©2012 Engage Healthcare Communications, LLC

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Chicago, IL—“Precision medicine” isthe new catch phrase in oncology,and examples of it were evidentacross the vast halls of McCormickPlace at the 2012 American Society ofClinical Oncology (ASCO) meeting.

Precision medicine is the next itera-tion of “personalized medicine,” amoniker perhaps meant to convey theincreasing refinement of the molecu-lar targets that underlie tumors. It hasbecome evident that mutations that

Molecular Profiling GuidingCancer Therapy“Precision Medicine” Focus of ASCO 2012 By Caroline Helwick

Novel T-DM1 Prolongs Remissionin Metastatic Breast Cancer: ANew “Smart Bomb”By Audrey Andrews

Chicago, IL—The media darling atASCO 2012 was a novel agent somecalled a “smart bomb,” because of itshighly targeted and potent effect thatspares surrounding healthy tissue.

Trastuzumab emtansine, betterknown as T-DM1, the antibody-drugconjugate linking trastuzumab to acytotoxic agent, delivers its punchdirectly into the tumor of patients withHER2-positive metastatic breast can-cer, and this agent is associated withlittle toxicity. T-DM1 is one of an

entirely new class of agents that couldhave a major impact on the disease.

Early results from EMILIA, an inter-national phase 3 clinical trial presentedat the meeting’s plenary session,showed an increase of approximately30% in progression-free survival (PFS)with T-DM1 compared with a stan-dard treatment regimen.

“For patients facing metastaticbreast cancer, this is a breakthrough,”said lead author Kimberly L.Blackwell, MD, of Duke Cancer

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PERSONALIZED MEDICINE . . . . . . . 6Patients willing to pay for genetictesting to assess cancer riskWhy hasn’t genomic testingchanged the landscape?

HEALTH ECONOMICS . . . . . . . . . . . . . 8High OOP costs in MedicareCancer screening is cost-effective

GI CANCERS . . . . . . . . . . . . . . . . . . . . . . 11New therapies on the horizon

LUNG CANCER . . . . . . . . . . . . . . . . . . 16Afatinib boosts PFS in EGFRmutations

PROSTATE CANCER . . . . . . . . . . . . 17Abiraterone before chemotherapy a promising strategy

RENAL CANCER . . . . . . . . . . . . . . . . . 20Tivozanib outperforms sorafenib as first-line therapy

MULTIPLE MYELOMA . . . . . . . . . . . 23Pomalidomide shows strong activityin relapsed/refractory disease

DRUG PIPELINE . . . . . . . . . . . . . . . . . 25PAYERS’ PERSPECTIVES . . . . . . 26Payers collaborate with providers to adopt oncology pathways?

IN THIS ISSUE

AUGUST 2012 I VOL 5, NO 5 I SPECIAL ISSUE ASCO 2012: Payers’ Perspectives

Quality of Life Drives Patient Preference for Metastatic RCC DrugPazopanib winner in head-to-head QOL comparisonBy Wayne Kuznar

Chicago, IL—The surprising results ofthe head-to-head randomized clinicaltrial PISCES on patient preference forone cancer therapy over another showthat patient-reported quality-of-life(QOL) differences influence treatmentpreference far more than physicianshad imagined, suggested researchers atASCO 2012.

In a double-blind, crossover trial,168 patients with metastatic renal-cell

carcinoma (mRCC) were randomized1:1 to 10 weeks of 800 mg of pazopanibor 50 mg of sunitinib as first-line can-cer treatment; after a 2-week washoutperiod, patients received 10 weeks ofthe alternate treatment. The primaryend point was patient preference,measured at 22 weeks.

Because patients with mRCC re -ceive therapies for many months oreven years, the researchers assessed

Continued on page 20

Patient Adherence Rises with Costof Oral Cancer Drugs A potential “designer drug” phenomenonBy Caroline Helwick

Chicago, IL—Canadian researchersreported a finding at the 2012American Society of Clinical Oncol -ogy meeting that runs contrary towhat other researchers have ob servedin the majority of studies. In this

study, as oral drug costs increas ed, sodid the likelihood of patients adher-ing to a prescribed regimen.

Low adherence rates have beendocumented for many oral therapiesin various diseases, and medication

is a registered trademark of Incyte Corporation.©

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information

reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, withthe most frequent being thrombocytopenia and anemia.A complete blood count must be performed before initiating therapy with Jaka� . Complete blood counts should be monitored as clinically indicated and dosingadjusted as required

reactions were bruising, dizziness and headache9/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 Jaka� . If clinically indicated, platelet transfusions may be administered

Dose modi� cations of Jaka� for patients developing anemia may also be considered

9/L) was generally reversible and was managed by temporarily withholding Jaka�

serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before

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How PROs were successfully integrated into the Jaka� ® (ruxolitinib) drug development program1

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bene� ts in clinical trials.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.

means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make better-informed decisions.

TAILORING a PRO tool for myelo� brosis

characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegalyand core symptoms of MF were incorporated into the phase III,

was the primary and biologic endpoint, and a reduction in total

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

speci� cally developed. After patient interviews, advice fromclinical experts and extensive input from the FDA, the modi� ed Myelo� brosis Symptom Assessment Form, version

Ultimately, Jaka� was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s � rst approved drug and also the � rst oncology medicine approved with symptom data in its label since the FDA ’s draft guidance on

gresswith patient-reported outcomes

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a As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase IIIstudy with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume frombaseline 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 modi� ed 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 “absent” and 10 representing “worst imaginable” 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 Jaka� group and 16.5 in the placebo group.9,10

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: Patient-reported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on ClinicalCancer 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. (Epubahead of print). 9. Jaka� Prescribing Information. Incyte Corporation. November 2011. 10. Data on File, Incyte Corporation.

renal or hepatic impairment [see Dosage and Administration].

based on safety and ef� cacy

in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

nursing or discontinue the drug, taking into account the importance of the drug to the mother

PROVIDING proof of patient bene� t

MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jaka� 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

with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jaka� has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and

1,8 The approval

8

JAKAFI endpoints included both biologic and patient-reported outcomes8,9

Please see Brief Summary of Full PrescribingInformation on the following page.

1-2 5 2:28 PM

VOL. 5 NO. 5 SPECIAL ISSUE4 AMERICAN HEALTH & DRUG BENEFITS August 2012

describe certain tumors—such as theepidermal growth factor receptor(EGFR) mutation in non–small-celllung cancer (NSCLC)—may be presentto some extent in a variety of apparent-ly unrelated cancers. This means thatdrugs targeted to one tumor type maybe useful in small subsets of other

types of cancers. This has implicationsfor drug development, clinical trials,and the treatment of patients.

“We now understand that it’s notsufficient to identify a tumor based onthe histology or the organ of origin, aswe did traditionally, but rather thattumors are heterogeneous. We need to

understand the particular moleculardriver of the tumor to select appropri-ate therapy,” said ASCO outgoing pres -ident Michael P. Link, MD, during apress briefing.

As medicine has become “president”in recent years, molecular profiling ofthe patient has become a standard prac-

tice, at least for many tumors and inacademic centers. But this is an expen-sive process, and sessions at ASCO 2012were devoted to best practices in thisarea, at least for lung cancer, colorectalcancer, and neuro-oncology.

In some instances, molecular profil-ing may be life-saving, said Nicholas J.Vogelzang, MD, Chair of ASCO’sCancer Communications Committeeand Chair and Medical Director, USOncology Research, Houston, TX, andan oncologist at ComprehensiveCancer Centers of Nevada, Las Vegas.Dr Vogelzang pointed out that it is nolonger uncommon for patients withdisease refractory to established treat-ments to go hunting for unsuspectedmutations that might be targeted bydrugs that would otherwise never beconsidered. “It’s not intuitive,” hesaid. “Unusual tumors have thesemutations, so you have to test them.”

Drugs that Are “Crossing Over”

For several drugs that were consid-ered breakthroughs in one tumor type,treatment niches are emerging in othercancers. A striking example is crizo-tinib, the ALK inhibitor that elicitsrobust responses (70%-80%) in the 5%of patients with NSCLC who haveALK gene abnormalities. Investigatorsreported at ASCO that crizotinib isalso an active treatment for a pheno-typically unrelated set of aggressivepediatric cancers.

In a phase 1 study of 70 children,treatment with crizotinib led to com-plete responses in 88% of patientswith anaplastic large-cell lymphomaand produced complete and partialresponses in patients with othertumor types as well. Many of theseyoung patients have maintained theirresponses to crizotinib for more than2 years, reported Yael P. Mossé, MD,Assistant Professor, Perelman Schoolof Medicine at the University ofPennsylvania, and an attendingphysician at the Children’s Hospitalof Philadelphia.

“It’s remarkable that this targetedoral medication provided such a sub-stantial benefit in these children withhighly aggressive cancers, most ofwhom had already undergone everyavailable therapy,” Dr Mossé said.

Dr Vogelzang, who commented onthe results, said he had also witnesseda dramatic response to crizotinib in anadult with ALK-positive anaplasticlarge-cell lymphoma. “The patient wasvery, very ill. She achieved a completeresponse with crizotinib and was ableto receive a transplant. So, this drugdoes have dramatic potential in olderpatients as well, and in patients withother tumors.”

Molecular Profiling Guiding Cancer Therapy... Continued from page 1

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 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-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 treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith 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 andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

Personalized Medicine

Continued on page 5

5www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL BOARDEDITOR-IN-CHIEFDavid B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N.Grandon Professor, Jefferson School ofPopulation Health, Philadelphia, PA

DEPUTY EDITORSJoseph D. Jackson, PhDProgram Director, Applied HealthEconomics and Outcomes Research,Jefferson University School ofPopulation Health, Philadelphia, PALaura T. Pizzi, PharmD, MPH, RPhAssociate Professor, Department ofPharmacy Practice, Jefferson School ofPharmacy, Philadelphia, PA

AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSF, CMDProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of Medicine, Associate Directorfor Clinical InvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern University, ILPast President, ACCCPast Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCOProfessor of Internal MedicineHematology/OncologyAssistant Dean for ResearchAssociate Director, Faculty GroupPractice, University of Michigan Medical School, MI

EMPLOYERSArthur F. Shinn, PharmD, FASCPPresident, Managed Pharmacy Consultants, LLC, Lake Worth, FLF. Randy Vogenberg, RPh, PhDPrincipal, Institute for IntegratedHealthcare and BentteligenceSharon, MA

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDExecutive Director, Research,Development & DisseminationSutter Health, Concord, CA

GOVERNMENTKevin B. “Kip” Piper, MA, FACHEPresident, Health Results Group, LLCWashington, DC

HEALTH INFORMATION TECHNOLOGY Kelly Huang, PhDPresident, HealthTronics, Inc.Austin, TX J. B. Jones, PhD, MBAResearch Investigator, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director for Innovation and Social EntrepreneurshipUniversity of Michigan, School of Public Health and MedicineAnn Arbor, MI

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes ResearchCenter, Director of OutcomesPersonalized Health Care Program,University of UtahSalt Lake City, UTJoseph Couto, PharmD, MBAClinical Program ManagerCigna Corporation, Bloomfield, CT Steve Miff, PhDSenior Vice PresidentVHA, Inc., Irving, TXKavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver, COGary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PAAndrew M. Peterson, PharmD, PhDDean, Mayes School of HealthcareBusiness and Policy, Associate ProfessorUniversity of the SciencesPhiladelphia, PASarah A. Priddy, PhDDirector, Competitive Health AnalyticsHumana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPhExecutive Director, Strategic Accounts Xcenda, Palm Harbor, FLVincent J. Willey, PharmDAssociate Professor, Philadelphia Schoolof Pharmacy, University of the SciencesPhiladelphia, PADavid W. Wright, MPHPresident, Institute for Interactive PatientCare, Bethesda, MD

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PATIENT ADVOCACY William E. Fassett, BSPharm, MBA,PhD, FAPhAProfessor of Pharmacy Law & EthicsDept. of Pharmacotherapy, College ofPharmacy, Washington State University, Spokane, WAMike PucciSr VP, Commercial Operations andBusiness Development, PhytoChemPharmaceuticalsLake Gaston, NC

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Molecular Profiling Guiding Cancer Therapy... Continued from page 4

Personalized Medicine

BRAF inhibitors may also havecrossover appeal, because colorectaland lung cancers also harbor BRAFmutations.

A “Blueprint” for Change

In keeping with the rapidly emerg-ing molecular landscape, ASCO ispushing for an accompanying para-digm shift in cancer research anddrug development. In November2011, ASCO issued a report that laysout its vision for transforming clinicaland translational research to delivermore effective and personalized can-cer therapies faster.

“Advances in cancer prevention,detection, and treatment havealready extended the lives of mil-lions of adults and children livingwith cancer—but the critical ques-

tion is, ‘Where do we go fromhere?’” said Dr Link. “This reportaims to set us on a path to deliverthe new therapies that patientsurgently need.” �

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“We now understand that it’s notsufficient to identify a tumor based onthe histology or the organ of origin…butrather that tumors are heterogeneous.We need to understand the particularmolecular driver of the tumor to selectappropriate therapy.” —Michael P. Link, MD

VOL. 5 NO. 5 SPECIAL ISSUE6 AMERICAN HEALTH & DRUG BENEFITS August 2012

Chicago, IL—“Economic evaluationsof personalized medicine should incor-porate the cost of testing for biomark-ers,” said Natasha B. Leighl, MD, med-ical oncologist at Princess MargaretHospital in Toronto, Canada, during asession on the cost of treating non–small-cell lung cancer (NSCLC) atASCO 2012.

In essentially half of advanced adeno -carcinomas of the lung, a mutation isdetected, and this will only increase asmore is learned about the tumor’s biol-ogy. Although targeted agents areundoubtedly effective in selected pop-ulations, the cost-effectiveness of deter-mining these patient groups has yet tobe fully shown, Dr Leighl said.

Erlotinib Cost-Effective in Highly

Targeted Group

The first targeted agent in NSCLCwas erlotinib. In unselected patients inthe pivotal NCIC CTG BR.21 trial,treatment with erlotinib led to anabsolute 2-month improvement inmedian survival, representing a 30%reduction in mortality risk. A cost-effectiveness analysis of the pivotaltrial showed that the drug itself is onlymarginally cost-effective.

Weighing the magnitude of survivalbenefit and expense, the incrementalcost-effectiveness ratio (ICER) forerlotinib in the trial population was$94,638 (2007 Canadian dollars) perlife-year gained.

However, when the analysis wasrestricted to groups that benefit mostfrom the drug, treatment appeared tobe cost-saving. The following ICERswere found among selected clinicaland molecular subgroups, who alsoderived the greatest clinical benefit:• In never-smokers: ICER $39,487 ver-

sus $504,911 for current smokers• Epidermal growth factor receptor

(EGFR) high copay: ICER $33,353versus $109,792

• EGFR mutation–positive: ICER$138,168 versus $87,994.“The key in personalized medicine is

defining the target population. Youmust identify the molecular subtypethat will benefit,” Dr Leighl said.

A number of international studieshave evaluated the cost-effectivenessof using EGFR tyrosine kinaseinhibitors (ie, erlotinib and gefitinib) inpatients with advanced NSCLC. Usedfirst-line in patients with EGFR muta-tions, under the “test-and-treat” strate-gy, the ICERs have ranged fromapproximately €26,000 to €70,000 perquality-adjusted life-year (QALY), andin some circumstances the drugs werecost-saving.

In a study in which patients with thewild-type genotype received gefitinibthird-line (based on the idea that thedrug has modest benefit in the patientswho do not have the mutation), theincremental benefit was diluted, andthe ICER rose to >$80,000/QALY.

Is Crizotinib Cost-Effective

in NSCLC?

The excitement over the targetedagent crizotinib for patients withNSCLC and the ALK rearrangementmeans that testing for this mutationwill also become standard, with costimplications. “The cost varies by typeof test and laboratory,” she said.

A 2012 study examined the impact ofdifferent predictive biomarker screen-ing techniques and population enrich-ment criteria on the cost-effectivenessof treating ALK-positive NSCLC(Atherly AJ, et al. Br J Cancer. 2012;106:1100-1106). The study showed the unitcost of FISH (fluorescence in situhybridization) testing, which detects100% of cases, to be $1400, whereasimmunohistochemistry and the re -verse transcriptase polymerase chainreaction, which detect 60% to 70% ofcases, cost only $600 to $900.

The screening of all patients withadvanced NSCLC for the ALK muta-tion using the FISH assay would be

$106,707/QALY, but this decreases to$4756 when only a highly enrichedpopulation is screened (adenocarcino-ma, never-smokers, EGFR-positive,KRAS wild-type), because this increas-es the biomarker frequency from 1.6%to 36%. But this approach would missapproximately half of the patients,resulting in some patients not beingoptimally treated.

“The cost would be reduced signifi-cantly because the likelihood of findingpositive cases significantly increases,”Dr Leighl explained.

The study showed that cost-effec-tiveness of <$100,000 per QALY gainedis not achievable at biomarker fre-quencies <5% (assuming drug costs of$1-$5000 per month and screeningcosts of $600-$1400 per person).

The researchers concluded that“Cost-effectiveness of oncology drugswhose prescribing is restricted to bio-marker-positive subgroups shouldaddress the cost of detecting marker-positive patients. The cost of screeningdominates at low frequencies, andstrategies to improve cost-effective-ness, based on the assay cost, drug cost,and group screened, should be consid-ered in these scenarios.”

Finally, Dr Leighl said, “The rapidevolution of testing technology and thecosts should factor into policy deci-sions” about the targeted treatment ofcancers, and this needs to be a continu-al process. �

Is Biomarker Testing in NSCLC Cost-Effective?By Caroline Helwick

“Economic evaluations ofpersonalized medicine shouldincorporate the cost oftesting for biomarkers.”

—Natasha B. Leighl, MD

Chicago, IL—In a cohort of patients atrisk for colorectal cancer (CRC), themajority were willing to pay some out-of-pocket (OOP) expenses forgenetic testing, Fox Chase CancerCenter researchers reported in a posterpresented at ASCO 2012 and earned anASCO Merit Award.

“These participants are fearful of apositive result and anticipate benefitsafforded by genetic testing in control-ling cancer risk,” said Jennifer M.Matro, MD, a medical oncology fellowat Fox Chase in Philadelphia.

The increasing availability of genetictesting in cancer care has been paral-leled by increasing cost-sharing prac-tices by payers. Little is known aboutthe factors that may influence a high-risk patient’s willingness to pay forthese genetic tests. The study was con-ducted to obtain such informationfrom a cohort of patients referred forgenetic risk assessment.

At enrollment in the Gastro intes -tinal Tumor Risk Assessment Registry,406 participants (73% female) comp -leted a survey that presented the fol-lowing 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

patients were willing to pay OOP and20% would want the test only if insur-ance covered the full cost.

The percentages of patients willingto pay OOP (if the test was not coveredby 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 will-ingness to pay included the expecta-tion of a positive result, confidence inbeing able to better control cancerrisk, fewer perceived barriers to CRCscreening, and belief that benefit isderived from having screening guid-ance. Patients willing to pay a higheramount were more likely to be male,be more educated, have greater can-

cer worries and fewer first-degree rel-atives with CRC, and have more pos-itive attitudes toward genetic testing.

Dr Matro speculated on why partic-ipants with more first-degree relativesand a history of colon cancer were lesslikely to pay more: “The reasons forthis may include that these patientsassume the test will be positive, or feelmore comfortable navigating thehealthcare system and getting appro-priate care without the test result.”

Despite the analysis being controlledfor household income, women andless-educated patients were willing topay a smaller sum, indicating that theymay face greater individual barriersfrom high co pays, she reported.

“Identifying patient-level factorsassociated with willingness to pay forgenetic services is increasingly im -portant as genetic testing is integratedinto routine cancer care,” Dr Matrosaid.—CH �

Patients Willing to Pay for Genetic Testing to Assess Cancer Risk

“These participants arefearful of a positive resultand anticipate benefitsafforded by genetic testingin controlling cancer risk.”

—Jennifer M. Matro, MD

See also Lung Cancer

Personalized Medicine

7www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Personalized Medicine

Chicago, IL—The “omics” revolutionproduced much optimism that tumorbiomarker tests based on the analysis ofmultiple factors, sometimes thousands,would result in truly personalized can-cer care. The field encompasses biologicmolecules such as DNA (“genomics”),several RNAs (“transcriptomics”), pro-teins (“proteomics”), and metabolites(“metabolomics”). Massive amounts ofdata are used to produce a profile,which is incorporated into a test thatcould guide patient care.

But 10 years later, the promise has yetto be realized. A panel of researchersand clinicians discussed the reasons forthis slow progress at ASCO 2012.

“Unfortunately, the field of tumorbiomarker research has been chaoticand haphazard, leading to many pub-lished papers in the peer-reviewed lit-erature but very few markers thattruly have clinical utility or that can berecommended for routine patientcare,” said Dan Hayes, MD, a scientistand breast cancer specialist at theUniversity of Michigan.

This situation has raised 2 keyissues—the use of biomarkers in theabsence of solid evidence supportingtheir clinical utility, and a lack of bio-markers that can lead to truly person-alized cancer care.

Many Markers, Few Chosen

In a recent review of the literature,researchers found >400 new genomicand other omics-based tests in transi-tion from bench to bedside, the vastmajority of which are related to cancer

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

According to Muin J. Khoury, MD,PhD, of the National Cancer Institute(NCI), one obstacle is “semantics.” Forinstance, the word “validation” meansmany things to many people, he said.Precise definitions are critical to anybranch of science; therefore, the inde-pendent Evaluation of Genomic Appli -cations in Practice and Prevention(EGAPP) Working Group is helping toorganize the field semantically. Thegoal of the EGAPP Initiative is toestablish and test a systematic, evi-dence-based process for evaluatinggenetic tests and other applications ofgenomic technology in transition fromresearch to practice, in a manner thatminimizes conflicts of interest and ispublicly accountable.

The EGAPP Working Group is

beginning to make some recommen-dations. The first is to support genetictesting strategies in individuals with anew diagnosis of colorectal cancer, toreduce morbidity and mortality fromLynch syndrome in relatives. TheEGAPP Working Group is also nowevaluating the use of prostate cancersingle-nucleotide polymorphism pan-els in risk assessment and screening, aswell as the value of pharmacogenomictesting of tumor tissue in patients withmetastatic colorectal cancer, for build-ing decisions regarding therapy withagents targeted against the epidermalgrowth factor receptor.

The most uncertain factor in thisfield is the assurance that outcomesare improved when biomarkers areused to select patients for treatment.David Ransohoff, MD, an epidemiol-ogist at the University of NorthCarolina, said the question is, “Doesthe biomarker discriminate; is theresult trustworthy?” He noted thatcomputational models may performwell during the discovery phase ofomics-based research but frequentlyfail when applied to an independentspecimen or data set.

But the field has not been bereft ofsuccess, Dr Ransohoff said, citing the21-gene recurrence score (OncotypeDX) and the 70-gene signature(MammaPrint) in breast cancer. TheOncotype DX is being prospectivelyevaluated in the randomized MIND -ACT trial to determine whether it canguide the use of adjuvant chemother-apy in node-negative patients.

What Needs to Be Done

“It is imperative that the field takemajor actions to break the vicious cyclethat has led to these circumstances andto do the rigorous research needed toprovide proper assessments,” Dr Hayessaid. “A bad tumor marker is as bad asa bad drug.”

“When these factors are recognizedand incorporated into tumor biomarkerstudies, the dream of personalizedoncologic care will be more likely tobecome a reality,” he said.

Ideally, to generate higher levels ofevidence, investors should developprospectively designed and conductedtrials to “test the test,” the speakerssaid. A few such trials are occurring inbreast and colorectal cancers.

Comparative effectiveness research(CER) in genomics and personalizedmedicine will also be valuable as pay-ers grapple with the cost of these newtools. Between 2009 and 2012, the NCIhas funded 7 groups across the coun-try to conduct CER.

“Yes, we can have an evidence-basedprocess for precision medicine,” DrKhoury predicted, “but it’s not goingto be cheap. It’s going to be costly.” �

Why Hasn’t Genomic Testing Changed the Landscape?“A bad tumor marker is as bad as a bad drug”By Caroline Helwick

“Yes, we can have anevidence-based process forprecision medicine, but it’snot going to be cheap.”

—Muin J. Khoury, MD, PhD

“The field of tumorbiomarker research has beenchaotic and haphazard,leading to many publishedpapers in the peer-reviewedliterature but very fewmarkers that truly haveclinical utility.”

—Dan Hayes, MD

Chicago, IL—A family history of can-cer is not always documented by pri-mary care or specialty practices, eventhough the identification of family can-cer history is an integral feature ofhigh-risk screening guidelines, accord-ing to data from a pilot project.

“Family history is important notonly for the identification of individu-als without cancer who have a strongfamily history and can be candidatesfor accelerated screening and interven-tion, but [also in] individuals who havecancer, [and in] those who have a fam-ily history and are at increased risk forsecond primary cancer,” said MarieWood, MD, Director of the Familial

Cancer Program, and Deputy Directorof Hematology/Oncology, Universityof Vermont, Burlington, at ASCO 2012.

Data were taken from 213 practicesthat were pilot tested for the imple-mentation of ASCO’s Quality Onco -logy Practice Initiative, designed toassess family history taking and genet-ic counseling/genetic testing (GC/GT)referral. Researchers assessed the pres-ence of cancer family history in first-and second-degree relatives, thepatient’s age at diagnosis, referral forGC/GT, and referral outcomes.

Data were available for 10,466patients—6569 with breast cancer and3897 with colorectal cancer; 77.4% of

their charts had documented cancerfamily history in first-degree relatives,and 61.5% contained documentation insecond-degree relatives. History takingof cancer in first-degree relatives wasdone in more patients with breast can-cer than those with colon cancer, aswell as in second-degree relatives. Theage at time of cancer diagnosis in rela-tives, however, was documented inonly 30.7% of all charts.

In 22.1% of reviewed charts, thepatients were referred for GC/GT. Agreater number of patients with—than those without—a positive familyhistory of cancer were referred forGC/GT, but this number reached

only 42.7%. Referrals were greater inpatients with breast cancer than thosewith colorectal cancer (29.1% vs19.6%, respectively). Similarly, inpatients with a hereditary risk forcancer—defined by selected riskguidelines—52.2% of those withbreast cancer and 26.4% with colorec-tal cancer were referred for GC/GT.

“We were glad to find high rates offirst-degree family documentation forall breast and colon cancer patients.However, there were very low rates ofdocumentation of the age of an indi-vidual at cancer diagnosis,” said DrWood. “Referral rates must be higher,because this impacts cancer care.” �

Family History of Cancer/Genetic Counseling Often Lacking forPatients First Presenting with MalignancyBy Wayne Kuznar

VOL. 5 NO. 5 SPECIAL ISSUE8 AMERICAN HEALTH & DRUG BENEFITS August 2012

Health Economics

Chicago, IL—Older patients with can-cer and Medicare coverage oftenincur greater out-of-pocket (OOP)expenses compared with their coun-terparts without cancer. Factors con-tributing to the greater expenses forthose patients include comorbiditiesand lack of supplemental insurance.As a result, older patients often hesi-tate to seek treatment for cancerbecause of financial concerns, accord-ing to a study presented by Amy J.Davidoff, PhD, MS, Assistant Pro -fessor, Pharmaceutical Health Ser -vices Research, University of Mary -land School of Pharmacy, Balti more,and colleagues at the 2012 AmericanSociety of Clinical Oncology meeting.

The team used Medicare CurrentBeneficiary Survey (MCBS) data from1997 to 2007 that was linked toMedicare claims for their analysis. Pa -tients with a new diagnosis of can cerwere chosen based on Inter nationalClassification of Diseases, Ninth Re vision,Clinical Modification (ICD-9-CM) codeson claims after a 12-month washoutperiod subsequent to the cancer diag-nosis. OOP costs were noted via thepatients’ own reporting.

The study included 1869 Medicarebeneficiaries with cancer and 10,057without cancer. Those with cancertended to be older, have more comor-bidities, and typically did not havesupplemental insurance comparedwith those without cancer.

For a patient with cancer, the total

OOP spending was $4727 (11.4% oftotal spending); the OOP differencebetween patients with and without

cancer was $1518. After adjusting forpatient characteristics, those with can-cer had an incremental increase of $956in OOP cost.

Among patients with cancer,approximately 28% spent ≥20% oftheir income on OOP expenses com-pared with 16% of those without can-cer who used ≥20% of their income onOOP expenses.

Comorbid conditions, undergoingcancer-specific radiation therapy, re -ceiving antineoplastic therapy, andhaving greater assets led to more OOPexpense.

Supplemental Insurance

A separate analysis of the sameMCBS database showed that the useof antineoplastic therapy amongMedi care recipients is influenced bythe availability, but not the type, ofsupplemental coverage. This analy-

sis—based in large part on databefore the addition of Medicare PartD (in 2006)—demonstrated that oral

antineoplastic agents were receivedby many patients with cancer usingantineoplastic therapy (non–Part Bdrugs), yet there was less spending on

this therapy than on infused/injectedchemotherapy (Part B drugs). Therewere no notable differences in use or

spending on antineoplastic therapyfor the post–Part D period relative tothe reference period.

“With the large number of relative-ly new oral prescription antineoplas-tic agents, and with more in thepipeline, monitoring the role of sup-plemental insurance, and particularlythe role of Part D in access and spend-ing, is a critical area for ongoingresearch,” said Dr Davidoff.

For this retrospective analysis, com-munity-based MCBS participantswith new cancer diagnoses were cho-sen based on ICD-9-CM diagnosiscodes. A total of 1836 beneficiarieswho had a new diagnosis of cancerwere enrolled.

Of the 559 patients who were treatedwith antineoplastic therapy, 395 (21.5%)received infused/injected chemothera-py and 254 received oral antineoplasticagents. Patients using antineoplastictherapy spent $7841 (any coverage),$10,364 (Part B coverage), and $1535(non–Part B coverage).

If beneficiaries had supplementalcoverage, the antineoplastic therapyrates and spending were greater rela-tive to those who did not have supple-mental coverage. After adjustment,patients with supplemental insurancefrom any source were more likely toreceive treatment for cancer.

A major predictor of antineoplastictherapy use and spending was the siteof the cancer. Also, older age was asso-ciated with less spending. �

High OOP Costs for Medicare Patients with CancerBy Mark Knight

Older patients often hesitate to seektreatment for cancer because offinancial concerns.

—Amy J. Davidoff, PhD, MS

With more oralantineoplastic agents in thepipeline, “monitoring therole of supplementalinsurance, and particularlythe role of Part D in accessand spending, is a criticalarea for ongoing research.”

—Amy J. Davidoff, PhD, MS

Chicago, IL—Improved cancer screen -ing can save lives, and despite thehigh cost of implementing such ameasure, it was found cost-effectiveand therefore valuable in a recentanalysis using quality-adjusted life-years (QALYs), said Michael S.Broder, MD, President of Partnershipfor Health Analytic Research, LLC(PHAR), CA, and colleagues, at the2012 American Society of ClinicalOncology meeting.

Cancer care spending in the UnitedStates has increased from $13.1 billionin 1980 to $104 billion in 2006, butthere is much controversy over thesufficiency of the benefit of thisspending.

Cancer screening may reduce can-cer-related morbidity, but to studywhether such screening is cost-effec-

tive, Dr Broder and colleagues fromPHAR; the University of California,Los Angeles, Center for SurgicalOutcomes and Quality; and RAND

Health in Santa Monica, CA, devel-oped a framework for measuring thevalue of improving compliance withmeasures for cancer screening com-pared with other quality measures.

Value of Quality Improvement

Dr Broder and colleagues used theirframework to examine 18 HEDIS 2010quality measures. Quality improve-ment (QI)-adjusted incremental cost-effectiveness ratios (ICERs) for 3 can-cer screening measures—cervical,breast, and colon—were comparedwith the remaining measures. ICERswere reported for measures represent-ing a tradeoff (ie, between greater costand greater health, or cost-savings andworse health).

To reach 95% compliance on these 3cancer screening measures wouldcost $5.1 billion and add 160,000QALYs—$32,640/QALY. This rate ofcompliance with all 18 measureswould cost $13.4 billion and add 5.8million QALYs, which translates to$2313/QALY. That would make QI a

good value and very cost-effectivecompared with most health improve-ments, which can cost more than$50,000 to $80,000 per QALY, accord-ing to Dr Broder.

Although these costs were substan-tial, resulting in an increase of 50% to200% in the ICER for the cancer screen-ing measures, after incorporating QIcosts, the mean QI-adjusted ICER forthese 3 measures suggests that improv-ing cancer screening compliance is cost-effective at a $50,000/QALY willing-ness-to-pay threshold.

“Our analysis shows that complyingwith cancer screening measures iscost-effective, even considering there sources required to change estab-lished practices,” said Dr Broder.Addressing overuse of care can savemoney, he added. �

“Compliance with cancerscreening measures is cost-effective, even consideringthe resources required tochange established practices.”

—Michael S. Broder, MD

Cancer Screening Is Cost-Effective, Saves LivesBy Wayne Kuznar

9www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

nonadherence is often the primarycause of treatment failure. “To ourknowledge, cost-related adherence tooral therapy in the context of malig-nancy has not been studied extensive-ly,” said Jalal Ebrahim, MD, of StMichael’s Hos pital, University ofToronto, Ontario, Canada.

He and his colleagues conducteda study of 453 patients with cancer at3 outpatient hematology/oncologyclinics. They used a 7-item survey toin vestigate patient self-reported ad -herence to oral medication, type ofcoverage, and patients’ perceived costof the drugs.

Of the 453 patients, 50% had a privatedrug plan, 24% paid for the drug outof pocket, 44% had government fund-ing, and 4% said their physician hadarranged funding for their medication.

Approximately 50% of the patientshad a drug cost of ≥$100 monthly.Patients paying out of pocket weresignificantly less likely than all otherpatients to have oral drug costs of≥$500 monthly (11% vs 19%, respec-tively). There was also a significant

relationship between drug coverageand oral drug costs.

Patients with annual incomes of≥$70,000 were more likely than thosewith lower incomes to have monthlydrug costs of ≥$1000 (18% vs 9%,

respectively). “It is possible thatpatients are provided with more edu-cation regarding newer and moreexpensive agents than they are forolder and cheaper agents, regardlessof efficacy,” according to Dr Ebrahim.

Strong Adherence to

High-Cost Drugs

“A strong correlation was observed

between monthly oral drug cost andadherence to the regimen,” he said.

A low monthly drug cost was notassociated with higher adherencerates. The adherence rates related tomonthly 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 patientsconsider more expensive drugs to bemore valuable, and therefore should notbe wasted. This “designer drug” phe-

nomenon may explain the in creasedadherence rates that were found to beassociated with high-cost drugs.

“Poor communication betweenphysicians and patients can lead topoor adherence. A lack of educationregarding older, cheaper medicationscould be a catalyst for nonadher-ence,” Dr Ebrahim suggested.

The disparities found in this studyin medication costs for patients withprivate drug plans versus those with-out private plans suggest that finan-cial restrictions may affect prescrip-tion patterns, the team noted. �

Health Economics

“A strongcorrelation wasobserved betweenmonthly oral drug cost andadherence to theregimen.”

—Jalal Ebrahim, MD

The surprising finding in this study suggests thatpatients with cancer consider more expensivedrugs to be more valuable,and should there fore be taken as prescribed.

Chicago, IL—Drug shortages in cancercare remain a threat significant enoughto warrant pending US legislation,though the frequency of these short-ages appears to be on the decline. Apanel that was convened at ASCO 2012addressed the impact of drug short-ages on cancer treatment and proposedresolutions.

Legislation that is currently beingdebated in Congress aims to tackledrug shortages directly. Supporting theneed for legislation, experts note thatthe availability of many drugs remainsunpredictable. “We never know whena drug will go out of supply, which cre-ates tremendous uncertainty and anxi-ety on the part of patients,” and makesplanning difficult for physicians, saidRichard L. Schilsky, MD, Chair, ASCOGovern ment Relations Committee, andSection Chief of Hematology/Oncology,Depar tment of Medicine, Universityof Chicago. “Patient care is threatenedas a result of such drug shortages,” hecommented.

In addition, 22 oncology therapieseither are or have been in short supplyin the past 2 years, adds Michael Link,MD, ASCO outgoing president andChief of the Division of Pediatric Hema -tology/Oncology, Stanford Uni ver sitySchool of Medicine, Palo Alto, CA.

Specific cancer therapies in limitedsupply or nearly impossible to obtaininclude nitrogen mustard, cisplatin,and paclitaxel, as well as fluorouracil.According to a spokesperson from theUS Food and Drug Administration(FDA), 12 cancer drugs are currentlyon the FDA’s list of medicines in shortsupply, but most issues are beingaddressed.

According to Dr Link, 4 months agooncology practices were down to a 2-week supply of methotrexate to treatchildhood leukemia, which is report-edly 90% curable when drugs are avail-able. “That crisis was averted withstopgap measures we had in place,”said Dr Link.

According to Dr Link, the shortageeven extends to drugs used to alleviatediscomfort associated with anticancertherapy, such as sodium bicarbonate,which can accompany methotrexate, orleucovorin, used with 5-fluorouracil.

The proposed legislation calls onpharmaceutical manufacturers to keepUS regulators abreast of unanticipateddrug supply issues. Draft laws reintro-duce user fees for brand-name phar-maceuticals to cover the cost of newmedicine assessments by the FDA; forthe first time, the legislation also buildsin fees for generic drug manufacturers,as well as for potential manufacturersof biosimilars.

The addition of generic-drug userfees would generate approximately$1.5 billion in federal funding withinseveral years, Dr Schilsky said. Thefunding could help reduce reviewtimes for New Drug Applications forgeneric drugs, trimming the currentlead time of 30 months to 10 monthsor less. This represents a huge stepforward in recruiting new manufac-turers to get drugs on the market, DrSchilsky said.

The downside is that the legislation isnot expected to include provisions tolevy cash penalties on manufacturersthat fail to notify the agency of pending

shortages. Dr Schilsky adds that thereare concerns that “If there are no teeth inthat legislation, some companies maydecide not to report as required.”

Pending the passage of legislation,the FDA is seeking notification fromdrug companies if they expect a short-age, a policy that thus far has led topositive outcomes, according toSandra Kweder, MD, Deputy Directorof the FDA’s Office of New Drugs.

“Prevention of drug shortages atFDA is absolutely a priority—one ofour number 1 priorities here, as wellas in Congress and in the WhiteHouse,” Dr Kweder said. We canengage with companies quickly if weknow about them, to prevent short-ages from occurring.” In 2012 alone,advance notification has prevented atleast 50 drug shortages, although notall shortages are oncology-specific.Since October 2011, 150 drug shortageshave been prevented, she said.

The majority of drug shortages ingeneral are a direct result of manufac-turing and drug quality problems,according to Dr Kweder. A single facili-ty closing because of quality issues canlead to dozens of shortages. And quali-ty issues are often related to sterility.For example, particles of glass or metalshavings may be found in vials. �

“Prevention of drugshortages at FDA isabsolutely a priority—one ofour number 1 priorities. Wecan engage with companiesquickly if we know aboutthem, to prevent shortages.”

—Sandra Kweder, MD

Cancer Therapies in Short Supply Prompt a Response at the Federal LevelBy Wayne Kuznar

Patient Adherence Rises with High Cost of Oral... Continued from page 1

VOL. 5 NO. 5 SPECIAL ISSUE10 AMERICAN HEALTH & DRUG BENEFITS August 2012

Health Economics

Chicago, IL—Early institution of pal-liative care in patients with lung can-cer is not only humane, it is cost-effec-tive, according to Craig C. Earle, MD,Director of the Health Services Re -search Program for Cancer CareOntario and the Ontario Institute forCancer Research, at a session on thecost of lung cancer care at ASCO 2012.

“The costs of cancer treatment nearthe end of life can be significant, botheconomically and in terms of patientand caregiver quality of life. What wedo influences the cost of care, especial-ly at the end of life. We need to appre-ciate the limits of benefit associatedwith aggressive treatment as the endof life nears and know the potentialbenefits of early institution of pallia-tive care in this setting,” Dr Earle said.

The cost trajectory is a U-shapedcurve, he noted. “The cost is high atthe beginning, is less in the middle,and invariably rises rapidly at theend of life.” Palliative care, institutedat diagnosis when patients live 6months, costs approximately $6000per patient (mean reimbursement) inthe first couple of months but thenresults in much lower monthly costscompared with chemotherapy. Atmonth 6 (end of life), the mean re -imbursement for palliative care isapproximately $5000, whereas itclimbs to $8000 when chemotherapyis delivered, Dr Earle said.

The trend toward aggressive care atthe end of life has been increasingslowly during the past 15 years.Although this overuse became evidenta decade ago, little has been done tocurb its trajectory.

Evidence shows that aggressive useof chemotherapy near death is unrelat-ed to the likelihood of better outcomes,yet there are many rationales for futile

care: patients or families request it, it isseen as preserving hope, it is thoughtthat doing something is better thandoing nothing, it is easier for oncolo-gists to give chemotherapy than with-hold it, the occasional patient respondsand has meaningful palliation afteraggressive treatment, patients willaccept more toxicity than oncologiststhink they will, and, in some cases,

providers have financial incentives,he suggested.

“If oncologists don’t have support togive good palliation, then perhaps wecontinue to do what we were trainedto do, give chemotherapy,” Dr Earleurged. “But if we as healthcareproviders say we would not wantaggressive treatment ourselves, per-haps because we have a true idea ofthe tradeoffs, then maybe we shouldbe more paternal as we shepherdpatients through the disease course.”

The Value of Palliative Care

Perceptions were changed, to somedegree, by a couple of recent studiesthat confirmed that an aggressiveapproach continued to near-death doesnot improve outcomes and that earlyinstitution of symptomatic/palliativecare does not adversely affect survival.

In a study led by Dr Earle, overallsurvival among elderly patients withlung cancer was better in patients whoused a hospice versus those not in ahospice (25.7% vs 20.7%, respectively,at 1 year postdiagnosis, and 6.9% vs5.5%, respectively, at 2 years; P <.001).There was no significant differencebetween those with shorter and thosewith longer duration hospice stays(Saito AM, et al. J Palliat Med. 2011;14:929-939).

In another study (Temel JS, et al. NEngl J Med. 2010;363:733-742), early ini-tiation of palliative care was associatedwith less aggressive treatment and a 3-month survival advantage, as well asgreater patient and family satisfaction.Dr Earle noted that other studies haveshown that patient and caregiver satis-

faction is worse when chemotherapy isoverused, when death occurs in thehospital or in the intensive care unit,and when patients are not admitted(or admitted only briefly) into a hos-pice. More aggressive care also hasbeen associated with higher rates ofdepression among bereaved care-givers, he added.

Change Is Possible

As more emphasis is placed onavoiding futile chemotherapy, and aspathways are being developed toenforce this, the opposite trend isbeginning to emerge, Dr Earle said. Forexample, with feedback from ASCO’sQuality Oncology Practice Initiative(QOPI), the use of chemo therapy in thelast 2 weeks of life in one institutiondeclined from 50% to 20% (BlayneyDW, et al. J Clin Oncol. 2009;27:3802-3807). “Our practice changed towardthe QOPI national practice norm after apresentation of the results at a facultyresearch conference,” the authors ofthis article wrote. �

The Cost of Lung Cancer at the End of Life: EarlyInstitution of Palliative Care Improves SurvivalBy Caroline Helwick

“If we as healthcareproviders say we would notwant aggressive treatmentourselves, perhaps becausewe have a true idea of thetradeoffs, then maybe weshould be more paternal aswe shepherd patientsthrough the disease course.”

—Craig C. Earle, MD

“We need to appreciate thelimits of benefit associatedwith aggressive treatment asthe end of life nears andknow the potential benefitsof early institution ofpalliative care in this setting.”

—Craig C. Earle, MD

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Radiotherapy-Related Hospital Admissions Are FrequentChicago, IL—Approximately 1 in 5patients with cancer who are under-going radiotherapy as part of theirtreatment can count on unexpectedhospital stays—adding an economicand clinical burden on the patient andon the healthcare system, accordingto a study by Nabeel H. Arastu, BS,and colleagues at the Brody School ofMedi cine at East Carolina University,Greenville, NC, which was presentedat ASCO 2012.

Unanticipated admissions werecommon among nearly 33% of pa -tients who received radiotherapy totreat symptoms and were also likelyin more than 25% of those receivingsimultaneous chemoradiation.

Data were collected from the elec-tronic health records of 500 patientswith cancer. The patients had re -ceived external beam radiotherapyin 2010.

20% Unexpected Admissions

Of the 500 patients, 101 (20%) hadunexpected hospital stays, lasting amean of 4 days (range, 1-16 days). Themean length of time between a patientbeginning radiotherapy and going tothe hospital unexpectedly was 32 days(range, 0-86 days).

Reasons for hospital admissionincluded:• Pain (19% of cases)• Respiratory issues (15%)

• Neurologic conditions (13%)• Malaise (7%)• Fever (5%).

In addition, 33% of patients whowere treated palliatively ended upbeing admitted to the hospital com-pared with 16% of curative-focusedpatients.

According to a univariate analysis,26% of patients who had simultaneousradiotherapy and chemotherapy hadunplanned hospital admissions com-pared with 17% of those receiving onlyradiotherapy. Unexpected hospitalstays were tied to chemotherapy, treat-ment goals, and marital status. Therewere highly inconsistent rates of unex-pected hospital visits based on diagno-

sis—including 37% for metastases;19% for gastrointestinal, genitourinary,gynecologic, ear, nose, and throat can-cers; and 4% for breast cancer.

Patients who were treated with asecond or third round of radiotherapycould expect higher admission rates(average, 27%) compared with thosewho received only 1 treatment round(16%). Furthermore, patients whowere undergoing treatment for sec-ondary metastases typically experi-enced a much higher rate of unexpect-ed hospital visits, possibly becausepatients undergoing multiple roundsof chemotherapy for secondary metas-tases are typically sicker and havemore comorbidities.—CH �

See also Lung Cancer

11www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

GI Cancers

Chicago, IL—The addition of new tar-geted agents, as well as prolonged useof bevacizumab even beyond diseaseprogression, extend overall survival(OS) and improve progression-freesurvival (PFS) in patients withmetastatic colorectal cancer (mCRC),according to several studies presentedat ASCO 2012.

The More Bevacizumab, the Better

In the phase 3 clinical trial TML18147, which was highlighted at apress briefing, the administration ofthe anti-VEGF (vascular endothelialgrowth factor) bevacizumab beyondthe point of disease progression in -creased survival.

“This is the first randomized trial toprospectively evaluate bevacizumabbeyond first progression. The studyconfirms that continuing bevacizu -mab beyond progression when chang-ing chemotherapy is beneficial forpatients, and this finding has translat-ed into a significant improvement inOS in metastatic colorectal cancerpatients, as well as progression-freesurvival,” said Dirk Arnold, MD, ofthe University Clinic Eppendorf inHamburg, Germany.

The TML 18147 trial enrolled 820patients with mCRC whose diseasehad progressed after first-line chemo -therapy. The patients received anirinotecan-based or oxaliplatin-basedregimen plus bevacizumab. Upon dis-ease progression, the patients were

randomized to second-line therapywith the regimen they did not receivefirst, with or without concomitantbevacizumab.

The median OS was 11.2 monthswith maintenance bevacizumab com-pared with 9.8 months with chemo -therapy alone, for a 19% reduction inmortality risk (P = .062). Median PFSwas 5.7 months and 4.1 months,respectively (P <.001).

This study tested an important bio-logic concept for antiangiogenicdrugs, showing that duration of treat-ment does matter. In addition,although the current evidence comesfrom research in mCRC, this principlecould hold true for lung and breastcancer as well, some believe.

Dr Arnold said that although beva-cizumab produced mixed results inother cancers, it plays a significantlyfavorable role in mCRC. “These find-ings indicate that this might serve as anew model for a treatment approachby multiple treatment lines in metasta-tic colorectal cancer and across othertumor types,” he said.

Axel Grothey, MD, a CRC specialistat the Mayo Clinic, Rochester, MN,agreed that using bevacizumab be -yond progression represents a newtreatment approach that is currentlybeing tested in other tumor types.

Press briefing moderator Bruce J.Roth, MD, of Washington Universityin St. Louis, commented that oncolo-gists have been trained to discontinuecytotoxic chemotherapy at the time ofprogression, “but the issue is morecomplicated for anti-VEGF therapieslike bevacizumab, and this issue hasbeen raised in other tumor types.” Hesaid that the mechanism of resistanceto anti-VEGF agents may be different,which may explain the benefit.

Potential New mCRC Therapies

Two additional studies presented atthe meeting showed benefits fromadding kinase inhibitors or an epider-mal growth factor receptor (EGFR) tomCRC regimens.

In the phase 3 clinical trial COR-RECT, the investigational oral multi -kinase inhibitor regorafenib was com-pared with placebo in 760 patients with

mCRC whose disease was refractoryto chemotherapy.

The use of regorafenib significantlyextended OS from 5.5 months withplacebo to 6.6 months, hazard ratio0.77 (95% confidence interval, 0.64-0.94; P = .052). Although the absolutedifference in OS was only 1 month,Dr Grothey emphasized that theseresults are best viewed in terms of thehazard ratio. He noted that manypatients with mCRC are still fit andable to undergo further treatment afterthey become resistant to chemothera-py, and regorafenib addresses thatunmet need.

A New Drug Application was sub-mitted to the US Food and Drug Ad -ministration for regorafenib on May 23,2012, for the treatment of patients withmCRC.

In the phase 3 GERCOR DREAMtrial, patients with previously untreat-ed mCRC received chemotherapy plusbevacizumab, and those without dis-ease progression were randomized tomaintenance therapy with bevacizu -mab alone or with bevacizumab plusthe EGFR erlotinib.

Median PFS was improved with theaddition of erlotinib from 4.6 monthsto 5.8 months (P = .005). There was,however, an increase in diarrhea andskin toxicity with erlotinib. Neverthe -less, the study suggests that theremay be a role for dual targeting ofVEGF and EGFR in CRC, according toDr Grothey. �

Chicago, IL—Regorafenib, the orallyadministered investigational tyrosinekinase inhibitor (TKI) that has shownactivity in metastatic chemorefractorycolorectal cancer, dramatically delayeddisease progression in patients with atreatment-refractory metastatic gas-trointestinal stromal tumor (GIST) inGRID, a phase 3 clinical trial, said leadinvestigator George D. Demetri, MD,Associate Professor, Department ofMedicine, Harvard Medical School,and Director, Center for Sarcoma andBone Oncology, Dana-Farber CancerInstitute, at ASCO 2012.

The median progression-free sur-vival (PFS) reached 4.8 months withregorafenib compared with only 0.9months in the placebo arm, for a 73%reduction in risk (P <.001). The diseasecontrol rate at 12 months was 52.6%

with regorafenib and 9.1% with placebo.“There was a significant robust

effect, regardless of the number ofprior inhibitors that these patients hadbeen exposed to. Regorafenib has thepotential to fulfill an unmet need forGIST patients progressing after im -atinib and sunitinib, and potentiallyrepresents a new standard of care,” DrDemetri said.

GIST is the most common subtypeof sarcoma, and until the marketingof imatinib and then sunitinib, thiscondition was essentially untreat-able. The TKIs changed the typicalcourse of this disease, with prognosisranging from ≤6 months, survival to≥5 years.

However, the tumors almost univer-sally eventually become resistant tothese 2 approved TKIs, Dr Demetri said.

GRID was an international, random-ized, placebo-controlled trial thatquickly accrued 236 patients with

metastatic, unresectable GIST whowere intolerant of imatinib and suni-tinib, or whose disease progresseddespite treatment with these agents.The patients were assigned to dailyregorafenib or to placebo plus best

supportive care; 74% of the patientshad received 2 previous lines of thera-py and 59% had received >2 lines.

Despite the significant difference inPFS between the 2 arms, the overallsurvival rate was similar, presumablybecause 85% of the placebo-recipientpatients crossed over to receive regora -fenib upon disease progression. Mediansurvival has not yet been reached ineither arm.

Treatment-related adverse eventswere similar to what is typically seenwith multitargeting TKIs.

Grant McArthur, PhD, of the PeterMacCallum Cancer Centre, East Mel -bourne, Australia, commented on thestudy, saying, “Clearly, this is a positivestudy, and there is no doubt that rego-rafenib is a viable third-line treatmentoption now for our patients.”—CH �

For Advanced GIST, Regorafenib Shows Robust Effect

Metastatic Colorectal Cancer: Prolonged BevacizumabImproves Outcomes, New Targeted Therapies on the HorizonBy Caroline Helwick

“There is no doubt thatregorafenib is a viable third-line treatment option nowfor our patients.”

—Grant McArthur, PhD

“The study confirms thatcontinuing bevacizumabbeyond progression whenchanging chemotherapy isbeneficial for patients, andthis finding has translatedinto a significantimprovement in OS inmetastatic colorectal cancer patients.”

—Dirk Arnold, MD

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

If you defi ne 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 InformationINDICATIONVELCADE is indicated for the treatment of patients with multiple myeloma.

CONTRAINDICATIONSVELCADE 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 modifi cation or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefi t 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 infi ltrative pulmonary disease has been reported

Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fl uid replacement

Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment

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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 REACTIONSMost 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

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*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the effi cacy 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-specifi ed interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in signifi cantly 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.

V

Chicago, IL—Crizotinib—which pro-duces robust responses in patients withnon–small-cell lung cancer who haveabnormalities in the anaplastic lymphomakinase (ALK) gene—may also have animpact on a number of aggressive pedi-atric tumors, according to a phase 1

dose-escalation study conducted by theChildren’s Oncology Group and report-ed by lead investigator Yael Mosse,MD, of the Children’s Hospital ofPhiladelphia, at ASCO 2012.

Crizotinib halted tumor growth inchildren with anaplastic large-cell lym-

phoma (ALCL), inflammatory myofi-broblastic tumors (IMTs), and aggres-sive forms of neuroblastoma; in somecases, crizotinib eradicated all signs ofcancer, Dr Mosse said.

Abnormalities in the ALK gene arefound in approximately 80% to 95% of

patients with ALCL, 50% of those withIMTs, and 10% to 15% of patients withaggressive neuroblastomas.

“It’s remarkable that this targetedoral medication provided such a sub-stantial benefit in these children withhighly aggressive cancers, most ofwhom had already undergone everyavailable therapy. Now that we knowmuch more about the drivers of somepediatric cancers, we can target thosechanges and treat patients in a muchsmarter and potentially safer way,” DrMosse said.

This study included 70 children(median age, 10 years) with refractorysolid tumors and ALCL. The outcomesby 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 minorresponse (tumor shrinkage), and 5are too early to evaluate

• Neuroblastoma: of the 35 patientsenrolled, 27 were evaluable; of these,8 patients have known ALK muta-tions; in this group, 1 had a completeresponse, 1 had a minor response,and 1 had stable disease. Among the19 patients whose ALK gene status isunknown, 1 had a complete responseand 6 had prolonged stable disease. The responses tend to be durable,

with some patients continuing treat-ment for >18 months. Compared withALCL, the benefit of crizotinib is lessclear in IMT and in neuroblastoma,although subsets of these patients doappear to respond, Dr Mosse said.These findings have implicationsbeyond these pediatric cancers. “Withnext-generation sequencing, we maydiscover that the ALK gene is relevantto multiple human cancers.”

Michael Link, MD, outgoing presi-dent of ASCO and a pediatric oncolo-gist himself, said the study has far-ranging implications. “The moleculardriver [ALK] is present in very differentand sometimes unrelated tumor types,and thus this ALK inhibitor may workin very different cancers,” he predicted.“We have a glimpse at a new paradigmof understanding cancer and drugdevelopment, that it will someday notbe sufficient to identify tumors by theirhistology or organ of origin.” �

VOL. 5 NO. 5 SPECIAL ISSUE14 AMERICAN HEALTH & DRUG BENEFITS August 2012

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.

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 V-12-0095 6/12

Pediatric Cancer

“Now that we know muchmore about the drivers ofsome pediatric cancers, wecan target those changes andtreat patients in a muchsmarter and potentially safer way.” —Yael Mosse, MD

Crizotinib Effective in Aggressive Pediatric TumorsBy Caroline Helwick

15www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Institute at Duke University, Winston-Salem, NC.

Louis Weiner, MD, Director, George -town-Lombardi Cancer Center inWashington, DC, the invited discus-sant for the study, commented, “Statedsimply, T-DM1 really works in thispatient population. It is an importantnew weapon in the therapeutic arma-mentarium for breast cancer.”

The EMILIA Study

EMILIA included 991 HER2-positivepatients who had locally advanced ormetastatic breast cancer and who hadpreviously received a taxane andtrastuzumab. Patients were random-ized to receive intravenous T-DM1 orcapecitabine plus lapatinib (XL) every3 weeks, until progression.

The median PFS for the T-DM1 armwas 9.6 months compared with 6.4months for XL, representing a 35%

reduction in the risk of progression(P <.001), Dr Blackwell reported.

Median overall survival (OS) wasnot reached with T-DM1 and was 23.3months with XL, for a 38% reductionin mortality risk (hazard ratio, 0.621;95% confidence interval, 0.475-0.813;P <.005). This result, however, did notmeet the prespecified threshold forstatistical significance for this endpoint at the first analysis. Never -theless, after 2 years, 65.4% of thepatients receiving T-DM1 were alivecompared with only 47.5% of thosereceiving the XL regimen.

Dr Weiner predicted that a signifi-cant improvement in OS will eventu-ally be observed, and this will be“particularly notable, since effectivepalliative treatment has rarely beenassociated with improved survival in

the metastatic setting.” Dose reductions were required for

16.3% of the patients receiving T-DM1compared with 53.4% of those in the

capecitabine arm and 27.3% in thelapatinib arm. Diarrhea, vomiting,hand-foot syndrome, and alopeciawere reported with the chemotherapyregimen but not with T-DM1. �

Novel T-DM1 Prolongs Remission in Metastatic... Continued from page 1

“T-DM1 really works in thispatient population. It is animportant new weapon in the therapeuticarmamentarium for breast cancer.”

—Louis Weiner, MD

Breast Cancer

Chemotherapy-Related Toxicity Adds to Economic Burden in Metastatic Breast CancerBy Caroline Helwick

Chicago, IL—Adverse events relatedto chemotherapy for metastatic breastcancer lead to a substantial economicburden that is primarily ex plained byincreased inpatient, outpatient, andpharmacy costs, said lead investiga-tor Sara A. Hurvitz, MD, Director ofthe Oncology Breast Can cer Programat University of Califor nia, LosAngeles (UCLA) Jonsson Compre -hensive Cancer Center and AssistantClinical Professor at UCLA School ofMedicine, who presented an econom-ic analysis at ASCO 2012.

“An analysis of healthcare costsstratified by the number of adverseevents reported by patients showed aclear trend: the economic burden ofadverse events increases with thenumber of adverse events reported,”Dr Hurvitz said. The study is the firstto assess costs associated withadverse events during treatment formetastatic breast cancer.

Patients were selected from thePharMetrics Integrated Database, usingpharmacy and medical claims from>100 US health plans, representing>70 million lives in the period between2000 and 2010.

The eligible cohort included 3222patients who used a taxane (ie, doce -taxel, paclitaxel) first-line, capecita -bine first-line, taxane second-line, orcapecitabine second-line. Patientstreated with both classes during the

same episode were excluded. The listof adverse events included almost 2dozen possibilities. Adverse eventswere seen in each of the 4 studycohorts.

Incremental Monthly Costs

The incremental costs associatedwith chemotherapy-related complica-tions were estimated by comparing theaverage costs between the cohorts

with and without adverse events forthe 4 treatment groups:• Taxanes first-line: adverse events

were associated with a 38.7%increase in monthly costs overpatients without adverse events($3547). These incremental costswere mainly driven by increasedinpatient costs and other drug costs(other than those for chemotherapy)

• Taxanes second-line: adverse eventswere associated with a 69.5%increase in monthly costs ($5320).Incremental costs were mainly driv-en by incremental pharmacy costsfor chemo therapy and other drugs

• Capecitabine first-line: adverseevents were associated with a 9%increase in monthly costs ($4933).Incremental costs were mainly driv-en by inpatient and outpatient costs

• Capecitabine second-line: adverseevents were associated with an82.9% increase in monthly costs($4933). Incremental costs weremainly driven by outpatient andinpatient costs.

Increasing Adverse Events per

Episode Led to Higher Costs

The more adverse events perepisode, the greater the cost of care,the analysis found. For example, for

taxane first-line therapy, the mean costof a treatment without an adverseevent episode was approximately$10,000, which rose to approximately$11,000 in the setting of 1 or 2 adverseevents, and to almost $15,000 in thesetting of >4 adverse events.

For second-line capecitabine, treat-ment without an adverse eventepisode cost approximately $6000, butrose to approximately $14,000 in thesetting of >4 adverse events.

The average monthly costs per typeof adverse event were highest for skintoxicity with taxanes and for constitu-tional symptoms with capecita bine,both approaching $16,000 on average.

“Further research evaluating theclinical and economic consequencesof chemotherapy-related adverseevents in a prospective manner canfurther characterize the effects seenhere,” Dr Hurvitz concluded. �

“For patients facingmetastatic breast cancer, thisis a breakthrough.”

—Kimberly L. Blackwell, MD

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“An analysis of healthcarecosts stratified by thenumber of adverse eventsreported by patients showeda clear trend; the economicburden of adverse eventsincreases with the number ofadverse events reported.”

—Sara A. Hurvitz, MD

Estimated Breast Cancer Rates, 2012

According to data from the American Cancer Society, an estimated 229,060new cases of breast cancer will occur in the United States in 2012; of these226,870 are women and 2190 are men.

In addition, an estimated 39,920 patients with breast cancer will die of thedisease in 2012.

Source: American Cancer Society, Inc., Surveillance Research, 2012.

VOL. 5 NO. 5 SPECIAL ISSUE16 AMERICAN HEALTH & DRUG BENEFITS August 2012

Lung Cancer

Chicago, IL—Searching for ways toimprove outcomes and increase accessto molecular testing for patients withnon–small-cell lung cancer (NSCLC),investigators have shown that it is pos-sible to perform high-grade moleculartesting regularly for NSCLC in areacommunity hospitals that are not tiedto academic medical centers.

Some of the most effective drugs forthe treatment of NSCLC work optimal-ly only in patients with tumors thatcontain certain molecular biomarkers.Targeted therapies to treat NSCLCinclude erlotinib, which targets EGFR1(epidermal growth factor receptor 1),and crizotinib, which targets cancerswith a translocation in the anaplasticlymphoma kinase (ALK) gene.

“Because of advances in moleculartesting technologies for these bio-markers and the ease of doing thistest ing today in many laboratories,our research shows that state-of-the-

art personalized medicine is possiblein community hospitals, and not justin advanced academic medical cen-ters,” said lead investigator ThomasZander, MD, of University Hospital inCologne, Germany, and the NetworkGenomic Medicine Lung Cancer, aregional screening network in theCologne-Bonn region of Germany.

The Network Genomic MedicineLung Cancer was built for this study,which involved a number of commu-nity hospitals in the Cologne-Bonnregion of Germany that were not affil-iated with academic centers in 2010.

For the study, 77% of 1782 lungtumor samples collected from biopsiesin community hospitals were shippedto a laboratory to be tested for themolecular features mentioned above.

The molecular testing revealedKRAS mutations in 32% of the samples,EGFR mutations in 13%, and ALKmodifications in 3%; BRAF, ERBB2, and

PIK3CA mutations were each detectedin 2% of samples. Among patients withsquamous-cell cancer, FGFR1 amplifi-cation was detected in 15%.

Approximately 35% of cancers inpatients with NSCLC have known tar-getable lesions. Of the NSCLC samplesthat had genetic mutations, 40% couldbe managed with currently availabletargeted treatments. Crizotinib wasgiven to eligible patients with ALK

mutations. Erlotinib and similar drugswere administered to approximatelythree fourths of patients who hadEGFR modifications.

KRAS, BRAF, PIK3CA, ERBB2, andFGFR1 are all genetic markers that areexpected to influence NSCLC out-comes. Work is under way on investi-gational drugs to target these geneticmarkers as well.

Previously, genetic testing for any ofthese markers was usually offeredonly in academic medical centers, andaccess by patients in community hos-pitals was low. Of note, the cost ofoffering such testing in communityhospital settings is not overly prohibi-tive, according to Dr Zander. This costis equal to approximately 1 to 2 weeksof therapy in the United States.

“High-quality molecular diagnos-tics and a personalized treatment ap -proach lead to significant benefit forpatients,” he said. �

Chicago, IL—Based on the results of aphase 3 study, patients with advancedlung adenocarcinomas that harborepidermal growth factor receptor (EGFR)mutations experience extended pro-gression-free survival (PFS) whentreated with the investigational ErbBreceptor family blocker afatinib assingle-agent therapy compared withstandard chemotherapy.

The international trial, known asLUX-lung 3, showed that the use of afa-tinib, an ErbB family blocker of epider-mal growth factor, HER2, and ErbB4receptors, doubled PFS in most patientswho had 1 of the 2 prevalent EGFRmutation types, deletion 19 or L858R.

“With 4.2 months of PFS improve-ment in the overall population and 6.7months in patients with common muta-tions, afatinib is a clinically relevantfirst-line treatment option,” said leadinvestigator James Chih-Hsin Yang,MD, PhD, Professor at National TaiwanUniversity, Taipei, at ASCO 2012.

The randomized trial, the largest ofits kind to evaluate EGFR mutation–positive lung cancer, involved theevaluation of afatinib, comparing itagainst a recent first-line regimenoption for advanced but not yet treat-ed lung adenocarcinoma—combinedpemetrexed and cisplatin chemothera-

py. Unlike reversible EGFR (ErbB1)tyrosine kinase inhibitors, afatinib irre-versibly blocks the entire ErbB familyof receptors.

“By more broadly and effectivelyblocking the molecular pathways thatfacilitate the growth of these cancers,afatinib appears to be more potentthan other therapies,” said Dr Yang.“This new treatment could not onlyhelp patients live a longer period oftime without further cancer progres-sion, but because it’s given orally, itmay also require fewer visits to thedoctor’s office than standard chemo -therapy—another important quality oflife advantage.”

In the study, 345 patients were ran-domized to oral afatinib or standardcombination intravenous chemother-apy (pemetrexed and cisplatin) in a

2:1 ratio. Every patient had an EGFRmutation. Baseline traits were similarin the 2 study arms: 65% of patientswere female, 72% were Asian, 68%never smoked, and the median agewas 61 years.

After a median follow-up of 8months, afatinib delayed disease pro-gression by more than 4 months overstandard therapy (PFS, 11.1 months vs6.9 months, respectively). PFS wasdelayed further (13.6 months vs 6.9months, respectively) for 308 patients

with the more prevalent EGFR muta-tions—deletion 19 or L858R.

Common symptoms of lung cancer,such as cough and dyspnea, did notoccur as quickly (40% delay) inpatients taking afatinib comparedwith those receiving chemotherapy,said Dr Yang.

He noted that adverse events were“as expected” with EGFR inhibition,consistent with earlier studies, andwere manageable, reversible, andpredictable.

Adverse events related to the drugsincluded diarrhea (95%), rash/acne(62%), and paronychia (57%) with afa-tinib, and nausea (66%), reducedappetite (53%), and vomiting (42%)with combination chemotherapy. Theseadverse events led to an 8% discontinu-ation rate among study patients.

Patients who received afatinib expe-rienced greater tumor shrinkage thanthose who received the standardchemotherapy, according to Dr Yang.The response rate for people whoreceived afatinib was 56%, and in thoseassigned to chemotherapy it was 23%.

On a questionnaire to assess qualityof life, patients randomized to afatinibrated their quality of life in overallhealth status higher than those receiv-ing chemotherapy.—WK �

Non–Small-Cell Lung Cancer Testing Can Be OfferedRoutinely in Community HospitalsBy Wayne Kuznar

Afatinib Boosts PFS in EGFRMutation–Positive Lung CancerNew irreversible ErbB receptor blocker seems more potent than other therapies

“This new treatment could not onlyhelp patients live a longer period oftime without further cancerprogression, but because it’s givenorally, it may also require fewer visitsto the doctor’s office than standardchemotherapy—another importantquality of life advantage.”

—James Chih-Hsin Yang, MD, PhD

“Our research shows thatstate-of-the-art personalizedmedicine is possible incommunity hospitals, andnot just in advancedacademic medical centers.”

—Thomas Zander, MD

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17www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Chicago, IL—Abiraterone acetate(Zytiga) delays disease progressionwhen used with prednisone beforechemotherapy in men with metastaticcastration-resistant prostate cancer,said Charles J. Ryan, MD, AssociateProfessor of Clinical Med icine, HelenDiller Family Compre hensive CancerCenter at the University of California,San Fran cisco, who reported a plannedinterim analysis of a phase 3 study atASCO 2012.

The finding represents a potentialnew use of abiraterone in prostate cancer; the drug is now approved only for men with metastatic castra-tion-resistant prostate cancer in whomdo cetaxel (Taxo tere) chemo therapyhas failed.

“These data merit consideration asproviding a new standard approach in this highly prevalent populationfaced with an unmet medical need,”said Dr Ryan.

The trial included 1088 men withmetastatic castration-resistant prostatecancer that was no longer responsiveto hormonal therapy. The men were

randomized to abiraterone plus pred-nisone or to placebo plus prednisone.

The trial was terminated early, with43% of total events reported, given thefavorable response on overall survival(OS) and progression-free survival

(PFS) observed with abiraterone. Atthis point, the Independent DataMonitoring Committee recommendedun blinding the study and offering theplacebo recipients active treatmentwith abiraterone.

The median survival in this studywas 14.8 months, with an improve-ment of 3.9 months over the pred-

nisone control arm, “thus reflecting theadvanced clinical stage of the popula-tion tested,” said Dr Ryan.

“A reality is that much of the life ofa patient with metastatic castration-resistant prostate cancer is lived beforechemotherapy, and, in fact, a large pro-portion of patients never receive it,”Dr Ryan stated in explaining therationale for studying abiraterone inchemotherapy-naïve patients.

There was a 57% improvement inradiographic PFS, a coprimary endpoint, in men randomized to abir -aterone. The median time to progres-sion was 8.3 months in the controlgroup, but the median time to PFS hadnot yet been reached in the abir ateronegroup at the time the trial was sus -pended. “This represents an approx -imate doubling of the radio graphicprogression-free survival,” he said.

The median survival in the pred-nisone control arm was 27.2 months,whereas the median survival had notyet been reached in the abirateronearm, which conforms to a 25%improvement in survival, “a strong

trend in favor of abiraterone,” Dr Ryanpointed out. This trend did not reachstatistical significance because of theearly termination of the trial.

Some 60.3% of the prednisone con-trol group required additional thera-pies for prostate cancer, including do -cetaxel (the most common subsequenttreatment) compared with only 44.3%of the abir aterone arm.

Abiraterone significantly de layedthe time (by 31%) before patients need-ed opiates to control pain and the time(by 42%) to initiate chemotherapy.

Susan Halabi, PhD, Associate Pro -fessor of Biostatistics and Bio infor -matics at Duke University MedicalCenter, Durham, NC, said that althoughthe study represents the first to showactivity of abiraterone in chemothera-py-naïve patients, she questionedearly termination of the trial, beforethe difference in OS observed withabiraterone could achieve statisticalsignificance.

Never theless, the survival benefitwith abiraterone is most likely real,she said.—WK �

Abiraterone Before Chemotherapy a Successful Strategy in Prostate Cancer

“These data meritconsideration as providing anew standard approach inthis highly prevalentpopulation faced with anunmet medical need.”

—Charles J. Ryan, MD

Prostate Cancer

Chicago, IL—The novel androgenreceptor–signaling inhibitor enzalu-tamide, also known as MDV3100, sig-nificantly prolonged overall survival(OS), slowed disease progression, andimproved quality-of-life (QOL) meas-ures in men with castration-resistantprostate cancer after docetaxel failure,according to results from a large phase3 clinical trial.

In this double-blind, randomizedtrial, OS improved from 13.6 monthsin the placebo group to 18.4 monthsin the enzalutamide group, for a 37%reduction in the risk of death, saidJohann S. de Bono, MB, ChB, MSc, PhD,of the Institute of Cancer Research andthe Royal Marsden National HealthService Foundation Trust, UnitedKingdom, at ASCO 2012.

“I think these are the best survivaldata we’ve seen in the postchemother-apy setting,” Dr de Bono said.

A total of 1199 patients with castra-tion-resistant prostate cancer who hadreceived docetaxel-based chemother-apy were randomized in a 2:1 ratioto daily enzalutamide or to placebo.Therapy was continued through minorchanges in prostate-specific antigen

(PSA) level. Treatment with glucocorti-coids was allowed but not required.

More than 25% of patients had soft-tissue disease involving the liver or thelung. More than 90% of patients hadbone metastases. Approximately 50%of the patients in each arm had ≥3 pre-vious lines of hormonal drug therapy.

The trial was unblinded early afterthe independent data monitoring com-mittee determined that the risk-to-ben-efit ratio with MDV3100 was favor-able; eligible patients in the placeboarm were offered treatment with enza-lutamide.

With a median follow-up of 14.4months, enzalutamide conferred a sur-vival advantage across all identifiedsubgroups.

“Impressively, enzalutamide had avery high PSA response rate,” said Drde Bono. With enzalutamide, 25% ofpatients had a >90% fall in PSA levelcompared with only 1% with placebo.

“I never thought I’d see a 50% and90% fall in PSA in this population ofpatients, with 54% of patients having amore than 50% confirmed PSA fall,”Dr de Bono said.

All of the secondary end points in

the study favored the treatment arm.PSA progression-free survival (PFS)was extended from 3.0 months in theplacebo group to 8.3 months in theenzalutamide group. Similarly, theradiographic PFS was 2.9 months inthe placebo group and 8.3 months inthe enzalutamide group, for a hazard

ratio of 0.40 in favor of enzalutamide.Objective response rates (complete

and partial) based on the ResponseEvaluation Criteria in Solid Tumors(RECIST) trial were 3.8% in the place-bo arm and 28.9% in the enzalu-tamide arm.

The time to a first skeletal eventwas again superior in the enzalu-tamide arm (16.7 months) comparedwith the placebo arm (13.3 months)—a 38% reduction in the risk of a skele-tal-related event.

QOL responses as measured by theFunctional Assessment of CancerTherapy-Prostate (FACT-P) were alsosuperior with enzalutamide. In thatgroup, 43.2% had at least a 10-pointincrease in the overall FACT-P scorecompared with 18.3% in the placebogroup.

A smaller proportion of patientstreated with enzalutamide had grade≥3 adverse events (AEs) comparedwith placebo (45.3% vs 53.1%, respec-tively). Serious AEs also occurred at alower rate with enzalutamide thanplacebo (28.4% vs 33.6%). Seizure rateswere 0.6% with enzalutamide and 0%with placebo. �

New Androgen Receptor–Signaling Inhibitor ExtendsSurvival, Improves QOL in Advanced Prostate CancerBy Wayne Kuznar

“These arethe bestsurvivaldata we’veseen in the

postchemotherapy setting.Impressively, enzalutamidehad a very high PSAresponse rate. I neverthought I’d see a 50% and90% fall in PSA in thispopulation of patients.”

—Johann S. de Bono, MB, ChB,MSc, PhD

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VOL. 5 NO. 5 SPECIAL ISSUE18 AMERICAN HEALTH & DRUG BENEFITS August 2012

Prostate Cancer

Agent that Targets Heat Shock Protein Shows Activity in Castration-Resistant Prostate CancerBy Wayne Kuznar

Chicago, IL—OGX-427, a second-generation investigational antisensecompound that targets heat shockprotein-27 (Hsp-27), is well tolerated,and when combined with prednisonein patients with chemotherapy-naivemetastatic castration-resistant pros -tate cancer (CRPC), it reduces diseaseprogression compared with pred-nisone alone.

In a recent clinical study, morepatients who took OGX-427 plus pred-nisone were without disease progres-sion at 12 weeks and more haddeclines in levels of prostate-specificantigen (PSA) compared with thosetaking prednisone alone, reported KimChi, MD, medical oncologist andAssociate Professor of Medicine at BCCancer Agency, British Columbia,Canada, and the primary study inves-tigator, at ASCO 2012.

Hsp-27 is a cell-survival proteinexpressed in many types of cancers.Overexpression of Hsp-27 is thoughtto be an important factor leading to thedevelopment of treatment resistanceand is correlated with a poorer prog-nosis in patients with various tumor

types. “It also increases after castrationtherapy as a stress survival responseand is shown to be overexpressedhighly in metastatic CRPC tissues,”said Dr Chi.

Of 72 planned patients, 64 have beenrandomized to the study, and data on42 patients (22 who received OGX-427plus prednisone, and 20 who receivedprednisone alone) are now available ator beyond the 12-week assessmenttime point.

The median treatment duration is24 weeks in the OGX-427 plus pred-nisone arm versus 14 weeks in theprednisone alone arm. Treatment isongoing in approximately 30% ofpatients in each arm. Of the 14patients in the prednisone alone arm

who have come off treatment, 13 havedone so because of disease progres-sion, said Dr Chi. For this reason, 10of the 20 patients in the prednisonealone arm crossed over to the OGX-427 plus prednisone arm.

The primary efficacy end point inthe study was progression-free sur-vival (PFS) at 12 weeks. Disease pro-gression is based on any of the follow-ing parameters: PSA levels, measurabledisease, bone lesions, global deteriora-tion, or a requirement for palliativeradiation therapy.

In the OGX-427 plus prednisone arm,PFS was 71% at 12 weeks comparedwith 40% in the prednisone alone arm.A ≥50% decline in PSA was experienced

by 50% of patients who were random-ized to OGX-427 plus prednisone, ver-sus 20% of patients who were random-ized to prednisone alone.

Among the 21 patients with baselinemeasurable disease, 44% (4 of 9) in theOGX-427 plus prednisone arm had ameasurable disease response com-pared with 0% (0 of 12) in the pred-nisone alone arm.

There was 1 complete response in theOGX-427 plus prednisone arm. “Thishas lasted for almost a year, and he stillhas not progressed,” said Dr Chi.

Circulating tumor cells declinedfrom ≥5/7.5 mL to <5/7.5 mL in 55%of patients receiving OGX-427 plusprednisone compared with 41% in theprednisone alone group.

Adverse events have been predo m -inantly grade 1 to 2 and related toinfusion reactions. “These are pre-dominantly in the first couple of infu-sions; patients tend to build tolerance,and the reactions are brief and self-limited,” he said. There were 3 grade4 adverse events reported, includingdizziness, pulmonary embolus, and 1case of hemolytic uremic syndrome. �

In the OGX-427 plusprednisone arm, progression-free survival was 71% at 12weeks compared with 40%in the prednisone alone arm.

Chicago, IL—A genomic test per-formed on a biopsy specimen thatwould discriminate between aggres-sive and indolent prostate cancer is astep closer to reality.

The goal of the test is to help guidetreatment decisions at the time ofprostate cancer diagnosis by lookingat the gene expression profile of thetumor biopsy, said Eric A. Klein, MD,Chair of the Glickman Urologicaland Kidney Institute, the ClevelandClinic (which is collaborating withGenomic Health to develop the test),at ASCO 2012.

Previous work by Dr Klein and col-leagues showed that a number ofgenes that were strongly associatedwith clinical recurrence, prostate can-cer death, and adverse pathologycould be identified from radicalprostatectomy specimens.

The current gene refinement studypresented by Dr Klein demonstratesthat these genes can predict adversepathology at the time of diagnosis by

quantitative assays performed onbiopsy-tissue tumor specimens.

The expression of these genes pro-vides risk information beyond thatobtained from traditional pathological

and clinical assessments (ie, biopsyGleason grade, level of prostate-specif-ic antigen [PSA], clinical stage), DrKlein noted.

“What we’ve learned is that if youmeasure the expression of a specificset of genes on a biopsy, you can pre-dict the likelihood that someone willhave an indolent course versus some-one who won’t,” he said. “We thinkthat the gene expression profile canhelp reveal patients with apparent‘low-risk’ disease who in fact haveaggressive tumors that are not identi-fied by the biopsy grade, clinicalstage, or PSA.”

The limited tissue sampled withprostate needle biopsies had been achallenge in the development of agenomic test in localized prostatecancer.

Radical prostatectomy specimensfrom 441 patients with localizedprostate cancer (low-to-intermediaterisk by American Urological Associa -tion criteria) were first used to identi-

fy 374 prognostic genes. The expres-sion of a subset of these genes and 5reference genes was quantified byreal-time polymerase chain reactionperformed on prostate tumor tissueobtained through needle biopsy.

“Predictive genes from the geneidentification study also predictedadverse pathology when assayed inbiopsy tumor tissue,” Dr Klein said.

Of the 81 genes evaluated in thebiopsy study, 58 (72%) predictedhigh-grade and/or nonorgan-con-fined disease.

The overexpression of androgen andcellular organization genes consistent-ly predicted lower risk, whereas theoverexpression of stromal responseand proliferation genes predictedhigher risk.

Dr Klein suggested that the testwould include approximately 20prognostic genes and will be validat-ed in an independent, prospectivelyde signed study of prostate biop-sies.—WK �

A Promising New Gene Test to Differentiate BetweenAggressive and Indolent Disease

“The geneexpressionprofile canhelp revealpatientswithapparent

‘low-risk’ disease who in facthave aggressive tumors thatare not identified by thebiopsy grade, clinical stage,or PSA.” —Eric A. Klein, MD

There was 1 completeresponse in the OGX-427 plusprednisone arm. “This haslasted for almost a year, andhe still has not progressed.”

—Kim Chi, MD

“Better informed teams provide better care.”

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VOL. 5 NO. 5 SPECIAL ISSUE20 AMERICAN HEALTH & DRUG BENEFITS August 2012

Renal-Cell Carcinoma

whether the drug’s toxicity would besignificant enough to make patientswant to continue treatment with eitherdrug or to switch therapy.

A total of 126 patients completed apreference questionnaire. In the pri-mary analysis, 70% of the patients pre-ferred pazopanib, 22% preferred suni-tinib, and 8% cited no preference. Afteradjustments for a modest sequenceeffect, the difference in preference was49% in favor of pazopanib. All otheranalyses showed a significant prefer-ence for pazopanib.

The most common reasons givenfor pazopanib preference were betterQOL and less fatigue. Patients taking

pazopanib had fewer dose reductionsthan those taking sunitinib (13% vs20%, respectively) and fewer treat-

ment interruptions (6% vs 12%,respectively). Ad verse events (AEs)were compatible with known profilesfor both drugs.

The researchers, led by Bernard J.Escudier, MD, from the InstitutGustave Roussy, Villejuif, France, saidthat they expected patients to preferone drug over the other because ofadverse effects, but “we didn’t everexpect such a big difference betweenthe 2 drugs.”

Physicians may perceive toxicity dif-ferences between 2 different therapiesas relatively minor, but to patients, evenlow-grade toxicities over a long periodhave a significant effect on QOL,

according to Dr Escudier and col-leagues. How patients feel when theytake a drug over many months is notreflected in traditional AE reporting.

A survey on physician therapy pref-erences, which was a secondary endpoint in this study, showed some dif-ference in physicians’ drug prefer-ences: 60% preferred pazopanib, 21%preferred sunitinib, and 21% had nopreference.

Patient-reported outcomes are in -creasingly being added to traditionalefficacy outcomes to better under-stand the clinical relevance of differ-ences in drug toxicities, Dr Escudierand colleagues noted. �

Quality of Life Drives Patient Preference... Continued from page 1

“We didn’tever expectsuch a bigdifferencebetween the2 drugs.”

—Bernard J. Escudier, MD

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Chicago, IL—In men with metastaticprostate cancer, especially those withminimal disease spread, continuousrather than intermittent hormonaltherapy should be considered the pre-ferred therapy, according to the resultsof a large multicenter phase 3 interna-tional trial.

In these men, the difference in medi-an survival favoring continuous thera-py was approximately 2 years, saidlead investigator Maha H. Hussain,MD, Professor of Medicine andUrology, University of MichiganComprehensive Cancer Center, AnnArbor, who presented the data at the2012 meeting of the American Societyof Clinical Oncology.

Continuous androgen deprivationtherapy has been the standard of carefor men with metastatic hormone-sensitive prostate cancer. In an effort tocurb side effects from hormone thera-py, such as loss of libido, weight gain,loss of muscle, and hot flashes, someoncologists have used intermittenthormone therapy with the belief thatefficacy would not be affected.

Early clinical trials showed thatintermittent therapy was feasible andmay be associated with an improve-ment in quality of life. Based on thesetrials, there was broad acceptance of intermittent therapy by patients,physicians, and insurers.

But the present study’s findings“clearly demonstrate that intermittent

hormonal therapy is not safe for allpatients with metastatic prostate can-cer,” said Dr Hussain.

She noted that these data are prac-tice changing. “This finding is strikingand surprising, because it goes againstthe conventional belief based on all ofthe trials that have been done thusfar,” she pointed out.

The study, which was sponsored bythe National Cancer Institute, included1535 patients with newly diagnosedhormone-sensitive metastatic prostatecancer whose serum prostate-specific

antigen level declined to ≤4 ng/mLafter 7 months of continuous hormon-al therapy with goserelin acetate incombination with bicalutamide. Afterstratifying them by disease extent, thepatients were randomly assigned toreceive intermittent hormonal therapyor continuous hormonal therapy.

The median age of the patients was70 years. Approximately 50% hadextensive disease, and 50% had mini-mal disease.

After a median follow-up of 9.2years, median overall survival (OS)was 5.1 years in the group assigned to

intermittent therapy versus 5.8 yearsfor those assigned to continuous thera-py, for a hazard ratio (HR) of 1.09. ThisHR did not meet the prespecified defi-nition for noninferiority, because the

upper confidence interval for the rela-tive increase in the risk of death exceed-ed 20% (the trial was designed to showwhether intermittent therapy was non-inferior to continuous therapy). In thearm receiving continuous therapy, 42%of patients were still alive at 7 yearscompared with 38% of the arm ran-domized to intermittent therapy.

For men with minimal diseasespread, the difference in survivalbetween the 2 groups was evengreater. In this subset, median OS was5.2 years in those receiving intermit-tent therapy versus 7.1 years for thosewho received continuous therapy. TheHR for death with intermittent thera-py was 1.23, which again did not meetthe criterion for noninferiority.

Among men with more extensivedisease spread, median survival wassimilar in the 2 arms (5 years withintermittent vs 4.4 years with continu-ous therapy). There were no differ-ences in the rate of grade 4 treatment-emergent adverse events.

According to Bruce J. Roth, MD,Professor of Medicine in the Divisionof Oncology at Washington University,St Louis, “prior underpowered studiessuggested that there was no downsideto intermittent therapy. This studydemonstrates for the first time thatthere is a price to pay.” He noted thatpatients with minimal disease are theones who have been most likely toreceive intermittent therapy. �

In Head-to-Head Comparison, Continuous Beats IntermittentHormonal Therapy for Metastatic Prostate CancerBy Wayne Kuznar

Prostate Cancer

“Priorunderpoweredstudiessuggested thatthere was nodownside to

intermittent therapy. Thisstudy demonstrates for thefirst time that there is a priceto pay.” —Bruce J. Roth, MD

“This finding is striking andsurprising, because it goesagainst the conventionalbelief based on all of thetrials that have been donethus far.”

—Maha H. Hussain, MD P

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21www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Chicago, IL—Tivozanib, a potent in -vestigational tyrosine kinase inhibitorwith a long half-life, demonstratedsignificant improvement in progres-sion-free survival (PFS) as first-linetargeted therapy for metastatic renal-cell carcinoma (mRCC), according toresults from a phase 3 randomized,open-label trial.

The results suggest that “tivozanibshould be considered a first-line treat-ment option for metastatic RCC,” saidRobert Motzer, MD, an oncologist atMemorial Sloan-Kettering CancerCenter, New York, and the trial’s leadinvestigator.

Tivozanib targets all 3 vascularendothelial growth factor (VEGF)receptors and is designed to optimizeblockade while minimizing off-targettoxicities. The long half-life permitsonce-daily dosing.

Impressive phase 2 safety data fortivozanib warranted a phase 3 trialcomparing tivozanib with sorafenib inpatients with mRCC as first-line, tar-geted therapy.

The study included 517 patientswith mRCC, who were randomized to

tivozanib once daily for 3 weeks (fol-lowed by 1 week of rest) or sorafenibtwice daily continuously in a 4-weekcycle. Patients were either treatment-naive or had received no more than 1prior systemic therapy for metastaticdisease. Treatment continued until

disease progression or intolerance.Patients randomized to the soraf -

enib arm were eligible to cross over totivozanib therapy under a separateprotocol after radiographic confirma-tion of disease progression, and manyof them did. No crossover protocolwas available for patients randomizedto the tivozanib arm.

In the overall study population,tivozanib demonstrated significantimprovement in PFS compared withsorafenib (median, 11.9 months vs 9.1months) when assessed by an inde-pendent panel, correspond ing to a 21%improvement with tivozanib. Whenassessed by the investigators, the dif-ference in PFS between the 2 groupswas 14.7 months with tivozanib versus9.6 months for sorafenib. The efficacyadvantage of tivozanib was consistentacross all subgroups.

Among the 70% of treatment-naivepatients, median PFS was 12.7 monthswith tivozanib versus 9.1 months withsorafenib, and the objective responserate was 33% versus 23%, respectively.

The tolerability of tivozanib wasalso more favorable than sorafenib’s,

as evidenced by a low rate of doseinterruptions (17% vs 35%, respective-ly) and reductions (12% vs 43%,respectively).

Treatment-emergent adverse eventsoccurred in 90% of patients in bothgroups, although important differ-ences were seen in the safety profilebetween the 2 drugs.

According to Dr Motzer, althoughhypertension is the predominantadverse event with tivozanib, thedevelopment of hypertension is asso-ciated with tivozanib’s greater efficacyand potency for the VEGF receptor.The hypertension was treatable, re -quiring dose reduction in only 2% anddose discontinuation in only 1% of thepatients treated with tivozanib.

“There’s clear evidence that thephase 2 safety profile has indeed beenconfirmed in phase 3,” said coinves -tigator Tim Eisen, MD, Professor of Medical Oncology, CambridgeResearch Institute, United Kingdom.The data require more careful evalua-tion over the next several months to“exclude any hypertension-relatedcomplication risk,” he said. �

Tivozanib Outperforms Sorafenib as First-LineTreatment in Advanced Renal-Cell Carcinoma By Wayne Kuznar

“Tivozanib should beconsidered a first-linetreatment option formetastatic RCC.”

—Robert Motzer, MD

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Chicago, IL—Upward dose titration ofaxitinib in patients who tolerate thestarting dose may optimize drug expo-sure and improve the efficacy of thedrug as a first-line therapy for meta -s tatic renal-cell carcinoma (mRCC),said Brian I. Rini, MD, AssociateProfessor of Medicine at the ClevelandClinic, at ASCO 2012.

Axitinib is a potent, selective, sec-ond-generation inhibitor of vascularendothelial growth factor receptorswith demonstrated efficacy as second-line treatment for mRCC.

Patients who receive the 5-mg twice-daily starting dosage of axitinib exhibitvariable levels of drug exposure; retro-spective analyses of phase 2 clinical tri-als indicate that higher drug exposureto axitinib enhances its efficacy. “A sig-nificant percentage of patients haveexposure that is below what is consid-ered to be a therapeutic threshold,”said Dr Rini. After upward dose titra-tion, to 7 mg, or 10 mg twice daily,most patients achieve therapeuticdrug levels.

Patients who achieved a therapeuticdrug exposure in previous studies hadsuperior progression-free survival(PFS) compared with those who didnot achieve a therapeutic threshold.The improvement in PFS was nearlydouble in those who achieved thera-peutic drug exposure, Dr Rini said. Hespeculated that dose titration based ontolerability may improve outcomes.

This randomized, phase 2 clinicaltrial evaluated the efficacy and safetyof axitinib dose titration from the stan-dard 5-mg twice-daily dose to a maxi-mum of 10 mg twice daily.

A total of 203 patients with treat-ment-naive mRCC received axitinib, 5mg twice daily, for a 4-week lead-inperiod (cycle 1). Of these, 112 patientswith 2 consecutive weeks of bloodpressure (BP) ≤150/90 mm Hg (use of≤2 antihypertensives was allowed);no axitinib-related toxicities grade <2;and no dose reductions were random-ized in a double-blind fashion to axi-tinib 5 mg twice daily, followed bydose titration with axitinib (arm A) or

placebo (arm B). The 91 patients whodid not meet the randomization eligi-bility criteria continued to receive≤5 mg twice daily, based on drug toler-ance (arm C).

Tumor assessments were performedat screening; at weeks 8, 16, and 24;and every 12 weeks thereafter. A sub-set of patients underwent ambulatoryBP monitoring at baseline and againon days 4 and 15 of cycle 1.

A pooled analysis of blinded datafrom arms A and B (eligible for dosetitration) showed an objective re -sponse rate (ORR) of 43%; the ORR inarm C (not eligible for dose titration)

was 59%. The median PFS was 14.5months in arms A and B combined,and 16.4 months in arm C.

Therapeutic drug exposure wasachieved more often in arm C: theAUC12 was 234 ng·h/mL in arm C ver-sus 99 ng·h/mL in arms A and B com-bined.

Median PFS in patients with drugexposure above the therapeutic thresh-old on day 15 was 13.4 months com-pared with 11.0 in those with subther-apeutic exposure. Patients with meanincreases of diastolic BP ≥15 mm Hghad a higher ORR than those withdiastolic BP increases <15 mm Hg.The AUC12 was generally higher inthose with greater changes in BP, saidDr Rini.

The most common adverse eventswere hypertension, diarrhea, andfatigue.

“Axitinib is effective in the first-linetreatment of metastatic renal cell car-cinoma as evidenced by a long PFSand a high objective response rate,”Dr Rini said.—WK �

Axitinib Dose Titration Up Enhances Outcomes inMetastatic Renal-Cell Carcinoma

“Axitinib is effective in thefirst-line treatment ofmetastatic RCC as evidencedby a long PFS and a highobjective response rate.”

—Brian I. Rini, MD

VOL. 5 NO. 5 SPECIAL ISSUE22 AMERICAN HEALTH & DRUG BENEFITS August 2012

Renal-Cell Carcinoma

Chicago, IL—The list of choices forfirst-line pharmacologic therapy ofmetastatic renal-cell carcinoma (mRCC)is ever increasing. There are now 7approved targeted therapies againstthe vascular endothelial growth factor(VEGF) and mammalian target ofrapamycin (mTOR) pathways, saidDaniel Y.C. Heng, MD, MPH, ClinicalAssociate Professor, Tom Baker CancerCenter, University of Calgary, Alberta,Canada, at ASCO 2012.

Oral VEGF tyrosine kinase in -hibitors (TKIs), such as sunitinib andpazopanib, and intravenous (IV) anti-VEGF antibodies, such as bevacizu -mab (in combination with interferon[IFN]-alpha), used as first-line agents,have extended progression-free sur-vival (PFS) in patients with a favorableor intermediate prognosis in mRCC,said Dr Heng. Sorafenib is anotheroption, and axitinib has been used asa second-line therapy after treatmentwith a cytokine or a VEGF inhibitor.

In patients with a poor prognosis,the mTOR inhibitor temsirolimus plusIFN-alpha has been shown to improveoverall survival (OS) compared withIFN-alpha alone. Everolimus wasapproved by the US Food and DrugAdministration (FDA) in 2011, al -though it is used as second-line thera-py after a VEGF inhibitor.

However, no predictors of responseto targeted therapy are available; there-fore, the choice of therapy is usuallybased on the patient’s prognostic pro-file, physician preference, route of deliv-ery (IV or oral), physician experience,and drug efficacy and toxicity profiles.

For example, a patient with poor pul-monary function “might not be the bestmTOR candidate, simply because of therisk of noninfectious pneumonitis,” Dr

Heng said. Patients with refractory dia-betes are also not good candidates formTOR inhibitors, because of the risk forhyperglycemia, and those with refrac-

tory hypertension who are taking sev-eral antihypertensive medicationswould not be good candidates for aVEGF inhibitor, he noted.

Recent and Emerging Comparative

Clinical Trials

“Probably, the most important con-sideration is efficacy,” but no evidencefrom head-to-head efficacy trials existsso far, said Dr Heng, although some areemerging. Retrospective comparisonanalyses show that PFS is approximate-ly 7.2 months with sunitinib as first-linetherapy, 7.3 months with sorafenib, and6.0 months with bevacizumab.

“What this means is that it’s unclearif there is a difference in efficacy withfirst-line therapy, and clinical trialresults are greatly anticipated,” he said.

PISCES was a head-to-head clinicaltrial, but its primary end point waspatient preference at 22 weeks, nottreatment efficacy. PISCES comparedthe tolerability and toxicity level ofsunitinib followed by pazopanib ver-sus pazopanib followed by sunitinib inpatients with mRCC, focusing on

whether the differences in tolerabilitywere significant enough to determinepatient preference, a measure that isincreasingly being included in the

decision-making paradigm of treat-ment selection. Pazopanib was pre-ferred by 70% of patients, sunitinibwas preferred by 22% of patients, and

8% did not have a preference (see arti-cle on page 1).

Results from the phase 3, head-to-head clinical trial COMPARZ are high-ly anticipated. COMPARZ is an open-label study comparing sunitinib withpazopanib as first-line therapy forpatients with mRCC, with a primaryend point of PFS duration and sec-ondary end points include OS andquality of life.

The potent and specific TKI tivozanib,which is not yet FDA approved formRCC, demonstrated an improve-

ment in PFS as first-line targeted treat-ment compared with sorafenib inclear-cell mRCC (see article on page21). “Pending FDA approval, tivozanibwill probably be incorporated into thetreatment algorithm,” said Dr Heng.

The RECORD-3 clinical trial is com-paring 2 treatment sequences—suni-tinib followed by everolimus versuseverolimus followed by sunitinib inpatients with mRCC; the primary endpoint is PFS duration associated withthe first-line therapy. “This gives anindication of first-line VEGF versusmTOR efficacy and sequencing,” DrHeng said.

Indicators of Treatment Response

Although there are externally vali-dated predictive biomarkers inmRCC, recent studies have demon-strated that the development ofhypertension during the first cycle ofsunitinib therapy, as well as othertherapy-related toxicities (eg, hand-foot syndrome, hypothyroidism) areassociated with improved outcomes,but these are only helpful once thera-py is initiated; these effects do nothelp guide the choice of therapy.

The presence of certain single-nucleotide polymorphisms (SNPs)can serve as a biomarker that mayindicate improved patient outcomes,but SNPs, too, require validation. Inaddition, results obtained by examin-ing genetic profiles are currentlyrestricted to the Caucasian popula-tion, because there are substantialracial differences in SNPs.

Immunotherapy on the Horizon?

Immunotherapy with a pro-grammed death 1 (PD-1) inhibitorcould also be on the horizon, but clini-cal trials are in their early stages.Higher PD-1 ligand levels in patientswith RCC have been associated withlarger tumors, advanced-stage tumors,higher-grade tumors, and tumors withnecrosis. In a trial that included 18patients with RCC, the overall objectiveresponse rate in the 16 patients whowere treated with a 10-mg/kg dose ofthe investigational PD-1 inhibitor BMS-936558 was 31.2%, and the medianduration of response was 4.0 months.

An autologous dendritic-cell im -mun otherapy (AGS-003) was studiedwith sunitinib in 21 patients with RCC,with an overall response rate of 38%and a median PFS of 11.2 months; thisis encouraging, because almost half ofthese patients had poor prognosticprofiles. �

First-Line Treatments for Metastatic Renal-CellCarcinoma Are EvolvingBy Wayne Kuznar

“Pending FDA approval,tivozanib will probably beincorporated into thetreatment algorithm.”

—Daniel Y.C. Heng, MD, MPH

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“What this means is that it’s unclearif there is a difference in efficacy withfirst-line therapy, and clinical trialresults are greatly anticipated.”

—Daniel Y.C. Heng, MD, MPH

23www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Chicago, IL—The novel immuno -modulatory drug (IMiD) pomalido-mide showed strong activity inpatients with multiple myeloma whoare not responding to current thera-pies, said Irene Ghobrial, MD, medicalstaff member in the Myeloma Programof the Dana Farber Cancer Institute,and Associate Professor of Medicine,Harvard Medical School, Boston.

“As myeloma patients live longerand longer, they need new agents oftherapy, and pomalidomide may beone of those,” said Dr Ghobrial, whopresented the results of this phase 2clinical trial during ASCO 2012.

“This agent is showing responseseven in patients who are resistant tobortezomib or lenalidomide,” DrGhobrial said, noting that adding a newIMiD to the available treatment optionswill be especially critical for patientswith relapsed/refractory disease.

Pomalidomide plus Dexamethasone

Ravi Vij, MD, Associate Professor,Department of Medicine, OncologyDivision, Bone Marrow Transplanta -tion and Leukemia Section, Washing -

ton University School of Medicine, StLouis, MO, presented updated resultsof a phase 2 clinical trial of pomalido-mide in combination with low-dosedexamethasone in 221 patients resist-ant to lenalidomide, to bortezomib, or

to both. The pomalidomide/dexam-ethasone combination in duced respon -ses in heavily pretreated patients,including patients who had receivedstem-cell transplantation.

The overall response rate to thepomalidomide/dexamethasone com-bination was 30% compared with 9%with pomalidomide alone, after amedian (number) of 5 cycles and amedian (time) of 2 months. Three

quarters of patients achieved stabledisease or better. Median progression-free survival (PFS) was 3.5 months forthe whole group.

A 1-year overall survival (OS) wasreached by 59% of the patients, andmedian OS was similar (approximately14 months) between the 2 arms, Dr Vijreported. Patients who had relapsedafter stem-cell transplantation had amedian PFS of approximately 4 months.No severe cases of peripheral neuropa-thy were reported.

In June, a New Drug Applicationfor pomalidomide in combinationwith low-dose dexamethasone wassubmitted to the US Food and DrugAdministration.

Adding Clarithromycin to the Mix

Another phase 2 clinical trial evaluat-ed pomalidomide in combination withclarithromycin and dexamethasone(ClaPD) in 73 heavily pretreated pa -tients with relapsed/refractory myelo-ma. The antibiotic clarithro mycin hasbeen shown to enhance the anti -myeloma activity of pomalidomide/dexamethasone.

The overall response rate was 56%.Even among the patients whose dis-ease was refractory to lenalidomideand to bortezomib, the response ratewas 58%.

Median PFS was 7.5 months, and, ata median follow-up of 12 months, 85%of the patients were alive and 42%remained progression-free.

“Response to ClaPD is rapid, welltolerated, and sustained over 7 monthsin most subjects,” said Adriana C.Rossi, MS, MD, Clinical Fellow, He -ma tology/Oncology, Weill CornellMedical College, New York. “Thesedata support the clinical efficacy ofpomalidomide-based regimens inrelapsed/refractory myeloma.” �

First Oral Proteasome Inhibitor Active in MyelomaChicago, IL—The first oral protea-some inhibitor to enter clinical inves-tigation in multiple myeloma isMLN9708. The data from a phase 1clinical trial presented at ASCO 2012suggest that this drug encouragesdisease control and durability of re -sponses in heavily pretreated patientswith multiple myeloma.

MLN9708 is a potent, reversible, andspecific inhibitor of the 20S protea-some that is similar to bortezomib instructure but is associated with lessneurotoxicity, said lead investigatorSagar Lonial, MD, Professor and ViceChair of Clinical Affairs, Departmentof Hematology and Medical Oncologyof Winship Cancer Institute at EmoryUniversity, Atlanta, GA.

“MLN9708 is well tolerated, withinfrequent peripheral neuropathy andnone that is grade 3 or higher,” DrLonial said.

This study of twice-weekly dosingof the oral agent included 58 patientswho had received multiple prior linesof therapy. The primary aim was toassess tolerability and to determine theoptimal dose.

“Unlike many other trials, patients

received no concomitant cortico -steroids. This is a pure proteasomeinhibitor trial,” Dr Lonial noted.

Of the 53 evaluable patients, 6achieved a partial response or better,including 1 confirmed stringent com-plete response in the proteasomeinhibitor–naive expansion cohort.“Many of these responses are quitedurable,” Dr Lonial said.

Disease stabilization was observedin another 32 patients, and a numberof these are in the relapsed and refrac-tory cohorts, he added.

The most common drug-relatedevents were fatigue (45%) and throm-bocytopenia (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 withbortezomib. You see that the baselineplatelet count increases among re -sponses, and it is not cumulative,” DrLonial observed.

“A major difference between thisdrug and bortezomib is that peripheralneuropathy is significantly lower,10%,” Dr Lonial said. “My longestpatient on study had developed grade3 neuropathy on bortezomib and hasbeen responding to MLN9708 with noneuropathy for over a year now.”

Discontinuations resulting fromadverse events were required in 12% ofpatients, predominantly because ofthrombocytopenia, pulmonary hy -pertension, pneumonia, orthostatichypotension, and pruritic rash, as wellas spinal cord compression and bonepain as a result of progressive disease.

Irene Ghobrial, MD, medical staffmember in the Myeloma Program ofthe Dana Farber Cancer Institute, andAssociate Professor of Medicine, Har -vard Medical School, Boston, discussedthe findings for the MLN9708 study atthe multiple myeloma oral session.

“In this population of heavily pre-treated patients given MLN9708 as asingle agent, the overall response rate

was 11%; 2 patients also had a mini-mal response, and many had stabledisease. This is the first oral protea-some inhibitor to be tested. We arenow looking at second-generationagents showing activity and less neu-ropathy and potentially greater con-venience. We know if we take theseupfront and put them in combinationwith im muno modulatory drugs andsteroids, we will see higher respons-es,” she said.—CH �

Multiple Myeloma

Pomalidomide Shows Strong Activity in Relapsed/Refractory MyelomaBy Caroline Helwick

“This agent [pomalidomide]is showing responses even inpatients who are resistant tobortezomib or lenalidomide.”

—Irene Ghobrial, MD

“Unlike many other trials,patients received noconcomitant corticosteroids.This is a pure proteasomeinhibitor trial.”

—Sagar Lonial, MD,

“Response to ClaPD is rapid,well tolerated, and sustainedover 7 months in mostsubjects.”

—Adriana C. Rossi, MS, MD

“This is the first oralproteasome inhibitor to betested. We are now lookingat second-generation agentsshowing activity and lessneuropathy and potentiallygreater convenience.”

—Irene Ghobrial, MD

VOL. 5 NO. 5 SPECIAL ISSUE24 AMERICAN HEALTH & DRUG BENEFITS August 2012

Leukemia

Chicago, IL—The treatment of chroniclymphocytic leukemia (CLL) is becom-ing more personalized and more effec-tive as prognostic markers are refinedand as agents with novel mechanismsof action show robust activity.

CLL is a heterogeneous entity.Although some patients live for 10years or more, others die within 1 year.The Rai staging system stratifiespatients based on blood counts andsymptoms, but this system does notreflect the variability in disease aggres-siveness. Thus, the ability to determineprognosis and predict response totreatment is an important goal in CLLresearch, said Neil E. Kay, MD, of theMayo Clinic, Rochester, MN, at the2012 ASCO meeting.

Newer molecular-based prognosticfactors have been established that canstrongly predict CLL disease progres-sion, such as chromosomal deletionsand alterations (17p deletion and 11qdeletion are common ones), and theexpression of cell-surface markers suchas CD38 and ZAP-70. These prognosticparameters, which can usually be deter-mined at the time of diagnosis, can helpdefine risk categories upon diagnosis.

Risk models that incorporate bothconventional and novel prognostic fac-tors have been developed, and thesecan predict disease progression andoverall survival. They will, therefore,be useful in risk-stratifying patientswith early-stage disease, Dr Kay said.

Promising Drugs for CLL

There is a clear unmet need for moreeffective therapies in CLL, said PeterHillmen, PhD, of St. James’s Uni -versity Hospital, West Yorkshire,United Kingdom. Current regimens,which are not molecularly targeted,are associated with significant toxicityand are especially hard on elderlypatients. Moreover, these regimenstypically do not lead to true completeremissions; leukemic cells becomeresistant and the disease relapses.

An effective treatment should targetthe disease pathophysiologically, DrHillmen said, as imatinib does forchronic myelogenous leukemia. There -fore, much emphasis is being placedon understanding the molecular andgenetic profiles of CLL, to guide drugdevelopment. Among the promisingnew approaches to CLL are:• The immunomodulatory drug lena -

lidomide, which shows immune-mediated effects and also direct anti-tumor activity against CLL cells; ithas been studied as a single agent

and in combination with rituximab• PI3 kinase-delta inhibitor GS-1101,

an orally available small-moleculeinhibitor that has substantial anti -tumor activity in refractory disease

• Ibrutinib (PCI-32765), an orally avail-able selective inhibitor of Bruton’styrosine kinase (Btk). The combina-tion of ibrutinib, bendamustine, andrituximab has produced responserates exceeding 90% in patients withrelapsed/refractory CLL

• Bcl-2 (anti-apoptosis) inhibitors,such as navitoclax (ABT-263) andGDC-0199.

Btk Inhibitor Shows Strong Activity

In an update of a study that madenews at the American Society ofHematology 2011 meeting, the Btkinhibitor ibrutinib produced highresponse rates in treatment-naivepatients with CLL. In a related studyby the same investigators, ibrutinibwas combined with ofatumumab, ananti-CD20 monoclonal antibody.

This oral agent is the first drugdesigned to target Btk, a protein that iscritical for B-cell receptor signaling inB lymphocytes and essential for cellsurvival and proliferation in CLL.

This single-agent phase 2 clinicaltrial included 31 patients with previ-ously untreated disease. The overallresponse rate was 75%, including 10%complete and 65% partial responseswith daily dosing. The rate of progres-

sion-free survival at 15 months was96%. Investigators had previouslyreported on the cohort of treatment-refractory patients, 70% of whomresponded to the novel drug.

“All subgroups responded equallywell. Overall, the great majority ofpatients gained benefit from this ther-apy,” said John C. Byrd, MD, of OhioState University, Columbus. “Thisdrug is like red wine. With time, it getsbetter. Responses increase, and manypatients are still in follow-up. The con-tinued daily dosing was well tolerated,which allows for extended treatment.”

Samantha Jaglowski, MD, also ofOhio State University, reported thatthe combination of ibrutinib and ofatu-mumab produced a 100% responserate in 27 patients with relapsed/refractory CLL and related diseases. At6.5-month follow-up, only 2 patientshave progressed. “The rapid onset ofresponse, low relapse rate, and favor-able safety profile make this noncyto-toxic combination worthy of furtherstudy,” she said.

Constantine S. Tam, MBBS, MD, StVincent’s Hospital, Melbourne, Aus -tralia, commented on these findings,“There is a long list of novel agents inchronic lymphocytic leukemia. I thinksome of the most promising are thosetargeting the B-cell receptor pathway.”He added that this group of drugs isgoing to completely change how wemanage CLL. �

Chicago, IL—The phase 3 clinical trialStiL NHL1 demonstrated that thecombination of bendamustine plusrituximab (BR) delays progression innon-Hodgkin lymphoma (NHL) long -er than standard treatment withcyclophosphamide-doxorubicin HCl-vincristine sulfate-prednisone chemo -therapy plus rituximab (R-CHOP).

In this multicenter trial, BR morethan doubled the median progression-free survival (PFS) compared with R-CHOP, reported Mathias J. Rummel,MD, PhD, Head of Hematology, Uni -versity Hospital in Giessen, Germany,at a plenary session at ASCO 2012.

“BR is not only less toxic but alsomore effective than the most-often-used first-line approach and should beconsidered a preferred first-line treat-ment for these patients,” he said.

Bendamustine is approved for chron-

ic lymphocytic leukemia and as a sec-ond-line therapy for rituximab-refrac-tory NHL, but US oncologists have notyet fully adopted this regimen, despitepositive results presented at the 2009American Society of Hematology meet-ing, which led to its approval in theUnited States. BR is listed as a recom-mended regimen by the NationalComprehensive Cancer Network.

The StiL NHL1 Trial Details

A total of 549 patients with a newdiagnosis of stage III or IV indolentNHL were randomized to standardR-CHOP or to BR. After a median fol-low-up of 45 months, the median PFSwas 69.5 months with BR versus 31.2months with R-CHOP, a 42% reduc-tion in the risk of progression (P<.001). The PFS benefit offered by BRwas seen across all subgroups, except

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

Dr Rummel explained that the lackof difference in OS is not unexpected,since patients with indolent lym-phoma live a long time. Also, manyin the R-CHOP arm crossed over to

receive BR when their disease pro-gressed, which dilutes a survival dif-ference between the arms. BR alsowas associated with significantly lesstoxicity, with only skin toxicity beingmore common with this simpler regi-men, he added.

Michael E. Williams, MD, Chief ofHematologic Malignancies at theUniversity of Virginia Cancer Center,Charlottesville, discussed the findings.“BR provides equivalent or betterresponses versus R-CHOP, and withless toxicity,” he said. “StiL NHL1establishes BR as a front line regimenfor indolent B-cell NHL and non–transplant-eligible mantle-cell lym-phoma patients.”

Studies of this regimen are ongoing.The StiL NHL 7-2008 trial will evaluatedata on the effect of rituximab mainte-nance after BR treatment.—CH �

Novel Agents Will Completely Change CLL TreatmentBy Caroline Helwick

Bendamustine Outperforms R-CHOP in NHL

The combination of ibrutinib,bendamustine, and rituximabhas produced response ratesexceeding 90% in patientswith relapsed/refractory CLL.

“BR is not only less toxic butalso more effective than themost-often-used first-lineapproach and should beconsidered a preferred first-line treatment.”

—Mathias J. Rummel, MD, PhD

Lymphoma

25www.AHDBonline.comVOL. 5 NO. 5 SPECIAL ISSUE

Chicago, IL—ASCO 2012 was repletewith data on emerging therapies cur-rently in development. The key find-ings presented at the meeting are sum-marized below.

Breast Cancer

Trastuzumab emtansine, betterknown as T-DM1, is a novel, intra-venous antibody-drug conjugate thathas reduced the risk of disease pro-gression by 35% in previously treatedpatients with HER2-positive metastat-ic breast cancer in the clinical trialEMILIA. In this study, median overallsurvival (OS) was not reached withT-DM1 and was 23.3 months withcapecitabine plus lapatinib, for a 38%reduction (P <.001) in mortality risk(see article on page 1).

Prostate Cancer

Enzalutamide (MDV3100), whenused in men with castration-resistantprostate cancer who have failed doce -taxel therapy, improved the OS byalmost 5 months over placebo andslowed disease progression (see articleon page 17).

OGX-427, a new agent that targetsheat shock protein-27, when used incombination with prednisone, im -proved the progression-free survival(PFS) from 40% to 71% compared withprednisone alone in patients withchemotherapy-naive metastatic castra-tion-resistant prostate cancer (see arti-cle on page 18).

Renal-Cell Carcinoma

Tivozanib, a potent and specifictyrosine kinase inhibitor (TKI), im -proved the PFS by almost 3 monthscompared with sorafenib when usedas a first-line targeted treatment forclear-cell metastatic renal-cell carcino-ma (see article on page 21).

Lung Cancer

Afatinib, an ErbB receptor familyblocker used as single-agent therapy,extended PFS by 4.2 months comparedwith pemetrexed and cisplatin chemo -therapy in patients with advancedlung adenocarcinomas harboring theepidermal growth factor (see article onpage 16).

LDK378, an investigational anaplas-tic lymphoma kinase (ALK) inhibitor,showed substantial clinical activity inpatients with ALK-positive non–small-cell lung cancer (NSCLC), with an over-all response rate of 81% in patients withNSCLC who were previously treatedwith the ALK inhibitor crizotinib.

Aflibercept, a novel agent that “traps”vascular endothelial growth factor,

when added to standard topotecantreatment in patients with small-celllung cancer, slowed disease progressionin a phase 2 clinical trial. The additionof aflibercept to topotecan increasedthe 3-month PFS rate to 27% comparedwith 10% with topotecan alone; how-ever, the median PFS remained only1.4 months in each group.

GIST and CRC

Regorafenib, an orally administeredTKI, showed robust activity inchemorefractory metastatic colorectalcancer (mCRC) and gastrointestinalstromal tumors (GISTs). In the treat-ment-refractory GIST population ofthe GRID phase 3 clinical trial, themedian PFS reached 4.8 months withregorafenib but was only 0.9 months inthe placebo arm, for a 73% reduction inrisk (see article on page 11).

In patients with treatment-refrac -tory mCRC in the phase 3 clinical trialCORRECT, regorafenib extended theOS to 6.6 months versus 5.5 monthswith placebo, for a 23% reduction inrisk (see article on page 11).

In patients with mCRC, afliberceptplus chemotherapy had a safety pro-file that was similar to that in patientswho had never received bevacizu -mab, according to a subanalysis ofVELOUR, a phase 3 clinical trial,which compared patients who hadreceived previous bevacizumab treat-ment and those who did not.Aflibercept plus chemotherapy pro-longed the PFS to almost the samedegree in patients who received beva-cizumab in the past and those whohad not. In a previous report, the regi-men of aflibercept plus chemotherapywas associated with significant im -provements in PFS and OS.

Anti–PD-1/PD-L1 in Solid Tumors

Treatments directed against pro-grammed death 1 (PD-1) protein—amediator of immunosuppression—and one of its ligands (PD-L1) inducedtumor regression in patients with lungcancer, melanoma, and renal-cell carci-noma. Nearly 300 adults with ad -vanced cancers were treated withanti–PD-1 antibody for up to 2 years.Objective tumor responses were seenin 18% of patients with NSCLC, 28% ofpatients with melanoma, and 27% ofthose with renal-cell carcinoma. Morethan half of the responses lasted ≥1year. Another clinical trial with 200patients who were treated with theanti–PD-L1 antibody showed objec-tive responses in melanoma, lung can-cer, and renal-cell carcinoma, as well asovarian cancer.

Leukemia

Inotuzumab ozogamicin, an anti-CD22 monoclonal antibody, produceda high response rate (52%) in heavilypretreated patients with relapsed orrefractory acute lymphocytic leukemia.Of the 27 evaluable patients, 3 patientsshowed complete remission (CR), 8patients had CR except for plateletrecovery, and 3 patients showed CR inthe bone marrow only. The medianPFS was 5 months, and the median OSwas 7 months.

In a phase 2 clinical trial of 31 treat-ment-naive patients with chroniclymphocytic leukemia (CLL), contin-ued daily dosing with ibrutinib pro-duced an overall response rate of75%, including 10% CR and 65% par-tial response rates; the PFS was 96% at15 months. This oral agent is the firstdrug designed to target Btk (Bruton’styrosine kinase), a protein that isessential for CLL cell survival andproliferation.

Blinatumomab, an anti-CD19 bispe-cific T-cell engager (BiTE) antibody,produced responses in a phase 2 clini-cal trial in 72% of patients withrelapsed or refractory B-precursoracute lymphocytic leukemia, and allbut 2 patients achieved a molecularresponse. The median OS was 9.0months, and the median duration ofresponse was 8.9 months. This drug isthe first in a new class of agents calledBiTEs, which are designed to harnessT cells to kill cancer.

Multiple Myeloma

Carfilzomib, the new proteasomeinhibitor was evaluated in phase 2 clin-ical trials in the setting of patients withmultiple myeloma (MM). Results haveshown carfilzomib to be associatedwith very high response rates whencombined with lenalidomide/dexa -methasone; a near CR was achieved by78% of patients after 8 cycles of treat-ment, a stringent CR was achieved by61% of patients, and the 1-year PFSwas 97%. A 4-drug combination—carfilzomib/cyclophosphamide/thali -domide/dexamethasone—produced a96% response rate after 4 cycles.Peripheral neuropathy rates were low.In July 2012, the US Food and DrugAdministration (FDA) approved carfil-zomib for the treatment of patientswith MM whose disease was resistantto and/or relapsed after treatmentwith bortezomib and either lenalido-mide or thalidomide.

The immunomodulatory drugpomalidomide, when combined withdexamethasone, produced a 30% re -sponse rate in a phase 2 clinical trial

that evaluated 221 patients with MMresistant to lenalidomide, to borte-zomib, or to both. The median PFS was3.8 months. Another phase 2 clinicaltrial evaluated pomalidomide in com-bination with clarithromycin and dex-amethasone in 73 heavily pretreatedpatients with relapsed or refractorydisease, demonstrating an overallresponse rate of 56% and a median PFSof 7.5 months (see article on page 23).

Melanoma

The investigational agents dabrafenib,a BRAF inhibitor, and trametinib, aMEK inhibitor, showed high activityas single agents in patients with theV600 BRAF mutation and advancedmelanoma; when these agents werecombined with each other, they wereespecially active. The combinationproduced a median PFS of 7.4months, which rose to 10.8 monthsamong patients who received theoptimal doses. Patients who wereoptimally dosed also achieved a 100%disease control rate (ie, response plusstable disease). Skin toxicity was seenin 14% of patients—a much lower ratethan is observed with vemurafenibalone. A phase 3 clinical trial investi-gating the optimal dose of this regi-men has begun.

Hepatocellular Carcinoma

The oral MET inhibitor tivantinibdemonstrated striking efficacy as a sin-gle agent in a randomized, phase 2clinical trial that included 107 patientswith unresectable hepatocellular carci-noma. Tivantinib improved the timeto progression by approximately 1week in the overall population, butthe effect was much more striking inthe subgroup of patients with highMET expression, which is associatedwith a poor prognosis. In thesepatients, the median time to progres-sion was 11.7 weeks with tivantinibversus 6.1 weeks with placebo, andthe OS was 7.2 months with tivantinibversus 3.8 months with placebo.

Medullary Thyroid Cancer

Cabozantinib, a multi-TKI, is beinginvestigated in patients with docu-mented progressive medullary thyroidcarcinoma. In the phase 3 clinical trialEXAM, cabozantinib improved thePFS to 11.2 months versus 4.0 monthswith placebo, for a 72% reduction inrisk. In addition, the 1-year PFSincreased from 7.2% to 47.3%, and themedian duration of response was 14.6months. The manufacturer submittedto the FDA a New Drug Applicationfor cabozantinib in May 2012. �

The Oncology Drug Pipeline Robust with Novel AgentsBy Caroline Helwick and Wayne Kuznar

Oncology Pipeline

Over the past year, the volume and intensity ofconcern about the unsustainable growth ofcancer care costs have mounted steadily.

Oncology clinical pathways, once widely disdainedas “cookbook medicine,” are being adopted throughsuccessful payer–provider collaboration and pro -vider compliance with pathways that generally hasexceeded early expectations.1,2 Emerging in parallelto clinical pathways are new cancer care deliverymodels—notably accountable care organizations(ACOs)—that are striving for sustainable cost andquality balance through better coordination of careand more effective integration of palliative care.

A recent survey of medical and pharmacy direc-tors was conducted in July 2012 by ReimbursementIntelli gence, a market access consulting firm. Thesurvey included 52 leading managed care plans, rep-resenting more than 100 million covered lives. Thegoal of the survey was to understand how payers areinitiating or collaborating with providers to imple-ment cost-management and delivery models.

Anticipated Expansion of Oncology Pathways

The responses to the survey showed that oncologyclinical pathways have been adopted (40%) or will be

adopted within 2 years (35.5%) by a total of morethan 75% of these payer groups. For plans that havealready 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 forpathway implementation, identifying breast, lung,and colorectal cancers as their initial priorities, fol-lowed by multiple myeloma (Figure 1). If payer pre-dictions are accurate, by 2014 pathway penetrationwill be close to 100% in colorectal cancer, more than90% in breast and lung cancers, and approaching80% in prostate cancer.

Payers rating specific criteria for selection of tumortypes for the development of clinical pathways identi-fied the cost burden associated with tumor treatmentand the need to improve quality of care as the 2 mostimportant criteria (71.5% and 71.4% of respondents,respectively). Other influential considerations are thedegree of clinical variation for a particular tumor type(66.6%) and prevalence of the tumor type (61.9%).

Payers report that their organizations have beenflexible with adjustments to pathways, with mostadjustments (84.2%) made to allow provider flexibil-ity regarding therapeutic options, such as allowingoff-pathway drugs to be used to avoid drug–druginteractions. Pathways generally have integrated tra-ditional cost-management measures, including priorauthorization (85.7%), step edits (71.4%), and formu-lary placement or tiering (52.3%).

In light of ongoing discussions about the cost-sav-ing potential of earlier implementation of palliativecare and end-of-life discussions,3 our survey specifi-cally probed payers about how palliative care isbeing addressed in oncology clinical pathways. Aminority of respondents (14.3%) indicated that pal-liative care will not be referenced in pathways; near-ly 3 times as many respondents (42.9%) stated that

palliative care will be recommended as a course ofaction when appropriate (eg, “palliative care shouldstrongly be considered”).

Consistent with reported findings from payerswho have already implemented pathways, payersparticipating in this survey reported that providercompliance with pathways generally exceededexpectations, especially when anticipated adherencewas in the more modest range, between 60% and70% (Figure 2).

Overall, although approximately one fourth(27.2%) of respondents anticipated pathways adher-ence in the 60% to 70% range, nearly two thirds ofplans (63.6%) estimated actual pathways withinthose ranges. Conversely, although 41% of plans esti-mated adherence at 80%, only 18.2% estimate thislevel of actual compliance. Adherence at the 90%level was substantially overestimated; although31.8% of plans reported this target level of adher-ence, less than 5% estimated it had been achieved.

Payer Formation of ACOs

This survey of leading payers confirmed that inter-est in ACOs as a cost-management mechanism foroncology is high. A minority of payers (20.8%) cur-rently have an ACO, but 53% of respondents plan tohave an ACO within 2 years. Payers anticipate mod-est first-year cost-savings after forming an ACO, butthey expect savings to increase substantially 3 yearslater (Figure 3).

The 3 primary potential contributors to ACO-relat-ed cost reductions were better coordination of care(85.7% of respondents), reducing inappropriate usesof therapies (81.0%), and earlier initiation of pallia-tive care when appropriate (71.4%).

When probed on ways in which an ACO potentiallycould influence oncologic drug costs, 2 prominentareas 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 inidentifying challenges to implementing new oncolo-gy care delivery models, with provider alignmentand infrastructure/data acquisition identified as the2 most significant challenges (86.5% and 71.2%,respectively), followed by care coordination, pro -vider incentives, and organizational structure (each65.4% of respondents).

Rapid Payer Adaptation to Change

The rate at which payers are adapting to substan-tial changes in oncology care delivery models isencouraging. Although precise calculations of cost-savings associated with clinical pathway adoptionand ACOs are difficult to quantify,1 our survey con-firmed that providers and payers are collaborating atthe community level to implement sweepingchanges to the oncology care model. �

References1. Feinberg BA, Lang J, Grzegorczyk J, et al. Implementation of cancer clinical carepathways: a successful model of collaboration between payers and providers. Am JManag 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.

VOL. 5 NO. 5 SPECIAL ISSUE26 AMERICAN HEALTH & DRUG BENEFITS August 2012

Payers’ Perspectives

Payers Collaborate with Providers to AdoptOncology Pathways, New Care Delivery ModelsBy Rhonda Greenapple, MSPH, Chief Executive Officer, Reimbursement Intelligence, Madison, NJ

33.39.5

28.6

28.6

38.1

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38.1

85.7

28.6

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61.961.9

19

100

90

80

70

60

50

40

30

20

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0 Breast Lung Colorectal Multiple Prostate Metastatic Non-Hodgkin myeloma melanoma lymphoma

Currently on pathwaysHigh priority for pathwaydevelopmenta

Figure 1 Payer prioritization of tumor types for pathwayimplementation

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?

Resp

onding

pay

ers, %

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

Q1:What percentage reduction in oncology costs would youanticipate achieving within 1 year after forming an ACO?

Q2:What percentage reduction in oncology costs would youanticipate achieving 3 years after forming an ACO?

0 1-5 6-10 11-15 16-20 ≥20

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40

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25

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Resp

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pay

ers, %

ACO indicates accountable care organization.

Figure 3 Payer estimates of oncology cost-savings 1 and 3years after ACO formation

≤50

60

70

80

90

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Figure 2 Payer estimates of provider adherence with 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)

Responding payers, %

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Anticipated cost-savings, %

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