report CINV and other chemotherapy-associated adverse events more often than do men, and elderly patients report fewer side effects than younger patients.5 History of CINV, emesis during pregnancy, motion sickness, alcohol use, tumor burden, anxiety, concomitant medication and medical conditions, and inadequate hydration are also significant contributors to CINV.2 In practice, CINV is classified into 3 categories—acute onset occurs within 24 hours of the initial administration of chemotherapy; delayed onset occurs 24 hours to several days after the initial treatment; and anticipatory CINV is triggered by senses, thoughts, or anxiety that patients associate with previous chemotherapy.2 Current emesis-related management guidelines focus on the emetogenic potential of chemotherapy drugs and divide agents into 4 risk groups, including high, moderate, low, and minimal. Table 1 summarizes the classification of chemotherapy drugs according to the National Comprehensive Cancer Network (NCCN) guidelines, and provides examples of agents in each risk group.3 Supportive care for patients receiving chemotherapy has dramatically improved during the past 20 years, with combination antiemetic regimens emerging as the standard of care for CINV control.6

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Four groups––the NCCN, the Multinational Association of Supportive Care in Cancer (MASCC), the European Society for Medical Oncology (ESMO), and the American Society of Clinical Oncology–– have published antiemetic guidelines.3,7,8 These groups broadly agree on the majority of key issues regarding the management of CINV.6

“

Supportive care products, such as Akynzeo, help ease the nausea and vomiting patients may experience as a side effect of cancer chemotherapy.

”

—JULIE BEITZ, MD

For acute emesis associated with highly emetogenic chemotherapy, as well as with the combination use of anthracycline and cyclophosphamide, antiemesis guidelines recommend triple therapy with a 5-hydroxytrypta mine (5-HT3) receptor antagonist, dexamethasone, and a neurokinin 1 (NK1) receptor agonist.3,7,8 For acute emesis associated with moderately emetogenic regimens, the MASCC/ESMO guidelines recommend double therapy with a 5-HT3 receptor antagonist (ideally, palonosetron) and dexamethasone. For low emetogenic

lassification of Emetogenic Risk Associated with Some Table 1 C Chemotherapy Agents Proportion of patients experiencing acute emesis Emetogenic risk without prophylaxis, % Examples of IV chemotherapies High

≥90

Cisplatin, high-dose cyclophosphamide, dacarbazine

Moderate

30-90

Carboplatin, high-dose cytarabine, doxorubicin, irinotecan, oxaliplatin

Low

10-30

Cabazitaxel, docetaxel, floxuridine, gemcitabine, pemetrexed, temsirolimus, topotecan

Minimal

<10

Bevacizumab, fludarabine, vincristine, vinorelbine

IV indicates intravenous. Source: National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): antiemesis. Version 2.2014. April 18, 2014.

MAY 2015

chemotherapy, dexamethasone monotherapy is adequate, but for minimal emetogenic chemotherapy, prophylaxis for acute emesis is not recommended.6,7 For delayed emesis associated with highly emetogenic chemotherapy, the MASCC/ESMO guidelines recommend the combination of dexamethasone and an NK1 receptor agonist. For delayed emesis associated with moderately emetogenic chemotherapy, such as anthracycline and cyclophosphamide–based regimens, the guidelines recommend aprepitant monotherapy. In other moderately emetogenic regimens, dexamethasone or a 5-HT3 receptor antagonist (presuming the latter was not part of the primary prophylactic treatment) are the preferred agents. For low- and minimal-emetogenic chemotherapy, no prophylaxis for delayed emesis is needed.6,7 Because maintaining dose intensity of chemotherapy is important, particularly in early-stage disease, recommendations for highly emetogenic chemotherapy should be followed when nausea and vomiting are not reduced by the recommended therapy for moderately emetogenic chemotherapy.5 Although the majority of patients with cancer are protected from CINV with these current therapies, other patients still experience nausea and vomiting associated with chemotherapy. Consequently, there remains a need for greater adherence to treatment guidelines and for more effective antiemetic agents.2,5 FDA Approves a Novel Combination Therapy for CINV

On October 10, 2014, the US Food and Drug Administration (FDA) approved the combination of netupitant plus palonosetron (Akynzeo; Eisai) for the prevention of acute and delayed nausea and vomiting associated with initial and repeated courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy in patients with cancer.9,10 The fixed combination capsule of netupitant plus palonosetron contains 300 mg of netupitant and 0.5 mg of palonosetron.10 Oral palonosetron was initially approved as a single agent in 2008 for the prevention of acute nausea and vomiting associated with initial and repeated cours-

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Drug Update es of moderately emetogenic chemotherapy in patients with cancer.9,11 Palonosetron prevents nausea and vomiting during the acute phase. Netupitant is a new drug that prevents nausea and vomiting during the acute and the delayed phases after the start of chemotherapy.9,10 “Supportive care products, such as Akynzeo, help ease the nausea and vomiting patients may experience as a side effect of cancer chemotherapy,” said Julie Beitz, MD, Director of the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research.9 Mechanism of Action

Palonosetron has a strong binding affinity for 5-HT3 receptors, acting as a 5-HT3 antagonist. Acute emesis is known to depend on serotonin and its 5-HT3 receptors.10 Netupitant is a selective antagonist of human substance P and NK1 receptors. These receptors are broadly distributed in the central and the peripheral nervous systems. Delayed emesis is associated with the activation of NK1 receptors by substance P. In vitro and in vivo studies demonstrated that netupitant inhibits substance P–mediated responses.10 Dosing and Administration

Netupitant plus palonosetron is a fixed-dose combination capsule containing netupitant (300 mg) and palonosetron (0.5 mg).10 For patients undergoing highly emetogenic chemotherapy, including cisplatin-based chemotherapy, the recommended dosage of netupitant plus palonosetron is 1 capsule given approximately 1 hour before starting chemotherapy, with oral dexamethasone 12 mg administered 30 minutes before the start of chemotherapy on day 1 and dexamethasone 8 mg once daily on days 2 to 4.10 For patients receiving anthracycline and cyclophosphamide or other chemotherapy that is not considered highly emetogenic, the recommended dosage of the new combination is 1 capsule approximately 1 hour before the start of chemotherapy, with dexamethasone 12 mg administered 30 minutes before the start of chemotherapy on day 1. The subsequent administration of dexamethasone is not necessary.10 Netupitant plus palonosetron can be taken with or without food.10

Clinical Trials

The efficacy and safety of fixed-dose netupitant plus palonosetron in combination with dexamethasone were evaluated in 2 randomized, parallel, double-blind, multicenter, controlled clinical trials––1 clinical trial in patients receiving highly emetogenic chemotherapy and 1 clinical trial in patients receiving moderately emetogenic chemotherapy.10

Study 1: Highly Emetogenic Chemotherapy

This multicenter, randomized, parallel, double-blind study enrolled 694 chemotherapy-naïve patients with cancer who were receiving cisplatin-based chemotherapy (median dose, 75 mg/m2).10,12 This trial evaluated 3 oral doses of netupitant (100 mg, 200 mg, and 300 mg) combined with oral palonosetron 0.5 mg and compared it with oral palonosetron 0.5 mg alone, all administered on day 1.10,12 A standard 3-day aprepitant and intravenous ondansetron regimen were included as an exploratory arm. All patients received oral dexamethasone on days 1 through 4.12 Of the 694 patients who enrolled in this clinical trial, 135 patients received netupitant plus palonosetron (netupitant 300 mg and palonosetron 0.5 mg), and 136 patients received oral palonosetron 0.5 mg alone.10 The majority of patients who received netupitant plus palonosetron were male (57%) and white (100%); the patients’ median age was 53 years (range, 19-77 years).10 During the study, 86% of patients who received netupitant plus palonosetron also received a concomitant chemotherapeutic agent in addition to cisplatin, including cyclophosphamide (34%), fluorouracil (24%), etoposide (21%), and doxorubicin (16%).10 The key efficacy end points were the complete response rates (defined as no emetic episode and no use of rescue medication) 0 to 24 hours after cisplatin treatment (acute phase), 25 to 120 hours after cisplatin treatment (delayed phase), and within 120 hours after cisplatin treatment (overall phase).10,12 Table 2 summarizes the efficacy data for netupitant plus palonosetron versus palonosetron alone, which show that the netupitant plus palonosetron combination offers clinically significant improvements in the complete response rates over palonosetron alone.10,12 Study 2: Moderately Emetogenic Chemotherapy

In this multicenter, randomized, parallel, double-blind, active-control superiority study, the efficacy and safety of a single oral dose of netupitant plus palonosetron were compared with a single oral dose of palonosetron 0.5 mg in 1450 chemotherapy-naïve patients with cancer who were scheduled to receive an thracycline and cyclophosphamide.10,13 Patients in this clinical trial also received a single oral dose of dexamethasone. After completing their first cycle of anthracycline and cyclophosphamide, patients could participate in a multiple-cycle extension in which they continued the same antiemetic treatment as assigned in cycle 1.10 A total of 725 patients received netupitant plus palonosetron, and 725 pa-

tudy 1: Netupitant plus Palonosetron versus Palonosetron Alone in Table 2 S Patients Receiving Highly Emetogenic Chemotherapy Complete response rate Phase after cisplatin chemotherapy

Netupitant 300 mg + palonosetron 0.5 mg, % (N = 135)

Palonosetron 0.5 mg, % (N = 136)

P value

98.5

89.7

.002

90.4

80.1

.032

89.6

76.5

.003

Acute phasea b

Delayed phase c

Overall

0-24 hours after treatment. 25-120 hours after treatment. c 0-120 hours after treatment. Source: Akynzeo (netupitant and palonosetron) capsules prescribing information; October 2014. a

tudy 2: Netupitant plus Palonosetron versus Palonosetron Alone in Table 3 S Patients Receiving Moderately Emetogenic Chemotherapy Complete response rate Status after anthracycline/ Netupitant 300 mg + Palonosetron cyclophosphamide palonosetron 0.5 mg, % 0.5 mg, % chemotherapy (N = 724) (N = 725) P value Acute phasea b

Delayed phase c

Overall

88.4

85.0

.047

76.9

69.5

.001

74.3

66.6

.001

0-24 hours after treatment. 25-120 hours after treatment. c 0-120 hours after treatment. Source: Akynzeo (netupitant and palonosetron) capsules prescribing information; October 2014. a

tients received palonosetron alone.10,13 Overall, 1438 patients completed cycle 1 of chemotherapy, and the majority (88%) of patients continued treatment in the multiple-cycle extension. A total of 907 (62%) patients finished the multiple-cycle extension for a maximum of 8 treatment cycles.10 The majority of patients who received the netupitant plus palonosetron combination were female (98%) and white (79%); the patients’ median age was 54 years (range, 22-79 years).10 Overall, nearly all patients (99.9%) received cyclophosphamide and an anthracycline; in addition, all patients received either doxorubicin (68%) or epirubicin (32%).10 During the first cycle of chemotherapy, 32% of pa tients who received netupitant plus palonosetron also received a concomitant chemotherapeutic agent in addition to the protocol- mandated regimens, including fluorouracil (28%) and docetaxel (3%).10 The efficacy end points included the complete response rates for the acute phase, the delayed phase, and the overall phase after chemotherapy with an an thracycline plus cyclophosphamide.10,13 Table 3 summarizes the efficacy data for netupitant plus palonosetron versus palonosetron monotherapy, which show that the combination of netupitant plus palonosetron offers significant improve-

ments in complete response rate over palonosetron monotherapy.10,13 Among the patients who participated in the multiple-cycle extension of the study, the antiemetic activity of netupitant plus palonosetron was maintained throughout the repeated cycles of chemotherapy.10 Adverse Reactions

The safety of netupitant plus palonosetron was evaluated in clinical trials that included more than 1500 healthy volunteers and patients with cancer.10 More than 1150 patients with cancer have been exposed to netupitant plus palonosetron, receiving at least 1 cycle of cancer chemotherapy in 1 of 3 active-controlled clinical trials, including 782 patients who were exposed to netupitant plus palonosetron for at least 4 cycles, and 321 patients who were exposed to netupitant plus palonosetron for at least 6 cycles, up to a maximum of 12 cycles of chemotherapy.10 All patients received a single oral dose of netupitant plus palonosetron 1 hour before the start of each chemotherapy cycle. In all the studies, dexamethasone was coadministered with netupitant plus palonosetron.10

Cisplatin-Based Highly Emetogenic Chemotherapy

In a single-cycle study of patients who received cisplatin-based highly emetoContinued on page 38

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Drug Update

Akynzeo (Netupitant and Palonosetron), a Dual-Acting Oral Agent, Approved by the FDA for the Prevention of Chemotherapy-Induced... Continued from page 37

genic chemotherapy, 136 patients received netupitant plus palonosetron.10 Adverse reactions that were reported at an incidence rate of at least 3% and for which the rate with netupitant plus palonosetron exceeded the rate with palonosetron alone included dyspepsia (4%), fatigue (4%), constipation (3%), and erythema (3%).10 Anthracycline and Cyclophosphamide–Based Moderately Emetogenic Chemotherapy

In a study of patients who received moderately emetogenic chemotherapy, 725 patients received netupitant plus palonosetron during the first cycle, and 635 of these patients continued for up to 8 cycles in a multiple-cycle extension.10 The adverse reactions that were reported at an incidence rate of at least 3% and for which the rate with netupitant plus palonosetron exceeded the rate with palonosetron alone during cycle 1 included headache (9%), asthenia (8%), and fatigue (7%).10 The adverse reactions associated with netupitant plus palonosetron during subsequent cycles of anthracycline and cyclophosphamide were similar to those observed in the first cycle.10 In both treatment arms of the clinical trials that compared netupitant plus palonosetron with oral palonosetron monotherapy, concomitant elevations of total bilirubin and transaminase levels of more than 3 times the upper limit of normal were reported, and the frequency of these elevations was similar with both treatments.10 The combination of netupitant plus palonosetron has no contraindications.10

Drug Interactions

Netupitant plus palonosetron should be used with caution in patients receiving cytochrome (CY) P3A4 substrates (eg, tacrolimus, imatinib, anastrozole, paclitaxel); inhibition of CYP3A4 can result in increased plasma concentrations of the concomitant drug that can last for 4 days or more. The concomitant use of netupitant plus palonosetron with CYP3A4 inducers (eg, rifampin, carba-

mazepine, phenobarbital, pioglitazone) should be avoided.10,14 Warnings and Precautions

Hypersensitivity. Hypersensitivity reactions, including anaphylaxis, have been reported after the use of other 5-HT3 receptor antagonists.10 Patients experiencing anaphylaxis may or may not have a known hypersensitivity to 5-HT3 receptor antagonists. Patients taking netupitant plus palonosetron should seek immediate medical attention if any signs or symptoms of a hypersensitivity reaction occur.10 Serotonin syndrome. The development of serotonin syndrome has been reported with 5-HT3 receptor antagonists, most often when serotonergic drugs (eg, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, mirtazapine, fentanyl, lithium, tramadol) were used concomitantly; several of the cases were fatal.10 The symptoms associated with serotonin syndrome can include mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia); neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination); and seizures, with or without gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). If symptoms of serotonin syndrome occur, netupitant/palonosetron should be discontinued and supportive treatment should be initiated.10 Use in Specific Populations

Pregnancy. Netupitant plus palonosetron is listed as pregnancy category C; there are no adequate and well-controlled studies with this combination in pregnant women. Netupitant plus palonosetron should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus.10 Nursing mothers. It is not known whether the components of netupitant plus palonosetron are present in human breast milk. Nursing or netupitant plus palonosetron therapy should be discon-

VALUE-BASED CANCER CARE

MAY 2015

tinued on the basis of the importance of the drug to the mother.10 Pediatric use. The safety and efficacy of netupitant plus palonosetron have not been established in pediatric patients aged <18 years.10 Geriatric use. Of the 1169 patients with cancer who received netupitant plus palonosetron in clinical trials, 18% were aged ≥65 years, and 2% were aged ≥75 years.10 The nature and the frequency of adverse events were similar between elderly patients and younger patients. In general, caution should be used when administering netupitant

This novel dual-acting prophylactic therapy is an important option for patients receiving chemotherapy, in part because adherence to antiemetic consensus guidelines remains low. plus palonosetron to elderly patients, because of their higher risk for hepatic, renal, and/or cardiac dysfunction, as well as concomitant diseases and multiple medications.10 Renal impairment. Patients with mild or moderate renal impairment do not require dose adjustment of netupitant plus palonosetron.10 Patients with severe renal impairment or end-stage renal disease should not receive netupitant plus palonosetron.10 Hepatic impairment. No dosage adjustment of netupitant plus palonosetron is recommended for patients with mild or with moderate hepatic impairment. Netupitant plus palonosetron is not recommended for use in patients with severe hepatic impairment.10 Conclusion

The new fixed-dose combination agent that targets 2 antiemetic pathways, netupitant plus palonosetron offers an effective and safe alternative for

patients undergoing initial and repeated courses of cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. This novel dual- acting prophylactic therapy is an important option for patients receiving chemotherapy, in part because adherence to antiemetic consensus guidelines remains low. As an oral single capsule, the use of netupitant plus palonosetron combination therapy may improve the management of patients with cancer who are at high risk for CINV. n References

1. Sun CC, Bodurka DC, Weaver CB, et al. Rankings and symptom assessments of side effects from chemotherapy: insights from experienced patients with ovarian cancer. Support Care Cancer. 2005;13:219-227. 2. Feyer P, Jordan K. Update and new trends in antiemetic therapy: the continuing need for novel therapies. Ann Oncol. 2011;22:30-38. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): antiemesis. Version 2.2014. April 18, 2014. www.nccn.org/professionals/physician_gls/pdf/antiemesis. pdf. Accessed February 23, 2015. 4. Tina Shih Y-C, Xu Y, Elting LS. Costs of uncontrolled chemotherapy- induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer. 2007;110: 678-685. 5. Morrow GR, Navari RM, Rugo HS. Clinical roundtable monograph: new data in emerging treatment options for chemotherapy-induced nausea and vomiting. Clin Adv Hematol Oncol. 2014;12(3 suppl 9):1-14; quiz 15. 6. Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358:2482-2494. 7. Roila F, Herrstedt J, Aapro M, et al; for the ESMO/ MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243. 8. Basch E, Prestrud AA, Hesketh PJ, et al; for the American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198. Erratum in: J Clin Oncol. 2014;32:2117. 9. US Food and Drug Administration. FDA approves Akynzeo for nausea and vomiting associated with cancer chemotherapy. Press release. October 10, 2014. www.fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm 418375.htm. Accessed February 20, 2015. 10. Akynzeo (netupitant and palonosetron) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; October 2014. 11. Aloxi (palonosetron HCl) capsules [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; September 2014. 12. Hesketh PJ, Rossi G, Rizzi G, et al. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study. Ann Oncol. 2014;25:1340-1346. 13. Aapro M, Rugo H, Rossi G, et al. A randomized phase III study evaluating the efficacy and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy. Ann Oncol. 2014;25:1328-1333. 14. Stenger M. Fixed-combination netupitant/palono setron for prevention of chemotherapy-induced nausea and vomiting. ASCO Post. 2014;5:119.

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