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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

AUGUST 2012 I VOL 5, NO 5 I SPECIAL ISSUE

ASCO 2012: Payers’ Perspectives

“Precision Medicine” Focus of ASCO 2012

Novel T-DM1 Prolongs Remission in Metastatic Breast Cancer: A New “Smart Bomb”

By Caroline Helwick

By Audrey Andrews

Molecular Profiling Guiding Cancer Therapy

Courtesy of ASCO/GMG/Phil McCarten 2012

Chicago, IL—The media darling at ASCO 2012 was a novel agent some called a “smart bomb,” because of its highly targeted and potent effect that spares surrounding healthy tissue. Trastuzumab emtansine, better known as T-DM1, the antibody-drug conjugate linking trastuzumab to a cytotoxic agent, delivers its punch directly into the tumor of patients with HER2-positive metastatic breast cancer, and this agent is associated with little toxicity. T-DM1 is one of an

entirely new class of agents that could have a major impact on the disease. Early results from EMILIA, an international phase 3 clinical trial presented at the meeting’s plenary session, showed an increase of approximately 30% in progression-free survival (PFS) with T-DM1 compared with a standard treatment regimen. “For patients facing metastatic breast cancer, this is a breakthrough,” said lead author Kimberly L. Blackwell, MD, of Duke Cancer Continued on page 15

Quality of Life Drives Patient Preference for Metastatic RCC Drug Chicago, IL—“Precision medicine” is the new catch phrase in oncology, and examples of it were evident across the vast halls of McCormick Place at the 2012 American Society of Clinical Oncology (ASCO) meeting.

Precision medicine is the next iteration of “personalized medicine,” a moniker perhaps meant to convey the increasing refinement of the molecular targets that underlie tumors. It has become evident that mutations that Continued on page 4

Patient Adherence Rises with Cost of Oral Cancer Drugs A potential “designer drug” phenomenon By Caroline Helwick Chicago, IL—Canadian researchers reported a finding at the 2012 American Society of Clinical Oncology meeting that runs contrary to what other researchers have observed in the majority of studies. In this

study, as oral drug costs increased, so did the likelihood of patients adhering to a prescribed regimen. Low adherence rates have been documented for many oral therapies in various diseases, and medication Continued on page 9

Pazopanib winner in head-to-head QOL comparison By Wayne Kuznar Chicago, IL—The surprising results of the head-to-head randomized clinical trial PISCES on patient preference for one cancer therapy over another show that patient-reported quality-of-life (QOL) differences influence treatment preference far more than physicians had imagined, suggested researchers at ASCO 2012. In a double-blind, crossover trial, 168 patients with metastatic renal-cell

Continued on page 20

IN THIS ISSUE PERSONALIZED MEDICINE . . . . . . .

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RENAL CANCER

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High OOP costs in Medicare Cancer screening is cost-effective GI CANCERS . . . . . . . . . . . . . . . . . . . . . .

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Afatinib boosts PFS in EGFR mutations

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Tivozanib outperforms sorafenib as first-line therapy MULTIPLE MYELOMA . . . . . . . . . . .

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Pomalidomide shows strong activity in relapsed/refractory disease DRUG PIPELINE

New therapies on the horizon LUNG CANCER

PROSTATE CANCER

Abiraterone before chemotherapy a promising strategy

Patients willing to pay for genetic testing to assess cancer risk Why hasn’t genomic testing changed the landscape? HEALTH ECONOMICS . . . . . . . . . . . . .

©2012 Engage Healthcare Communications, LLC

carcinoma (mRCC) were randomized 1:1 to 10 weeks of 800 mg of pazopanib or 50 mg of sunitinib as first-line cancer treatment; after a 2-week washout period, patients received 10 weeks of the alternate treatment. The primary end point was patient preference, measured at 22 weeks. Because patients with mRCC receive therapies for many months or even years, the researchers assessed

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PAYERS’ PERSPECTIVES

Payers collaborate with providers to adopt oncology pathways?


Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the JakafiÂŽ (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

130TBSFBOJNQPSUBOUNFBOTUPEFNPOTUSBUFUSFBUNFOU benefits in clinical trials. 6TFPGB130JOTUSVNFOUDBO evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. *ODPSQPSBUJOH130TJOUPBDMJOJDBMUSJBMQSPHSBNQSPWJEFTB means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make betterinformed decisions.

.ZFMPĂĽCSPTJT .' JTBMJGFUISFBUFOJOH QSPHSFTTJWFEJTFBTF characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, EPVCMFCMJOEQMBDFCPDPOUSPMMFETUVEZ $0.'035* GPS +BLBĂĽ4QMFFOSFEVDUJPO BTNFBTVSFECZJNBHJOH .3*PS$5  was the primary and biologic endpoint, and a reduction in total TZNQUPNTDPSF 544 UIF130NFBTVSF XBTBLFZTFDPOEBSZ endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 5PJODMVEF130TJOUIFUSJBM BOPWFMJOTUSVNFOUIBEUPCF specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version  NPEJĂĽFE.'4"'W XBTĂĽOBMJ[FEBTQBSUPGUIF4QFDJBM 1SPUPDPM"TTFTTNFOUQSJPSUPUIFJOJUJBUJPOPG$0.'035* Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on 130TXBTĂĽOBMJ[FEJO 

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information t5SFBUNFOUXJUI+BLBüDBODBVTFIFNBUPMPHJDBEWFSTF reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required t5IFUISFFNPTUGSFRVFOUOPOIFNBUPMPHJDBEWFSTF reactions were bruising, dizziness and headache t1BUJFOUTXJUIQMBUFMFUDPVOUT¨9/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered t1BUJFOUTEFWFMPQJOHBOFNJBNBZSFRVJSFCMPPEUSBOTGVTJPOT Dose modifications of Jakafi for patients developing anemia may also be considered t/FVUSPQFOJB "/$¨9/L) was generally reversible and was managed by temporarily withholding Jakafi t1BUJFOUTTIPVMECFBTTFTTFEGPSUIFSJTLPGEFWFMPQJOH serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before TUBSUJOH+BLBü1IZTJDJBOTTIPVMEDBSFGVMMZPCTFSWFQBUJFOUT receiving Jakafi for signs and symptoms of infection JODMVEJOHIFSQFT[PTUFS BOEJOJUJBUFBQQSPQSJBUF treatment promptly t"EPTFNPEJüDBUJPOJTSFDPNNFOEFEXIFOBENJOJTUFSJOH +BLBüXJUITUSPOH$:1"JOIJCJUPSTPSJOQBUJFOUTXJUI


JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patient’s response.

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 5IF'%"BQQSPWBMJODMVEFEQBUJFOUTXJUIJOUFSNFEJBUFSJTLBOEIJHISJTL BTXFMMBTQBUJFOUT with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and BDBEFNJDFYQFSUTUPEFWFMPQSFMFWBOUBOEWBMJEBUFE130JOTUSVNFOUTUIBUDBOCFJODPSQPSBUFEJOUPDMJOJDBMUSJBMT1,8 The approval PG+BLBüNBSLTBTJHOJüDBOUNJMFTUPOFJOXIJDIWBMJEBUFE130JOTUSVNFOUTDBOQSPWJEFTZNQUPNEBUBBOEEFNPOTUSBUF DMJOJDBMCFOFüU5IFFYQFSJFODFXJUI+BLBüNBZQSPWJEFBNPEFMGPSUIFGVUVSFVTFPG130TJONBSLFUJOHBQQMJDBUJPOT8

renal or hepatic impairment [see Dosage and Administration]. 1BUJFOUTTIPVMECFDMPTFMZNPOJUPSFEBOEUIFEPTFUJUSBUFE based on safety and efficacy t5IFSFBSFOPBEFRVBUFBOEXFMMDPOUSPMMFETUVEJFTPG+BLBĂĽ in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus t8PNFOUBLJOH+BLBĂĽTIPVMEOPUCSFBTUGFFE%JTDPOUJOVF nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials. 3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901. 6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≼35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≼50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absentâ€? and 10 representing “worst imaginableâ€? symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a registered trademark of Incyte Corporation. Š 2012, Incyte Corporation. All rights reserved. RUX-1130A 05/12


Personalized Medicine

Molecular Profiling Guiding Cancer Therapy... describe certain tumors—such as the epidermal growth factor receptor (EGFR) mutation in non–small-cell lung cancer (NSCLC)—may be present  to some   extent in a  varietyof apparent   ly unrelated cancers. This means that drugs targeted to one tumor type may be useful in small subsets of other

types of cancers. This has implications for drug development, clinical trials, and the treatment of patients. “We now understand that it’s not sufficient to identify a tumor based on the histology or the organ of origin, as we did traditionally, but rather that tumors are heterogeneous. We need to

understand the particular molecular driver of the tumor to select appropriate therapy,” said ASCO outgoing president Michael P. Link, MD, during a press briefing. As medicine has become “president” in recent years, molecular profiling of the patient has become a standard prac-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the 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 teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. 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 Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 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 Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d Urinary Tract Infections 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences 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 Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site 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 hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. 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 (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Continued from page 1

tice, at least for many tumors and in academic centers. But this is an expensive process, and sessions at ASCO 2012 were devoted to best practices in this area, at least for lung cancer, colorectal cancer, and neuro-oncology. In some instances, molecular profiling may be life-saving, said Nicholas J. Vogelzang, MD, Chair of ASCO’s Cancer Communications Committee and Chair and Medical Director, US Oncology Research, Houston, TX, and an oncologist at Comprehensive Cancer Centers of Nevada, Las Vegas. Dr Vogelzang pointed out that it is no longer uncommon for patients with disease refractory to established treatments to go hunting for unsuspected mutations that might be targeted by drugs that would otherwise never be considered. “It’s not intuitive,” he said. “Unusual tumors have these mutations, so you have to test them.” Drugs that Are “Crossing Over” For several drugs that were considered breakthroughs in one tumor type, treatment niches are emerging in other cancers. A striking example is crizotinib, the ALK inhibitor that elicits robust responses (70%-80%) in the 5% of patients with NSCLC who have ALK gene abnormalities. Investigators reported at ASCO that crizotinib is also an active treatment for a phenotypically unrelated set of aggressive pediatric cancers. In a phase 1 study of 70 children, treatment with crizotinib led to complete responses in 88% of patients with anaplastic large-cell lymphoma and produced complete and partial responses in patients with other tumor types as well. Many of these young patients have maintained their responses to crizotinib for more than 2 years, reported Yael P. Mossé, MD, Assistant Professor, Perelman School of Medicine at the University of Pennsylvania, and an attending physician at the Children’s Hospital of Philadelphia. “It’s remarkable that this targeted oral medication provided such a substantial benefit in these children with highly aggressive cancers, most of whom had already undergone every available therapy,” Dr Mossé said. Dr Vogelzang, who commented on the results, said he had also witnessed a dramatic response to crizotinib in an adult with ALK-positive anaplastic large-cell lymphoma. “The patient was very, very ill. She achieved a complete response with crizotinib and was able to receive a transplant. So, this drug does have dramatic potential in older patients as well, and in patients with other tumors.” Continued on page 5

4

AMERICAN HEALTH & DRUG BENEFITS

August 2012

VOL. 5

NO. 5

SPECIAL ISSUE


THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

Personalized Medicine Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 Executive Vice President Engage Managed Markets Chuck Collins ccollins@engagehc.com 732-992-1894 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 National Accounts Manager Zach Ceretelle zach@engagehc.com 732-992-1898 Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com T: 732-992-1892; F: 732-992-1881 American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks 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 American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits 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. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright.com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.

Molecular Profiling Guiding Cancer Therapy... Continued from page 4 BRAF inhibitors may also have crossover appeal, because colorectal and lung cancers also harbor BRAF mutations. A “Blueprint” for Change In keeping with the rapidly emerging molecular landscape, ASCO is pushing for an accompanying paradigm shift in cancer research and drug development. In November 2011, ASCO issued a report that lays out its vision for transforming clinical and translational research to deliver more effective and personalized cancer therapies faster.

“We now understand that it’s not sufficient to identify a tumor based on the histology or the organ of origin…but rather that tumors are heterogeneous. We need to understand the particular molecular driver of the tumor to select appropriate therapy.” —Michael P. Link, MD “Advances in cancer prevention, detection, and treatment have already extended the lives of millions of adults and children living with cancer—but the critical ques-

Photo by © ASCO/Scott Morgan 2012

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

tion is, ‘Where do we go from here?’” said Dr Link. “This report aims to set us on a path to deliver the new therapies that patients urgently need.” ■

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health, Philadelphia, PA DEPUTY EDITORS

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia, PA Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Department of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia, PA AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University, IL Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine Hematology/Oncology Assistant Dean for Research Associate Director, Faculty Group Practice, University of Michigan Medical School, MI EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare and Bentteligence Sharon, MA ENDOCRINOLOGY RESEARCH

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX J. B. Jones, PhD, MBA Research Investigator, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship University of Michigan, School of Public Health and Medicine Ann Arbor, MI HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes Personalized Health Care Program, University of Utah Salt Lake City, UT Joseph Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steve Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver, CO Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor University of the Sciences Philadelphia, PA Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, Philadelphia School of Pharmacy, University of the Sciences Philadelphia, PA David W. Wright, MPH President, Institute for Interactive Patient Care, Bethesda, MD

POLICY & PUBLIC HEALTH

Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

William E. Fassett, BSPharm, MBA, PhD, FAPhA Professor of Pharmacy Law & Ethics Dept. of Pharmacotherapy, College of Pharmacy, Washington State University, Spokane, WA Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC PERSONALIZED MEDICINE

Emma Kurnat-Thoma, PhD, MS, RN Director, Research Services URAC, Washington, DC PHARMACOECONOMICS

Josh Feldstein President & CEO CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Senior VP, PBM Leader Humana Solutions, Louisville, KY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate Menlo Park, CA Michael S. Jacobs, RPh Vice President, National Accounts HEALTH & VALUE PROMOTION Truveris, Inc., New York, NY Craig Deligdish, MD Matthew Mitchell, PharmD, MBA Hematologist/Oncologist Manager, Pharmacy Services Oncology Resource Networks SelectHealth, Salt Lake City, UT Orlando, FL Paul Anthony Polansky, BSPharm, Thomas G. McCarter, MD, FACP MBA Chief Clinical Officer Senior Field Scientist, Health Outcomes Executive Health Resources, PA and PharmacoEconomics (HOPE) Albert Tzeel, MD, MHSA, FACPE Endo Health Solutions, Chadds Ford, PA National Medical Director Christina A. Stasiuk, DO, FACOI HumanaOne, Waukesha, WI Senior Medical Director Cigna, Philadelphia, PA MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHP Scott R. Taylor, BSPharm, MBA Senior Director, Medical Lead, Payer Executive Director, Industry Relations and Specialty Channel Strategy, Medical Geisinger Health System, Danville, PA Affairs, Pfizer Specialty Care Business Unit, PA

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute, Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, Practice and Administration School of Pharmacy University of Missouri Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA Executive Director Drug Information Association Horsham, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

Frank Casty, MD, FACP Chief Medical Officer Senior VP, Clinical Development Medical Science Endo Pharmaceuticals, Chadds Ford, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Senior Vice President Managed Markets/Clinical Services Diplomat Specialty Pharmacy Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics Collegeville, PA

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Personalized Medicine

Is Biomarker Testing in NSCLC Cost-Effective? By Caroline Helwick Chicago, IL—“Economic evaluations of personalized medicine should incorporate the cost of testing for biomarkers,” said Natasha B. Leighl, MD, medical oncologist at Princess Margaret Hospital in Toronto, Canada, during a session on the cost of treating non– small-cell lung cancer (NSCLC) at ASCO 2012. In essentially half of advanced adenocarcinomas of the lung, a mutation is detected, and this will only increase as more is learned about the tumor’s biology. Although targeted agents are undoubtedly effective in selected populations, the cost-effectiveness of determining these patient groups has yet to be fully shown, Dr Leighl said. Erlotinib Cost-Effective in Highly Targeted Group The first targeted agent in NSCLC was erlotinib. In unselected patients in the pivotal NCIC CTG BR.21 trial, treatment with erlotinib led to an absolute 2-month improvement in median survival, representing a 30% reduction in mortality risk. A costeffectiveness analysis of the pivotal trial showed that the drug itself is only marginally cost-effective. Weighing the magnitude of survival benefit and expense, the incremental cost-effectiveness ratio (ICER) for erlotinib in the trial population was $94,638 (2007 Canadian dollars) per life-year gained.

See also Lung Cancer However, when the analysis was restricted to groups that benefit most from the drug, treatment appeared to be cost-saving. The following ICERs were found among selected clinical and molecular subgroups, who also derived the greatest clinical benefit: • In never-smokers: ICER $39,487 versus $504,911 for current smokers • Epidermal growth factor receptor (EGFR) high copay: ICER $33,353 versus $109,792 • EGFR mutation–positive: ICER $138,168 versus $87,994. “The key in personalized medicine is defining the target population. You must identify the molecular subtype that will benefit,” Dr Leighl said. A number of international studies have evaluated the cost-effectiveness of using EGFR tyrosine kinase inhibitors (ie, erlotinib and gefitinib) in patients with advanced NSCLC. Used first-line in patients with EGFR mutations, under the “test-and-treat” strategy, the ICERs have ranged from approximately €26,000 to €70,000 per quality-adjusted life-year (QALY), and in some circumstances the drugs were cost-saving. In a study in which patients with the wild-type genotype received gefitinib third-line (based on the idea that the drug has modest benefit in the patients who do not have the mutation), the incremental benefit was diluted, and the ICER rose to >$80,000/QALY.

Is Crizotinib Cost-Effective in NSCLC? The excitement over the targeted agent crizotinib for patients with NSCLC and the ALK rearrangement means that testing for this mutation will also become standard, with cost implications. “The cost varies by type of test and laboratory,” she said.

“Economic evaluations of personalized medicine should incorporate the cost of testing for biomarkers.” —Natasha B. Leighl, MD

A 2012 study examined the impact of different predictive biomarker screening techniques and population enrichment criteria on the cost-effectiveness of treating ALK-positive NSCLC (Atherly AJ, et al. Br J Cancer. 2012;106: 1100-1106). The study showed the unit cost of FISH (fluorescence in situ hybridization) testing, which detects 100% of cases, to be $1400, whereas immunohistochemistry and the reverse transcriptase polymerase chain reaction, which detect 60% to 70% of cases, cost only $600 to $900. The screening of all patients with advanced NSCLC for the ALK mutation using the FISH assay would be

$106,707/QALY, but this decreases to $4756 when only a highly enriched population is screened (adenocarcinoma, never-smokers, EGFR-positive, KRAS wild-type), because this increases the biomarker frequency from 1.6% to 36%. But this approach would miss approximately half of the patients, resulting in some patients not being optimally treated. “The cost would be reduced significantly because the likelihood of finding positive cases significantly increases,” Dr Leighl explained. The study showed that cost-effectiveness of <$100,000 per QALY gained is not achievable at biomarker frequencies <5% (assuming drug costs of $1-$5000 per month and screening costs of $600-$1400 per person). The researchers concluded that “Cost-effectiveness of oncology drugs whose prescribing is restricted to biomarker-positive subgroups should address the cost of detecting markerpositive patients. The cost of screening dominates at low frequencies, and strategies to improve cost-effectiveness, based on the assay cost, drug cost, and group screened, should be considered in these scenarios.” Finally, Dr Leighl said, “The rapid evolution of testing technology and the costs should factor into policy decisions” about the targeted treatment of cancers, and this needs to be a continual process. ■

Patients Willing to Pay for Genetic Testing to Assess Cancer Risk Chicago, IL—In a cohort of patients at risk for colorectal cancer (CRC), the majority were willing to pay some out-of-pocket (OOP) expenses for genetic testing, Fox Chase Cancer Center researchers reported in a poster presented at ASCO 2012 and earned an ASCO Merit Award. “These participants are fearful of a positive result and anticipate benefits afforded by genetic testing in controlling cancer risk,” said Jennifer M. Matro, MD, a medical oncology fellow at Fox Chase in Philadelphia. The increasing availability of genetic testing in cancer care has been paralleled by increasing cost-sharing practices by payers. Little is known about the factors that may influence a highrisk patient’s willingness to pay for these genetic tests. The study was conducted to obtain such information from a cohort of patients referred for genetic risk assessment.

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“These participants are fearful of a positive result and anticipate benefits afforded by genetic testing in controlling cancer risk.” —Jennifer M. Matro, MD At enrollment in the Gastrointestinal Tumor Risk Assessment Registry, 406 participants (73% female) completed a survey that presented the following scenarios: • Have a genetic test for CRC only if my health insurance covers it • Have a genetic test for CRC even if I have to pay for it myself • For a genetic test for CRC, I would be willing to pay: $25, $50, $100, $200, $500, $1000, $2000. The results showed that 80% of

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patients were willing to pay OOP and 20% would want the test only if insurance covered the full cost. The percentages of patients willing to pay OOP (if the test was not covered by insurance) were: • 26% would pay up to $200 • 22% would pay $1000-$2000 • 20% would pay $500 • 20% would pay $100 • 12% would pay $25-$50. Who Was Most Willing to Pay for Genetic Testing? The independent predictors of willingness to pay included the expectation of a positive result, confidence in being able to better control cancer risk, fewer perceived barriers to CRC screening, and belief that benefit is derived from having screening guidance. Patients willing to pay a higher amount were more likely to be male, be more educated, have greater can-

cer worries and fewer first-degree relatives with CRC, and have more positive attitudes toward genetic testing. Dr Matro speculated on why participants with more first-degree relatives and a history of colon cancer were less likely to pay more: “The reasons for this may include that these patients assume the test will be positive, or feel more comfortable navigating the healthcare system and getting appropriate care without the test result.” Despite the analysis being controlled for household income, women and less-educated patients were willing to pay a smaller sum, indicating that they may face greater individual barriers from high copays, she reported. “Identifying patient-level factors associated with willingness to pay for genetic services is increasingly important as genetic testing is integrated into routine cancer care,” Dr Matro said.—CH ■

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Why Hasn’t Genomic Testing Changed the Landscape? “A bad tumor marker is as bad as a bad drug” By Caroline Helwick Chicago, IL—The “omics” revolution produced much optimism that tumor biomarker tests based on the analysis of multiple factors, sometimes thousands, would result in truly personalized cancer care. The field encompasses biologic molecules such as DNA (“genomics”), several RNAs (“transcriptomics”), proteins (“proteomics”), and metabolites (“metabolomics”). Massive amounts of data are used to produce a profile, which is incorporated into a test that could guide patient care. But 10 years later, the promise has yet to be realized. A panel of researchers and clinicians discussed the reasons for this slow progress at ASCO 2012. “Unfortunately, the field of tumor biomarker research has been chaotic and haphazard, leading to many published papers in the peer-reviewed literature but very few markers that truly have clinical utility or that can be recommended for routine patient care,” said Dan Hayes, MD, a scientist and breast cancer specialist at the University of Michigan. This situation has raised 2 key issues—the use of biomarkers in the absence of solid evidence supporting their clinical utility, and a lack of biomarkers that can lead to truly personalized cancer care. Many Markers, Few Chosen In a recent review of the literature, researchers found >400 new genomic and other omics-based tests in transition from bench to bedside, the vast majority of which are related to cancer

(Gwinn M, et al. Genet Med. 2011;13: 161-165). However, in 2012, few such tests have actually been widely adopted in the clinic, panel participants said.

“The field of tumor biomarker research has been chaotic and haphazard, leading to many published papers in the peer-reviewed literature but very few markers that truly have clinical utility.” —Dan Hayes, MD

According to Muin J. Khoury, MD, PhD, of the National Cancer Institute (NCI), one obstacle is “semantics.” For instance, the word “validation” means many things to many people, he said. Precise definitions are critical to any branch of science; therefore, the independent Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group is helping to organize the field semantically. The goal of the EGAPP Initiative is to establish and test a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology in transition from research to practice, in a manner that minimizes conflicts of interest and is publicly accountable. The EGAPP Working Group is

beginning to make some recommendations. The first is to support genetic testing strategies in individuals with a new diagnosis of colorectal cancer, to reduce morbidity and mortality from Lynch syndrome in relatives. The EGAPP Working Group is also now evaluating the use of prostate cancer single-nucleotide polymorphism panels in risk assessment and screening, as well as the value of pharmacogenomic testing of tumor tissue in patients with metastatic colorectal cancer, for building decisions regarding therapy with agents targeted against the epidermal growth factor receptor. The most uncertain factor in this field is the assurance that outcomes are improved when biomarkers are used to select patients for treatment. David Ransohoff, MD, an epidemiologist at the University of North Carolina, said the question is, “Does the biomarker discriminate; is the result trustworthy?” He noted that computational models may perform well during the discovery phase of omics-based research but frequently fail when applied to an independent specimen or data set. But the field has not been bereft of success, Dr Ransohoff said, citing the 21-gene recurrence score (Oncotype DX) and the 70-gene signature (MammaPrint) in breast cancer. The Oncotype DX is being prospectively evaluated in the randomized MINDACT trial to determine whether it can guide the use of adjuvant chemotherapy in node-negative patients.

What Needs to Be Done “It is imperative that the field take major actions to break the vicious cycle that has led to these circumstances and to do the rigorous research needed to provide proper assessments,” Dr Hayes said. “A bad tumor marker is as bad as a bad drug.”

“Yes, we can have an evidence-based process for precision medicine, but it’s not going to be cheap.” —Muin J. Khoury, MD, PhD “When these factors are recognized and incorporated into tumor biomarker studies, the dream of personalized oncologic care will be more likely to become a reality,” he said. Ideally, to generate higher levels of evidence, investors should develop prospectively designed and conducted trials to “test the test,” the speakers said. A few such trials are occurring in breast and colorectal cancers. Comparative effectiveness research (CER) in genomics and personalized medicine will also be valuable as payers grapple with the cost of these new tools. Between 2009 and 2012, the NCI has funded 7 groups across the country to conduct CER. “Yes, we can have an evidence-based process for precision medicine,” Dr Khoury predicted, “but it’s not going to be cheap. It’s going to be costly.” ■

Family History of Cancer/Genetic Counseling Often Lacking for Patients First Presenting with Malignancy By Wayne Kuznar Chicago, IL—A family history of cancer is not always documented by primary care or specialty practices, even though the identification of family cancer history is an integral feature of high-risk screening guidelines, according to data from a pilot project. “Family history is important not only for the identification of individuals without cancer who have a strong family history and can be candidates for accelerated screening and intervention, but [also in] individuals who have cancer, [and in] those who have a family history and are at increased risk for second primary cancer,” said Marie Wood, MD, Director of the Familial

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Cancer Program, and Deputy Director of Hematology/Oncology, University of Vermont, Burlington, at ASCO 2012. Data were taken from 213 practices that were pilot tested for the implementation of ASCO’s Quality Oncology Practice Initiative, designed to assess family history taking and genetic counseling/genetic testing (GC/GT) referral. Researchers assessed the presence of cancer family history in firstand second-degree relatives, the patient’s age at diagnosis, referral for GC/GT, and referral outcomes. Data were available for 10,466 patients—6569 with breast cancer and 3897 with colorectal cancer; 77.4% of

their charts had documented cancer family history in first-degree relatives, and 61.5% contained documentation in second-degree relatives. History taking of cancer in first-degree relatives was done in more patients with breast cancer than those with colon cancer, as well as in second-degree relatives. The age at time of cancer diagnosis in relatives, however, was documented in only 30.7% of all charts. In 22.1% of reviewed charts, the patients were referred for GC/GT. A greater number of patients with— than those without—a positive family history of cancer were referred for GC/GT, but this number reached

only 42.7%. Referrals were greater in patients with breast cancer than those with colorectal cancer (29.1% vs 19.6%, respectively). Similarly, in patients with a hereditary risk for cancer—defined by selected risk guidelines—52.2% of those with breast cancer and 26.4% with colorectal cancer were referred for GC/GT. “We were glad to find high rates of first-degree family documentation for all breast and colon cancer patients. However, there were very low rates of documentation of the age of an individual at cancer diagnosis,” said Dr Wood. “Referral rates must be higher, because this impacts cancer care.” ■

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Health Economics

High OOP Costs for Medicare Patients with Cancer By Mark Knight Chicago, IL—Older patients with cancer and Medicare coverage often incur greater out-of-pocket (OOP) expenses compared with their counterparts without cancer. Factors contributing to the greater expenses for those patients include comorbidities and lack of supplemental insurance. As a result, older patients often hesitate to seek treatment for cancer because of financial concerns, according to a study presented by Amy J. Davidoff, PhD, MS, Assistant Professor, Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, and colleagues at the 2012 American Society of Clinical Oncology meeting. The team used Medicare Current Beneficiary Survey (MCBS) data from 1997 to 2007 that was linked to Medicare claims for their analysis. Patients with a new diagnosis of cancer were chosen based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes on claims after a 12-month washout period subsequent to the cancer diagnosis. OOP costs were noted via the patients’ own reporting. The study included 1869 Medicare beneficiaries with cancer and 10,057 without cancer. Those with cancer tended to be older, have more comorbidities, and typically did not have supplemental insurance compared with those without cancer. For a patient with cancer, the total

OOP spending was $4727 (11.4% of total spending); the OOP difference between patients with and without

sis—based in large part on data before the addition of Medicare Part D (in 2006)—demonstrated that oral

Older patients often hesitate to seek treatment for cancer because of financial concerns. —Amy J. Davidoff, PhD, MS

cancer was $1518. After adjusting for patient characteristics, those with cancer had an incremental increase of $956 in OOP cost. Among patients with cancer, approximately 28% spent ≥20% of their income on OOP expenses compared with 16% of those without cancer who used ≥20% of their income on OOP expenses. Comorbid conditions, undergoing cancer-specific radiation therapy, receiving antineoplastic therapy, and having greater assets led to more OOP expense. Supplemental Insurance A separate analysis of the same MCBS database showed that the use of antineoplastic therapy among Medicare recipients is influenced by the availability, but not the type, of supplemental coverage. This analy-

antineoplastic agents were received by many patients with cancer using antineoplastic therapy (non–Part B drugs), yet there was less spending on

With more oral antineoplastic agents in the pipeline, “monitoring the role of supplemental insurance, and particularly the role of Part D in access and spending, is a critical area for ongoing research.” —Amy J. Davidoff, PhD, MS

this therapy than on infused/injected chemotherapy (Part B drugs). There were no notable differences in use or

spending on antineoplastic therapy for the post–Part D period relative to the reference period. “With the large number of relatively new oral prescription antineoplastic agents, and with more in the pipeline, monitoring the role of supplemental insurance, and particularly the role of Part D in access and spending, is a critical area for ongoing research,” said Dr Davidoff. For this retrospective analysis, community-based MCBS participants with new cancer diagnoses were chosen based on ICD-9-CM diagnosis codes. A total of 1836 beneficiaries who had a new diagnosis of cancer were enrolled. Of the 559 patients who were treated with antineoplastic therapy, 395 (21.5%) received infused/injected chemotherapy and 254 received oral antineoplastic agents. Patients using antineoplastic therapy spent $7841 (any coverage), $10,364 (Part B coverage), and $1535 (non–Part B coverage). If beneficiaries had supplemental coverage, the antineoplastic therapy rates and spending were greater relative to those who did not have supplemental coverage. After adjustment, patients with supplemental insurance from any source were more likely to receive treatment for cancer. A major predictor of antineoplastic therapy use and spending was the site of the cancer. Also, older age was associated with less spending. ■

Cancer Screening Is Cost-Effective, Saves Lives By Wayne Kuznar Chicago, IL—Improved cancer screening can save lives, and despite the high cost of implementing such a measure, it was found cost-effective and therefore valuable in a recent analysis using quality-adjusted lifeyears (QALYs), said Michael S. Broder, MD, President of Partnership for Health Analytic Research, LLC (PHAR), CA, and colleagues, at the 2012 American Society of Clinical Oncology meeting. Cancer care spending in the United States has increased from $13.1 billion in 1980 to $104 billion in 2006, but there is much controversy over the sufficiency of the benefit of this spending. Cancer screening may reduce cancer-related morbidity, but to study whether such screening is cost-effec-

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tive, Dr Broder and colleagues from PHAR; the University of California, Los Angeles, Center for Surgical Outcomes and Quality; and RAND

“Compliance with cancer screening measures is costeffective, even considering the resources required to change established practices.” —Michael S. Broder, MD

Health in Santa Monica, CA, developed a framework for measuring the value of improving compliance with measures for cancer screening compared with other quality measures.

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Value of Quality Improvement Dr Broder and colleagues used their framework to examine 18 HEDIS 2010 quality measures. Quality improvement (QI)-adjusted incremental costeffectiveness ratios (ICERs) for 3 cancer screening measures—cervical, breast, and colon—were compared with the remaining measures. ICERs were reported for measures representing a tradeoff (ie, between greater cost and greater health, or cost-savings and worse health). To reach 95% compliance on these 3 cancer screening measures would cost $5.1 billion and add 160,000 QALYs—$32,640/QALY. This rate of compliance with all 18 measures would cost $13.4 billion and add 5.8 million QALYs, which translates to $2313/QALY. That would make QI a

good value and very cost-effective compared with most health improvements, which can cost more than $50,000 to $80,000 per QALY, according to Dr Broder. Although these costs were substantial, resulting in an increase of 50% to 200% in the ICER for the cancer screening measures, after incorporating QI costs, the mean QI-adjusted ICER for these 3 measures suggests that improving cancer screening compliance is costeffective at a $50,000/QALY willingness-to-pay threshold. “Our analysis shows that complying with cancer screening measures is cost-effective, even considering the resources required to change established practices,” said Dr Broder. Addressing overuse of care can save money, he added. ■

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Patient Adherence Rises with High Cost of Oral... nonadherence is often the primary cause of treatment failure. “To our knowledge, cost-related adherence to oral therapy in the context of malignancy has not been studied extensively,” said Jalal Ebrahim, MD, of St Michael’s Hospital, University of Toronto, Ontario, Canada. He and his colleagues conducted a study of 453 patients with cancer at 3 outpatient hematology/oncology clinics. They used a 7-item survey to investigate patient self-reported adherence to oral medication, type of coverage, and patients’ perceived cost of the drugs. Of the 453 patients, 50% had a private drug plan, 24% paid for the drug out of pocket, 44% had government funding, and 4% said their physician had arranged funding for their medication. Approximately 50% of the patients had a drug cost of ≥$100 monthly. Patients paying out of pocket were significantly less likely than all other patients to have oral drug costs of ≥$500 monthly (11% vs 19%, respectively). There was also a significant

relationship between drug coverage and oral drug costs. Patients with annual incomes of ≥$70,000 were more likely than those with lower incomes to have monthly drug costs of ≥$1000 (18% vs 9%,

The surprising finding in this study suggests that patients with cancer consider more expensive drugs to be more valuable, and should therefore be taken as prescribed. respectively). “It is possible that patients are provided with more education regarding newer and more expensive agents than they are for older and cheaper agents, regardless of efficacy,” according to Dr Ebrahim. Strong Adherence to High-Cost Drugs “A strong correlation was observed

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“A strong correlation was observed between monthly oral drug cost and adherence to the regimen.” —Jalal Ebrahim, MD between monthly oral drug cost and adherence to the regimen,” he said. A low monthly drug cost was not associated with higher adherence rates. The adherence rates related to monthly out-of-pocket costs were: • 55% adherence with ≤$10 • 83% adherence with $10-$100 • 83% adherence with $100-$500 • 75% adherence with $500-$1000 • 85% adherence with ≥$1000. Dr Ebrahim believes that patients consider more expensive drugs to be more valuable, and therefore should not be wasted. This “designer drug” phe-

nomenon may explain the increased adherence rates that were found to be associated with high-cost drugs. “Poor communication between physicians and patients can lead to poor adherence. A lack of education regarding older, cheaper medications could be a catalyst for nonadherence,” Dr Ebrahim suggested. The disparities found in this study in medication costs for patients with private drug plans versus those without private plans suggest that financial restrictions may affect prescription patterns, the team noted. ■

Cancer Therapies in Short Supply Prompt a Response at the Federal Level By Wayne Kuznar Chicago, IL—Drug shortages in cancer care remain a threat significant enough to warrant pending US legislation, though the frequency of these shortages appears to be on the decline. A panel that was convened at ASCO 2012 addressed the impact of drug shortages on cancer treatment and proposed resolutions. Legislation that is currently being debated in Congress aims to tackle drug shortages directly. Supporting the need for legislation, experts note that the availability of many drugs remains unpredictable. “We never know when a drug will go out of supply, which creates tremendous uncertainty and anxiety on the part of patients,” and makes planning difficult for physicians, said Richard L. Schilsky, MD, Chair, ASCO Government Relations Committee, and Section Chief of Hematology/Oncology, Department of Medicine, University of Chicago. “Patient care is threatened as a result of such drug shortages,” he commented. In addition, 22 oncology therapies either are or have been in short supply in the past 2 years, adds Michael Link, MD, ASCO outgoing president and Chief of the Division of Pediatric Hematology/Oncology, Stanford University School of Medicine, Palo Alto, CA.

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Specific cancer therapies in limited supply or nearly impossible to obtain include nitrogen mustard, cisplatin, and paclitaxel, as well as fluorouracil. According to a spokesperson from the US Food and Drug Administration (FDA), 12 cancer drugs are currently on the FDA’s list of medicines in short supply, but most issues are being addressed.

“Prevention of drug shortages at FDA is absolutely a priority—one of our number 1 priorities. We can engage with companies quickly if we know about them, to prevent shortages.” —Sandra Kweder, MD

According to Dr Link, 4 months ago oncology practices were down to a 2week supply of methotrexate to treat childhood leukemia, which is reportedly 90% curable when drugs are available. “That crisis was averted with stopgap measures we had in place,” said Dr Link.

According to Dr Link, the shortage even extends to drugs used to alleviate discomfort associated with anticancer therapy, such as sodium bicarbonate, which can accompany methotrexate, or leucovorin, used with 5-fluorouracil. The proposed legislation calls on pharmaceutical manufacturers to keep US regulators abreast of unanticipated drug supply issues. Draft laws reintroduce user fees for brand-name pharmaceuticals to cover the cost of new medicine assessments by the FDA; for the first time, the legislation also builds in fees for generic drug manufacturers, as well as for potential manufacturers of biosimilars. The addition of generic-drug user fees would generate approximately $1.5 billion in federal funding within several years, Dr Schilsky said. The funding could help reduce review times for New Drug Applications for generic drugs, trimming the current lead time of 30 months to 10 months or less. This represents a huge step forward in recruiting new manufacturers to get drugs on the market, Dr Schilsky said. The downside is that the legislation is not expected to include provisions to levy cash penalties on manufacturers that fail to notify the agency of pending

shortages. Dr Schilsky adds that there are concerns that “If there are no teeth in that legislation, some companies may decide not to report as required.” Pending the passage of legislation, the FDA is seeking notification from drug companies if they expect a shortage, a policy that thus far has led to positive outcomes, according to Sandra Kweder, MD, Deputy Director of the FDA’s Office of New Drugs. “Prevention of drug shortages at FDA is absolutely a priority—one of our number 1 priorities here, as well as in Congress and in the White House,” Dr Kweder said. We can engage with companies quickly if we know about them, to prevent shortages from occurring.” In 2012 alone, advance notification has prevented at least 50 drug shortages, although not all shortages are oncology-specific. Since October 2011, 150 drug shortages have been prevented, she said. The majority of drug shortages in general are a direct result of manufacturing and drug quality problems, according to Dr Kweder. A single facility closing because of quality issues can lead to dozens of shortages. And quality issues are often related to sterility. For example, particles of glass or metal shavings may be found in vials. ■

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Health Economics

The Cost of Lung Cancer at the End of Life: Early Institution of Palliative Care Improves Survival By Caroline Helwick Evidence shows that aggressive use of chemotherapy near death is unrelated to the likelihood of better outcomes, yet there are many rationales for futile

Photo by © ASCO/Todd Buchan 2012

Chicago, IL—Early institution of palliative care in patients with lung cancer is not only humane, it is cost-effective, according to Craig C. Earle, MD, Director of the Health Services Research Program for Cancer Care Ontario and the Ontario Institute for Cancer Research, at a session on the cost of lung cancer care at ASCO 2012. “The costs of cancer treatment near the end of life can be significant, both economically and in terms of patient and caregiver quality of life. What we do influences the cost of care, especially at the end of life. We need to appreciate the limits of benefit associated with aggressive treatment as the end of life nears and know the potential benefits of early institution of palliative care in this setting,” Dr Earle said. The cost trajectory is a U-shaped curve, he noted. “The cost is high at the beginning, is less in the middle, and invariably rises rapidly at the end of life.” Palliative care, instituted at diagnosis when patients live 6 months, costs approximately $6000 per patient (mean reimbursement) in the first couple of months but then results in much lower monthly costs compared with chemotherapy. At month 6 (end of life), the mean reimbursement for palliative care is approximately $5000, whereas it climbs to $8000 when chemotherapy is delivered, Dr Earle said. The trend toward aggressive care at the end of life has been increasing slowly during the past 15 years. Although this overuse became evident a decade ago, little has been done to curb its trajectory.

See also Lung Cancer

“We need to appreciate the limits of benefit associated with aggressive treatment as the end of life nears and know the potential benefits of early institution of palliative care in this setting.” —Craig C. Earle, MD care: patients or families request it, it is seen as preserving hope, it is thought that doing something is better than doing nothing, it is easier for oncologists to give chemotherapy than withhold it, the occasional patient responds and has meaningful palliation after aggressive treatment, patients will accept more toxicity than oncologists think they will, and, in some cases,

providers have financial incentives, he suggested. “If oncologists don’t have support to give good palliation, then perhaps we continue to do what we were trained to do, give chemotherapy,” Dr Earle urged. “But if we as healthcare providers say we would not want aggressive treatment ourselves, perhaps because we have a true idea of the tradeoffs, then maybe we should be more paternal as we shepherd patients through the disease course.” The Value of Palliative Care Perceptions were changed, to some degree, by a couple of recent studies that confirmed that an aggressive approach continued to near-death does not improve outcomes and that early institution of symptomatic/palliative care does not adversely affect survival. In a study led by Dr Earle, overall survival among elderly patients with lung cancer was better in patients who used a hospice versus those not in a hospice (25.7% vs 20.7%, respectively, at 1 year postdiagnosis, and 6.9% vs 5.5%, respectively, at 2 years; P <.001). There was no significant difference between those with shorter and those with longer duration hospice stays (Saito AM, et al. J Palliat Med. 2011; 14:929-939). In another study (Temel JS, et al. N Engl J Med. 2010;363:733-742), early initiation of palliative care was associated with less aggressive treatment and a 3month survival advantage, as well as greater patient and family satisfaction. Dr Earle noted that other studies have shown that patient and caregiver satis-

faction is worse when chemotherapy is overused, when death occurs in the hospital or in the intensive care unit, and when patients are not admitted (or admitted only briefly) into a hospice. More aggressive care also has been associated with higher rates of depression among bereaved caregivers, he added.

“If we as healthcare providers say we would not want aggressive treatment ourselves, perhaps because we have a true idea of the tradeoffs, then maybe we should be more paternal as we shepherd patients through the disease course.” —Craig C. Earle, MD Change Is Possible As more emphasis is placed on avoiding futile chemotherapy, and as pathways are being developed to enforce this, the opposite trend is beginning to emerge, Dr Earle said. For example, with feedback from ASCO’s Quality Oncology Practice Initiative (QOPI), the use of chemotherapy in the last 2 weeks of life in one institution declined from 50% to 20% (Blayney DW, et al. J Clin Oncol. 2009;27:38023807). “Our practice changed toward the QOPI national practice norm after a presentation of the results at a faculty research conference,” the authors of this article wrote. ■

Radiotherapy-Related Hospital Admissions Are Frequent Chicago, IL—Approximately 1 in 5 patients with cancer who are undergoing radiotherapy as part of their treatment can count on unexpected hospital stays—adding an economic and clinical burden on the patient and on the healthcare system, according to a study by Nabeel H. Arastu, BS, and colleagues at the Brody School of Medicine at East Carolina University, Greenville, NC, which was presented at ASCO 2012. Unanticipated admissions were common among nearly 33% of patients who received radiotherapy to treat symptoms and were also likely in more than 25% of those receiving simultaneous chemoradiation.

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Data were collected from the electronic health records of 500 patients with cancer. The patients had received external beam radiotherapy in 2010. 20% Unexpected Admissions Of the 500 patients, 101 (20%) had unexpected hospital stays, lasting a mean of 4 days (range, 1-16 days). The mean length of time between a patient beginning radiotherapy and going to the hospital unexpectedly was 32 days (range, 0-86 days). Reasons for hospital admission included: • Pain (19% of cases) • Respiratory issues (15%)

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• Neurologic conditions (13%) • Malaise (7%) • Fever (5%). In addition, 33% of patients who were treated palliatively ended up being admitted to the hospital compared with 16% of curative-focused patients. According to a univariate analysis, 26% of patients who had simultaneous radiotherapy and chemotherapy had unplanned hospital admissions compared with 17% of those receiving only radiotherapy. Unexpected hospital stays were tied to chemotherapy, treatment goals, and marital status. There were highly inconsistent rates of unexpected hospital visits based on diagno-

sis—including 37% for metastases; 19% for gastrointestinal, genitourinary, gynecologic, ear, nose, and throat cancers; and 4% for breast cancer. Patients who were treated with a second or third round of radiotherapy could expect higher admission rates (average, 27%) compared with those who received only 1 treatment round (16%). Furthermore, patients who were undergoing treatment for secondary metastases typically experienced a much higher rate of unexpected hospital visits, possibly because patients undergoing multiple rounds of chemotherapy for secondary metastases are typically sicker and have more comorbidities.—CH ■

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GI Cancers

Metastatic Colorectal Cancer: Prolonged Bevacizumab Improves Outcomes, New Targeted Therapies on the Horizon By Caroline Helwick Chicago, IL—The addition of new targeted agents, as well as prolonged use of bevacizumab even beyond disease progression, extend overall survival (OS) and improve progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC), according to several studies presented at ASCO 2012. The More Bevacizumab, the Better In the phase 3 clinical trial TML 18147, which was highlighted at a press briefing, the administration of the anti-VEGF (vascular endothelial growth factor) bevacizumab beyond the point of disease progression increased survival. “This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. The study confirms that continuing bevacizumab beyond progression when changing chemotherapy is beneficial for patients, and this finding has translated into a significant improvement in OS in metastatic colorectal cancer patients, as well as progression-free survival,” said Dirk Arnold, MD, of the University Clinic Eppendorf in Hamburg, Germany. The TML 18147 trial enrolled 820 patients with mCRC whose disease had progressed after first-line chemotherapy. The patients received an irinotecan-based or oxaliplatin-based regimen plus bevacizumab. Upon disease progression, the patients were

randomized to second-line therapy with the regimen they did not receive first, with or without concomitant bevacizumab.

“The study confirms that continuing bevacizumab beyond progression when changing chemotherapy is beneficial for patients, and this finding has translated into a significant improvement in OS in metastatic colorectal cancer patients.” —Dirk Arnold, MD

The median OS was 11.2 months with maintenance bevacizumab compared with 9.8 months with chemotherapy alone, for a 19% reduction in mortality risk (P = .062). Median PFS was 5.7 months and 4.1 months, respectively (P <.001). This study tested an important biologic concept for antiangiogenic drugs, showing that duration of treatment does matter. In addition, although the current evidence comes from research in mCRC, this principle could hold true for lung and breast cancer as well, some believe.

Dr Arnold said that although bevacizumab produced mixed results in other cancers, it plays a significantly favorable role in mCRC. “These findings indicate that this might serve as a new model for a treatment approach by multiple treatment lines in metastatic colorectal cancer and across other tumor types,” he said. Axel Grothey, MD, a CRC specialist at the Mayo Clinic, Rochester, MN, agreed that using bevacizumab beyond progression represents a new treatment approach that is currently being tested in other tumor types. Press briefing moderator Bruce J. Roth, MD, of Washington University in St. Louis, commented that oncologists have been trained to discontinue cytotoxic chemotherapy at the time of progression, “but the issue is more complicated for anti-VEGF therapies like bevacizumab, and this issue has been raised in other tumor types.” He said that the mechanism of resistance to anti-VEGF agents may be different, which may explain the benefit. Potential New mCRC Therapies Two additional studies presented at the meeting showed benefits from adding kinase inhibitors or an epidermal growth factor receptor (EGFR) to mCRC regimens. In the phase 3 clinical trial CORRECT, the investigational oral multikinase inhibitor regorafenib was compared with placebo in 760 patients with

mCRC whose disease was refractory to chemotherapy. The use of regorafenib significantly extended OS from 5.5 months with placebo to 6.6 months, hazard ratio 0.77 (95% confidence interval, 0.640.94; P = .052). Although the absolute difference in OS was only 1 month, Dr Grothey emphasized that these results are best viewed in terms of the hazard ratio. He noted that many patients with mCRC are still fit and able to undergo further treatment after they become resistant to chemotherapy, and regorafenib addresses that unmet need. A New Drug Application was submitted to the US Food and Drug Administration for regorafenib on May 23, 2012, for the treatment of patients with mCRC. In the phase 3 GERCOR DREAM trial, patients with previously untreated mCRC received chemotherapy plus bevacizumab, and those without disease progression were randomized to maintenance therapy with bevacizumab alone or with bevacizumab plus the EGFR erlotinib. Median PFS was improved with the addition of erlotinib from 4.6 months to 5.8 months (P = .005). There was, however, an increase in diarrhea and skin toxicity with erlotinib. Nevertheless, the study suggests that there may be a role for dual targeting of VEGF and EGFR in CRC, according to Dr Grothey. ■

For Advanced GIST, Regorafenib Shows Robust Effect Chicago, IL—Regorafenib, the orally administered investigational tyrosine kinase inhibitor (TKI) that has shown activity in metastatic chemorefractory colorectal cancer, dramatically delayed disease progression in patients with a treatment-refractory metastatic gastrointestinal stromal tumor (GIST) in GRID, a phase 3 clinical trial, said lead investigator George D. Demetri, MD, Associate Professor, Department of Medicine, Harvard Medical School, and Director, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, at ASCO 2012. The median progression-free survival (PFS) reached 4.8 months with regorafenib compared with only 0.9 months in the placebo arm, for a 73% reduction in risk (P <.001). The disease control rate at 12 months was 52.6%

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with regorafenib and 9.1% with placebo. “There was a significant robust effect, regardless of the number of prior inhibitors that these patients had been exposed to. Regorafenib has the potential to fulfill an unmet need for GIST patients progressing after imatinib and sunitinib, and potentially represents a new standard of care,” Dr Demetri said. GIST is the most common subtype of sarcoma, and until the marketing of imatinib and then sunitinib, this condition was essentially untreatable. The TKIs changed the typical course of this disease, with prognosis ranging from ≤6 months, survival to ≥5 years. However, the tumors almost universally eventually become resistant to these 2 approved TKIs, Dr Demetri said.

GRID was an international, randomized, placebo-controlled trial that quickly accrued 236 patients with

“There is no doubt that regorafenib is a viable thirdline treatment option now for our patients.” —Grant McArthur, PhD

metastatic, unresectable GIST who were intolerant of imatinib and sunitinib, or whose disease progressed despite treatment with these agents. The patients were assigned to daily regorafenib or to placebo plus best

supportive care; 74% of the patients had received 2 previous lines of therapy and 59% had received >2 lines. Despite the significant difference in PFS between the 2 arms, the overall survival rate was similar, presumably because 85% of the placebo-recipient patients crossed over to receive regorafenib upon disease progression. Median survival has not yet been reached in either arm. Treatment-related adverse events were similar to what is typically seen with multitargeting TKIs. Grant McArthur, PhD, of the Peter MacCallum Cancer Centre, East Melbourne, Australia, commented on the study, saying, “Clearly, this is a positive study, and there is no doubt that regorafenib is a viable third-line treatment option now for our patients.”—CH ■

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IV R F O AN D D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU A D

VELCADEHCP.COM


If you define value as an overall survival advantage: VELCADE® (bortezomib) DELIVERED A >13-MONTH OVERALL SURVIVAL ADVANTAGE At 5-year median follow-up, VELCADE (bortezomib)+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-085]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you define value as defined length of therapy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you define value as medication cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,471 per 3.5-mg vial as of January 2012 Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen

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

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS Peripheral neuropathy, including severe cases, may occur — manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated Closely monitor patients with risk factors for, or existing heart disease Acute diffuse infiltrative pulmonary disease has been reported Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement. To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analyses were performed. Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.


Pediatric Cancer

Crizotinib Effective in Aggressive Pediatric Tumors By Caroline Helwick Chicago, IL—Crizotinib—which produces robust responses in patients with non–small-cell lung cancer who have abnormalities in the anaplastic lymphoma kinase (ALK) gene—may also have an impact on a number of aggressive pediatric tumors, according to a phase 1

dose-escalation study conducted by the Children’s Oncology Group and reported by lead investigator Yael Mosse, MD, of the Children’s Hospital of Philadelphia, at ASCO 2012. Crizotinib halted tumor growth in children with anaplastic large-cell lym-

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

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AMERICAN HEALTH & DRUG BENEFITS

August 2012

phoma (ALCL), inflammatory myofibroblastic tumors (IMTs), and aggressive forms of neuroblastoma; in some cases, crizotinib eradicated all signs of cancer, Dr Mosse said. Abnormalities in the ALK gene are found in approximately 80% to 95% of

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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“Now that we know much more about the drivers of some pediatric cancers, we can target those changes and treat patients in a much smarter and potentially safer way.” —Yael Mosse, MD patients with ALCL, 50% of those with IMTs, and 10% to 15% of patients with aggressive neuroblastomas. “It’s remarkable that this targeted oral medication provided such a substantial benefit in these children with highly aggressive cancers, most of whom had already undergone every available therapy. Now that we know much more about the drivers of some pediatric cancers, we can target those changes and treat patients in a much smarter and potentially safer way,” Dr Mosse said. This study included 70 children (median age, 10 years) with refractory solid tumors and ALCL. The outcomes by disease were: • ALCL: of the 8 patients enrolled, 7 achieved complete responses • IMT: of the 7 patients enrolled, 1 had a partial response, 1 had a minor response (tumor shrinkage), and 5 are too early to evaluate • Neuroblastoma: of the 35 patients enrolled, 27 were evaluable; of these, 8 patients have known ALK mutations; in this group, 1 had a complete response, 1 had a minor response, and 1 had stable disease. Among the 19 patients whose ALK gene status is unknown, 1 had a complete response and 6 had prolonged stable disease. The responses tend to be durable, with some patients continuing treatment for >18 months. Compared with ALCL, the benefit of crizotinib is less clear in IMT and in neuroblastoma, although subsets of these patients do appear to respond, Dr Mosse said. These findings have implications beyond these pediatric cancers. “With next-generation sequencing, we may discover that the ALK gene is relevant to multiple human cancers.” Michael Link, MD, outgoing president of ASCO and a pediatric oncologist himself, said the study has farranging implications. “The molecular driver [ALK] is present in very different and sometimes unrelated tumor types, and thus this ALK inhibitor may work in very different cancers,” he predicted. “We have a glimpse at a new paradigm of understanding cancer and drug development, that it will someday not be sufficient to identify tumors by their histology or organ of origin.” ■

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Breast Cancer

Institute at Duke University, WinstonSalem, NC. Louis Weiner, MD, Director, Georgetown-Lombardi Cancer Center in Washington, DC, the invited discussant for the study, commented, “Stated simply, T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.” The EMILIA Study EMILIA included 991 HER2-positive patients who had locally advanced or metastatic breast cancer and who had previously received a taxane and trastuzumab. Patients were randomized to receive intravenous T-DM1 or capecitabine plus lapatinib (XL) every 3 weeks, until progression. The median PFS for the T-DM1 arm

Photo by © ASCO/Todd Buchanan 2012

Novel T-DM1 Prolongs Remission in Metastatic...

“For patients facing metastatic breast cancer, this is a breakthrough.” —Kimberly L. Blackwell, MD was 9.6 months compared with 6.4 months for XL, representing a 35%

reduction in the risk of progression (P <.001), Dr Blackwell reported. Median overall survival (OS) was not reached with T-DM1 and was 23.3 months with XL, for a 38% reduction in mortality risk (hazard ratio, 0.621; 95% confidence interval, 0.475-0.813; P <.005). This result, however, did not meet the prespecified threshold for statistical significance for this end point at the first analysis. Nevertheless, after 2 years, 65.4% of the patients receiving T-DM1 were alive compared with only 47.5% of those receiving the XL regimen. Dr Weiner predicted that a significant improvement in OS will eventually be observed, and this will be “particularly notable, since effective palliative treatment has rarely been associated with improved survival in

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the metastatic setting.” Dose reductions were required for 16.3% of the patients receiving T-DM1 compared with 53.4% of those in the

“T-DM1 really works in this patient population. It is an important new weapon in the therapeutic armamentarium for breast cancer.” —Louis Weiner, MD capecitabine arm and 27.3% in the lapatinib arm. Diarrhea, vomiting, hand-foot syndrome, and alopecia were reported with the chemotherapy regimen but not with T-DM1. ■

Chemotherapy-Related Toxicity Adds to Economic Burden in Metastatic Breast Cancer By Caroline Helwick Chicago, IL—Adverse events related to chemotherapy for metastatic breast cancer lead to a substantial economic burden that is primarily explained by increased inpatient, outpatient, and pharmacy costs, said lead investigator Sara A. Hurvitz, MD, Director of the Oncology Breast Cancer Program at University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and Assistant Clinical Professor at UCLA School of Medicine, who presented an economic analysis at ASCO 2012. “An analysis of healthcare costs stratified by the number of adverse events reported by patients showed a clear trend: the economic burden of adverse events increases with the number of adverse events reported,” Dr Hurvitz said. The study is the first to assess costs associated with adverse events during treatment for metastatic breast cancer. Patients were selected from the PharMetrics Integrated Database, using pharmacy and medical claims from >100 US health plans, representing >70 million lives in the period between 2000 and 2010. The eligible cohort included 3222 patients who used a taxane (ie, docetaxel, paclitaxel) first-line, capecitabine first-line, taxane second-line, or capecitabine second-line. Patients treated with both classes during the

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same episode were excluded. The list of adverse events included almost 2 dozen possibilities. Adverse events were seen in each of the 4 study cohorts. Incremental Monthly Costs The incremental costs associated with chemotherapy-related complications were estimated by comparing the average costs between the cohorts

“An analysis of healthcare costs stratified by the number of adverse events reported by patients showed a clear trend; the economic burden of adverse events increases with the number of adverse events reported.”

• Taxanes second-line: adverse events were associated with a 69.5% increase in monthly costs ($5320). Incremental costs were mainly driven by incremental pharmacy costs for chemotherapy and other drugs • Capecitabine first-line: adverse events were associated with a 9% increase in monthly costs ($4933). Incremental costs were mainly driven by inpatient and outpatient costs • Capecitabine second-line: adverse events were associated with an 82.9% increase in monthly costs ($4933). Incremental costs were mainly driven by outpatient and inpatient costs. Increasing Adverse Events per Episode Led to Higher Costs The more adverse events per episode, the greater the cost of care, the analysis found. For example, for

taxane first-line therapy, the mean cost of a treatment without an adverse event episode was approximately $10,000, which rose to approximately $11,000 in the setting of 1 or 2 adverse events, and to almost $15,000 in the setting of >4 adverse events. For second-line capecitabine, treatment without an adverse event episode cost approximately $6000, but rose to approximately $14,000 in the setting of >4 adverse events. The average monthly costs per type of adverse event were highest for skin toxicity with taxanes and for constitutional symptoms with capecitabine, both approaching $16,000 on average. “Further research evaluating the clinical and economic consequences of chemotherapy-related adverse events in a prospective manner can further characterize the effects seen here,” Dr Hurvitz concluded. ■

—Sara A. Hurvitz, MD with and without adverse events for the 4 treatment groups: • Taxanes first-line: adverse events were associated with a 38.7% increase in monthly costs over patients without adverse events ($3547). These incremental costs were mainly driven by increased inpatient costs and other drug costs (other than those for chemotherapy)

Estimated Breast Cancer Rates, 2012 According to data from the American Cancer Society, an estimated 229,060 new cases of breast cancer will occur in the United States in 2012; of these 226,870 are women and 2190 are men. In addition, an estimated 39,920 patients with breast cancer will die of the disease in 2012. Source: American Cancer Society, Inc., Surveillance Research, 2012.

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Lung Cancer

Non–Small-Cell Lung Cancer Testing Can Be Offered Routinely in Community Hospitals By Wayne Kuznar Chicago, IL—Searching for ways to improve outcomes and increase access to molecular testing for patients with non–small-cell lung cancer (NSCLC), investigators have shown that it is possible to perform high-grade molecular testing regularly for NSCLC in area community hospitals that are not tied to academic medical centers. Some of the most effective drugs for the treatment of NSCLC work optimally only in patients with tumors that contain certain molecular biomarkers. Targeted therapies to treat NSCLC include erlotinib, which targets EGFR1 (epidermal growth factor receptor 1), and crizotinib, which targets cancers with a translocation in the anaplastic lymphoma kinase (ALK) gene. “Because of advances in molecular testing technologies for these biomarkers and the ease of doing this testing today in many laboratories, our research shows that state-of-the-

art personalized medicine is possible in community hospitals, and not just in advanced academic medical centers,” said lead investigator Thomas Zander, MD, of University Hospital in Cologne, Germany, and the Network Genomic Medicine Lung Cancer, a regional screening network in the Cologne-Bonn region of Germany. The Network Genomic Medicine Lung Cancer was built for this study, which involved a number of community hospitals in the Cologne-Bonn region of Germany that were not affiliated with academic centers in 2010. For the study, 77% of 1782 lung tumor samples collected from biopsies in community hospitals were shipped to a laboratory to be tested for the molecular features mentioned above. The molecular testing revealed KRAS mutations in 32% of the samples, EGFR mutations in 13%, and ALK modifications in 3%; BRAF, ERBB2, and

PIK3CA mutations were each detected in 2% of samples. Among patients with squamous-cell cancer, FGFR1 amplification was detected in 15%.

“Our research shows that state-of-the-art personalized medicine is possible in community hospitals, and not just in advanced academic medical centers.” —Thomas Zander, MD

Approximately 35% of cancers in patients with NSCLC have known targetable lesions. Of the NSCLC samples that had genetic mutations, 40% could be managed with currently available targeted treatments. Crizotinib was given to eligible patients with ALK

mutations. Erlotinib and similar drugs were administered to approximately three fourths of patients who had EGFR modifications. KRAS, BRAF, PIK3CA, ERBB2, and FGFR1 are all genetic markers that are expected to influence NSCLC outcomes. Work is under way on investigational drugs to target these genetic markers as well. Previously, genetic testing for any of these markers was usually offered only in academic medical centers, and access by patients in community hospitals was low. Of note, the cost of offering such testing in community hospital settings is not overly prohibitive, according to Dr Zander. This cost is equal to approximately 1 to 2 weeks of therapy in the United States. “High-quality molecular diagnostics and a personalized treatment approach lead to significant benefit for patients,” he said. ■

Afatinib Boosts PFS in EGFR Mutation–Positive Lung Cancer New irreversible ErbB receptor blocker seems more potent than other therapies

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py. Unlike reversible EGFR (ErbB1) tyrosine kinase inhibitors, afatinib irreversibly blocks the entire ErbB family of receptors.

—James Chih-Hsin Yang, MD, PhD

“By more broadly and effectively blocking the molecular pathways that facilitate the growth of these cancers, afatinib appears to be more potent than other therapies,” said Dr Yang. “This new treatment could not only help patients live a longer period of time without further cancer progression, but because it’s given orally, it may also require fewer visits to the doctor’s office than standard chemotherapy—another important quality of life advantage.”

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In the study, 345 patients were randomized to oral afatinib or standard combination intravenous chemotherapy (pemetrexed and cisplatin) in a

“This new treatment could not only help patients live a longer period of time without further cancer progression, but because it’s given orally, it may also require fewer visits to the doctor’s office than standard chemotherapy—another important quality of life advantage.”

Photo by © ASCO/Todd Buchanan 2012

Chicago, IL—Based on the results of a phase 3 study, patients with advanced lung adenocarcinomas that harbor epidermal growth factor receptor (EGFR) mutations experience extended progression-free survival (PFS) when treated with the investigational ErbB receptor family blocker afatinib as single-agent therapy compared with standard chemotherapy. The international trial, known as LUX-lung 3, showed that the use of afatinib, an ErbB family blocker of epidermal growth factor, HER2, and ErbB4 receptors, doubled PFS in most patients who had 1 of the 2 prevalent EGFR mutation types, deletion 19 or L858R. “With 4.2 months of PFS improvement in the overall population and 6.7 months in patients with common mutations, afatinib is a clinically relevant first-line treatment option,” said lead investigator James Chih-Hsin Yang, MD, PhD, Professor at National Taiwan University, Taipei, at ASCO 2012. The randomized trial, the largest of its kind to evaluate EGFR mutation– positive lung cancer, involved the evaluation of afatinib, comparing it against a recent first-line regimen option for advanced but not yet treated lung adenocarcinoma—combined pemetrexed and cisplatin chemothera-

August 2012

2:1 ratio. Every patient had an EGFR mutation. Baseline traits were similar in the 2 study arms: 65% of patients were female, 72% were Asian, 68% never smoked, and the median age was 61 years. After a median follow-up of 8 months, afatinib delayed disease progression by more than 4 months over standard therapy (PFS, 11.1 months vs 6.9 months, respectively). PFS was delayed further (13.6 months vs 6.9 months, respectively) for 308 patients

with the more prevalent EGFR mutations—deletion 19 or L858R. Common symptoms of lung cancer, such as cough and dyspnea, did not occur as quickly (40% delay) in patients taking afatinib compared with those receiving chemotherapy, said Dr Yang. He noted that adverse events were “as expected” with EGFR inhibition, consistent with earlier studies, and were manageable, reversible, and predictable. Adverse events related to the drugs included diarrhea (95%), rash/acne (62%), and paronychia (57%) with afatinib, and nausea (66%), reduced appetite (53%), and vomiting (42%) with combination chemotherapy. These adverse events led to an 8% discontinuation rate among study patients. Patients who received afatinib experienced greater tumor shrinkage than those who received the standard chemotherapy, according to Dr Yang. The response rate for people who received afatinib was 56%, and in those assigned to chemotherapy it was 23%. On a questionnaire to assess quality of life, patients randomized to afatinib rated their quality of life in overall health status higher than those receiving chemotherapy.—WK ■

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Prostate Cancer

New Androgen Receptor–Signaling Inhibitor Extends Survival, Improves QOL in Advanced Prostate Cancer Chicago, IL—The novel androgen receptor–signaling inhibitor enzalutamide, also known as MDV3100, significantly prolonged overall survival (OS), slowed disease progression, and improved quality-of-life (QOL) measures in men with castration-resistant prostate cancer after docetaxel failure, according to results from a large phase 3 clinical trial. In this double-blind, randomized trial, OS improved from 13.6 months in the placebo group to 18.4 months in the enzalutamide group, for a 37% reduction in the risk of death, said Johann S. de Bono, MB, ChB, MSc, PhD, of the Institute of Cancer Research and the Royal Marsden National Health Service Foundation Trust, United Kingdom, at ASCO 2012. “I think these are the best survival data we’ve seen in the postchemotherapy setting,” Dr de Bono said. A total of 1199 patients with castration-resistant prostate cancer who had received docetaxel-based chemotherapy were randomized in a 2:1 ratio to daily enzalutamide or to placebo. Therapy was continued through minor changes in prostate-specific antigen

(PSA) level. Treatment with glucocorticoids was allowed but not required. More than 25% of patients had softtissue disease involving the liver or the lung. More than 90% of patients had bone metastases. Approximately 50% of the patients in each arm had ≥3 previous lines of hormonal drug therapy. The trial was unblinded early after the independent data monitoring committee determined that the risk-to-benefit ratio with MDV3100 was favorable; eligible patients in the placebo arm were offered treatment with enzalutamide. With a median follow-up of 14.4 months, enzalutamide conferred a survival advantage across all identified subgroups. “Impressively, enzalutamide had a very high PSA response rate,” said Dr de Bono. With enzalutamide, 25% of patients had a >90% fall in PSA level compared with only 1% with placebo. “I never thought I’d see a 50% and 90% fall in PSA in this population of patients, with 54% of patients having a more than 50% confirmed PSA fall,” Dr de Bono said. All of the secondary end points in

Photo by © ASCO/Silas Crews 2012

By Wayne Kuznar

“These are the best survival data we’ve seen in the postchemotherapy setting. Impressively, enzalutamide had a very high PSA response rate. I never thought I’d see a 50% and 90% fall in PSA in this population of patients.” —Johann S. de Bono, MB, ChB, MSc, PhD the study favored the treatment arm. PSA progression-free survival (PFS) was extended from 3.0 months in the placebo group to 8.3 months in the enzalutamide group. Similarly, the radiographic PFS was 2.9 months in the placebo group and 8.3 months in the enzalutamide group, for a hazard

ratio of 0.40 in favor of enzalutamide. Objective response rates (complete and partial) based on the Response Evaluation Criteria in Solid Tumors (RECIST) trial were 3.8% in the placebo arm and 28.9% in the enzalutamide arm. The time to a first skeletal event was again superior in the enzalutamide arm (16.7 months) compared with the placebo arm (13.3 months)— a 38% reduction in the risk of a skeletal-related event. QOL responses as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) were also superior with enzalutamide. In that group, 43.2% had at least a 10-point increase in the overall FACT-P score compared with 18.3% in the placebo group. A smaller proportion of patients treated with enzalutamide had grade ≥3 adverse events (AEs) compared with placebo (45.3% vs 53.1%, respectively). Serious AEs also occurred at a lower rate with enzalutamide than placebo (28.4% vs 33.6%). Seizure rates were 0.6% with enzalutamide and 0% with placebo. ■

Abiraterone Before Chemotherapy a Successful Strategy in Prostate Cancer Chicago, IL—Abiraterone acetate (Zytiga) delays disease progression when used with prednisone before chemotherapy in men with metastatic castration-resistant prostate cancer, said Charles J. Ryan, MD, Associate Professor of Clinical Medicine, Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, who reported a planned interim analysis of a phase 3 study at ASCO 2012. The finding represents a potential new use of abiraterone in prostate cancer; the drug is now approved only for men with metastatic castration-resistant prostate cancer in whom docetaxel (Taxotere) chemotherapy has failed. “These data merit consideration as providing a new standard approach in this highly prevalent population faced with an unmet medical need,” said Dr Ryan. The trial included 1088 men with metastatic castration-resistant prostate cancer that was no longer responsive to hormonal therapy. The men were

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randomized to abiraterone plus prednisone or to placebo plus prednisone. The trial was terminated early, with 43% of total events reported, given the favorable response on overall survival (OS) and progression-free survival

“These data merit consideration as providing a new standard approach in this highly prevalent population faced with an unmet medical need.” —Charles J. Ryan, MD

(PFS) observed with abiraterone. At this point, the Independent Data Monitoring Committee recommended unblinding the study and offering the placebo recipients active treatment with abiraterone. The median survival in this study was 14.8 months, with an improvement of 3.9 months over the pred-

nisone control arm, “thus reflecting the advanced clinical stage of the population tested,” said Dr Ryan. “A reality is that much of the life of a patient with metastatic castrationresistant prostate cancer is lived before chemotherapy, and, in fact, a large proportion of patients never receive it,” Dr Ryan stated in explaining the rationale for studying abiraterone in chemotherapy-naïve patients. There was a 57% improvement in radiographic PFS, a coprimary end point, in men randomized to abiraterone. The median time to progression was 8.3 months in the control group, but the median time to PFS had not yet been reached in the abiraterone group at the time the trial was suspended. “This represents an approximate doubling of the radiographic progression-free survival,” he said. The median survival in the prednisone control arm was 27.2 months, whereas the median survival had not yet been reached in the abiraterone arm, which conforms to a 25% improvement in survival, “a strong

trend in favor of abiraterone,” Dr Ryan pointed out. This trend did not reach statistical significance because of the early termination of the trial. Some 60.3% of the prednisone control group required additional therapies for prostate cancer, including docetaxel (the most common subsequent treatment) compared with only 44.3% of the abiraterone arm. Abiraterone significantly delayed the time (by 31%) before patients needed opiates to control pain and the time (by 42%) to initiate chemotherapy. Susan Halabi, PhD, Associate Professor of Biostatistics and Bioinformatics at Duke University Medical Center, Durham, NC, said that although the study represents the first to show activity of abiraterone in chemotherapy-naïve patients, she questioned early termination of the trial, before the difference in OS observed with abiraterone could achieve statistical significance. Nevertheless, the survival benefit with abiraterone is most likely real, she said.—WK ■

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Prostate Cancer

Agent that Targets Heat Shock Protein Shows Activity in Castration-Resistant Prostate Cancer By Wayne Kuznar Chicago, IL—OGX-427, a secondgeneration investigational antisense compound that targets heat shock protein-27 (Hsp-27), is well tolerated, and when combined with prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (CRPC), it reduces disease progression compared with prednisone alone. In a recent clinical study, more patients who took OGX-427 plus prednisone were without disease progression at 12 weeks and more had declines in levels of prostate-specific antigen (PSA) compared with those taking prednisone alone, reported Kim Chi, MD, medical oncologist and Associate Professor of Medicine at BC Cancer Agency, British Columbia, Canada, and the primary study investigator, at ASCO 2012. Hsp-27 is a cell-survival protein expressed in many types of cancers. Overexpression of Hsp-27 is thought to be an important factor leading to the development of treatment resistance and is correlated with a poorer prognosis in patients with various tumor

types. “It also increases after castration therapy as a stress survival response and is shown to be overexpressed highly in metastatic CRPC tissues,” said Dr Chi.

In the OGX-427 plus prednisone arm, progressionfree survival was 71% at 12 weeks compared with 40% in the prednisone alone arm. Of 72 planned patients, 64 have been randomized to the study, and data on 42 patients (22 who received OGX-427 plus prednisone, and 20 who received prednisone alone) are now available at or beyond the 12-week assessment time point. The median treatment duration is 24 weeks in the OGX-427 plus prednisone arm versus 14 weeks in the prednisone alone arm. Treatment is ongoing in approximately 30% of patients in each arm. Of the 14 patients in the prednisone alone arm

who have come off treatment, 13 have done so because of disease progression, said Dr Chi. For this reason, 10 of the 20 patients in the prednisone alone arm crossed over to the OGX427 plus prednisone arm. The primary efficacy end point in the study was progression-free survival (PFS) at 12 weeks. Disease progression is based on any of the following parameters: PSA levels, measurable disease, bone lesions, global deterioration, or a requirement for palliative radiation therapy.

There was 1 complete response in the OGX-427 plus prednisone arm. “This has lasted for almost a year, and he still has not progressed.” —Kim Chi, MD In the OGX-427 plus prednisone arm, PFS was 71% at 12 weeks compared with 40% in the prednisone alone arm. A ≥50% decline in PSA was experienced

by 50% of patients who were randomized to OGX-427 plus prednisone, versus 20% of patients who were randomized to prednisone alone. Among the 21 patients with baseline measurable disease, 44% (4 of 9) in the OGX-427 plus prednisone arm had a measurable disease response compared with 0% (0 of 12) in the prednisone alone arm. There was 1 complete response in the OGX-427 plus prednisone arm. “This has lasted for almost a year, and he still has not progressed,” said Dr Chi. Circulating tumor cells declined from ≥5/7.5 mL to <5/7.5 mL in 55% of patients receiving OGX-427 plus prednisone compared with 41% in the prednisone alone group. Adverse events have been predominantly grade 1 to 2 and related to infusion reactions. “These are predominantly in the first couple of infusions; patients tend to build tolerance, and the reactions are brief and selflimited,” he said. There were 3 grade 4 adverse events reported, including dizziness, pulmonary embolus, and 1 case of hemolytic uremic syndrome. ■

A Promising New Gene Test to Differentiate Between Aggressive and Indolent Disease Chicago, IL—A genomic test performed on a biopsy specimen that would discriminate between aggressive and indolent prostate cancer is a step closer to reality. The goal of the test is to help guide treatment decisions at the time of prostate cancer diagnosis by looking at the gene expression profile of the tumor biopsy, said Eric A. Klein, MD, Chair of the Glickman Urological and Kidney Institute, the Cleveland Clinic (which is collaborating with Genomic Health to develop the test), at ASCO 2012. Previous work by Dr Klein and colleagues showed that a number of genes that were strongly associated with clinical recurrence, prostate cancer death, and adverse pathology could be identified from radical prostatectomy specimens. The current gene refinement study presented by Dr Klein demonstrates that these genes can predict adverse pathology at the time of diagnosis by

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quantitative assays performed on biopsy-tissue tumor specimens.

“The gene expression profile can help reveal patients with apparent ‘low-risk’ disease who in fact have aggressive tumors that are not identified by the biopsy grade, clinical stage, or PSA.” —Eric A. Klein, MD

The expression of these genes provides risk information beyond that obtained from traditional pathological

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and clinical assessments (ie, biopsy Gleason grade, level of prostate-specific antigen [PSA], clinical stage), Dr Klein noted. “What we’ve learned is that if you measure the expression of a specific set of genes on a biopsy, you can predict the likelihood that someone will have an indolent course versus someone who won’t,” he said. “We think that the gene expression profile can help reveal patients with apparent ‘low-risk’ disease who in fact have aggressive tumors that are not identified by the biopsy grade, clinical stage, or PSA.” The limited tissue sampled with prostate needle biopsies had been a challenge in the development of a genomic test in localized prostate cancer. Radical prostatectomy specimens from 441 patients with localized prostate cancer (low-to-intermediate risk by American Urological Association criteria) were first used to identi-

fy 374 prognostic genes. The expression of a subset of these genes and 5 reference genes was quantified by real-time polymerase chain reaction performed on prostate tumor tissue obtained through needle biopsy. “Predictive genes from the gene identification study also predicted adverse pathology when assayed in biopsy tumor tissue,” Dr Klein said. Of the 81 genes evaluated in the biopsy study, 58 (72%) predicted high-grade and/or nonorgan-confined disease. The overexpression of androgen and cellular organization genes consistently predicted lower risk, whereas the overexpression of stromal response and proliferation genes predicted higher risk. Dr Klein suggested that the test would include approximately 20 prognostic genes and will be validated in an independent, prospectively designed study of prostate biopsies.—WK ■

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â&#x20AC;&#x153;Better informed teams provide better care.â&#x20AC;? Matthew P. Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Salt Lake City, UT

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Prostate Cancer

In Head-to-Head Comparison, Continuous Beats Intermittent Hormonal Therapy for Metastatic Prostate Cancer By Wayne Kuznar antigen level declined to ≤4 ng/mL after 7 months of continuous hormonal therapy with goserelin acetate in combination with bicalutamide. After stratifying them by disease extent, the patients were randomly assigned to receive intermittent hormonal therapy or continuous hormonal therapy. The median age of the patients was 70 years. Approximately 50% had extensive disease, and 50% had minimal disease. After a median follow-up of 9.2 years, median overall survival (OS) was 5.1 years in the group assigned to

Photo by © ASCO/Scott Morgan 2012

“This finding is striking and surprising, because it goes against the conventional belief based on all of the trials that have been done thus far.” —Maha H. Hussain, MD

hormonal therapy is not safe for all patients with metastatic prostate cancer,” said Dr Hussain. She noted that these data are practice changing. “This finding is striking and surprising, because it goes against the conventional belief based on all of the trials that have been done thus far,” she pointed out. The study, which was sponsored by the National Cancer Institute, included 1535 patients with newly diagnosed hormone-sensitive metastatic prostate cancer whose serum prostate-specific

“Prior underpowered studies suggested that there was no downside to intermittent therapy. This study demonstrates for the first time that there is a price to pay.” —Bruce J. Roth, MD

Photo by © ASCO/Scott Morgan 2012

Chicago, IL—In men with metastatic prostate cancer, especially those with minimal disease spread, continuous rather than intermittent hormonal therapy should be considered the preferred therapy, according to the results of a large multicenter phase 3 international trial. In these men, the difference in median survival favoring continuous therapy was approximately 2 years, said lead investigator Maha H. Hussain, MD, Professor of Medicine and Urology, University of Michigan Comprehensive Cancer Center, Ann Arbor, who presented the data at the 2012 meeting of the American Society of Clinical Oncology. Continuous androgen deprivation therapy has been the standard of care for men with metastatic hormonesensitive prostate cancer. In an effort to curb side effects from hormone therapy, such as loss of libido, weight gain, loss of muscle, and hot flashes, some oncologists have used intermittent hormone therapy with the belief that efficacy would not be affected. Early clinical trials showed that intermittent therapy was feasible and may be associated with an improvement in quality of life. Based on these trials, there was broad acceptance of intermittent therapy by patients, physicians, and insurers. But the present study’s findings “clearly demonstrate that intermittent

intermittent therapy versus 5.8 years for those assigned to continuous therapy, for a hazard ratio (HR) of 1.09. This HR did not meet the prespecified definition for noninferiority, because the

upper confidence interval for the relative increase in the risk of death exceeded 20% (the trial was designed to show whether intermittent therapy was noninferior to continuous therapy). In the arm receiving continuous therapy, 42% of patients were still alive at 7 years compared with 38% of the arm randomized to intermittent therapy. For men with minimal disease spread, the difference in survival between the 2 groups was even greater. In this subset, median OS was 5.2 years in those receiving intermittent therapy versus 7.1 years for those who received continuous therapy. The HR for death with intermittent therapy was 1.23, which again did not meet the criterion for noninferiority. Among men with more extensive disease spread, median survival was similar in the 2 arms (5 years with intermittent vs 4.4 years with continuous therapy). There were no differences in the rate of grade 4 treatmentemergent adverse events. According to Bruce J. Roth, MD, Professor of Medicine in the Division of Oncology at Washington University, St Louis, “prior underpowered studies suggested that there was no downside to intermittent therapy. This study demonstrates for the first time that there is a price to pay.” He noted that patients with minimal disease are the ones who have been most likely to receive intermittent therapy. ■

Renal-Cell Carcinoma

Quality of Life Drives Patient Preference...

20

“We didn’t ever expect such a big difference between the 2 drugs.”

Photo by © ASCO/Scott Morgan 2012

whether the drug’s toxicity would be significant enough to make patients want to continue treatment with either drug or to switch therapy. A total of 126 patients completed a preference questionnaire. In the primary analysis, 70% of the patients preferred pazopanib, 22% preferred sunitinib, and 8% cited no preference. After adjustments for a modest sequence effect, the difference in preference was 49% in favor of pazopanib. All other analyses showed a significant preference for pazopanib. The most common reasons given for pazopanib preference were better QOL and less fatigue. Patients taking

—Bernard J. Escudier, MD

pazopanib had fewer dose reductions than those taking sunitinib (13% vs 20%, respectively) and fewer treat-

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ment interruptions (6% vs 12%, respectively). Adverse events (AEs) were compatible with known profiles for both drugs. The researchers, led by Bernard J. Escudier, MD, from the Institut Gustave Roussy, Villejuif, France, said that they expected patients to prefer one drug over the other because of adverse effects, but “we didn’t ever expect such a big difference between the 2 drugs.” Physicians may perceive toxicity differences between 2 different therapies as relatively minor, but to patients, even low-grade toxicities over a long period have a significant effect on QOL,

Continued from page 1 according to Dr Escudier and colleagues. How patients feel when they take a drug over many months is not reflected in traditional AE reporting. A survey on physician therapy preferences, which was a secondary end point in this study, showed some difference in physicians’ drug preferences: 60% preferred pazopanib, 21% preferred sunitinib, and 21% had no preference. Patient-reported outcomes are increasingly being added to traditional efficacy outcomes to better understand the clinical relevance of differences in drug toxicities, Dr Escudier and colleagues noted. ■

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Renal-Cell Carcinoma

Tivozanib Outperforms Sorafenib as First-Line Treatment in Advanced Renal-Cell Carcinoma Chicago, IL—Tivozanib, a potent investigational tyrosine kinase inhibitor with a long half-life, demonstrated significant improvement in progression-free survival (PFS) as first-line targeted therapy for metastatic renalcell carcinoma (mRCC), according to results from a phase 3 randomized, open-label trial. The results suggest that “tivozanib should be considered a first-line treatment option for metastatic RCC,” said Robert Motzer, MD, an oncologist at Memorial Sloan-Kettering Cancer Center, New York, and the trial’s lead investigator. Tivozanib targets all 3 vascular endothelial growth factor (VEGF) receptors and is designed to optimize blockade while minimizing off-target toxicities. The long half-life permits once-daily dosing. Impressive phase 2 safety data for tivozanib warranted a phase 3 trial comparing tivozanib with sorafenib in patients with mRCC as first-line, targeted therapy. The study included 517 patients with mRCC, who were randomized to

Photo by © ASCO/Silas Crews 2012

By Wayne Kuznar

“Tivozanib should be considered a first-line treatment option for metastatic RCC.” —Robert Motzer, MD tivozanib once daily for 3 weeks (followed by 1 week of rest) or sorafenib twice daily continuously in a 4-week cycle. Patients were either treatmentnaive or had received no more than 1 prior systemic therapy for metastatic disease. Treatment continued until

disease progression or intolerance. Patients randomized to the sorafenib arm were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression, and many of them did. No crossover protocol was available for patients randomized to the tivozanib arm. In the overall study population, tivozanib demonstrated significant improvement in PFS compared with sorafenib (median, 11.9 months vs 9.1 months) when assessed by an independent panel, corresponding to a 21% improvement with tivozanib. When assessed by the investigators, the difference in PFS between the 2 groups was 14.7 months with tivozanib versus 9.6 months for sorafenib. The efficacy advantage of tivozanib was consistent across all subgroups. Among the 70% of treatment-naive patients, median PFS was 12.7 months with tivozanib versus 9.1 months with sorafenib, and the objective response rate was 33% versus 23%, respectively. The tolerability of tivozanib was also more favorable than sorafenib’s,

as evidenced by a low rate of dose interruptions (17% vs 35%, respectively) and reductions (12% vs 43%, respectively). Treatment-emergent adverse events occurred in 90% of patients in both groups, although important differences were seen in the safety profile between the 2 drugs. According to Dr Motzer, although hypertension is the predominant adverse event with tivozanib, the development of hypertension is associated with tivozanib’s greater efficacy and potency for the VEGF receptor. The hypertension was treatable, requiring dose reduction in only 2% and dose discontinuation in only 1% of the patients treated with tivozanib. “There’s clear evidence that the phase 2 safety profile has indeed been confirmed in phase 3,” said coinvestigator Tim Eisen, MD, Professor of Medical Oncology, Cambridge Research Institute, United Kingdom. The data require more careful evaluation over the next several months to “exclude any hypertension-related complication risk,” he said. ■

Axitinib Dose Titration Up Enhances Outcomes in Metastatic Renal-Cell Carcinoma Chicago, IL—Upward dose titration of axitinib in patients who tolerate the starting dose may optimize drug exposure and improve the efficacy of the drug as a first-line therapy for metastatic renal-cell carcinoma (mRCC), said Brian I. Rini, MD, Associate Professor of Medicine at the Cleveland Clinic, at ASCO 2012. Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with demonstrated efficacy as secondline treatment for mRCC. Patients who receive the 5-mg twicedaily starting dosage of axitinib exhibit variable levels of drug exposure; retrospective analyses of phase 2 clinical trials indicate that higher drug exposure to axitinib enhances its efficacy. “A significant percentage of patients have exposure that is below what is considered to be a therapeutic threshold,” said Dr Rini. After upward dose titration, to 7 mg, or 10 mg twice daily, most patients achieve therapeutic drug levels.

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Patients who achieved a therapeutic drug exposure in previous studies had superior progression-free survival (PFS) compared with those who did not achieve a therapeutic threshold. The improvement in PFS was nearly double in those who achieved therapeutic drug exposure, Dr Rini said. He speculated that dose titration based on tolerability may improve outcomes. This randomized, phase 2 clinical trial evaluated the efficacy and safety of axitinib dose titration from the standard 5-mg twice-daily dose to a maximum of 10 mg twice daily. A total of 203 patients with treatment-naive mRCC received axitinib, 5 mg twice daily, for a 4-week lead-in period (cycle 1). Of these, 112 patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mm Hg (use of ≤2 antihypertensives was allowed); no axitinib-related toxicities grade <2; and no dose reductions were randomized in a double-blind fashion to axitinib 5 mg twice daily, followed by dose titration with axitinib (arm A) or

placebo (arm B). The 91 patients who did not meet the randomization eligibility criteria continued to receive ≤5 mg twice daily, based on drug tolerance (arm C).

“Axitinib is effective in the first-line treatment of metastatic RCC as evidenced by a long PFS and a high objective response rate.” —Brian I. Rini, MD Tumor assessments were performed at screening; at weeks 8, 16, and 24; and every 12 weeks thereafter. A subset of patients underwent ambulatory BP monitoring at baseline and again on days 4 and 15 of cycle 1. A pooled analysis of blinded data from arms A and B (eligible for dose titration) showed an objective response rate (ORR) of 43%; the ORR in arm C (not eligible for dose titration)

was 59%. The median PFS was 14.5 months in arms A and B combined, and 16.4 months in arm C. Therapeutic drug exposure was achieved more often in arm C: the AUC12 was 234 ng·h/mL in arm C versus 99 ng·h/mL in arms A and B combined. Median PFS in patients with drug exposure above the therapeutic threshold on day 15 was 13.4 months compared with 11.0 in those with subtherapeutic exposure. Patients with mean increases of diastolic BP ≥15 mm Hg had a higher ORR than those with diastolic BP increases <15 mm Hg. The AUC12 was generally higher in those with greater changes in BP, said Dr Rini. The most common adverse events were hypertension, diarrhea, and fatigue. “Axitinib is effective in the first-line treatment of metastatic renal cell carcinoma as evidenced by a long PFS and a high objective response rate,” Dr Rini said.—WK ■

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Renal-Cell Carcinoma

First-Line Treatments for Metastatic Renal-Cell Carcinoma Are Evolving By Wayne Kuznar Chicago, IL—The list of choices for first-line pharmacologic therapy of metastatic renal-cell carcinoma (mRCC) is ever increasing. There are now 7 approved targeted therapies against the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways, said Daniel Y.C. Heng, MD, MPH, Clinical Associate Professor, Tom Baker Cancer Center, University of Calgary, Alberta, Canada, at ASCO 2012. Oral VEGF tyrosine kinase inhibitors (TKIs), such as sunitinib and pazopanib, and intravenous (IV) antiVEGF antibodies, such as bevacizumab (in combination with interferon [IFN]-alpha), used as first-line agents, have extended progression-free survival (PFS) in patients with a favorable or intermediate prognosis in mRCC, said Dr Heng. Sorafenib is another option, and axitinib has been used as a second-line therapy after treatment with a cytokine or a VEGF inhibitor. In patients with a poor prognosis, the mTOR inhibitor temsirolimus plus IFN-alpha has been shown to improve overall survival (OS) compared with IFN-alpha alone. Everolimus was approved by the US Food and Drug Administration (FDA) in 2011, although it is used as second-line therapy after a VEGF inhibitor. However, no predictors of response to targeted therapy are available; therefore, the choice of therapy is usually based on the patient’s prognostic profile, physician preference, route of delivery (IV or oral), physician experience, and drug efficacy and toxicity profiles. For example, a patient with poor pulmonary function “might not be the best mTOR candidate, simply because of the risk of noninfectious pneumonitis,” Dr

Heng said. Patients with refractory diabetes are also not good candidates for mTOR inhibitors, because of the risk for hyperglycemia, and those with refrac-

whether the differences in tolerability were significant enough to determine patient preference, a measure that is increasingly being included in the

“What this means is that it’s unclear if there is a difference in efficacy with first-line therapy, and clinical trial results are greatly anticipated.” —Daniel Y.C. Heng, MD, MPH

tory hypertension who are taking several antihypertensive medications would not be good candidates for a VEGF inhibitor, he noted. Recent and Emerging Comparative Clinical Trials “Probably, the most important consideration is efficacy,” but no evidence from head-to-head efficacy trials exists so far, said Dr Heng, although some are emerging. Retrospective comparison analyses show that PFS is approximately 7.2 months with sunitinib as first-line therapy, 7.3 months with sorafenib, and 6.0 months with bevacizumab. “What this means is that it’s unclear if there is a difference in efficacy with first-line therapy, and clinical trial results are greatly anticipated,” he said. PISCES was a head-to-head clinical trial, but its primary end point was patient preference at 22 weeks, not treatment efficacy. PISCES compared the tolerability and toxicity level of sunitinib followed by pazopanib versus pazopanib followed by sunitinib in patients with mRCC, focusing on

decision-making paradigm of treatment selection. Pazopanib was preferred by 70% of patients, sunitinib was preferred by 22% of patients, and

“Pending FDA approval, tivozanib will probably be incorporated into the treatment algorithm.” —Daniel Y.C. Heng, MD, MPH 8% did not have a preference (see article on page 1). Results from the phase 3, head-tohead clinical trial COMPARZ are highly anticipated. COMPARZ is an openlabel study comparing sunitinib with pazopanib as first-line therapy for patients with mRCC, with a primary end point of PFS duration and secondary end points include OS and quality of life. The potent and specific TKI tivozanib, which is not yet FDA approved for mRCC, demonstrated an improve-

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August 2012

ment in PFS as first-line targeted treatment compared with sorafenib in clear-cell mRCC (see article on page 21). “Pending FDA approval, tivozanib will probably be incorporated into the treatment algorithm,” said Dr Heng. The RECORD-3 clinical trial is comparing 2 treatment sequences—sunitinib followed by everolimus versus everolimus followed by sunitinib in patients with mRCC; the primary end point is PFS duration associated with the first-line therapy. “This gives an indication of first-line VEGF versus mTOR efficacy and sequencing,” Dr Heng said. Indicators of Treatment Response Although there are externally validated predictive biomarkers in mRCC, recent studies have demonstrated that the development of hypertension during the first cycle of sunitinib therapy, as well as other therapy-related toxicities (eg, handfoot syndrome, hypothyroidism) are associated with improved outcomes, but these are only helpful once therapy is initiated; these effects do not help guide the choice of therapy. The presence of certain singlenucleotide polymorphisms (SNPs) can serve as a biomarker that may indicate improved patient outcomes, but SNPs, too, require validation. In addition, results obtained by examining genetic profiles are currently restricted to the Caucasian population, because there are substantial racial differences in SNPs. Immunotherapy on the Horizon? Immunotherapy with a programmed death 1 (PD-1) inhibitor could also be on the horizon, but clinical trials are in their early stages. Higher PD-1 ligand levels in patients with RCC have been associated with larger tumors, advanced-stage tumors, higher-grade tumors, and tumors with necrosis. In a trial that included 18 patients with RCC, the overall objective response rate in the 16 patients who were treated with a 10-mg/kg dose of the investigational PD-1 inhibitor BMS936558 was 31.2%, and the median duration of response was 4.0 months. An autologous dendritic-cell immunotherapy (AGS-003) was studied with sunitinib in 21 patients with RCC, with an overall response rate of 38% and a median PFS of 11.2 months; this is encouraging, because almost half of these patients had poor prognostic profiles. ■

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Multiple Myeloma

Pomalidomide Shows Strong Activity in Relapsed/ Refractory Myeloma By Caroline Helwick Chicago, IL—The novel immunomodulatory drug (IMiD) pomalidomide showed strong activity in patients with multiple myeloma who are not responding to current therapies, said Irene Ghobrial, MD, medical staff member in the Myeloma Program of the Dana Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston. “As myeloma patients live longer and longer, they need new agents of therapy, and pomalidomide may be one of those,” said Dr Ghobrial, who presented the results of this phase 2 clinical trial during ASCO 2012. “This agent is showing responses even in patients who are resistant to bortezomib or lenalidomide,” Dr Ghobrial said, noting that adding a new IMiD to the available treatment options will be especially critical for patients with relapsed/refractory disease. Pomalidomide plus Dexamethasone Ravi Vij, MD, Associate Professor, Department of Medicine, Oncology Division, Bone Marrow Transplantation and Leukemia Section, Washing-

ton University School of Medicine, St Louis, MO, presented updated results of a phase 2 clinical trial of pomalidomide in combination with low-dose dexamethasone in 221 patients resistant to lenalidomide, to bortezomib, or

“This agent [pomalidomide] is showing responses even in patients who are resistant to bortezomib or lenalidomide.” —Irene Ghobrial, MD

to both. The pomalidomide/dexamethasone combination induced responses in heavily pretreated patients, including patients who had received stem-cell transplantation. The overall response rate to the pomalidomide/dexamethasone combination was 30% compared with 9% with pomalidomide alone, after a median (number) of 5 cycles and a median (time) of 2 months. Three

quarters of patients achieved stable disease or better. Median progressionfree survival (PFS) was 3.5 months for the whole group. A 1-year overall survival (OS) was reached by 59% of the patients, and median OS was similar (approximately 14 months) between the 2 arms, Dr Vij reported. Patients who had relapsed after stem-cell transplantation had a median PFS of approximately 4 months. No severe cases of peripheral neuropathy were reported. In June, a New Drug Application for pomalidomide in combination with low-dose dexamethasone was submitted to the US Food and Drug Administration. Adding Clarithromycin to the Mix Another phase 2 clinical trial evaluated pomalidomide in combination with clarithromycin and dexamethasone (ClaPD) in 73 heavily pretreated patients with relapsed/refractory myeloma. The antibiotic clarithromycin has been shown to enhance the antimyeloma activity of pomalidomide/ dexamethasone.

The overall response rate was 56%. Even among the patients whose disease was refractory to lenalidomide and to bortezomib, the response rate was 58%.

“Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects.” —Adriana C. Rossi, MS, MD

Median PFS was 7.5 months, and, at a median follow-up of 12 months, 85% of the patients were alive and 42% remained progression-free. “Response to ClaPD is rapid, well tolerated, and sustained over 7 months in most subjects,” said Adriana C. Rossi, MS, MD, Clinical Fellow, Hematology/Oncology, Weill Cornell Medical College, New York. “These data support the clinical efficacy of pomalidomide-based regimens in relapsed/refractory myeloma.” ■

First Oral Proteasome Inhibitor Active in Myeloma Chicago, IL—The first oral proteasome inhibitor to enter clinical investigation in multiple myeloma is MLN9708. The data from a phase 1 clinical trial presented at ASCO 2012 suggest that this drug encourages disease control and durability of responses in heavily pretreated patients with multiple myeloma. MLN9708 is a potent, reversible, and specific inhibitor of the 20S proteasome that is similar to bortezomib in structure but is associated with less neurotoxicity, said lead investigator Sagar Lonial, MD, Professor and Vice Chair of Clinical Affairs, Department of Hematology and Medical Oncology of Winship Cancer Institute at Emory University, Atlanta, GA. “MLN9708 is well tolerated, with infrequent peripheral neuropathy and none that is grade 3 or higher,” Dr Lonial said. This study of twice-weekly dosing of the oral agent included 58 patients who had received multiple prior lines of therapy. The primary aim was to assess tolerability and to determine the optimal dose. “Unlike many other trials, patients

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received no concomitant corticosteroids. This is a pure proteasome inhibitor trial,” Dr Lonial noted. Of the 53 evaluable patients, 6 achieved a partial response or better, including 1 confirmed stringent complete response in the proteasome inhibitor–naive expansion cohort. “Many of these responses are quite durable,” Dr Lonial said.

“Unlike many other trials, patients received no concomitant corticosteroids. This is a pure proteasome inhibitor trial.” —Sagar Lonial, MD,

Disease stabilization was observed in another 32 patients, and a number of these are in the relapsed and refractory cohorts, he added. The most common drug-related events were fatigue (45%) and thrombocytopenia (41%). Nausea (36%), vomiting (26%), rash (28%), and diar-

rhea (21%) were also observed. “We saw the typical sawtooth curve of thrombocytopenia that we see with bortezomib. You see that the baseline platelet count increases among responses, and it is not cumulative,” Dr Lonial observed. “A major difference between this drug and bortezomib is that peripheral neuropathy is significantly lower, 10%,” Dr Lonial said. “My longest patient on study had developed grade 3 neuropathy on bortezomib and has been responding to MLN9708 with no neuropathy for over a year now.” Discontinuations resulting from adverse events were required in 12% of patients, predominantly because of thrombocytopenia, pulmonary hypertension, pneumonia, orthostatic hypotension, and pruritic rash, as well as spinal cord compression and bone pain as a result of progressive disease. Irene Ghobrial, MD, medical staff member in the Myeloma Program of the Dana Farber Cancer Institute, and Associate Professor of Medicine, Harvard Medical School, Boston, discussed the findings for the MLN9708 study at the multiple myeloma oral session.

“In this population of heavily pretreated patients given MLN9708 as a single agent, the overall response rate

“This is the first oral proteasome inhibitor to be tested. We are now looking at second-generation agents showing activity and less neuropathy and potentially greater convenience.” —Irene Ghobrial, MD

was 11%; 2 patients also had a minimal response, and many had stable disease. This is the first oral proteasome inhibitor to be tested. We are now looking at second-generation agents showing activity and less neuropathy and potentially greater convenience. We know if we take these upfront and put them in combination with immunomodulatory drugs and steroids, we will see higher responses,” she said.—CH ■

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Leukemia

Novel Agents Will Completely Change CLL Treatment By Caroline Helwick Chicago, IL—The treatment of chronic lymphocytic leukemia (CLL) is becoming more personalized and more effective as prognostic markers are refined and as agents with novel mechanisms of action show robust activity. CLL is a heterogeneous entity. Although some patients live for 10 years or more, others die within 1 year. The Rai staging system stratifies patients based on blood counts and symptoms, but this system does not reflect the variability in disease aggressiveness. Thus, the ability to determine prognosis and predict response to treatment is an important goal in CLL research, said Neil E. Kay, MD, of the Mayo Clinic, Rochester, MN, at the 2012 ASCO meeting. Newer molecular-based prognostic factors have been established that can strongly predict CLL disease progression, such as chromosomal deletions and alterations (17p deletion and 11q deletion are common ones), and the expression of cell-surface markers such as CD38 and ZAP-70. These prognostic parameters, which can usually be determined at the time of diagnosis, can help define risk categories upon diagnosis. Risk models that incorporate both conventional and novel prognostic factors have been developed, and these can predict disease progression and overall survival. They will, therefore, be useful in risk-stratifying patients with early-stage disease, Dr Kay said.

Promising Drugs for CLL There is a clear unmet need for more effective therapies in CLL, said Peter Hillmen, PhD, of St. James’s University Hospital, West Yorkshire, United Kingdom. Current regimens, which are not molecularly targeted, are associated with significant toxicity and are especially hard on elderly patients. Moreover, these regimens typically do not lead to true complete remissions; leukemic cells become resistant and the disease relapses.

The combination of ibrutinib, bendamustine, and rituximab has produced response rates exceeding 90% in patients with relapsed/refractory CLL. An effective treatment should target the disease pathophysiologically, Dr Hillmen said, as imatinib does for chronic myelogenous leukemia. Therefore, much emphasis is being placed on understanding the molecular and genetic profiles of CLL, to guide drug development. Among the promising new approaches to CLL are: • The immunomodulatory drug lenalidomide, which shows immunemediated effects and also direct antitumor activity against CLL cells; it has been studied as a single agent

and in combination with rituximab • PI3 kinase-delta inhibitor GS-1101, an orally available small-molecule inhibitor that has substantial antitumor activity in refractory disease • Ibrutinib (PCI-32765), an orally available selective inhibitor of Bruton’s tyrosine kinase (Btk). The combination of ibrutinib, bendamustine, and rituximab has produced response rates exceeding 90% in patients with relapsed/refractory CLL • Bcl-2 (anti-apoptosis) inhibitors, such as navitoclax (ABT-263) and GDC-0199. Btk Inhibitor Shows Strong Activity In an update of a study that made news at the American Society of Hematology 2011 meeting, the Btk inhibitor ibrutinib produced high response rates in treatment-naive patients with CLL. In a related study by the same investigators, ibrutinib was combined with ofatumumab, an anti-CD20 monoclonal antibody. This oral agent is the first drug designed to target Btk, a protein that is critical for B-cell receptor signaling in B lymphocytes and essential for cell survival and proliferation in CLL. This single-agent phase 2 clinical trial included 31 patients with previously untreated disease. The overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The rate of progres-

sion-free survival at 15 months was 96%. Investigators had previously reported on the cohort of treatmentrefractory patients, 70% of whom responded to the novel drug. “All subgroups responded equally well. Overall, the great majority of patients gained benefit from this therapy,” said John C. Byrd, MD, of Ohio State University, Columbus. “This drug is like red wine. With time, it gets better. Responses increase, and many patients are still in follow-up. The continued daily dosing was well tolerated, which allows for extended treatment.” Samantha Jaglowski, MD, also of Ohio State University, reported that the combination of ibrutinib and ofatumumab produced a 100% response rate in 27 patients with relapsed/ refractory CLL and related diseases. At 6.5-month follow-up, only 2 patients have progressed. “The rapid onset of response, low relapse rate, and favorable safety profile make this noncytotoxic combination worthy of further study,” she said. Constantine S. Tam, MBBS, MD, St Vincent’s Hospital, Melbourne, Australia, commented on these findings, “There is a long list of novel agents in chronic lymphocytic leukemia. I think some of the most promising are those targeting the B-cell receptor pathway.” He added that this group of drugs is going to completely change how we manage CLL. ■

Lymphoma

Bendamustine Outperforms R-CHOP in NHL Chicago, IL—The phase 3 clinical trial StiL NHL1 demonstrated that the combination of bendamustine plus rituximab (BR) delays progression in non-Hodgkin lymphoma (NHL) longer than standard treatment with cyclophosphamide-doxorubicin HClvincristine sulfate-prednisone chemotherapy plus rituximab (R-CHOP). In this multicenter trial, BR more than doubled the median progressionfree survival (PFS) compared with RCHOP, reported Mathias J. Rummel, MD, PhD, Head of Hematology, University Hospital in Giessen, Germany, at a plenary session at ASCO 2012. “BR is not only less toxic but also more effective than the most-oftenused first-line approach and should be considered a preferred first-line treatment for these patients,” he said. Bendamustine is approved for chron-

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ic lymphocytic leukemia and as a second-line therapy for rituximab-refractory NHL, but US oncologists have not yet fully adopted this regimen, despite positive results presented at the 2009 American Society of Hematology meeting, which led to its approval in the United States. BR is listed as a recommended regimen by the National Comprehensive Cancer Network. The StiL NHL1 Trial Details A total of 549 patients with a new diagnosis of stage III or IV indolent NHL were randomized to standard R-CHOP or to BR. After a median follow-up of 45 months, the median PFS was 69.5 months with BR versus 31.2 months with R-CHOP, a 42% reduction in the risk of progression (P <.001). The PFS benefit offered by BR was seen across all subgroups, except

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for patients with marginal zone lymphoma, where PFS was comparable. The 5-year overall survival (OS) rates, however, were similar—80.1% with BR and 77.8% with R-CHOP.

“BR is not only less toxic but also more effective than the most-often-used first-line approach and should be considered a preferred firstline treatment.” —Mathias J. Rummel, MD, PhD Dr Rummel explained that the lack of difference in OS is not unexpected, since patients with indolent lymphoma live a long time. Also, many in the R-CHOP arm crossed over to

receive BR when their disease progressed, which dilutes a survival difference between the arms. BR also was associated with significantly less toxicity, with only skin toxicity being more common with this simpler regimen, he added. Michael E. Williams, MD, Chief of Hematologic Malignancies at the University of Virginia Cancer Center, Charlottesville, discussed the findings. “BR provides equivalent or better responses versus R-CHOP, and with less toxicity,” he said. “StiL NHL1 establishes BR as a front line regimen for indolent B-cell NHL and non– transplant-eligible mantle-cell lymphoma patients.” Studies of this regimen are ongoing. The StiL NHL 7-2008 trial will evaluate data on the effect of rituximab maintenance after BR treatment.—CH ■

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Oncology Pipeline

The Oncology Drug Pipeline Robust with Novel Agents By Caroline Helwick and Wayne Kuznar Chicago, IL—ASCO 2012 was replete with data on emerging therapies currently in development. The key findings presented at the meeting are summarized below. Breast Cancer Trastuzumab emtansine, better known as T-DM1, is a novel, intravenous antibody-drug conjugate that has reduced the risk of disease progression by 35% in previously treated patients with HER2-positive metastatic breast cancer in the clinical trial EMILIA. In this study, median overall survival (OS) was not reached with T-DM1 and was 23.3 months with capecitabine plus lapatinib, for a 38% reduction (P <.001) in mortality risk (see article on page 1). Prostate Cancer Enzalutamide (MDV3100), when used in men with castration-resistant prostate cancer who have failed docetaxel therapy, improved the OS by almost 5 months over placebo and slowed disease progression (see article on page 17). OGX-427, a new agent that targets heat shock protein-27, when used in combination with prednisone, improved the progression-free survival (PFS) from 40% to 71% compared with prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (see article on page 18). Renal-Cell Carcinoma Tivozanib, a potent and specific tyrosine kinase inhibitor (TKI), improved the PFS by almost 3 months compared with sorafenib when used as a first-line targeted treatment for clear-cell metastatic renal-cell carcinoma (see article on page 21). Lung Cancer Afatinib, an ErbB receptor family blocker used as single-agent therapy, extended PFS by 4.2 months compared with pemetrexed and cisplatin chemotherapy in patients with advanced lung adenocarcinomas harboring the epidermal growth factor (see article on page 16). LDK378, an investigational anaplastic lymphoma kinase (ALK) inhibitor, showed substantial clinical activity in patients with ALK-positive non–smallcell lung cancer (NSCLC), with an overall response rate of 81% in patients with NSCLC who were previously treated with the ALK inhibitor crizotinib. Aflibercept, a novel agent that “traps” vascular endothelial growth factor,

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when added to standard topotecan treatment in patients with small-cell lung cancer, slowed disease progression in a phase 2 clinical trial. The addition of aflibercept to topotecan increased the 3-month PFS rate to 27% compared with 10% with topotecan alone; however, the median PFS remained only 1.4 months in each group. GIST and CRC Regorafenib, an orally administered TKI, showed robust activity in chemorefractory metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GISTs). In the treatment-refractory GIST population of the GRID phase 3 clinical trial, the median PFS reached 4.8 months with regorafenib but was only 0.9 months in the placebo arm, for a 73% reduction in risk (see article on page 11). In patients with treatment-refractory mCRC in the phase 3 clinical trial CORRECT, regorafenib extended the OS to 6.6 months versus 5.5 months with placebo, for a 23% reduction in risk (see article on page 11). In patients with mCRC, aflibercept plus chemotherapy had a safety profile that was similar to that in patients who had never received bevacizumab, according to a subanalysis of VELOUR, a phase 3 clinical trial, which compared patients who had received previous bevacizumab treatment and those who did not. Aflibercept plus chemotherapy prolonged the PFS to almost the same degree in patients who received bevacizumab in the past and those who had not. In a previous report, the regimen of aflibercept plus chemotherapy was associated with significant improvements in PFS and OS. Anti–PD-1/PD-L1 in Solid Tumors Treatments directed against programmed death 1 (PD-1) protein—a mediator of immunosuppression— and one of its ligands (PD-L1) induced tumor regression in patients with lung cancer, melanoma, and renal-cell carcinoma. Nearly 300 adults with advanced cancers were treated with anti–PD-1 antibody for up to 2 years. Objective tumor responses were seen in 18% of patients with NSCLC, 28% of patients with melanoma, and 27% of those with renal-cell carcinoma. More than half of the responses lasted ≥1 year. Another clinical trial with 200 patients who were treated with the anti–PD-L1 antibody showed objective responses in melanoma, lung cancer, and renal-cell carcinoma, as well as ovarian cancer.

Leukemia Inotuzumab ozogamicin, an antiCD22 monoclonal antibody, produced a high response rate (52%) in heavily pretreated patients with relapsed or refractory acute lymphocytic leukemia. Of the 27 evaluable patients, 3 patients showed complete remission (CR), 8 patients had CR except for platelet recovery, and 3 patients showed CR in the bone marrow only. The median PFS was 5 months, and the median OS was 7 months. In a phase 2 clinical trial of 31 treatment-naive patients with chronic lymphocytic leukemia (CLL), continued daily dosing with ibrutinib produced an overall response rate of 75%, including 10% CR and 65% partial response rates; the PFS was 96% at 15 months. This oral agent is the first drug designed to target Btk (Bruton’s tyrosine kinase), a protein that is essential for CLL cell survival and proliferation. Blinatumomab, an anti-CD19 bispecific T-cell engager (BiTE) antibody, produced responses in a phase 2 clinical trial in 72% of patients with relapsed or refractory B-precursor acute lymphocytic leukemia, and all but 2 patients achieved a molecular response. The median OS was 9.0 months, and the median duration of response was 8.9 months. This drug is the first in a new class of agents called BiTEs, which are designed to harness T cells to kill cancer. Multiple Myeloma Carfilzomib, the new proteasome inhibitor was evaluated in phase 2 clinical trials in the setting of patients with multiple myeloma (MM). Results have shown carfilzomib to be associated with very high response rates when combined with lenalidomide/dexamethasone; a near CR was achieved by 78% of patients after 8 cycles of treatment, a stringent CR was achieved by 61% of patients, and the 1-year PFS was 97%. A 4-drug combination— carfilzomib/cyclophosphamide/thalidomide/dexamethasone—produced a 96% response rate after 4 cycles. Peripheral neuropathy rates were low. In July 2012, the US Food and Drug Administration (FDA) approved carfilzomib for the treatment of patients with MM whose disease was resistant to and/or relapsed after treatment with bortezomib and either lenalidomide or thalidomide. The immunomodulatory drug pomalidomide, when combined with dexamethasone, produced a 30% response rate in a phase 2 clinical trial

that evaluated 221 patients with MM resistant to lenalidomide, to bortezomib, or to both. The median PFS was 3.8 months. Another phase 2 clinical trial evaluated pomalidomide in combination with clarithromycin and dexamethasone in 73 heavily pretreated patients with relapsed or refractory disease, demonstrating an overall response rate of 56% and a median PFS of 7.5 months (see article on page 23). Melanoma The investigational agents dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor, showed high activity as single agents in patients with the V600 BRAF mutation and advanced melanoma; when these agents were combined with each other, they were especially active. The combination produced a median PFS of 7.4 months, which rose to 10.8 months among patients who received the optimal doses. Patients who were optimally dosed also achieved a 100% disease control rate (ie, response plus stable disease). Skin toxicity was seen in 14% of patients—a much lower rate than is observed with vemurafenib alone. A phase 3 clinical trial investigating the optimal dose of this regimen has begun. Hepatocellular Carcinoma The oral MET inhibitor tivantinib demonstrated striking efficacy as a single agent in a randomized, phase 2 clinical trial that included 107 patients with unresectable hepatocellular carcinoma. Tivantinib improved the time to progression by approximately 1 week in the overall population, but the effect was much more striking in the subgroup of patients with high MET expression, which is associated with a poor prognosis. In these patients, the median time to progression was 11.7 weeks with tivantinib versus 6.1 weeks with placebo, and the OS was 7.2 months with tivantinib versus 3.8 months with placebo. Medullary Thyroid Cancer Cabozantinib, a multi-TKI, is being investigated in patients with documented progressive medullary thyroid carcinoma. In the phase 3 clinical trial EXAM, cabozantinib improved the PFS to 11.2 months versus 4.0 months with placebo, for a 72% reduction in risk. In addition, the 1-year PFS increased from 7.2% to 47.3%, and the median duration of response was 14.6 months. The manufacturer submitted to the FDA a New Drug Application for cabozantinib in May 2012. ■

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Payers’ Perspectives

Payers Collaborate with Providers to Adopt Oncology Pathways, New Care Delivery Models By Rhonda Greenapple, MSPH, Chief Executive Officer, Reimbursement Intelligence, Madison, NJ

O

ver the past year, the volume and intensity of concern about the unsustainable growth of cancer care costs have mounted steadily. Oncology clinical pathways, once widely disdained as “cookbook medicine,” are being adopted through successful payer–provider collaboration and provider compliance with pathways that generally has exceeded early expectations.1,2 Emerging in parallel to clinical pathways are new cancer care delivery models—notably accountable care organizations (ACOs)—that are striving for sustainable cost and quality balance through better coordination of care and more effective integration of palliative care. A recent survey of medical and pharmacy directors was conducted in July 2012 by Reimbursement Intelligence, a market access consulting firm. The survey included 52 leading managed care plans, representing more than 100 million covered lives. The goal of the survey was to understand how payers are initiating or collaborating with providers to implement cost-management and delivery models.

Anticipated Expansion of Oncology Pathways The responses to the survey showed that oncology clinical pathways have been adopted (40%) or will be Figure 1 Payer prioritization of tumor types for pathway implementation Q1: For which tumor types has your plan already developed pathways? Q2: What are your plan’s next priorities for development of clinical pathways in oncology?

Responding payers, %

100

Currently on pathways High priority for pathway developmenta

38.1

90

9.5

80

85.7

33.3

38.1

70 19.1

60

61.9

61.9

28.6

50

28.6

47.6

40

42.9

30 28.6

20

19

10

adopted within 2 years (35.5%) by a total of more than 75% of these payer groups. For plans that have already adopted pathways, the top 5 goals were to: • Improve quality • Reduce clinical variation across providers • Reduce oncology drug costs • Reduce overall cost • Reduce costs associated with end-of-life care. Payers have targeted specific tumor types for pathway implementation, identifying breast, lung, and colorectal cancers as their initial priorities, followed by multiple myeloma (Figure 1). If payer predictions are accurate, by 2014 pathway penetration will be close to 100% in colorectal cancer, more than 90% in breast and lung cancers, and approaching 80% in prostate cancer. Payers rating specific criteria for selection of tumor types for the development of clinical pathways identified the cost burden associated with tumor treatment and the need to improve quality of care as the 2 most important criteria (71.5% and 71.4% of respondents, respectively). Other influential considerations are the degree of clinical variation for a particular tumor type (66.6%) and prevalence of the tumor type (61.9%). Payers report that their organizations have been flexible with adjustments to pathways, with most adjustments (84.2%) made to allow provider flexibility regarding therapeutic options, such as allowing off-pathway drugs to be used to avoid drug–drug interactions. Pathways generally have integrated traditional cost-management measures, including prior authorization (85.7%), step edits (71.4%), and formulary placement or tiering (52.3%). In light of ongoing discussions about the cost-saving potential of earlier implementation of palliative care and end-of-life discussions,3 our survey specifically probed payers about how palliative care is being addressed in oncology clinical pathways. A minority of respondents (14.3%) indicated that palliative care will not be referenced in pathways; nearly 3 times as many respondents (42.9%) stated that

0 Breast

Lung

Colorectal

Multiple myeloma

Prostate

Metastatic Non-Hodgkin melanoma lymphoma

a Combined responses “4” and “5” on a 1-to-5 scale (1 = low priority; 5 = high priority).

Payer estimates of oncology cost-savings 1 and 3 Figure 3 years after ACO formation Q1: What percentage reduction in oncology costs would you anticipate achieving within 1 year after forming an ACO? Q2: What percentage reduction in oncology costs would you anticipate achieving 3 years after forming an ACO?

Payer estimates of provider adherence with Figure 2 oncology pathways generally exceeds targets Q1: What is the target level of adherence to oncology pathways? Q2: What is the actual level of adherence to oncology pathways (please estimate to the best of your ability of data not available)

45 40.4

40

40.9

60

13.6 22.7

70

13.6 18.2

80

35

Responding payers, %

Adherence level, %

0

Year 1 savings Savings after 3 years

36.5

Estimated actual adherence Target adherence

13.6

≤50

40.4

30 26.9 25 19.2

20 15 11.5 10

40.9 3.8

3.8 3.8 1.9

4.5 90

0

31.8

0 0

5

10

15

20

25

30

35

40

Responding payers, %

26

AMERICAN HEALTH & DRUG BENEFITS

1-5

6-10

11-15

16-20

Anticipated cost-savings, %

45

ACO indicates accountable care organization.

August 2012

Payer Formation of ACOs This survey of leading payers confirmed that interest in ACOs as a cost-management mechanism for oncology is high. A minority of payers (20.8%) currently have an ACO, but 53% of respondents plan to have an ACO within 2 years. Payers anticipate modest first-year cost-savings after forming an ACO, but they expect savings to increase substantially 3 years later (Figure 3). The 3 primary potential contributors to ACO-related cost reductions were better coordination of care (85.7% of respondents), reducing inappropriate uses of therapies (81.0%), and earlier initiation of palliative care when appropriate (71.4%). When probed on ways in which an ACO potentially could influence oncologic drug costs, 2 prominent areas were identified by a majority of respondents— more conservative use of supportive care therapies (71.2%) and earlier initiation of palliative care (69.2%). Overall, payers were realistic and pragmatic in identifying challenges to implementing new oncology care delivery models, with provider alignment and infrastructure/data acquisition identified as the 2 most significant challenges (86.5% and 71.2%, respectively), followed by care coordination, provider incentives, and organizational structure (each 65.4% of respondents). Rapid Payer Adaptation to Change The rate at which payers are adapting to substantial changes in oncology care delivery models is encouraging. Although precise calculations of costsavings associated with clinical pathway adoption and ACOs are difficult to quantify,1 our survey confirmed that providers and payers are collaborating at the community level to implement sweeping changes to the oncology care model. ■

5.8

5.8 5

palliative care will be recommended as a course of action when appropriate (eg, “palliative care should strongly be considered”). Consistent with reported findings from payers who have already implemented pathways, payers participating in this survey reported that provider compliance with pathways generally exceeded expectations, especially when anticipated adherence was in the more modest range, between 60% and 70% (Figure 2). Overall, although approximately one fourth (27.2%) of respondents anticipated pathways adherence in the 60% to 70% range, nearly two thirds of plans (63.6%) estimated actual pathways within those ranges. Conversely, although 41% of plans estimated adherence at 80%, only 18.2% estimate this level of actual compliance. Adherence at the 90% level was substantially overestimated; although 31.8% of plans reported this target level of adherence, less than 5% estimated it had been achieved.

≥20

References 1. Feinberg BA, Lang J, Grzegorczyk J, et al. Implementation of cancer clinical care pathways: a successful model of collaboration between payers and providers. Am J Manag Care. 2012;18:e194-e199. 2. Sullivan WJ. Demystifying pathways in oncology. Manag Care. 2012;21:34-38. 3. Smith TJ, Hillner BE. Bending the cost curve in cancer care. N Engl J Med. 2011;364:2060-2065.

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AUGUST 2012 I VOL 5, NO 5 I SPECIAL ISSUE  

ASCO 2012: Payers’ Perspectives, PEER-REVIEWED FORUM, EVIDENCE IN BENEFIT DESIGN