VBCC JULY 2012, VOL 3, NO 5

Over the past 2 years, we havewritten about the impact ofaccountable care organiza-

tions, value-based purchasing, healthinsurance exchanges, and other pro-grams relevant to the oncology com-munity. These initiatives were all bornout of the Affordable Care Act (ACA),which, on June 28, 2012, had its majorday of reckoning. In a 5 to 4 decision

authored by Chief Justice JohnRoberts, the US Supreme Courtupheld the ACA’s individual man-date—the requirement that mostAmericans obtain health insurancethat meets the definition of minimumessential coverage.The Court also issued a fractured

opinion on Congress’s authority to

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-resistant

prostate cancer after docetaxel failure,according to results from a large phase3 clinical trial.In this double-blind, randomized

trial, OS improved from 13.6 monthsin the placebo group to 18.4 months in

Houston, TX—Patient navigation as -sures timely access to care for manypatients, especially the medicallyunderserved population, and it willsoon become mandated for institu-tions accredited by the Commissionon Cancer, reported Mandi Pratt-

Chapman, MA, Associate Director ofthe Community Programs, Codirectorof the Center for the Advancement ofCancer Survivorship, Navigation andPolicy, George Washington CancerInstitute, Washington, DC, at theThe Affordable Care Act:

The Day of Reckoning ArrivesRoss D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPHMr Margulies is a Health Policy Specialist, Foley Hoag, LLP, and Mr Slotnik isa Partner, Health Policy Strategies, LLC, Washington, DC

Defining the Roles ofPatient Navigation CanRemove Barriers toQuality CareBy Caroline Helwick

©2012 Engage Healthcare Communications, LLC

www.ValueBasedCancerCare.com

Continued on page 26


JULY 2012 VOL 3 NO 5

IN THE LITERATURE . . . . . . . . . . . . . . .4Brentuximab vedotin shows highresponse in relapsed/refractory lymphoma

Regorafenib active in advanced GIST

ASCO ANNUAL MEETING . . . . . . . . .9High OOP costs for Medicare patients with cancer

QOL drives patient preference forpazopanib vs sunitinib

Tivozanib outperforms sorafenib inadvanced RCC

CONFERENCE . . .17Guidelines critical for value-basedbenefit design in oncology

Involving the patient in end-of-lifedecisions

Pathways offer providers true value

AMCP ANNUAL MEETING . . . . . . .28Vemurafenib does not impact health plan budget

Cost-effective analysis of pemetrexed/platinum in NSCLC

CONTINUING EDUCATION . . . . . . .32Considerations in multiple myeloma

I N S I D E

Can Drug Cost Drive OralMedication Adherence Up?A potential “designer drug” phenomenon in oncology By Audrey Andrews

New Androgen Receptor–SignalingInhibitor Extends Survival,Improves QOL in AdvancedProstate CancerBy Mark Knight


HEALTH POLICY

ASCO 2012 ANNUAL MEETING


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Chicago, IL—Canadian researchers reported a finding at the 2012 AmericanSociety of Clinical Oncol ogy meeting that runs contrary to what other researchershave ob served in the majority of studies. In this study, as oral drug costs increas -ed, so did the likelihood of patients adhering to a prescribed regimen.Low adherence rates have been documented for many oral therapies in

various diseases, and medication nonadherence is often the primary cause oftreatment failure. “To our knowledge, cost-related adherence to oral therapy in the context of malignancy has not been studied extensively,” said Jalal

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VELCADEHCP.COM

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

Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus

Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE 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

Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233).

*Melphalan+prednisone.† VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the 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.

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1 6 2:17 PM

High Response Rate withBrentuximab Vedotin inPatients with Relapsed/Refractory Hodgkin LymphomaDespite significant improvements

in the treatment of patients withadvanced-stage, newly diagnosedHodgkin lymphoma (HL) with com-

bined chemotherapy and radiotherapythat have led to durable remissionrates of approximately 60% to 80%, alarge proportion of patients are notcured and new therapies are needed.Patients with relapsed and/or refrac-tory HL have poor prognosis. Newlyreported results of a phase 2 clinical

trial have shown that treatment withthe antibody-drug conjugate brentux-imab vedotin achieves high responserates in patients with relapsed orrefractory HL whose disease has pro-gressed even after receiving auto -logous stem-cell transplant (auto-SCT)salvage therapy (Younes A, et al. J Clin

Oncol. 2012;30:2183-2189).This multinational, open-label study

included 102 patients (median age, 31years) with relapsed (71%) and/or re -fractory (42%) HL after chemotherapyand auto-SCT. All patients receivedbrentuximab vedotin 1.8 mg/kg intra-venously every 3 weeks. Those whodid not progress or did not have pro-hibitive adverse events continued withthis therapy for a maximum of 16 cycles. Overall response rate (ORR) was the

primary end point. Tumor reductions were seen in 94%

of patients, and the ORR was 75%(95% confidence interval [CI], 64.9%-82.6%). Of all patients, 34% achieved acomplete response (CR) and 96% metthe classification of overall diseasecontrol (CR plus partial remission plusstable disease). The estimated 12-month survival

was 89% (95% CI, 83%-95%). At amedian period of 1.5 years (range, 1.8-23.5 months), 31 of the 102 patientswere alive and free of disease progres-sion, and 28 patients died.Adverse events were manageable

with standard supportive care, andmost were grade 1 or 2. A total of 56patients had a grade ≥3 event after pro-longed use of the drug; most of theseevents were neutropenia (20%), throm-bocytopenia (8%), and anemia (6%).These results have prompted further

investigation of brentuximab vedotinfor earlier-stage disease and in combina-tion with other therapies. A phase 1 trialis investigating this drug with multia-gent chemotherapy in treatment-naïvepatients with HL, and a phase 3 clinicaltrial is evaluating the impact of brentux-imab vedotin on pro gression-free sur-vival and overall survival in high-riskpatients with HL after auto-SCT.

Regorafenib Active inAdvanced GIST after FailingStandard TherapyThe treatment of metastatic gas-

trointestinal stromal tumor (GIST) wasrevolutionized with the introductionof imatinib as first-line therapy, with60% control rates and median progres-sion-free survival (PFS) of 27 weekswith sunitinib in the second-line set-ting. Neverthe less, resistance to tyro-sine kinase inhibitor therapy eventual-ly develops in the majority of patientswith advanced GIST; no third-linetherapy is yet approved. New datasuggest that regorafenib, a uniqueinhibitor of several kinase-associatedcancers, has a wide-range activity inthis patient population (George S, et al.J Clin Oncol. 2012;30:2401-2407). This multicenter, phase 2 clinical

trial included 34 patients (33 evalu-able) with metastatic and/or unre-

4 VALUE-BASED CANCER CARE I JULY 2012 VOL. 3 I NO. 5

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

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In The Literature

5VOL. 3 I NO. 5 JULY 2012 I www.ValueBasedCancerCare.com

VALUE PROPOSITIONS

Precision Diagnostics Currently the True Value ofPersonalized Medicine According to Genome Health Solutions cofounder Mark S. Boguski,

MD, PhD, FCAP, Harvard Medical School’s Center for BiomedicalInformatics and Beth Israel Deaconess Medical Center, at this point intime, the promise of genomics lies “not so much in therapeutics or diseaseprevention, but in precision diagnostics that will really enable personal-ized medicine.”Dr Boguski and his cofounder Richard Kellner have set the goal for

their new company to provide genomic-related management services andtechnological/biological know-how to the healthcare industry, with theintent “to finally bring the benefits of genomics to patients.” The center’smission is “to accelerate the translation of genome science and technolo-gies into cost-effective health services.” The center will focus on cancer asthe key to the science of personalized medicine. Dr Boguski, who had participated in the Human Genome Project,

suggests that genomic medicine is now “in the third wave, which is thatprecision diagnostics will lead to better outcomes. If we can understandin any given tumor which genes are the driver mutations—not just onaverage for a population, but in that individual patient—we can useadvanced multiplex technologies to get that information. That opens upthe possibility for more targeted therapy, which you expect would bemore effective.” Insight & Intelligence; July 3, 2012

New Biomarker a Promising Development in Ewing’s SarcomaA team of researchers from the University of Colorado led by Tyler

Robin, PhD, Department of OB/GYN, Denver Anschutz MedicalCampus, has discovered a new biomarker in Ewing’s sarcoma thatexplains the lack of disease response to current chemotherapy in somepatients with this cancer, who until now have had a very poor prognosis.The identification of EYA3 protein as a novel biomarker—a mediator ofchemoresistance—in Ewing’s sarcoma explains the mechanism of EYA3overexpression as the culprit in the resistance to chemotherapy in this dis-ease. This discovery will be used to direct therapy, by identifying patientswith elevated EYA3 levels to either reduce the protein levels directly or tointervene in the EYA3 overproduction process. “First, levels of EYA3could be a tool in offering accurate prognosis and choosing how aggres-sively to treat Ewing’s sarcoma, and, second, we hope that by loweringlevels of EYA3, we could help increase the effectiveness of existing thera-pies for Ewing’s sarcoma,” Dr Robin noted. Furthermore, this new under-standing will likely lead to the development of new therapies, accordingto coinvestigator Heide Ford, PhD. “Our next step is to test small-mole-cule inhibitors against EYA3 to determine which inhibitors best sensitizeEwing’s sarcomas to chemotherapy,” she said. Colorado Cancer Blogs;June 29, 2012

World’s First Pediatric Lymphoma Research Center LaunchedTexas Children’s Cancer Center has opened the first center dedicated

entirely to the research, care, and treatment of children with lymphoma.The Fayez Sarofim Lymphoma Center at Texas Children’s Cancer Centerwas made possible by a gift of $10 million to Texas Children’s Hospital. Lymphomas are the third most common cancers in childhood;

chemotherapy is still the mainstay of lymphoma therapies, and it issometimes supplemented by radiation. Despite much progress in thisarea, many patients with lymphoma do not respond to initial treatment,and a significant proportion of patients whose disease responds to avail-able therapies will eventually develop drug resistance, requiring newtherapies. The Fayez Sarofim Lymphoma Center will focus on researching the

biology of lymphomas to develop new approaches to therapy, including

new diagnostic methods and targeted therapies. The Texas Children’sCancer Center has a translational research infrastructure already in place,focusing on rapid translation of laboratory and clinical research into clin-ical studies. “Our researchers have already developed effective cell-based therapies

that have demonstrated extremely exciting clinical results, and we are alsoevaluating new chemotherapeutic agents with significant clinical prom-ise,” said Catherine Bollard, MD, Director of the Fayez SarofimLymphoma Center. Potential advances made at the center will be sharedwith pediatric oncologists around the world. Kenneth McClain, MD, Clinical Director of the new center, addressed

the potential clinical benefits of the new endeavor, noting that this finan-cial gift “will help expand the number of innovative therapies that will beavailable to treat our young patients. Our ultimate goal is to find a cure forall children with lymphoma.” Texas Children’s Hospital press release;June 26, 2012

First US Hospital Integrates Psychosocial SupportServices in Its Cancer CenterGreenville Hospital System (GHS) has launched the Center for

Integrative Oncology and Survivorship, which offers emotional servicesfor cancer survivors developed by Cancer Support Community (CSC), aninternational provider of cancer-related social and emotional services.“Research shows that social and emotional support is as important asmedical care in the fact of a cancer diagnosis,” said Larry Gluck, MD,Medical Director, GHS Cancer Center, SC. “Cancer Support Communityis a leader in psychosocial oncology, and we are pleased to integrate itsevidence-based programs and services into our cancer care deliverymodel.” This is the first US hospital to offer CSC’s services within the hos-pital setting itself, including distress screening program, personalizedassessment and care plan, support groups, health and wellness programs,and educational programs. The cost for these services runs between$60,000 and $100,000; however, GHS will provide them for free, thanks tofunding from the Palmetto Peloton Project. Greenville Hospital Services;June 26, 2012

Researchers Highlight Benefits of Exercise forPatients with CancerSeveral researchers at the University of Rochester Medical Center

have been studying the effects of exercise on patients with cancer for sometime now. “In 15 years, we have gone from being afraid to recommend exercise to

people with cancer to having enough data that show, by and large, that itis safe and effective, particularly for relief of treatment side effects,” sug-gests Karen Mustian, PhD, MPH, Assistant Professor of RadiationOncology, University of Rochester Medical Center, NY. Lisa K. Sprod, PhD, with the James P. Wilot Cancer Center at the

University of Rochester Medical Center, analyzed a national sample ofnearly 14,900 people. She found that patients with cancer or cancer sur-vivors are less physically active than people without cancer, a reality thathas been linked to increased risk for cancer recurrence and reduced sur-vival in this patient population. Dr Sprod notes that it is not clear whethercancer treatment contributes to such reduced physical activity or whetherpatients with cancer and their physicians are concerned with safety issuesfor these patients. Yet a third researcher at the university, Luke J. Peppone, PhD, has

shown that women with breast cancer who participated in a weekly yogaprogram and were taking aromatase inhibitors reported reduced medica-tion side effects, including less pain, reduced muscle aches, and less over-all physical discomfort. These new data reinforce the value of exercise foroverall well-being and improved quality of life for patients with cancer.University of Rochester Medical Center newsroom; May 30, 2012


PublisherNicholas [email protected] DirectorDalia [email protected] PublisherAmerican Health & Drug BenefitsMaurice [email protected]

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Mission StatementValue-Based Cancer Care provides a forum for payers,providers, and the entire oncology team to considerthe cost-value issues particular to cancer treatments.This unique focus is achieved through news coveragefrom major hematology/oncology meetings and thecancer literature, supplemented with commentariesand perspectives from those involved in evaluatingtherapies, treating patients, and paying for care.

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Value-Based Cancer Care, ISSN 2153-4888 (print);ISSN 2153-4896 (online), is published 8 times ayear by Engage Healthcare Communica tions, LLC,241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Copyright © 2012 by Engage HealthcareCommunications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark ofEngage Health care Communi cations, LLC. No partof this publication may be reproduced or transmittedin any form or by any means now or hereafter known,electronic or mechanical, including photocopy,recording, or any informational storage and retrievalsystem, without written permission from the publish-er. Printed in the United States of America.

The ideas and opinions expressed in Value-BasedCancer Care do not necessarily reflect those of theeditorial board, the editors, or the publisher.Publication of an advertisement or other productmentioned in Value-Based Cancer Care should not beconstrued as an endorsement of the product or themanufacturer’s claims. Readers are encouraged tocontact the manufacturers about any features or limi-tations of products mentioned. Neither the editorsnor the publisher assume any responsibility for anyinjury and/or damage to persons or property arisingout of or related to any use of the material mentionedin this publication.Postmaster: Correspondence regarding subscriptionsor change of address should be directed to CIRCU-LATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township,NJ 08831. Fax: 732-992-1881. Yearly subscriptionrates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

IN THE LITERATUREBrentuximab vedotin has high response rate inrelapsed/refractory lymphomaRegorafenib active in advanced GISTAnti–PD-1/PD-L1 antibodies show promisingantitumor activity More….

ASCO ANNUAL MEETINGHigh OOP costs for Medicare patients with cancerQuality of life drives patient preference forpazopanib over sunitinibPatients willing to pay out of pocket for genetictesting to assess colon cancer riskEndocrine therapy underutilized in low-incomepatients with breast cancer Tivozanib outperforms sorafenib in RCCMore….

CONFERENCEEvidence-based guidelines critical for value-basedbenefit design in oncologyCollaborate to achieve value in oncologyInvolving the patient in end-of-life decisions:Aetna’s oncology strategyTough times for small oncology practicesPathways offer providers a true value propositionMore….

AMCP ANNUAL MEETINGVemurafenib does not impact health plan budgetCost-effective analysis of pemetrexed/platinumin NSCLCMore….

CONTINUING EDUCATIONConsiderations in multiple myeloma

Ed Pezalla, MD, MPHNational Medical Director ofPharmacy Policy and StrategyAetna, Hartford, CT

Denise K. PierceDK Pierce & AssociatesZionsville, IN

Jatin J. Shah, MDM.D. Anderson Cancer CenterHouston, TX

Jayson Slotnik, JD, MPHPartnerHealth Policy Strategies, LLCWashington, DC

Brian K. Solow, MD, FAAFPChief Medical Officer Prescription Solutions/OptumRxIrvine, CA

Timothy Tyler, PharmD, FCSHPDirector of Pharmacy ServicesComprehensive Cancer CenterDesert Regional Medical CenterPalm Springs, CA

G. Rhys Williams, ScD, MSAmgenThousand Oaks, CA

Winston Wong, PharmD CareFirst BlueCross BlueShieldBaltimore, MD

Yu-Ning Wong, MD, MSCEFox Chase Cancer CenterPhiladelphia, PA

Burt Zweigenhaft, BSBioPharma Partners, LLCNew York, NY

Section EditorDawn Holcombe, FACMPE, MBA,ACHEPresident, DGH ConsultingSouth Windsor, CT

VBCC Editorial BoardIra Klein, MD, MBAAetnaHartford, CT

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI CommunityCancer Centers Program Towson, MD

Mary KruczynskiDirector of Policy AnalysisCommunity Oncology Alliance

Crystal Kuntz, MPAAstellas Pharma USWashington, DC

John L. Marshall, MDDirector, The Ruesch Center for the Cure of GI CancersChief, Hematology and OncologyAssociate Director, Lombardi ComprehensiveCancer CenterGeorgetown University Medical CenterWashington, DC

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Lee Newcomer, MD, MHAUnitedHealthcareMinnetonka, MN

Lynn Nishida, RPhDirector, Clinical ServicesCatamaran Center of Excellence Northwest RegionPortland, OR

Ted Okon, BS, MBAExecutive DirectorCommunity Oncology Alliance

Naimish Pandya, MDUniversity of MarylandBaltimore, MD

Al B. Benson III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter of Northwestern UniversityChicago, ILPast President, ACCCPast Chair, NCCN Board of Directors

Scott Breidbart, MDChief Medical OfficerEmpire BlueCross BlueShield, NY

Bruce A. Cutter, MD, MMMCutter HealthCare ConsultingSpokane, WA

Craig Deligdish, MDChief Medical OfficerOncology Resource NetworksOrlando, FL

Peter G. Ellis, MDUniversity of Pittsburgh School ofMedicine and UPMC Cancer CentersPittsburgh, PA

Arlene A. Forastiere, MDSenior Vice PresidentMedical Affairs eviti, Inc

Tracy Gosselin, RN, MSNDuke University Medical CenterDurham, NC

Scott Gottlieb, MDMount Sinai Medical Center and American Enterprise InstituteNew York, NY

David Hom, MBASoluciaFarmington, CT

Philip E. Johnson, MS, RPh, CPhH. Lee Moffitt Cancer CenterTampa, FL

In This Issue

New Test for Aiding BiopsyDecision after PSA TestThe US Food and Drug Admin -

istration (FDA) has approved theAccess Hybritech p2PSA (BeckmanCoulter) test, which measures a form ofprostate-specific antigen (PSA) called [-2]proPSA in the blood and can helpmen whose PSA test scores are elevat-ed decide whether they should have abiopsy to rule out prostate cancer. The Access Hybritech p2PSA test is

approved for use in men aged ≥50years whose PSA test score is between4 and 10 ng/mL but a digital rectalexamination does not show any signsof cancer. A PSA test score between 4and 10 ng/mL often prompts physi-cians to recommend a prostate biopsy.The FDA approval was based on

a clinical trial with nearly 660 men, of whom approximately half hadprostate cancer. The phi score was bet-ter than the PSA score at distinguishingbetween benign conditions and pros -tate cancer. In addition, the studyshowed that the phi score level was apredictor of cancer, with a higher scoreassociated with increased probability ofdetecting prostate cancer after a biopsy. According to Barry Kramer, MD,

Director of the National Cancer Insti -tute Division of Cancer Prevention, the study was not designed to deter-mine whether the phi test reduces the risk of dying from prostate cancer.There is, however, no standard phi

score that points out whether to have abiopsy. According to the FDA, “Thechoice of an appropriate…phi score tobe used in guiding clinical decision-making may vary for each patient andmay depend in part on other clinicallyimportant factors or on family historyof disease.”The Access Hybritech p2PSA is

expected to be available in the UnitedStates this year, according to the man-ufacturer. (June 14, 2012)

ODAC RecommendsCarfilzomib for MyelomaThe FDA’s Oncologic Drugs Advi -

sory Committee (ODAC) recommend-ed in an 11 to 0 vote (and 1 absentee) toapprove carfilzomib (Kyprolis; Onyx),a new-generation proteasome inhib -itor, for the treatment of patients withrefractory and relapsed multiplemyeloma who have failed at least 2other myeloma therapies—the protea-some inhibitor bortezomib (Velcade)and the immunomodulatory druglenalidomide (Revlimid). The company applied for accelerat-

ed approval of this agent based on theresults from a phase 2 clinical trial of266 patients with refractory andrelapsed myeloma who had receivedat least 2 previous treatments (with

lenalidomide and with bortezomib),resulting in an approximate 22% over-all response rate (ORR). However, thetoxicity profile was problematic. Theside effects seen in this study includedserious heart problems, such as cardiacarrest, chest pain, pneumonia, andshortness of breath, including 5

deaths. According to the FDA report,>70% of patients receiving carfilzomibhad lung complications. The ODAC report says that because

the ORR for carfilzomib was “only 22%in the primary efficacy study, it maynot provide an advantage over avail-able therapy. FDA is very concerned

with the severe toxicities, includingdeaths, that are associated with the useof this agent. The pathogenesis of thesetoxicities is not understood.” However,the ODAC report states that carfil-zomib’s benefits outweigh its risks,and is recommending its approval bythe FDA. (June 20, 2012) �


FDA Update

sectable GIST whose disease pro-gressed after therapy with imatiniband sunitinib. The primary end pointwas a composite of complete responserate, partial response rate, and stable

disease after ≥16 weeks. All patients received oral rego-

rafenib 160 mg daily on days 1 to 21 ofa 28-day cycle. After a median follow-up of 10.9 months, 21 patients contin-ued to receive the drug, and 16 of themremained disease free. In addition, 5patients continued to receive rego-

rafenib after disease progression,because of perceived continued bene-fit. A total of 12 patients discontinuedthe study because of disease progres-sion. Overall, the clinical benefit ratewas 79%; 4 patients achieved partialresponse, and 22 showed stable dis-ease after ≥16 weeks. The median PFS

was 10.0 months. The most commongrade 3 events were hypertension andhand-foot-skin reaction. A phase 3 clinical trial of regorafe -

nib versus placebo in this setting isongoing.


In The Literature


Regorafenib Active inAdvanced GIST...Continued from page 4

Anti–PD-1/PD-L1 AntibodiesShow Promising AntitumorActivity in Several CancersThe programmed death 1 (PD-1)

receptor is expressed by activated Tcells and mediates immunosuppres-sion involved in tumor growth. Resultsfrom two phase 1 clinical trials—oneevaluating an anti–PD-1 antibody(Topalian SL, et al. N Engl J Med. 2012;366:2443-2454) and the second evaluat-ing an anti–PD-1 ligand (PD-L1) anti-body (Brahmer JR, et al. N Engl J Med.2012;366:2455-2465)—suggest that tar-geting the PD-1/PD-L1 pathway maybe beneficial in treating certain types of solid tumors, including advancedmelanoma, non–small-cell lung cancer(NSCLC), and renal-cell cancer.In the first study, 296 patients with

advanced melanoma, NSCLC, castra-tion-resistant prostate cancer, renal-cell cancer, or colorectal cancerreceived the anti–PD-1 antibody for upto twelve 8-week treatment/evalua-tion cycles. Most patients had beenheavily pretreated. Among the 236 evaluable patients,

dose-related objective responses (par-tial or complete) were seen in patientswith melanoma (range, 19%-41%),NSCLC (range, 6%-32%), and renal-cell cancer (range, 24%-31%), but noresponses were seen in patients withcolorectal or prostate cancer.Objective responses of ≥1 year were

seen in small but substantial propor-tions, ranging from 1 in 5 to 1 in 4 pa -tients with melanoma, NSCLC, or renal-cell cancer. The response in patientswith NSCLC was unexpected and sug-gests that that drug’s activity may gobeyond immunogenic tumor types.In a secondary analysis of 25 pa -

tients with PD-L1–positive tumors, 9(36%) had an objective response com -pared with no response among the 17patients with PD-L1–negative tumors. The adverse event profile seen in

this study was consistent withimmune-related causes. The incidenceof grade 3 or 4 drug-related adverseevents was low enough (14% of 296patients) to suggest potential therapydelivery in an outpatient setting.In the second study, patients with

NSCLC, melanoma, colorectal cancer,renal-cell cancer, ovarian cancer, pan-creatic cancer, gastric cancer, or breastcancer received an anti–PD-L1 anti-body for up to sixteen 6-week treat-ment cycles.

BRIEF SUMMARY OF PRESCRIBING INFORMATIONNeulasta® (pegfilgrastim) injection, for subcutaneous use

INDICATIONS AND USAGENeulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

CONTRAINDICATIONSDo not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

WARNINGS AND PRECAUTIONSSplenic RuptureSplenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta.

Acute Respiratory Distress SyndromeAcute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS.

Serious Allergic ReactionsSerious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim.

Use in Patients With Sickle Cell DisordersSevere sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim.

Potential for Tumor Growth Stimulatory Effects on Malignant CellsThe granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in other sections of the Brief Summary:• Splenic Rupture [See Warnings and Precautions ]• Acute Respiratory Distress Syndrome [See Warnings

and Precautions ]• Serious Allergic Reactions [See Warnings and Precautions ]• Use in Patients with Sickle Cell Disorders [See Warnings

and Precautions ]• Potential for Tumor Growth Stimulatory Effects on Malignant

Cells [See Warnings and Precautions ]The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity.Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Neulasta clinical trials safety data are based upon 932 patients receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles.The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other.Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients.

Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2

(N = 467)

Musculoskeletal and connective tissue disordersBone pain 26% 31%Pain in extremity 4% 9%

LeukocytosisIn clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies.

ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay.The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading.

Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) reported frequency of the reaction, or (3) strength of causal relationship to Neulasta.Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions ]Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions ]Hypersensitivity reactions: Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema and flushing [see Warnings and Precautions ]Respiratory, thoracic, and mediastinal disorder: ARDS [see Warnings and Precautions ]General disorders and administration site conditions: Injection site reactionsSkin and subcutaneous tissue disorders: Sweet’s syndrome, Cutaneous vasculitis

DRUG INTERACTIONSNo formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. Pegfilgrastim was embryotoxic and increased pregnancy loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing MothersIt is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman.

Pediatric UseSafety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC

0-inf) of pegfilgrastim after subcutaneous

administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

Geriatric UseOf the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

Renal ImpairmentIn a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary.

DOSAGE AND ADMINISTRATIONThe recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim)

Manufactured by:Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799

© 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436)

v 13.0 65481-R1-V1

Chicago, IL—Older patients withcancer 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, Baltimore,and colleagues at the 2012 AmericanSociety of Clinical Oncology meeting.The team used Medicare Current

Beneficiary Survey (MCBS) data from1997 to 2007 that was linked to

Medicare claims for their analysis.Pa tients with a new diagnosis of can cer were chosen based on Inter -national Classification of Diseases, NinthRe vision, Clinical Modification (ICD-9-CM) codes on claims after a 12-month washout period subsequent to the cancer diagnosis. OOP costs

were noted via the patients’ ownreporting.The study included 1869 Medicare

beneficiaries with cancer and 10,057without cancer. Those with cancertended to be older, have more comor-bidities, and typically did not havesupplemental insurance compared

with those without cancer. For a patient with cancer, the total

OOP spending was $4727 (11.4% oftotal spending); the OOP differencebetween patients with and withoutcancer was $1518. After adjusting forpatient characteristics, those withcancer had an incremental increase of$956 in OOP cost.Among patients with cancer, ap -

proximately 28% spent ≥20% of theirincome on OOP expenses comparedwith 16% of those without cancer whoused ≥20% of their income on OOPexpenses.Comorbid conditions, undergoing

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


ASCO 2012 Meeting


High OOP Costs for Medicare Patients with CancerBy Mark Knight

Older patients often hesitate to seek treatment for cancer because of financial concerns.

—Amy J. Davidoff, PhD, MS

Unforeseen Hospital Admissions Are Frequent forPatients Receiving RadiotherapyPotential marker of quality of care in cancer therapy By Wayne Kuznar

Chicago, IL—Approximately 1 in 5patients with cancer who are undergo-ing radiotherapy as part of their treat-ment can count on unexpected hospi-tal stays—adding an economic andclinical burden on the patient and onthe healthcare system, according to ananalysis by Nabeel H. Arastu, BS, andcolleagues at the Brody School ofMedicine at East Carolina University,Greenville, NC, which was presentedat the 2012 ASCO meeting.Unanticipated admissions were

common among nearly 33% ofpatients who received radiotherapyto treat symptoms and were also like-ly in more than 25% of those receivingsimultaneous chemoradiation.As part of the analysis, data were

collected from the electronic healthrecords of 500 patients with cancer.The patients had received externalbeam radiotherapy in 2010 at a facili-ty at the University of North CarolinaSchool of Medicine in Chapel Hill.Relevant clinical information andunexpected hospital stays that tookplace within 90 days of radiotherapytreatment startup were documented.The objective was to find out

whether there are any clinical markerspre-radiotherapy to understand if

some patients are more likely than oth-ers to be admitted to the hospital unex-pectedly.

A 20% Unexpected Admissions

Rate

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 admission

included:• Pain (19% of cases)• Respiratory issues (15%)• Neurologic conditions (13%)• Malaise (7%)• Fever (5%). Other clinical factors that may influ-

ence future unplanned hospital visitsinclude use of pain medicine to controlsymptoms, weight loss issues, andreceipt of intravenous fluid.In addition, 33% of patients who

were 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 simultane-

ous radiotherapy and chemotherapyhad unplanned hospital admissionscompared with 17% of those receivingonly radiotherapy. A multivariateexamination indicated that unexpect-

ed hospital stays were tied tochemotherapy, treatment goals, andmarital status. There were highlyinconsistent rates of unexpected hos-pital visits based on diagnosis—including 37% for metastases; 19% forgastrointestinal, genitourinary, gyne-cologic, ear, nose, and throat cancers;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. According to theresearchers, the reason may be thatpatients undergoing multiple roundsof chemotherapy or treatment for sec-ondary metastases are typically sickerand have more comorbidities thanother patients.

Preventive Measures

Mr Arastu and colleagues note thatit is important to consider preventiveapproaches in higher-risk patients sothat admission rates can be lowered.They add that unexpected hospitalvisits may serve as a marker for qual-ity of care in cancer therapy. To develop measures to trim admis-

sion rates and the costs associatedwith them, the team suggests that it isnecessary to understand the frequen-cy of such visits, as well as reliablepredictors of why the visits occur inthe first place. �

It is important to consider preventiveapproaches in higher-riskpatients so that admissionrates can be lowered.Unexpected hospital visits may serve as a marker for quality of care in cancer therapy.

Supplemental Insurance

A separate analysis of the sameMCBS database showed that the use ofantineoplastic therapy among Medi -care recipients is influenced by theavailability, but not the type, of supple-mental coverage. This analysis—basedin large part on data before the addi-tion of Medicare Part D (in 2006)—demonstrated that oral antineoplasticagents were received by many patientswith cancer using antineoplastic thera-py (non–Part B drugs), yet there wasless spending on this therapy than oninfused/injected chemotherapy (PartB drugs). There were no notable differ-ences in use or spending on antineo-plastic therapy for the post–Part Dperiod relative to the reference period. “With the large number of relatively

new oral prescription antineoplasticagents, and with more in the pipeline,monitoring the role of supplementalinsurance and particularly the role of

Part D in access and spending, is a crit-ical area for ongoing research,” said DrDavidoff.For this retrospective analysis,

community-based MCBS participantswith new cancer diagnoses were cho-sen based on ICD-9-CM diagnosis

codes. A total of 1836 beneficiarieswho had a new diagnosis of cancerwere enrolled.Of the 559 patients who were

treated with antineoplastic therapy,395 (21.5%) received infused/inject-ed chemotherapy and 254 receivedoral antineoplastic agents. Patientsusing antineoplastic therapy spent$7841 (any coverage), $10,364 (Part Bcoverage), and $1535 (non–Part Bcoverage). If beneficiaries had supplemental

coverage, 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 antineoplastic

therapy use and spending was the siteof the cancer. Also, older age was asso-ciated with less spending. �

High OOP Costs for Medicare... Continued from page 9

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


ASCO 2012 Meeting

Quality of Life Drives Patient Preference for Metastatic Renal-Cell Carcinoma DrugPazopanib gets thumbs up from patients and providers By Wayne Kuznar

Chicago, IL—The surprising results ofa randomized trial on patient prefer-ence for one cancer therapy overanother show that patient-reportedquality-of-life (QOL) differences influ-ence treatment preference far morethan physicians had imagined, sug-gested researchers at the 2012American Society of Clinical Oncologymeeting.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 team assessed whetherthe drug toxicity would be significantenough to make patients want to con-tinue treatment with either drug or toswitch therapy.A total of 126 patients completed a

preference 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 was

49% in favor of pazopanib. All otheranalyses showed a significant prefer-ence for pazopanib.

The most common reasons given forpazopanib preference were betterQOL and less fatigue. Patients takingpazopanib had fewer dose reductionsthan those taking sunitinib (13% vs20%, respectively) and fewer treat-ment interruptions (6% vs 12%, respec-tively). Ad verse events (AEs) were

compatible with known profiles forboth 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

differences between 2 different thera-pies as relatively minor, but topatients, even low-grade toxicitiesover a long period have a significanteffect on QOL, according to DrEscudier and colleagues. How patientsfeel when they take a drug over manymonths is not reflected in traditionalAE 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 understandthe clinical relevance of differences indrug toxicities, Dr Escudier and col-leagues noted. �

at a glance� Patient-reported QOL

differences influence treatment

preference more than physicians

realize

� Even low-grade toxicities over

a long period can significantly

affect patient QOL

� A significant majority of

patients preferred pazopanib

over sunitinib as a treatment for

mRCC, because of better QOL

and less fatigue

� Patient-reported outcomes

are gaining importance as a

clinical end point

We expected patients to prefer onedrug over the other because ofadverse effects, but “we didn’t everexpect such a big difference betweenthe 2 drugs.”

—Bernard J. Escudier, MD

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In the primary analysis, 70% of the patientspreferred pazopanib, 22% preferred sunitinib, and 8% cited no preference.

at a glance� Elderly patients often

hesitate to seek treatment

for cancer because of financial

concerns

� Approximately 28% of

Medicare beneficiaries with

cancer spent ≥20% of their

income on OOP expenses

between 1997 and 2007

� Increased OOP expense

is associated with comorbidities,

cancer-specific radiation use,

antineoplastic therapy, and

higher income

� Treatment is more likely

for patients with cancer

who have supplemental

insurance from any source

Ebrahim, MD, of St Michael’s Hos -pital, University of Toronto, Onta -rio,Canada.He and his colleagues conducted a

study of 453 patients with cancer at 3outpatient hematology/oncology clin-ics. They used a 7-item survey to in -vestigate patient self-reported adher-

ence to oral medication, type ofcoverage, and patients’ perceived costof the drugs. Of the 453 patients, 50% had a pri-

vate drug plan, 24% paid for the drugout of pocket, 44% had governmentfunding, and 4% said their physician

had arranged funding for their med-ication. Approximately 50% of the patients

had 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 significantrelationship 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, regardless ofefficacy,” according to Dr Ebrahim.

Strong Adherence to

High-Cost Drugs

“A strong correlation was observedbetween monthly oral drug cost andadherence to the regimen,” he said.A low monthly drug cost was not

associated with higher adherencerates. The adherence rates related to

monthly out-of-pocket costs were:• 55% adherence with ≤$10 • 83% adherence with $10-$100 • 83% adherence with $100-$500 • 75% adherence with $500-$1000• 85% adherence with ≥$1000.Dr Ebrahim believes that patients

consider more expensive drugs to be more valuable, and thereforeshould not be wasted. This “designerdrug” phenomenon may explain the in creased adherence rates thatwere found to be associated with

high-cost drugs. “Poor communication between

physicians and patients can lead topoor adherence. A lack of educationregarding older, cheaper medicationscould be a catalyst for nonadherence,”Dr Ebrahim suggested. The disparities found in this study

in medication costs for patients withprivate drug plans versus those with-out private plans suggest that financialrestrictions may affect prescriptionpatterns, the team noted. �


ASCO 2012 Meeting

“A strongcorrelation wasobservedbetweenmonthly oraldrug cost andadherence tothe regimen.”—Jalal Ebrahim, 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 posterthat was presented at the 2012American Society of Clinical Oncology(ASCO) meeting and earned an ASCOMerit Award.“These participants are fearful of a

positive 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 genet-

ic testing in cancer care has been par-alleled by increasing cost-sharingpractices by payers. Little is knownabout the factors that may influence ahigh-risk patient’s willingness to payfor these genetic tests. The study wasconducted 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) complet-ed a survey that collected detaileddemographic data, cancer history, andpsychosocial items related to cancer

risk. The patients were presented withthe following scenarios:• I plan to have genetic testing forCRC only if my health insurancecovers it

• I plan to have a genetic test for CRC,even if I have to pay for it myself

• For a genetic test for CRC, I wouldbe willing to pay: $25, $50, $100,

$200, $500, $1000, $2000.The results showed that 80% of

patients were willing to pay OOP,whereas 20% would want the test onlyif insurance covered the full cost,reported Dr Matro.The percentages of patients willing

to 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 ofwillingness to pay included theexpectation of a positive result, confi-dence in being able to better controlcancer risk, fewer perceived barriersto CRC screening, and belief that ben-efit is derived from having screeningguidance. Patients willing to pay ahigher amount were more likely to be male, be more educated, have

greater cancer worries and fewerfirst-degree relatives with CRC, andhave more positive attitudes towardgenetic 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 feel more comfortable navigating thehealthcare system and getting appro-priate care without the test result,” shesuggested. Despite the analysis being con-

trolled for household income,women and less-educated patientswere willing to pay a smaller sum,indicating that they may face greaterindividual barriers from high co -pays, she reported.“Identifying patient-level factors

associated with willingness to pay for genetic services is increasinglyimportant as genetic testing is inte-grated into routine cancer care,” DrMatro said. �

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

—Jennifer M. Matro, MD

Patients Willing to Pay Out of Pocket for Genetic Testing to Assess Colorectal Cancer RiskBy Audrey Andrews

Can Drug Cost Drive Oral Medication... Continued from cover

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.

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

receiving Jaka� for signs and symptoms of infection

treatment promptly

a A

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Prescribing Information. Incyte Corporation. November 2011. 1

i during pregnancy is not r

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has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and

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

A novel approach to engage clinicians and FDA

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

Making

PRO

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Placebo (n = 145)Jaka� (n = 145)

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

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Placebo (n = 153)Jaka� (n = 155)

COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

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

I is indicated for treatment of patients with intermediate

o

for patients developing anemia m

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

Chicago, IL—Improved cancer screen-ing can save lives, and despite the highcost of implementing such a measure,it was found cost-effective and there-fore valuable in a recent analysis using

quality-adjusted life-years (QALYs),said Michael S. Broder, MD, Presidentof Partnership for Health AnalyticResearch, LLC (PHAR), CA, and col-leagues, at the 2012 American Society

of Clinical Oncology meeting.Cancer care spending in the United

States has increased from $13.1 billionin 1980 to $104 billion in 2006, butthere is much controversy over the suf-

ficiency of the benefit of this spending.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 RANDHealth 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 cancerscreening measures—cervical, breast,and colon—were compared to theremaining measures. ICERs werereported for measures representing atradeoff (ie, between greater cost andgreater health, or cost-savings andworse health).To reach 95% compliance on these 3

cancer screening measures would cost$5.1 billion and add 160,000 QALYs—$32,640/QALY. This rate of compli-ance with all 18 measures would cost$13.4 billion and add 5.8 millionQALYs, which translates to $2313/QALY. That would make QI a goodvalue and very cost-effective com-pared 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 for these 3 measures suggests thatimproving cancer screening compli-ance is cost-effective at a $50,000/QALY willingness-to-pay threshold. “Our analysis shows that complying

with cancer screening measures is cost-effective, even considering the re -sources required to change establishedpractices,” said Dr Broder. Addressingoveruse of care can save money, headded. �


ASCO 2012 Meeting

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

Cancer Screening Saves Lives, Is Cost-EffectiveBy Wayne Kuznar

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

—Michael S. Broder, MD

Chicago, IL—Researchers from theUniversity of North Carolina inChapel Hill reported at the 2012American Society of Clinical Oncologymeeting that endocrine therapy is sub-stantially underutilized among thelow-income breast cancer population.For women with estrogen receptor

(ER)-positive or progesterone receptor(PR)-positive disease, endocrine thera-py reduces the 5-year recurrence riskby as much as 40%, but this studyshowed that low income may be anobstacle to receiving this guideline-recommended treatment. Using Medicaid claims data

matched to North Carolina CentralCancer Registry records, the research -ers identified factors that predicted the use of guideline-recommendedendocrine therapy among low-incomewomen aged 18 to 64 years who were

diagnosed with in situ stage I or stage II breast cancer be tween 2004and 2007.Of the 269 ER- or PR-positive

women in this sample, only 49% filleda prescription for endocrine therapywithin 15 months of diagnosis, report-ed Racquel E. Kohler, MSPH, ResearchAssociate at the University of NorthCarolina, and colleagues.Tamoxifen was the most common

therapy among the 132 patients whoreceived adjuvant endocrine therapy(59%). Less common therapies in -cluded anastrozole (18%), letrozole(10%), exemestane (2%), and multipleagents (11%).In a multivariate analysis, the only

factor significantly associated withreceiving guideline-recommended en -docrine therapy was involvement inthe Breast and Cervical Cancer Control

Program (BCCCP; P = .01). On aver-age, participating in the BCCCP wasassociated with a 29.9% increase in the

likelihood of receiving endocrine treat-ment compared with women whowere not in the BCCCP, controlling for

other factors, Ms Kohler reported.The BCCCP provides free or low-

cost breast and cervical cancer screen-ings and follow-up to eligible women,mostly through local health depart-ments, community health centers, hos-pitals, and private physicians’ offices.Other independent variables were

not significantly associated in the multivariate analysis; however, in the bivariate analysis, women whoreceived endocrine therapy were morelikely to receive radiation (64% vs 50%who did not get endocrine therapy)and to be enrolled in the BCCCP (29% vs 10%, respectively). “Our results suggest that endocrine

therapy is substantially underutilizedin this low-income, vulnerable popula-tion, and that intervention efforts toimprove its use may be important,”Ms Kohler pointed out. �

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 Mardsen National HealthService Foundation Trust, UnitedKingdom, at the 2012 American Societyof Clinical Oncology meeting.“I think these are the best survival

data we’ve seen in the postchemother-apy setting,” Dr de Bono said.A total of 1199 patients with castra-

tion-resistant prostate cancer who had

received docetaxel-based chemothera-py were randomized in a 2:1 ratio todaily 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 after

the Independent Data MonitoringCommittee determined that the risk-to-benefit ratio with MDV3100 wasfavorable; eligible patients in theplacebo arm were offered treatmentwith enzalutamide.With a median follow-up of 14.4

months, enzalutamide conferred a sur-vival advantage across all identifiedsubgroups.“Impressively, enzalutamide had a

very 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% and

90% fall in PSA in this population ofpatients, with 54% of patients havinga more 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 the

placebo 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 hazardratio 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 event was

again superior in the enzalutamidearm (16.7 months) compared with theplacebo arm (13.3 months)—a 38%reduction in the risk of a skeletal-relat-ed event.QOL responses as measured by the

Functional 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 patients

treated 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. �


at a glance� Enzalutamide (MDV3100), a

novel androgen receptor–

signaling inhibitor, prolonged

OS, slowed disease progression,

and improved QOL in men with

castration-resistant prostate

cancer

� With enzalutamide, PFS was

extended by more than 5

months, and 25% of patients

had a >90% fall in PSA versus

1% with placebo

� A smaller proportion of

patients taking enzalutamide

had grade ≥3 AEs compared

with those receiving placebo

“I think these are the bestsurvival data we’ve seen inthe postchemotherapysetting. Impressively,enzalutamide had a veryhigh PSA response rate. Inever thought I’d see a 50%and 90% fall in PSA in thispopulation of patients.”

—Johann S. de Bono, MB, ChB,MSc, PhD

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ASCO 2012 Meeting

Endocrine Therapy Substantially Underutilized Among Low-Income Patients with Breast CancerBy Caroline Helwick

“Our results suggest thatendocrine therapy issubstantially underutilized inthis low-income, vulnerablepopulation, and thatintervention efforts toimprove its use may beimportant.”

—Racquel E. Kohler, MSPH

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 (RCC), according toresults from a phase 3 randomized,open-label trial.The results suggest that “tivozanib

should 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 vascular

endothelial 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 for

tivozanib warranted a phase 3 trialcomparing tivozanib with sorafenib inpatients with metastatic RCC as first-line, targeted therapy.The study included 517 patients

with clear-cell advanced RCC, priornephrectomy, Response EvaluationCriteria In Solid Tumors–defined

measurable disease, and EasternCooperative Oncology Group per-formance status of 0 or 1. Patients wererandomized to tivozanib once daily for3 weeks (followed by 1 week of rest) orsorafenib twice daily continuously in a4-week cycle. Patients were eithertreatment-naive or had received nomore than 1 prior systemic therapy for

metastatic disease. Treatment contin-ued until either disease progression orintolerance.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 a statisticallysignificant improvement in PFS com-pared with sorafenib (median, 11.9months vs 9.1 months) when assessedby an independent panel, correspond -ing to a 21% improvement withtivozanib. When assessed by the inves-tigators, the difference in PFS betweenthe 2 groups was 14.7 months withtivozanib versus 9.6 months forsorafenib, for a 28% improvement. Theefficacy advantage of tivozanib wasconsistent across all subgroups.Among the 70% of treatment-naive

patients, median PFS was 12.7 monthswith tivozanib versus 9.1 months withsorafenib, and the objective responserate was 33% versus 23%, respectively. Tolerability of tivozanib was also

more favorable than sorafenib’s, asevidenced by a low rate of dose inter-ruptions (17% vs 35%, respectively)and reductions (12% vs 43%, respec-tively); the discontinuation rates were4% and 5%, respectively.Treatment-emergent adverse events

were present in 90% of patients in bothgroups, although important differ-ences were seen in the safety profilebetween the 2 drugs. According to Dr Motzer, although

hypertension 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.“I think there’s clear evidence that

the phase 2 safety profile has indeedbeen confirmed in phase 3,” said coin-vestigator 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. �


ASCO 2012 Meeting

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

Chicago, IL—Adverse events (AEs)related to chemotherapy for metastaticbreast cancer create a substantial eco-nomic burden that is primarily ex -plained by increased inpatient, outpa-tient, and pharmacy costs, said leadinvestigator Sara A. Hurvitz, MD,Director of the Oncology Breast Can cerProgram at University of Califor nia,Los Angeles (UCLA) Jonsson Compre -hensive Cancer Center and AssistantClinical Professor at UCLA School ofMedicine, who presented an economicanalysis at the 2012 Ameri can Societyof Clinical Oncology meeting.“An analysis of healthcare costs

stratified by the number of AEsreported by patients showed a cleartrend: the economic burden of AEsincreases with the number of AEsreported,” Dr Hurvitz said. The studyis the first to assess costs associat -ed with AEs during treatment formetastatic breast cancer.Patients were selected from the

PharMetrics Integrated Database, usingpharmacy and medical claims from>100 US health plans, representing >70million lives between 2000 and 2010.The eligible cohort included 3222

patients who used a taxane (ie, doce -taxel, paclitaxel) first-line, capecita binefirst-line, taxane second-line, orcapecitabine second-line. Patientstreated with both classes during thesame episode were excluded. The listof AEs included almost 2 dozen possi-bilities. AEs were seen in each of the 4study cohorts.

Incremental Monthly Costs

The incremental costs associatedwith chemotherapy-related complica-tions were estimated by comparing theaverage costs between the cohortswith and without AEs for the 4 treat-ment groups:• Taxanes first-line: AEs were associ-ated with a 38.7% increase inmonthly costs over patients without

AEs ($3547). These incrementalcosts were mainly driven byincreased inpatient costs and otherdrug costs (other than those forchemotherapy)

• Taxanes second-line: AEs were asso-ciated with a 69.5% increase inmonthly costs ($5320). Incrementalcosts were mainly driven by incre-mental pharmacy costs for chemo -therapy and other drugs

• Capecitabine first-line: AEs wereassociated with a 9% increase inmonthly costs ($4933). Incrementalcosts were mainly driven by inpa-tient and outpatient costs

• Capecitabine second-line: AEs wereassociated with an 82.9% increase inmonthly costs ($4933). Incrementalcosts were mainly driven by outpa-tient and inpatient costs.

Increasing AEs per Episode Led to

Higher Costs

The more AEs per episode, the

greater the cost of care, the analysisfound. For example, for taxane first-line therapy, the mean cost of a treat-ment without an AE episode wasapproximately $10,000, which rose toapproximately $11,000 in the setting of1 or 2 AEs, and to almost $15,000 in thesetting of >4 AEs.For second-line capecitabine, treat-

ment without an AE episode costapproximately $6000, but rose toapproximately $14,000 in the setting of>4 AEs.The average monthly costs per

type of AE were highest for skin toxicity with taxanes and for consti-tutional symptoms with capecita -bine, both approaching $16,000 onaverage.“Further research evaluating the

clinical and economic consequencesof chemotherapy-related AEs in aprospective manner can further char-acterize the effects seen here,” DrHurvitz concluded. �

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

—Robert Motzer, MD

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


2nd Conference

Second Annual Conference of the As -sociation for Value-Based Cancer Care.Patient navigation is a coordinated

process that addresses barriers toquality care by providing individual-ized assistance to patients, survivors,and families, and facilitating timelyaccess to services.Patient navigation is a way to

address healthcare disparities, and itserves as an antidote to the fragment-ed and complex healthcare system, MsPratt-Chapman maintained. The goalis to identify and eliminate barriers tocare, and to provide culturally compe-tent interventions based on specificpopulation needs.“We know that issues faced by

patients with cancer can have devas-tating consequences, and the health-care system at large is labyrinthine.Many patients must fight their waythrough this dysfunctional system,while trying to save their own lives,”she noted. “Navigation is not a cure-all, but it is an approach that helps.”

Evolution of Patient Navigation

Patient navigation was conceived in1990 by Harold P. Freeman, MD, whoobserved socioeconomic and racialdisparities for cancer care in Harlem.After access to screening and patientnavigation, 5-year cancer survivalrates improved from 39% to 70%(Freeman HP, et al. Cancer. 1989;63:2562-2569). These positive results ledto an expansion of the concept acrossthe cancer continuum and to the inclu-sion of families and caregivers.

Navigators now include nurses,social workers, trained laypersons,and community health workers whoserve in a variety of capacities at vari-ous points from screening into sur-vivorship. The roles of navigators andthe framework of the program atGeorge Washington Cancer Instituteare outlined in the Figure.“Navigation suffers from lack of

definition, but we are trying to anchornavigation in meeting each patient’sspecific needs,” Ms Pratt-Chapmansaid. “We are not fixing the system. Weare facing the reality of the system andhelping patients navigate a system weknow is broken.”Navigators educate individuals

about screening, diagnosis, and treat-ment; build partnerships in the com-munity; facilitate access to clinical tri-als; coordinate appointments withproviders; maintain communicationbetween patients and providers;ensure that medical records are avail-able for appointments; arrange forsupport services (ie, language, finan-cial, transportation, child care, homehealthcare); and help patients learn tonavigate themselves.Navigators, who are trained to rec-

ognize patients with special needs orbarriers to care, answer different needswithin the various clinical depart-ments. At George Washington CancerInstitute, there are navigators in radi-ology, in the breast care center, inhematology, and one navigator that isshared by urology and radiation on -

cology. These individuals meet week lyto discuss cases that may overlap. Ms Pratt-Chapman suggested that

attendees at the session focus on bar-riers specific to their institutions anddevelop the appropriate navigationstructure, with a clear scope of prac-tice for the navigators. “Delineatingthese roles can be key to your suc-cess,” she said. “The determination ofwho should navigate should be deter-mined by the skill level required.”

Current Impact, Future Trends

More than 30 US sites have beenevaluated by research programs fund-ed by the National Cancer Institute,the Centers for Medicare & MedicaidServices, and the Health Resource andServices Administration. These proj-ects showed that navigation signifi-cantly shortens the time to definitivediagnosis, reduces stress levels forpatients, increases satisfaction, andimproves care. There is some indica-tion that time to treatment may beslightly prolonged, although “webelieve this may reflect having secondopinions and an improved under-standing of treatment options,” MsPratt-Chapman suggested.As for future trends, Ms Pratt-

Chapman noted that institutionsaccredited through the Commissionon Cancer must develop and institutea patient navigation process through aphased-in approach by 2015. “You willbe asked to identify a patient naviga-tion process using existing staff or newhires, but you will need to be respon-sive to the needs of your population,and be regularly evaluated,” she said.This requirement may “fill in gaps”because of the oncology workforceshortage, she added.Policy papers are also in develop-

ment that should raise awareness on the institutional and national lev-els, she added, and should providean evidence basis for moving for-ward and to inform reimbursementpractices. �

Defining the Roles of Patient Navigation... Continued from cover

“Many patients must fight their way through this dysfunctional system,while trying to save theirown lives. Navigation is not a cure-all, but it is anapproach that helps.”

—Mandi Pratt-Chapman, MA

at a glance� Patient navigation will soon

be mandated by institutions

accredited by the Commission

on Cancer

� The goal of these programs is

to address healthcare disparities

by eliminating barriers to care

for underserved populations

� Get involved in delineating

the roles of navigators in your

institution to improve

the process

GWCI’s Framework for Longitudinal Patient NavigationFigure

GWCI indicates George Washington Cancer Institute.

Longitudinal Patient Navigation

Abnormal results/diagnosis Diagnosis Treatment Survivorship

Screening Navigation

Outreach

Education

Screening

Initial Contact

Treatment Navigation

Screening, abnormal finding, diagnostic resolution, treatment palliative care, end-of-life care, survivorship

Eliminate critical delivery gap for populationsexperiencing disparities

Provide seamless transition from screeningthrough treatment and survivorship

Survivorship Navigation

Rehabilitation


Evidence-Based Guidelines/Pathways Critical for Value-Based Benefit Design in OncologyBy Caroline Helwick

Houston, TX—There is no questionthat evidence-based guidelines andpathways are critical to the success ofvalue-based oncology, but not allstakeholders have an equal voice, saidCraig Deligdish, MD, Chief MedicalOfficer at Oncology Resource Net -works of America at the SecondAnnual Meeting of the Association forValue-Based Cancer Care. The goalsinherent in value-based oncology ben-efit programs include:• Improving outcomes• Enhancing efficiency for practicesand health plans

• Reducing the cost of care for prac-tices and health plans

• Simplifying and obviating the priorauthorization process

• Reducing the cost of care at the endof life

• Improving care, with a focus onvalue, outcomes, and fiscal pre-dictability

• Sustaining community-based care.“Clearly, we want to improve out-

comes and we want to reduce costs,but at the same time we need to thinkabout the patients who are often notrepresented in meetings such as this,”he said.“The question is, what does the

patient have to say about this?” DrDeligdish continued. “One day, wemay all be patients.”

The other participant often absentin these conversations, he added, isthe government, “which is the ele-phant in the room.” The future of

healthcare is being decided at the fed-eral level through the healthcarereform legislation. And on the statelevel, changes are also occurring.Many states are unloading theresponsibility for healthcare onto thecommercial payers, moving health-care from the traditional Medicaidprograms to managed Medicaid. Suchchanges cannot be ignored, he said.“We all know that chemotherapy is

costly, and there have been tremen-dous advancements in cancer thera-pies. What we really need to recog-nize is that the cost of drugs is onlyabout 20% to 23% of the overall spendfor the treatment of a patient withcancer. This is a fraction of the $100billion that is spent annually in theUnited States on cancer treatmentalone,” Dr Deligdish said.

Evidence-Based Guidelines and

Pathways: Features and Benefits

Evidence-based guidelines thathave been issued by organizations

such as the National ComprehensiveCancer Network and the AmericanSociety of Clinical Oncology help toensure standards and predictability inpatient care. The goal is not to insti-tute “cookbook medicine” but to“provide some order to what many ofyou see as a very chaotic approach,”Dr Deligdish said.Evidence-based guidelines offer an

established process for reviewingpathways and ensuring appropriate-ness and relevance. They are used tocreate evidence-based pathways thataim to provide value, even enhancedvalue, and generally at a reduced cost.Pathways not only apply to chemo -therapy but to supportive care, radia-tion therapy, molecular diagnostics,advanced illness, and other compon -ents of care.The many benefits of evidence-

based guidelines and pathways are clear: consistent delivery ofappropriate and cost-effective care topatients, more predictable and lowerpatient care costs, lower administra-tion expenses, less hassle for mem-bers and providers, less treatmentdelay, greater provider and healthplan efficiency, and elimination ofunnecessary services, according to Dr Deligdish.Although pathway programs may

appear relatively straightforward,

their integration is complex, he noted(Figure). The challenge is to take themost promising pilot programs anddemonstration projects and imple-ment them in a scalable fashion thatmakes an impact, Dr Deligdish added.

Options for Payers

Payers have a variety of options formanaging the overall value and cost ofcancer treatment: primarily, pharmacybenefit managers, specialty pharmacybenefit managers, radiology benefitmanagers, oncology benefit managers,and health plans. As medicinebecomes more complex and these pro-grams become increasingly common,they become integrated into the hospi-tal setting, where more care is nowdelivered. “This is probably not the most effi-

cient approach or the optimal place toreceive treatment,” he maintained,“because treatment takes longer andcosts 3 times as much as when deliv-ered in the community.”The overarching challenge, he said,

is for all those who manage patientcare and who aim to control costs tocollaborate. “If stakeholders do notfind a way to work together, inclusiveof the government, we will be in amuch worse situation than the one wehave today, and at a much highercost,” Dr Deligdish concluded. �

“What we really need torecognize is that the cost ofdrugs is only about 20% to23% of the overall spend forthe treatment of a patientwith cancer.”

—Craig Deligdish, MD

“If stakeholders do not finda way to work together,inclusive of the government,we will be in a much worsesituation than the one wehave today, and at a muchhigher cost.”

—Craig Deligdish, MD

Figure Pathway Integration

Data integrator

EAPprovider

Broker/consultant/actuary

Employer Eligibility file(monthly)

Incentive data

(to payroll)

Disabilityadministration

Employeesatisfaction

Internal datamanagement

PBM Health plan Benefits administration

EAP data(annually)

STD (quarterly)

FMLAPharmacy

claims (quarterly)

Medical claims(quarterly)

Demographics(weekly)

Wellness information

HRA screening(annually)

Disease managementComplex casemanagement(as needed)

Utilizationmanagement

Provider file

Worker’s compensation

AbsencesTime-keeping

system

Productivity

Benefit selections

EmployeesatisfactionEmployee

commitment(annually)

LTD (quarterly)

Satisfactionwith wellness

offerings (satisfaction

assessed butnot reported)

2nd Conference

EAP indicates employee assistance program; FMLA, Family and Medical Leave Act of 1993; HRA, health

risk assessment; LTD, long-term disability; PBM, pharmacy benefits management; STD, short-term disability.

©2012 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

Image: Colored scanning electron micrograph (SEM) of a lymphoma cancer cell.

One focus: discovering and delivering breakthrough medicines to combat cancer.

Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in

oncology worldwide — with more than 17 compounds in development for a broad range of solid and

hematological cancers.

Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease

pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition,

apoptosis, immunomodulators and hormone regulation.

We are dedicated to a strong partnership with the oncology community. Together we can make a

dramatic impact on cancer therapeutics over the next decade.

Houston, TX—“Collaboration, coordi-nation, data, and innovation are key to achieving value-based cancer care,”said Loreen M. Brown, MSW, VicePresident of Reimbursement andAccess Consulting, Xcenda, Ameri -sourceBergen Consulting Services.Speaking at the Second Annual

Conference of the Association forValue-Based Cancer Care, Ms Brownmade the following points about the“evolving market” of oncology: • Advances in science are leading toadditional, more targeted therapiesfor smaller population groups

• Cost pressures are leading to newand more restrictive coverage andreimbursement policies, although insome states mandates dictate reim-bursements

• Scrutiny of the value of new thera-pies is increasing

• Cancer is becoming a chronic dis-ease that requires more focus oncoordination and planning; cancersurvivors will number 18 million by2020, a 27% increase from 2010.

In the past, utilization managementmainly centered around prior authori-zation to ensure appropriate use perthe labeled indication. As oncologyevolves to a more value-based process,

coverage policies must be founded onvalue-based decisions that take intoaccount meaningful outcomes, com-parative effectiveness, and preferredtherapies per treatment pathways orguidelines, Ms Brown noted. The availability of multiple treat-

ment options, oral oncolytics, generics,and eventually biosimilars in additionto standard intravenous (IV) chemo -therapy drugs will further complicatethe decision-making process.

“Value” Varies by Stakeholder

Stakeholders perceive “value” dif-ferently within the various compo-nents of cancer care (Figure): • For patients, clinical trial data, reflect-ing efficacy and safety, matter most,followed by out-of-pocket costs

• For providers, value is an out-growth of practice economics

• For payers, value is determined bythe net price of all aspects of treatment.In the current oncology system, bal-

ancing these priorities across stakehold-

er lines is challenging, Ms Brown said.Today’s system pays providers for vol-ume of services and drugs, lacks theability to collect and/or capture datafor analysis, and offers no real basis forevaluating outcomes or value in a clini-cal, financial, or quality sense. “Withoutthese things, it is hard to determine out-comes for value,” she said.From the provider’s perspective,

reimbursement is diminishing, patientout-of-pocket costs are increasing,shrinking margins are greatly impact-ing uncompensated services, reim-bursement for managing self-admin -istered therapies is lacking, andrisk-/case-based reimbursements (ie,Medicare Shared Savings Program) arepart of the picture.In a 2011 survey of oncologists,

Xcenda researchers asked how route ofdrug administration influences choiceof therapy. Although 38% said it didnot influence their selection, 17% pre-ferred IV products because the copayis less for the patient, and 7% preferredIV products because they were eco-nomically beneficial to their practices.Oral agents were preferred by 13% as aresult of patient convenience.“These were all rational responses,

but they were different due to compet-ing priorities,” Ms Brown said. To illus-trate this at the conference, she present-ed hypothetical treatment choicesrepresenting different reimbursement,copay, and other cost variables thatmay be preferred by some stakeholdersfor different reasons (Table). “Prioritiesare different, based on numbers likethese,” she commented.At the same time, administrative

complexity is a growing problem espe-cially for oncology practices. Payersrequire more management (priorauthorizations, treatment pathways,and guidelines), and there is increaseduse of health information technologyresources requiring electronic medicalrecords and e-prescribing, decision-support tools, drug inventory cabinets,and data analytics tools.“Practices that lack a skilled admin-

istrator are limited in their ability to run an efficient practice,” sheobserved. “This is increasing the num-ber of mergers, hospital affiliations,and practices that are closing.”

Collaborative, Tiered Approach

in Oncology

AmerisourceBergen, in partnershipwith IM Solutions and US Bioservices,has developed a collaborative and


2nd Conference

Collaborate, Coordinate to Achieve Value in OncologyAmerisourceBergen taking a tiered approach to value-based care By Caroline Helwick

“Collaboration, coordination,data, and innovation are keyto achieving value-basedcancer care.”

—Loreen M. Brown, MSW

Table Hypothetical Treatment Choices

Weekly genericEvery-3-week

generic Weekly brandEvery-3-week

brandRetail-

dispensed oralIn-office–

dispensed oralDrug reimbursement $60/wk $95/wk $1600/wk $4200/wk $0 $667/mo

Administratorreimbursement $150/wk $210/wk $150/wk $150/wk $75/visita $75/visita

Total payercost $1900/12 wk $915/12 wk $15,750/12 wk $13,050/12 wk $15,000/12 wk $15,000/12 wk

Drug margin $32/12 wk $17/12 wk $865/12 wk $750/12 wk $0 $2000/12 wk

Patient copay $380/12 wk $185/12 wk $3150/12 wk $2600/12 wk $1500 $1500

Visits, N 9 3 9 3 3 3

aOne mid-level evaluation and management code per visit.Continued on page 21

Value Varies by StakeholderFigure

ICER indicates incremental cost-effectiveness ratio.

Patient out-of-pocket costAdherence, dosing, tolerability,

convenience

Trial and real-world data relative tocomparators in payer-specific setting

(effectiveness and safety)

Trial data (range of end points) relative to comparator (efficacy and safety)

Mechanism of action

Net price

ICER

Patient

Mechanism of action

Practice economics

Patient adherence

Net price

Net price

ICER

Physician

Mechanism of action

ICER—indirect offsets orexternal data

Direct cost offsets determinedthrough reliable data

Adherence, dosing, convenience

US Commercial Payer

High

Relativeperceivedvalue

Low

Variable

Houston, TX—Payer-sponsored pro-grams that promote appropriate end-of-life care are beneficial to all stake-holders, according to Ira M. Klein,MD, MBA, Chief of Staff to the ChiefMedical Officer, Aetna OncologyStrategy. At the Second Annual Conference of

the Association for Value-Based CancerCare, Dr Klein discussed advanced-care directives and emphasized thatthe patient and family “should be atthe center of what you do.”Studies have shown that although

70% of Americans express the wish todie at home, only 25% actually do.And 90% of terminally ill patients withcancer cite their homes as their pre-ferred site of death, yet only 33% actu-ally die there, Dr Klein noted.“It is not a mystery to us when death

is approaching. We have more thanadequate clinical signals,” he said. “So,what is going on?” Among Aetna mem-bers, only 1% generate 33% of its claimcosts. When these patients develop ter-minal conditions, he noted, “We knowwho they are, their families know, yetthey do not end up in the right place.”“Just having a signed advanced-care

directive does not mean that all partieshave ‘done their duty,’” Dr Kleinpointed out. “Unfortunately, discus-sions with patients and familiesregarding terminal care and availableoptions happen too late or not at all.”Lacking a more structured approach

to end-of-life care, patients are treatedwithin the traditional and expensiveframework that is not beneficial, DrKlein concluded.

Aetna’s Approach to

End-of-Life Care

Aetna offers an “innovative and

member-centric” case managementprogram that combines patient sup-port with benefit design. Key compo-nents are the use of an outsourced ven-

dor for patient counseling on end-of-life issues, an insourced high-intensitycomplex case management program,and transition to “compassionate care”

that allows patients interventions toimprove functional status. The outsourced Vital Decisions

Living Well Program was founded onthe knowledge that end-of-life inter-ventions increase feelings of empower-ment for the patient, reduce hospitaladmissions and emergency depart-ment visits, and reduce costs.“If you employ these services, you

do not shorten patients’ lives; you in -crease patient satisfaction, you improvepatients’ attitudes, you resolve con-flicts within families, and you usefewer resources,” Dr Klein said. “Weknew this, we saw end-of-life discus-sions as an unmet need, and we decid-ed to do something.”The Vital Decisions Living Well

Program acts as a catalyst for planningand decision-making. The vendor,Vital Decisions, is a bioethics services


2nd Conference

Involving the Patient in End-of-Life Care Decisions:Aetna’s Oncology StrategyBy Caroline Helwick

Collaborate, Coordinate to Achieve... Continued from page 20

tiered approach to oncology caredelivery. The program coordinatespractice networks in multiple stateswith national and regional/local pay-ers, and integrates with US Bioservicescontracts and capabilities for oraldrugs, injectables, and medicationtherapy management.The first tier, the program’s founda-

tion, includes an innovative compensa-tion program, provider/payer portal,reporting and analysis, and nucleustreatment pathways. The second tier,“value acceleration,” includes an

advanced-care planning program, stan-dard nurse triage program, and nucleusdata exchange. The third tier, “program enhancements,” features aquality initiative program and a patientportal for educational purposes.The model “pulls together much

more data than you see on a claimsform,” she said. “The payer andprovider forum is useful for exchangeof information. It is all implementedelectronically, and it interacts with thedrug ordering process and practicemanagement software. The innovative

compensation program takes the mar-gin out of the drug and gives a man-agement fee. There are variations onthis theme, but, in general, this is whatwe are doing.”Ms Brown concluded that “success”

in achieving value in cancer care willrequire programs such as these thatare developed through provider andpayer (and even patient) partnerships.“Effective, evidence-based tools thatwork in concert with key stakeholdersdo exist,” she said, “and are continu-ing to evolve.” � Continued on page 22

Vital Decisions Living Well Program Goal and StrategyFigure 1

Outsourced programCreate members who proactively participate in their care by identifying, communicating, and

incorporating their priorities into current and future care decisions

Current medical situation

Future medical situation scenarios

Current/future care decisions and alternatives

Transition points

Communication vehicles and support

Create an informed patient

Create an active patient

Stage-based behavioral change strategies and activities embedded in process (Prochaska transtheoretical model)

Active on current and future scenarios

Integrate priorities into care decisions

Care decisions that support priorityachievement

Current and future

Develop plan, communicate, and revise

Ensure effectuation of priorities throughout end of life

Integrate with providers

Identify end-of-life priorities

Independence, interactivity, comfort

Current and future

Identification of the Most Highly Fragile Members Earlier in the ProcessFigure 2

New process: member-centric high-intensity complexcase management

Algorithm identifieshighly fragile members (1-2 per 1000)

Home visit/assessment initiated

Case managerbegins to work closely with providerto support member

Compassionate care benefit enhancement (commercial)

Opportunity to improve case managementfor highly fragile members

Current process

Nurse case manager manually identifies member forcompassionate care

Member enters hospice ifchooses

12 months 9 months 6 months 3 months 1 month

company staffed by highly trainedsocial workers. For Aetna, the goal isto create members who proactivelyparticipate in their care by identifying,communicating, and incorporatingtheir priorities into current and futurecare decisions (Figure 1, page 21). Thecounselor helps patients becomeempowered through understandingand choosing among options for care,and developing a plan they can take totheir physicians. “Patients are often in the back pas-

senger seat in this journey, and theytell their physicians to ‘just drive.’When patients have no directions forwhere the journey is going, they do notalways get the best plan for care.Under our program, this changes. Thepatient says ‘I have a plan,’ and thephysician treats in a manner consistentwith this.” Physicians as well as pa -tients appreciate the clarity inherent inthis process, Dr Klein added.From claims data, patients are iden-

tified for the Vital Decisions programon the basis of end-of-life clinical trig-gers. For patients with cancer, it is usu-ally when metastasis develops thatperformance status (Eastern Coop -erative Oncology Group Per formanceStatus ≥2 or Karnofsky PerformanceStatus ≤70) declines or that patientsbecome dependent in activities ofdaily living. The timing is such thatpatients can be engaged in discussionswhen there is “some certainty aboutthe finality of mortality yet the func-tional status is still high,” he said.Vital Decisions is given the patient’s

name, and the company then obtainsthe physician’s approval and thepatient’s consent to initiate the service. The second component—the high-

intensity complex case managementprogram—is also part of Aetna’s goalof early identification of fragile mem-bers and referral to the compassionatecare program (Figure 2, page 21). Theprogram is a member-centric modelwith high-touch and face-to-facepatient assessment by staff with inten-sive training in motivational inter-viewing, end-of-life issues, and cultur-al competency.When appropriate, patients are

entered into the compassionate careprogram, which “gives patients and

their families a landing place wherethey do not feel abandoned as theysometimes do going into hospice,” hesaid. The program provides traditionalhospital measures of support, painmanagement, and symptom control,with psychologic and spiritual supportas well. “We now have the right benefit for

the right condition. We are matchingthe solution to the problem,” Dr Kleincommented. Results of a 3-year study of program

participants show a >70% increase inhospice use, and an almost doubling inthe average number of days in hos-pice; for Medicare patients, an 82%reduction in acute hospitalization daysand an 88% reduction in intensive careunit stays; and considerable reduc-tions in emergency department visitsfor all program participants.

Lessons Learned about

End-of-Life Care

Dr Klein shared lessons learnedfrom Aetna’s experience with struc-tured end-of-life counseling services:• Physicians should direct end-of-life

care, not payers, but payers canfacilitate care by providing tools forpatients to be “proactive”

• Payers should create an environ-ment in which bioethics discussionshappen, in an “opt-in” permissivemanner

• Physicians welcome assistance inengaging patients in end-of-life carediscussions

• Patients value the availability ofskilled and focused bioethics coun-

seling services• The guiding principle for these serv-ices is 2-way communication

• A dedicated hospice benefit re -moves barriers and improves thedelivery of needed services.“What we are doing is empower-

ing patients, not directing them.When they see their oncologists, theyare ready to have these discussionsand they value this,” Dr Klein point-ed out. �


2nd Conference

Involving the Patient in End-of-Life Care Decisions... Continued from page 21

Talking to Patients about End of LifeOne of the biggest challenges in oncology is around end-of-life care and limiting

waste on futile therapy. At the Second Annual Conference of the Association forValue-Based Cancer Care, Roy A. Beveridge, MD, Chief Medical Officer of USOncology Network/McKesson Specialty Health; Peter G. Ellis, MD, DeputyDirector of Clinical Services and Associate Chief Medical Officer for theUniversity of Pittsburgh Cancer Centers, Pittsburgh, PA; and Craig Deligdish,MD, Chief Medical Officer at Oncology Resource Networks, Orlando, FL,responded to questions on this topic.

Q: How do you engage physicians to discuss this with their patients?Dr Beveridge: Changing physician behavior is difficult. We have found

that no one likes to have end-of-life discussions with patients. Physiciansdon’t like to do it, nurse practitioners don’t like to do it, nurses do not liketo do it. To do this properly in terms of scale, the practice has to have a pow-erful educational methodology built into the information technology infra-structure, so that providers cannot not do it.And the responsibility should not be placed solely on the physician, but

should be the responsibility of a manager within a practice or group, per-haps a nurse practitioner. I think it is a team approach. And it is not just oneconversation but multiple conversations. In practices that implement thissuccessfully, we find that this does eventually change the global attitude ofthe oncology practice environment.I also want to put a plug in for a system like pathways for educating

physicians. Many of the pathway programs have written into them somealgorithms for end-of-life conversations.Dr Deligdish: There really is no one answer to how best to prepare

patients for the end of life and how to educate providers for these conversa-tions. There are many different issues involved. Fortunately, there are organ-izations within the healthcare system that have individuals who are special-ly trained to have those conversations with patients.The truth is that there is so much going on in a busy oncology practice, it’s

unrealistic to think providers will be able to sit down with the patient anddevote the time necessary for this. It is not one conversation, but a series. Itis not something we can generally accomplish in the span of 15 minutes.These patients have to be handled in a more sophisticated way by nursesand social workers in a team approach.

Q: When do you first introduce the topic of goals of treatment?Dr Ellis: When a chemotherapy regimen is ordered, it should be

explained to the patient and documented whether this is for curative or pal-liative intent. This begets the entire discussion of end of life with the patient.At the University of Pittsburgh and Via Oncology, whenever a patient withmetastatic disease is placed on a chemotherapy regimen that question isasked. Therefore the conversation is hopefully prompted.Dr Beveridge: One needs to be moderately sophisticated in determining

when that conversation should occur. If you have stage IV pancreatic ornon–small-cell lung cancer you had best have that conversation early. Butwith breast cancer and myeloma, for example, patients are living years andyears with stage IV disease. It has to be individualized.

“Although 70% ofAmericans express the wish to die at home, only25% actually do. And 90% of terminally ill patients with cancer cite their homesas their preferred site ofdeath, yet only 33% actuallydie there.”

—Ira M. Klein, MD, MBA

Houston, TX—Hard times are gettingeven tougher for small oncology prac-tices, said Leonard Natelson, ChiefExecutive Officer, Hematology/On -cology Associates, Rockland, NY, at the Second Annual Conference ofthe Association for Value-BasedCancer Care. Hematology/Oncology Associates

is an independent practice of 5 physi-cians, which in the Northeast region isconsidered “large,” Mr Natelson said.He cited 5 main challenges facing com-munity oncologists today: • The gridlock in Washington, DC,and the lack of progress in fixing thesustainable growth rate (SGR)

• Drug shortages• Implementation of HIPAA (HealthInsurance Portability and Account -ability Act of 1996) 5010 and ICD-10(International Classification of Dis -eases, Tenth Revision)

• Reduced reimbursements• Leadership in the transformation ofcancer care.

The inability to settle the SGR con-tinues to plague practices such as Mr Natelson’s. With a “lame duck”Congress around the bend, progressthis year seems doubtful, he said. Inaddition, should the SGR not be“patched” again, providers will be hit

with a 30% cut in reimbursement inJanuary 2013, and this, compoundedby other potential economic difficul-ties, will worsen the payment delaysthat continually threaten the fiscalviability of oncology communitypractices.Mr Natelson suggests that using

bundled payments is not the solutionto the current fiscal unpredictability,because this approach eliminates flexi-bility. “With the patients we see, thiswould be problematic,” he said. Nor is hospital-based cancer care

the answer. “Does Congress reallybelieve that pushing physicians to ahospital setting will cut costs forMedicare? Costs are 34% higher in thehospital for the same type of patientvisit,” Mr Natelson said. “This wastried 15 years ago, and it did notwork” so care was pushed back intothe community. “This time, therewould be fewer community practicesto push back out to.” Further driving practice inefficiency

of community practice is the drugshortage crisis. In 2005, 61 drugs werein short supply; this number nowapproaches 250. The causes includelow profit margins for generic drugs,few manufacturers, and poor qualitycontrol. “I am chasing my tail all thetime,” Mr Natelson said.Conversion difficulties with HIPAA

5010 compliance and the future ICD-10coding system create additional work,without increasing revenue. “My prac-tice spent $30,000 on information tech-nology infrastructure upgrades, andthis does not generate more revenuefor me, but it does generate expense. Iam also hearing that practices thathave converted to 5010 are gettingerroneous denials of claims, which isdelaying payments,” he said. “Somepractices are still waiting for paymentsfrom November.”

A decrease in reimbursement is anobvious challenge. Of Mr Natelson’spractice’s drugs, 46% are “underwater,” and this makes it “much morechallenging to provide the kind of carewe want to provide,” he said. “Weneed wiggle room so that our physi-cians can spend time with patients.” His practice is also experiencing

more denials caused by medicallyunlikely edits. “Any time we have topay for a drug up front, and we do notget reimbursed in time to pay that bill,these denials put us further behind,”he added.The last of the 5 issues considered

most critical by Mr Natelson pertainsto leadership in the transformation ofcancer care. The question is whether

community-based oncology will con-tinue to be relevant in the delivery ofcancer care, he said. “Two hospitals are after me, as is

another large consortium. I do notwant to be owned by a hospital. Thiswill only drive up cost, not improvethe quality of care I give,” he main-tained. Ironically, community oncology is

in the best position to operate effi-ciently and “bend the cost curve,” MrNatelson said. “We are a small busi-ness. It is more real time in communi-ty practice. We have to watch whatwe spend, what we take in, make surepeople pay us. We do not have deeppockets like the large institutions thatget by if they are not paid for 6 weeks.I would hate to see all oncology prac-tices move to the hospital setting, andthen we figure out that it costs more—which is something we alreadyknow.” �

Should the SGRnot be “patched”again, providerswill be hit with a30% cut inreimbursement in January2013.

—Leonard Natelson

at a glance� Cost concerns and reduced

reimbursement, as well as who

will lead the transformation of

cancer care, threaten the

survival of small community

centers

� Costs are 34% higher in the

hospital than in community

practice for the same type

of service

� Hospitals are seeking to

incorporate small practices into

their business platform for

financial gains

� Ironically, community oncology

is in the best position to offer

efficient cancer care and “bend

the cost curve”

Tough Times for Small Oncology PracticesHow one Northeast practice views its challenges By Caroline Helwick

“Two hospitals are after me,as is another largeconsortium. I do not want to be owned by a hospital.This will only drive up cost,not improve the quality of care I give.”

—Leonard Natelson

2nd Conference



2nd Conference

Houston, TX—“The key question oneveryone’s mind is, how do we mone-tize the value of pathways?” said PeterG. Ellis, MD, Deputy Director ofClinical Services and Associate ChiefMedical Officer, University of Pitts -burgh Cancer Centers, PA, at theSecond Annual Conference of theAssociation for Value-Based CancerCare. Clearly, Dr Ellis said, the use ofpathways has internal practice value.Pathways:• Drive consistency and quality ofcare for patients

• Lower bad-debt risk by reducingpayer denials

• Increase practice efficiencies throughuniformity of care

• Reduce emergency department visits

• Have the potential to reduce med-ical errors

• Support clinical trial participation• Serve as marketing tools for practices. Pathways do all this while achieving

clinical outcomes that are at leastequivalent to off-pathway practices.“We say that pathways are good for

patients, good for physicians, andgood for the insurance companies.Why isn’t everyone using them?” heasked.Providers make a financial invest-

ment in using pathways, and thesepathways produce savings that accrueto payers. “So shouldn’t payers haveskin in the game?” Dr Ellis asked.He suggested that, “in a perfect

world,” payers would increase exist-ing fee schedules or pay managementfees to physicians, contract for gainshare on savings, steer patients topractices that use pathways throughpreferred network status, and modifypatients’ benefit designs to allow forlower copays or coinsurance for usingpractices with pathways. Although these things are all pos -

sible, they do not happen, mostlybecause:• The majority of payers’ membersare self-insured: new program costs

must be approved by their cus-tomers; otherwise, savings gostraight to the customer, but costsare borne by the plan

• Cancer is not a top priority for payers

• Some payers think oncologists arealready paid too much and shouldnot need more money for providing“quality”

• Payers are not accustomed to out-sourcing utilization management tothe providers themselves

• Pathways is a novel program in apolitically sensitive area (cancer);payers do not understand it or whoin their organization “owns” thepathways or will oversee it

• Payers want easily scaled solutionsbrought to them by companies thatoffer a suite of products and speaktheir language.As a practicing oncologist, Dr Ellis

pointed out how operating an oncolo-gy practice is expensive in ways thatpayers may not appreciate. He sug-

gested ways that providers can con-tract with payers to help them stay incommunity practices.

Opportunities to Recoup the

Costs of Practice

Providers could try to avoid im -pending rate cuts or extend their cur-rent satisfactory reimbursement rates,by showing payers how they are“doing things better,” he said. Theycould enlist payers in attempting toreduce their administrative burden byeliminating precertifications andprior authorizations. Providers couldtry to prevent the payer from pullingdrugs out of the practice via specialtypharmacy or infusion centers, andthey could try to avoid reverse ratedecreases.“But practitioners should be careful

what they wish for,” he cautioned. “Ifpayers move forward and contractwith third-party vendors for path-ways-type programs, is this always agood thing for oncology practices andpatients?” he asked.

The result could be that multiplepayers require multiple pathways in asingle practice, which would be com-plicated logistically and ethically, andcould lead to the kind of variabilitywithin practice that is never beneficial,he said.Practices may be better served to

select and implement the pathwaysprogram that they want, and usethem to preempt payer-imposed pro-grams, Dr Ellis suggested. Physician-

driven pathways are likely to offer amuch larger value proposition.

Healthcare Reform Trends Will

Affect Oncology Practices

The healthcare reform is also goingto impact oncology practices by: • Shifting responsibility for total costof care to accountable care organiza-tions (ACOs)

• Rewarding medical home practicesfor managing the entire spectrum oftheir patient’s care, including costs

• Consolidating practices to ensureleverage with payers

• Encouraging hospital acquisitionsof oncology practices.These situations offer pathways con-

tracting opportunities. Hospital/pri-vate practice affiliations will also needpathways, he noted. Physicians whohave experience in running their ownpractices are well equipped for imple-menting programs (ie, pathways) thatwill drive quality and savings and thatwill unite the various groups withinthe system; they can be financiallyrewarded for this, he suggested.Pathways can also be used with

nonaffiliated oncologists to helpdevelop a clinically integrated net-work that will be able to contract bet-ter with payers.Pathways will also help a patient-

centered medical home deliver stan-dardized and efficient care. Medicalhomes that do not manage patientswith cancer will outsource this to thepractice that can demonstrate qualityof care at the lowest cost. “That is apathways practice,” Dr Ellis noted.Similarly, oncologists will partici-

pate in ACOs, either directly or byreferrals, and those practices withpathways will be able to prove quali-ty and will likely “win the bid” to bethe preferred oncology providers.Dr Ellis emphasized that pathways

will help providers prove their valueto key stakeholders and will ensurethe viability of their practices for thefuture. “Take control before someoneelse does,” he suggested. �

Pathways Offer Providers a True Value Proposition They can also help prove their value to key stakeholders By Caroline Helwick

“We say that pathways are good for patients, goodfor physicians, and good for the insurance companies.Why isn’t everyone using them?”

—Peter G. Ellis, MD

“If payers move forward andcontract with third-partyvendors for pathways-typeprograms, is this always agood thing for oncologypractices and patients?”

—Peter G. Ellis, MD

“The most significant value to all attendees was being able tospeak, in both public and private forums, with many of the otherattendees all in one place. On this theme, we should always seek outdiverse stakeholders in the oncology care delivery process and notshy away from controversy. The crowd loves it!”—Ira M. Klein, MD, MBA, FACP

�� Editor in ChiefSagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of Medicine

Editor in ChiefStephanie A. Gregory, MDThe Elodia Kehm Chair of Hematology Professor of MedicineDirector, Lymphoma ProgramRush University Medical Center/Rush University

Topics include:• Newly Diagnosed Patients• Maintenance Settings• Transplant-Eligible and -Ineligible Patients• Retreatment Settings• Bone Health

Newsletter Series

�� ™

��

Topics include:• Mantle Cell Lymphoma• Follicular Lymphoma

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AccreditationThese activities will be accredited for physicians, nurses, and pharmacists.

For complete accreditation information, please refer to each activity.

This activity is jointly sponsored by Medical Learning Institute, Inc.and Center of Excellence Media, LLC.

ALL NEW CONTENT FOR 2012

YOUR QUESTIONS ANSWERED

COEKsize71612AskExperts

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Spectrum Pharmaceuticals.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company

and Celgene Corporation.

� ��

expand Medicaid to a larger portion of the population (and Congress’sauthority to penalize states that didnot wish to participate in the expan-sion). Although the Court upheld theauthority of Congress to expand theMedicaid program to states that want-ed to participate, the Court also heldthat Congress could not withholdexisting Medicaid funds from states inan effort to penalize a state’s refusal toparticipate in the expansion.What does the decision mean for the

oncology community? First and fore-most, the path to implementation ofthe ACA will move forward. Programsthat promise to have the most impacton the cost–value debate in oncologywill progress: the Independent Pay -ment Advisory Board, the Patient-Centered Outcomes Research Insti tute,and other cost-saving institutions willcontinue their task of finding the mostvalue in healthcare dollars. Oncologistscan expect their patient pools to rise asmillions more Ameri cans gain access tohealth insurance through state healthinsurance exchanges.The question of the future Medicaid

expansion, however, looms large in thewake of the decision. Under the ACA,Medicaid eligibility was expandedand simplified, beginning in 2014, bycreating an overarching Medicaid eli-gibility category for all individualsaged <65 years with incomes less than

133% of the federal poverty level whomeet citizenship/lawful US status andstate residency requirements and who do not meet any of the program’sother multiple categorical groupings.Although the Court ruled that Con -gress is allowed to expand Medicaid tocover the new population underCongress’s spending powers, a major-ity also ruled that states that do notwish to participate in the Medicaidexpansion cannot be penalized for thisdecision by having their existing

Medicaid funds withheld.It remains unclear whether states

will proceed with the planned expan-sion or opt for a smaller Medicaid pop-ulation. On the one hand, the directcost to states in expanding eligibility islimited because the federal govern-ment will fund the vast majority ofthese costs. On the other hand, 6Repub lican governors have alreadypublicly stated that they will opt out ofthe expansion. Whether this is politicalposturing or a political reality remains

to be seen. What is clear, however, isthat until the issue of the Medicaidexpansion is solidified, oncology

providers and manufacturers remainin limbo. The expansion offers an extended

patient population (albeit with a less-than-generous payer) and a moresimplified eligibility system. Shouldseveral states begin to opt out of theexpansion, this national eligibilitysystem will become a patchwork ofdifferent eligibility standards and aheadache for oncologists. Guidance is expected from the Centers forMedicare & Medicaid Services in thecoming months, which will provideanswers to many of these questions.The ultimate decision of whether astate will participate in the expan-sion, however, may not come forsome time. �


Health Policy

Oncology Genetic Testing: Pharmacists’ Knowledge Gap San Francisco, CA—Knowledge ofpharmacogenomics—the genomic fac-tors contributing to individual vari-ability in response to drug therapy (orpersonalized medicine)—enhances theability to diagnose, prevent, and treatdisease, especially a variety of cancers.The correct application of pharma-cogenomics to patient management isessential for providing cost-effectivecare, but many providers, includ -ing physicians and pharmacists, are lacking appropriate knowledge of the science. Other barriers includelack of transparency in clinical utilityand in appropriate reimbursementstrategies.At the 2012 Academy of Managed

Care Pharmacy annual meeting, AngelaLuong, PharmD, and colleagues atOPTUMInsight described the results oftheir survey of pharmacists regardingtheir knowledge of genetic testing and

utilization strategies. A total of 19 pharmacists at 4 dif-

ferent managed care organizationsresponded to the survey; theirresponses revealed a basic lack ofknowledge of pharmacogenomics.The majority (84%) of respondentsagreed or strongly agreed that phar-macogenomics will have an impacton healthcare expenditures andpharmacists should have a good

knowledge base of related drug ther-apies and tests; however, they admit-ted they did not have much educa-tion in this area. Overall, 95% ofparticipants scored <60% on a phar-macogenomics test.In addition, knowledge of pharma-

cogenomics does not appear to imme-diately have a direct impact on patientcare or benefit design. Only 47% ofrespondents said their plan requires

prior authorization (PA) for the use of the US Food and Drug Admin -istration–approved companion diag-nostic test for vemurafenib comparedwith 58% of respondents whose plansrequire a PA for the companion test forcrizotinib. By contrast, only 16% of respon-

dents said their plans require testingfor HER2 mutation before prescribingtrastuzumab compared with 58% ofrespondents whose plans do notrequire testing and 26% (n = 5) whodid not know whether their plansrequire such testing.Furthermore, the majority of re -

spondents did not know whethertheir plans had reimbursement poli-cies related to pharmacogenomics.Overall, this survey reveals gaps inpharmacists’ knowledge of personal-ized medicine utility and its relationto benefit design strategies. �

The majority (84%) of respondents agreed or strongly agreedthat pharmacogenomics will have an impact on healthcareexpenditures and pharmacists should have a goodknowledge base of related drug therapies and tests;however, they admitted they did not have much education in this area.

AMCP 2012 Annual Meeting

The Affordable Care Act... Continued from cover

What does the decision mean for the oncology community?Oncologists can expect their patient pools to rise, as millions more Americans gain access to health insurancethrough state health insurance exchanges.

Should several states beginto opt out of the expansion,this national eligibilitysystem will become apatchwork of differenteligibility standards and aheadache for oncologists.

Ross D. Margulies, JD, MPH Jayson Slotnik, JD, MPH

See also pages 28, 30

“Managing patients with myeloma means staying current.”

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Vemurafenib Does Not Impact Health Plan BudgetBy Caroline Helwick

San Francisco, CA—Although theupfront cost of vemurafenib is high, itsuse to treat patients with metastaticmelanoma actually results in a cost-savings per health plan member permonth (PMPM), according to ananalysis presented at the 2012Academy of Managed Care Pharmacyannual meeting.In a hypothetical health plan of

500,000 enrollees, the use of vemu-rafenib for the treatment of patientswith BRAF V600E mutation is cost-saving by $0.04 PMPM, reportedWilliam B. Wong, MS, PharmD, of theUniversity of Washington, Seattle. “Overall, our findings imply that

providing vemurafenib therapy willhave relatively minimal budget impactand may possibly be cost-saving,” DrWong said.The BRAF inhibitor vemurafenib is

designed to inhibit the V600E-mutatedform of the BRAF protein, which playsan important role in progression of thisdisease. The drug was approved lastyear for patients with BRAF V600Emutation–positive unresectable ormetastatic melanoma. For this study,researchers developed a budget im -

pact model as a tool that can be usedby healthcare plans to assess the budg-etary impact of covering vemurafenibfor treatment-naïve and previouslytreated patients.

The researchers considered 2 hypo-thetical scenarios when (1) vemu-rafenib is not a treatment option formelanoma with BRAF V600Emutationand (2) vemurafenib is a treatmentoption in treatment-naïve and previ-ously treated patients, and is useduntil disease progression or unaccept-able toxicity for a proportion of eligiblepatients.The model was based on a health

plan with 500,000 enrollees; the esti-mated annual costs were based on sev-

eral variables of treating this eligiblepatient population. Patients who tested positive for the

mutation received vemurafenib firstline and other agents as second andthird line on progression. If they testednegative, they never received vemu-rafenib but did receive alternativetreatments. Patients who were not test-ed received alternative agents butwere tested for the mutation after sec-ond-line treatments failed. If appropri-ate, the patients received vemurafenibat that time. Cost data sources included the

Analysource drug database and 2011Centers for Medicare & MedicaidServ ices national payment rates.

Cost Impact

The analysis found that 6.6 cases ofmetastatic melanoma (stage IIIC unre-sectable and stage IV) were expected ina 500,000-member plan annually, in -cluding 4.9 new cases and 1.7 recurrentcases. The total costs and PMPM costswere $1,215,838 for patients in scenar io1 who did not receive vemurafenib and$978,129 for those in scenario 2 whowere treated with the drug.

The results were relatively sensitiveto the proportion of patients receivingipilimumab (also recently approvedfor the first-line treatment of metastat-ic melanoma), the cost of ipilimumab,the proportion of patients receivingvemurafenib, the percentage of pa -tients positive for the V600Emutation,and the percentage of patients receiv-ing first-line treatment.Dr Wong acknowledged that the

model only includes therapies that areapproved by the US Food and DrugAdministration and are recommendedby the National ComprehensiveCancer Network guidelines, but hesaid that “the effect of excluding sometherapies is likely to be minor, sincethe proportion of patients receivingthese treatments is small.” Unresectable stage IIIC patients and

patients with recurrence after ≥5 yearswere not included, because of thesmall population sizes. The model didnot consider efficacy beyond its imme-diate impact on expenditures, and thedistribution of patients estimated toreceive these treatment options isbased on market research dataobtained by surveys of physicians. �

“Overall, our findings implythat providing vemurafenibtherapy will have relativelyminimal budget impact andmay possibly be cost-saving.”

—William B. Wong, MS, PharmD

Does CMS’s Coverage Decision for Sipuleucel-T Herald More Restrictive Policy?San Francisco, CA—In its national cov-erage decision (NCD) for sipuleucel-Tin the treatment of advanced prostatecancer, the Centers for Medicare &Medicaid Services (CMS) left the cov-erage decision for any off-label use ofmedications to the discretion of thelocal Medicare contractors, citing anabsence of data on which to make acoverage decision. Charles A. Stevens, JD, MBA, Vice

President and General Manager ofCommercialization Strategy at ParexelConsulting, Waltham, MA, and col-leagues suggested at the 2012Academy of Managed Care Pharmacyannual meeting that this could be anemerging trend for future expensivetherapies.“Budget concerns, the high price of

new products, and widespread off-label use of new therapies have com-bined to place tremendous pressure onthe CMS as it evaluates new drugs andbiologics under its NCD process,”observed Mr Stevens and colleagues ina poster presentation. Their goal was to assess how CMS

may exercise various NCD options to

control drug coverage in light of therecent coverage concerns for sipuleu-cel-T, a high-priced vaccine for castra-tion-resistant prostate cancer that islikely to be used off-label, Mr Stevensnoted. The 4 factors that lead to anNCD review by CMS are:• The price of the drug• Lack of the drugmaker’s communi-cation with CMS

• Data sharing between the US Foodand Drug Administration and CMS

• Private versus payer concerns. In addition, there are 5 options for

CMS related to an NCD: • Coverage• Coverage with evidence development• Coverage for on-label use only, andno off-label coverage

• More restrictive coverage impactingon on-label use

• Lack of coverage of the drug.An analysis of NCDs showed that

CMS has historically regulated med-ical devices using the NCD processmore often than for drugs or biologicswhen there has been a concern overunwarranted product utilization thatincreases costs over existing products

without added benefits, Mr Stevensand colleagues noted. These decisionshave led to restricted coverage forsuch products. In the case of sipuleucel-T, the CMS

review resulted in an NCD thatallowed coverage only for theapproved-label use of this drug,reserving off-label coverage decisionsfor local contractors. Effective for services performed on

or after June 30, 2011, CMS proposedthat “the evidence is adequate to conclude that the use of autologouscellular immunotherapy treatment—sipuleucel-T—improves health out-comes for Medicare beneficiarieswith asymptomatic or minimallysymptomatic metastatic castrate-resistant (hormone refractory)prostate cancer, and thus is reason-able and necessary for this on-labelindication. Coverage of all off-label uses…is left to the dis cretion ofthe local Medicare AdministrativeContractors.”Based on this NCD, it is reasonable

to assume that “CMS may continue to make overall coverage decisionsregarding on-label indications whenadequate data exist to demonstratevalue,” noted Mr Stevens. “If the dataon treatment value are incomplete,CMS may defer off-label coveragedeterminations to the local contractors.There is also a strong indication thatCMS may strictly limit reimbursementto the labeled indication in the absenceof data demonstrating value for otherindications.”—CH �

“Budget concerns, the high price of new products,and widespread off-label use of new therapies havecombined to placetremendous pressure on the CMS as it evaluates newdrugs and biologics under its NCD process.”

—Charles A. Stevens, JD, MBA

Durable tumor regression as seen byobjective response (range, 6%-17%)and prolonged stabilization of diseaseat 24 weeks (range, 12%-41%) wereachieved in 160 patients, includingsome who had received extensive pre-vious therapy. As with the first study, there was an

unexpected response in patients withNSCLC, but no objective responseswere seen in patients with colorectal orprostate cancer. Of the 17 patients withovarian cancer, 1 had an objectiveresponse. Most of the adverse eventswith the study drug were immunerelated. Grade 3 or 4 effects were seenin 9% of 207 patients.Although the drugs were not com-

pared directly, these data suggest thatthe anti–PD-L1 antibody may producea smaller response than the anti-PD-1antibody. These early results point to apotential role for this anti-PD-1 anti-body as a targeted therapy.

Updated USPSTF CervicalCancer ScreeningRecommendationsCervical cancer remains an impor-

tant public health issue. The US Pre -ventive Services Task Force (USPSTF)has issued an update to its 2003 cervi-cal cancer screening recommendationsbased on current evidence (Moyer VA, on behalf of the USPSTF. AnnIntern Med. 2012;156:880-891). The keyupdated points in the new guidelinesinclude:• Cytology screening should be doneevery 3 years in women aged 21 to65 years

• Women aged <21 years should notbe screened, for lack of evidence fora net benefit

• There is no substantial difference intest performance between liquid-based and conventional cytology forthe detection of cervical intraepithe-lial neoplasia grade 2 or worse(CIN2+) and CIN3+ lesions

• Women aged <30 years should notbe screened with human papillo-mavirus (HPV) testing

• HPV testing plus cytology every 5years is an acceptable strategy forwomen aged 30 to 65 years.In addition, the guidelines recom-

mend against cervical cancer screeningin older women (≥65 years) who havehad adequate previous screening andare not otherwise at high risk for cervi-cal cancer.These guidelines apply to women

who have a cervix, regardless of sexualhistory, but not to women with high-grade precancerous cervical lesions orcervical cancer, women who were

exposed in utero to diethylstilbestrol,or immunocompromised women.The new guidelines are based on a

systematic review of the relevant evi-dence, including the benefits andharms of cervical cancer screening, aswell as a computerized decision analy-sis. The USPSTF points out that forpolicy and coverage decisions, consid-

erations beyond clinical benefits andharms are applicable.

Childhood Cancer Survivorsat Risk for GI Cancers Laterin Life: ScreeningRecommendedIn childhood cancer survivors, sub-

sequent malignant neoplasms are a

leading cause of premature death, second only to recurrence of the pri-mary cancer. The Childhood CancerSurvivor Study included a cohort of14,337 childhood cancer survivors(which is believed to be the largestcohort of this type) and assessed therisk for gastrointestinal (GI) malig nant



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In The Literature

Anti–PD-1/PD-L1 AntibodiesShow Promising Antitumor...Continued from page 8



In Colorectal Cancer, Treatment Efficacy Is High Among the ElderlyBy Caroline Helwick

San Francisco, CA—The vast majorityof published evidence indicates thatthe relative treatment effect ofchemotherapy for stage III colon can-cer is as good for elderly patients as itis for younger ones, according to a sys-tematic literature review by AnnaHung, a student in the program, andC. Daniel Mullins, PhD, Professor,Pharmacoeconomics, PharmaceuticalHealth Services Research Department,Associate Director, Center on Drugsand Public Policy. The study was pre-sented at the 2012 Academy of Man -aged Care Pharmacy annual meeting.The effectiveness of chemotherapy

in clinical practice may vary from theefficacy demonstrated in clinical trials,particularly for populations that areunderrepresented in clinical trials,such as the elderly, Ms Hung noted.“There is limited evidence regardinghow chemotherapy impacts the prog-nosis of elderly patients compared tononelderly patients.”

The study synthesized the availableevidence and examined the relativeeffectiveness of chemotherapy forstage III colon cancer among elderlyversus nonelderly patients through asystematic review of the literaturefrom 2001 to 2011, using the Agencyfor Healthcare Research and Qualityapproach.

A total of 24 articles met the eligibil-ity criteria, which were: patients weretreated for stage III colon cancer with a

chemotherapy treatment recommend-ed by the National ComprehensiveCancer Network guidelines; studieswere clinical trials phase 2, 3, or 4, orobservational studies with empiricalanalyses; studies examined the effec-tiveness of chemotherapy; studiesincluded patients aged >65 years. The chemotherapy regimens evalu-

ated included FOLFOX (5-fluorouracil[FU], leucovorin, oxaliplatin); CapeOx(capecitabine plus oxaliplatin); cape -citabine alone; 5-FU/leucovorin; irino -tecan-based treatment with or without5-FU/leucovorin or capecitabine;bevacizumab with or without 5-FUand oxaliplatin; and multiple regimensbased on 5-FU with or without iri -notecan, oxaliplatin, bevacizumab, orcetuximab.Among 13 studies that reported

overall survival (OS) data, the OS wassimilar between elderly (aged ≥70years) and nonelderly (aged <70 years)patients; only 3 studies reported lower

OS in the elderly, 2 that evaluated 5-FU/leucovorin and 1 that evaluatedmultiple chemotherapy regimens. Disease-free survival, time to pro-

gression (TTP), and overall responserates (ORRs) were also similar; onesample reported higher TTP and ORRamong the elderly.Adverse event rates were similar

overall, with a few exceptions. Whenstudies reported higher adverse eventrates among elderly patients, thegreater toxicities included fatigue,diarrhea, and neutropenia. There wereno reports of higher rates for pain,hand-foot syndrome, stomatitis, neu-ropathy, or nausea and vomiting.“Chemotherapy has similar relative

effectiveness and safety outcomes inelderly versus nonelderly patients,”Ms Hung noted.Furthermore, she noted that the

findings do not support the conceptthat elderly patients have lower ratesof chemotherapy use. �

“Chemotherapy has similarrelative effectiveness andsafety outcomes in elderly versus nonelderlypatients.”

—Anna Hung

Is Pemetrexed/Platinum Therapy Cost-Effective in NSCLC?By Audrey Andrews

San Francisco, CA—In what appearsto be the first study to use real-world,non–clinical trial data to evaluate thecost-effectiveness of pemetrexed/plat-inum (Pem/P) therapy used first linein patients with advanced non–small-cell lung cancer (NSCLC), this combi-nation trended toward being moreeffective and less costly than carbo-platin/paclitaxel plus bevacizumab(C/Pa+B), reported Manan Shah,PharmD, PhD, with Xcenda, PalmHarbor, FL, and colleagues at the 2012Academy of Managed Care Pharmacyannual meeting.In a second comparison, Pem/P was

costlier than C/Pa alone (withoutbevacizumab), but had a potentialincremental clinical benefit, accordingto this study. “Therefore, depending on society’s

or payers’ willingness to pay, Pem/Pmay be seen as more cost-effectivecompared to C/Pa due to the fact thatPem/P demonstrated effectiveness ata higher cost,” Dr Shah and colleaguesnoted.Recent phase 3 trials have shown the

effectiveness of certain doublet andtriplet first-line combination therapies,such as Pem/P, C/Pa, and C/Pa+B, inadvanced nonsquamous NSCLC, but

the cost-effectiveness of these regi-mens has not been documented. Thisretrospective analysis compared thereal-world incremental cost-effective-

ness of the 3 regimens based on datafrom the International OncologyNetwork database, which represents20 large US community oncology prac-tices. The study included data from2006 to 2010; the index date was whenfirst-line treatment was initiated.Patients were followed for 12 monthsto assess progression, death, and asso-ciated cost of care.Comparator patient cohorts receiv-

ing first-line C/Pa or C/Pa+B werematched to patients in the Pem/Pcohort based on index year, stage atdiagnosis, sex, performance status,and age. A total of 900 patients included 300

in the Pem/P cohort (carboplatin, N = 222; cisplatin, N = 78) and 300matched pairs in each of the other 2treatment cohorts.

Improved PFS, Lower Costs with

Pem/P versus C/Pa+B

Patients receiving Pem/P had a sig-nificant median progression-free sur-vival (PFS) benefit (134 days) com-pared with patients receiving C/Pa+B(126 days), with a first event occurringin 86% versus 94% of patients, respec-tively (hazard ratio [HR], 0.68; P<.001). Overall survival (OS) was high-er, although not significantly different,with Pem/P (298 days) than withC/Pa+B (271 days). Patients receiving Pem/P had sig-

nificantly lower mean costs comparedwith patients receiving C/Pa+B. MeanPFS costs were $33,745 with Pem/P

and $48,905 with C/Pa+B, for a differ-ence of $15,160. Overall costs were$33,969 with Pem/P versus $53,915with C/Pa+B, for a $19,946 difference. The probability that Pem/P was

more effective and less costly thanC/Pa+B was 69.5% for PFS and 85%for OS.

Pem/P versus C/Pa

Similarly, patients receiving Pem/Phad longer PFS (134 days) than thosereceiving C/Pa (106 days), but alsohigher costs. The mean PFS costs were$21,841 higher with Pem/P comparedwith C/Pa, and the overall cost was$19,137 with the former comparedwith the latter. “Pem/P had a higherprobability of being more costly butmore effective than C/Pa,” Dr Shahand colleagues noted. OS was 298 days with Pem/P versus

218 days with C/Pa, with events occur-ring in 66% versus 74% of patients,respectively (HR, 0.88; P = .08).Based on PFS, OS, and cost results,

although Pem/P was more costly thanC/Pa, it nevertheless had a potentialcost-effective benefit. The analyses did not evaluate the

entire continuum of care in terms ofcost, the investigators said. �

“Depending on society’s or payers’ willingness to pay, Pem/P may be seen as more cost-effective compared withC/Pa, due to the fact that Pem/P demonstrated effectiveness at a higher cost.”

—Manan Shah, PharmD, PhD


neoplasms in this population(Henderson TO, et al. Ann Intern Med.2012;156:757-766).Results show that survivors of child-

hood cancer, especially patients whoreceived abdominal radiation, thosewho survived Hodgkin lymphoma orWilms’ tumor, and those who took cer-tain chemotherapies (high-dose pro-carbazine and platinum drugs), are atan increased risk for GI cancers. All participants were diagnosed

with cancer before age 21 years, weretreated at 1 of 26 centers in the UnitedStates and Canada, and survived for atleast 5 years after the initial cancerdiagnosis; their data were comparedwith a general population from anational cancer database.The risk for GI cancer later in life was

4.6-fold higher in the childhood cancersurvivors than in the general popula-tion (95% confidence interval [CI], 3.4-6.1). The highest risk for GI cancer wasassociated with abdominal radiation,although survivors who were notexposed to radiation were also atincreased risk. Among 11,807 patientswith complete data available, the riskfor GI cancer later in life was increasedwith the use of platinum drugs (relativerisk [RR], 7.6; CI, 2.3-25.5) and high-dose procarbazine (RR, 3.2; CI, 1.1-9.4).One limitation of this study is that

most cancer survivors had not yetattained an age when GI cancer typi-cally occurs in the general population,so additional cases and risk factorsmay yet be identified.These results support the recom-

mendation to consider screening forGI cancers earlier in patients who sur-vive childhood cancer.

New Test May Spare theNeed for Surgery to DiagnoseThyroid Cancer Diagnostic surgery is often used to

evaluate the 15% to 30% of thyroid nod-ules that cannot be judged benign ormalignant by the use of fine-needleaspiration (FNA). However, such sur-gery is associated with a 2% to 10% riskof serious complications. A new gene-expression test may soon be used forthe diagnosis of such nodules, whichcould reduce the use of diagnostic sur-gery in this population (Alexander EK,et al. N Engl J Med. Epub 2012 Jun 25).This prospective, double-blind

study involved 4812 FNA samplesfrom 3789 patients over a 19-monthperiod. Of these samples, 577 cytologi-cally indeterminate nodules were fur-ther examined to determine their clini-cal significance. The gene-expressiontest was performed on the tissue from

the patients who also had the surgeryand therefore had histopathologicalreview results to serve as a referencestandard.Of 265 nodules that met the inclu-

sion criteria based on a blindedhistopathological review, 85 weremalignant. The use of the gene-expression test identified 78 of the 85

malignant nodules, yielding a sensi-tivity of 92% (95% confidence inter-val, 84-97). The negative predictivevalues for “atypia (or follicular lesion)of undetermined clinical significance”and “follicular neoplasm or lesionsuspicious for follicular neoplasm”were 95% and 94%, respectively.These values suggest that for aspi-

rates with either of these subtypesand a benign gene-expression testresult, the probability of malignancyis as low as that for nodules shown tobe benign with FNA. The researchers suggested that rou -

tine use of the gene-expression testmay potentially offer cost-savings byreducing unnecessary surgery. �

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In The Literature

Childhood Cancer Survivorsat Risk for GI Cancers...Continued from page 29


CONTINUING EDUCATION

CONSIDERATIONS inMultiple Myeloma™5th Annual

ASK THE EXPERTS: Maintenance Settings

Amrita Y. Krishnan, MD, FACPDirector, Multiple Myeloma ProgramAssociate Director, Medical Educationand Training Department of Hematology/HCTCity of Hope Cancer CenterDuarte, CA

Christina Boeckman, RN, ANP-C,AOCNPNurse PractitionerDepartment of Hematology/HCTCity of Hope Cancer CenterDuarte, CA

Sepideh Shayani, PharmD, BCOPClinical Manager, Pharmacy ServicesDepartment of Pharmaceutical ServicesCity of Hope Cancer CenterDuarte, CA

Supported by educational grants from Celgene Corporation andMillennium: The Takeda Oncology Company.

PUBLISHING STAFF

President & CEOBrian F. Tyburski

Chief Operating OfficerPam Rattananont Ferris

Director, Medical & ScientificServices

Linda M. Ritter, [email protected]

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[email protected]

CopyeditorDana Delibovi

Director, Production and ManufacturingAlaina Pede

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Circulation [email protected]

Center of Excellence Media, LLC241 Forsgate Drive

Suite 205BMonroe Township, NJ 08831

LETTER FROM THE EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). Thisis due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinicalinvestigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria fordiagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management ofcomorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regardingthe application and interpretation of recent clinical advances.

In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently askedquestions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questionsare answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowl-edge, and professional experience regarding evidence-based care. In this second issue, experts from City of Hope CancerCenter answer questions pertaining to the management of patients in the maintenance setting.

Sincerely,

Sagar Lonial, MDProfessorVice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer InstituteEmory University School of MedicineAtlanta, GA

This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

FACULTY

JULY 2012 • VOLUME 5 • NUMBER 2

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CONSIDERATIONS IN MULTIPLE MYELOMA

IntroductionDespite the development of more effective induction regimens

and the increased use of autologous stem cell transplant (ASCT), most

patients with multiple myeloma (MM) eventually relapse and suc-

cumb to progressive disease. Novel agents that have demonstrated

good clinical activity in the frontline and relapsed settings continue to

be evaluated as maintenance therapy, with the goal of delaying

relapse and extending survival. However, important questions related

to the use of these therapies remain unresolved. In this article, Amrita

Y. Krishnan, MD, FACP, shares her insight on recent clinical data and

ongoing issues in the maintenance setting for myeloma.

When do you consider maintenance therapy for your patientswith MM?

I am most likely to recommend maintenance for patients with high-riskcytogenetics and for those who do not achieve a complete response (CR)after ASCT. Unfavorable cytogenetics in both transplant and nontransplantcandidates portend a high risk of relapse or disease progression. In addition,an important objective posttransplant is CR or at least very good partial

response, as this has been correlated with improved overall survival (OS).1,2

Maintenance therapy with novel agents can contribute to these treatmentgoals, especially in patients who do not achieve a CR with transplant alone. I am less likely to use maintenance in standard-risk patients who achieve

CR, because of concern that the risk of continued drug treatment may out-weigh benefit in this population. Of course, there are always exceptions, andthe approach to therapy must be individualized to the patient. Many questionsremain on the optimal use of maintenance therapy, because we do not yethave unequivocal evidence that it prolongs OS in specific MM subgroups.3,4

What evidence has influenced your approach to maintenancetherapy?

In patients with high-risk cytogenetics who exhibit the translocationt(4;14), I tend to use bortezomib. The HOVON-65/GMMG-HD4 trialshowed a benefit in progression-free survival (PFS) in patients with t(4;14)who received this agent as maintenance. There is controversy, however,because HOVON-65/GMMG-HD4 did not prove that it was the mainte-nance that produced this clinical benefit, since patients received bortezomibduring induction as well in one arm of the study, whereas the other arm didnot receive bortezomib during induction or maintenance (Figure).5

There has also been debate regarding the efficacy of bortezomib mainte-nance in patients with deletion 17p (del[17p]). A study by Avet-Loiseau andcolleagues reported that bortezomib-based therapy could not overcome thischromosomal abnormality. However, patients in this trial received bortez -omib short-term (4 cycles) with no maintenance.6 Results of HOVON-

Recent Advances and Ongoing Controversiesin the Maintenance Setting

Amrita Y. Krishnan, MD, FACPDirector, Multiple Myeloma ProgramAssociate Director, Medical Education and Training, Department of Hematology/HCTCity of Hope Cancer Center, Duarte, CA

SponsorThis activity is jointly sponsored by Medical Learning Institute, Inc.,and Center of Excellence Media, LLC.

Target AudienceThe activity was developed for physicians, nurses, and pharmacistsinvolved in the treatment of patients with multiple myeloma (MM).

Educational ObjectivesUpon completion of this activity, the participant will be able to:• Describe recent advances in maintenance therapy that can po -

tentially prolong survival and improve quality of life in patientswith MM

• Identify specific patient- and disease-related factors that may im -pact the choice of maintenance therapy in MM

• Review recent safety and efficacy data on novel agents used in themaintenance setting for MM

Commercial Support AcknowledgmentThis activity is supported by educational grants from CelgeneCorporation and Millennium: The Takeda Oncology Company.

Instructions for Credit

There is no fee for this activity. To receive credit after reading this CME/CEactivity in its entirety, participants must complete the pretest, posttest, andevaluation. The pretest, posttest, and evaluation can be completed onlineat www.mlicme.org/P12026.html. Upon completion of the evaluationand scoring 70% or better on the posttest, you will immediately receiveyour certificate online. If you do not achieve a score of 70% or better onthe posttest, you will be asked to take it again. Please retain a copy of theCertificate for your records.

For questions regarding the accreditation of this activity, please contactMLI at 609-333-1693 or [email protected].

Physician Credit DesignationThe Medical Learning Institute, Inc. (MLI) designates this enduringmaterial for a maximum of 1.25 AMA PRA Category 1 Credits™.Physicians should claim only the credit commensurate with the extentof their participation in the activity. This activity has been planned andimplemented in accordance with the Essential Areas and policies of theAccreditation Council for Continuing Medical Education (ACCME)

through the joint sponsorship of the Medical Learning Institute, Inc.and the Center of Excellence Media, LLC. The Medical LearningInstitute, Inc. is accredited by the ACCME to provide continuing med-ical education for physicians.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI).Provider approved by the California Board of Registered Nursing,Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy DesignationMedical Learning Institute, Inc. (MLI) is accredited by the Accredi -tation Council for Pharmacy Education (ACPE) as a provider of

continuing pharmacy education. Completion of this activity provides for1.25 contact hours (0.125 CEUs) of continuing education credit. Theuniversal activity number for this activity is 0468-9999-12-024-H01-P.

DisclosuresBefore the activity, all faculty and anyone who is in a position to havecontrol over the content of this activity and their spouse/life partner willdisclose the existence of any financial interest and/or relationship(s) theymight have with any commercial interest producing healthcaregoods/services to be discussed during their presentation(s): honoraria,expenses, grants, consulting roles, speakers’ bureau membership, stockownership, or other special relationships. Presenters will inform partici-pants of any off-label discussions. All identified conflicts of interest arethoroughly vetted by MLI for fair balance, scientific objectivity of studiesmentioned in the materials or used as the basis for content, and appropri-ateness of patient care recommendations.

Planners’ and Managers’ DisclosuresDana Delibovi, Medical Writer, has nothing to disclose.William J. Wong, MD, MLI Reviewer, has nothing to disclose.Patricia A. Ensor, RPh, MBA, MLI Reviewer, has nothing to disclose.Judith A. Bonomi, RN, MS, MSN, OCN, MLI Reviewer, has dis-closed that her spouse is investigator on a study for Agenix and Lilly;on the data monitoring committee for Infinity; and on the data moni-toring committee and principal investigator on a study for Pfizer.

Faculty Disclosures*Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, CelgeneCorporation, Merck, Millennium: The Takeda Oncology Company,Novartis, and Onyx.

*Amrita Y. Krishnan, MD, FACP, is a consultant for CelgeneCorporation, and is on the speakers’ bureau for Celgene Corporation,Genentech, and Millennium: The Takeda Oncology Company.Christina Boeckman, RN, ANP-C, AOCNP, has nothing to disclose.*Sepideh Shayani, PharmD, BCOP, is on the advisory board forGenzyme.

*Content will include non–FDA-approved uses.

The associates of Medical Learning Institute, Inc., the accreditedprovider for this activity, and Center of Excellence Media, LLC, donot have any financial relationships or relationships to products ordevices with any commercial interest related to the content of thisCME/CE activity for any amount during the past 12 months.

Disclaimer The information provided in this CME/CE activity is for continuingeducation purposes only and is not meant to substitute for the inde-pendent medical judgment of a healthcare provider relative to diag-nostic and treatment options of a specific patient’s medical condition.Recommendations for the use of particular therapeutic agents are based onthe best available scientific evidence and current clinical guidelines. No biastowards or promotion for any agent discussed in this program should beinferred.

Agenda: 1.25 hoursArticles/Commentaries: 60 minutesEvaluation/Posttest: 15 minutes

Date of original release: July 12, 2012Valid for CME/CE credit through: July 12, 2013

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65/GMMG-HD4 suggested a benefit with bortezomib-based induction plusmaintenance,5 as did data from the Total Therapy 3 trial.7 In addition, arecent study by Neben and colleagues reported that patients with del(17p)who received bortezomib before and after ASCT had a median PFS of 26.2months compared with 12.0 months for patients who did not receive bor -tezomib (P=.024), with 3-year OS rates of 69% and 17%, respectively(P=.028).8 The results of this trial are changing the landscape of treatmentfor patients with del(17p).For patients with a partial response after ASCT, I generally use lenalido-

mide maintenance, based on results from the CALGB 100104 and IFM2005-02 trials.9,10 CALGB 100104 compared single-agent lenalidomidemaintenance with placebo in patients with stable disease or better (includingpatients who achieved CR) following ASCT. This study demonstrated signif-icantly longer time to progression and improved survival in the lenalidomidearm versus the placebo arm (Table).9 IFM 2005-02 also compared single-agent lenalidomide maintenance with placebo post-ASCT (after 2 courses oflenalidomide consolidation in both arms).10 In this study, lenalidomide main-tenance improved median PFS to 41 months versus 23 months with placebo(P<.001), with benefit across cytogenetic subgroups. Three-year and 4-yearOS rates were comparable in the lenalidomide versus placebo groups: 80%versus 84% (3-year) and 73% versus 75% (4-year), respectively. Recent data from the RV-MM-PI-209 trial add further support to the use

of lenalidomide maintenance after consolidation.11 Patients received induc-tion with lenalidomide and low-dose dexamethasone, followed by either

melphalan, prednisone, and lenalidomide (MPR) ± lenalidomide mainte-nance or melphalan/ASCT ± lenalidomide maintenance. A comparison ofall patients given lenalidomide maintenance (after either MPR or ASCT)versus all patients receiving no maintenance showed that maintenanceincreased PFS but not OS. The recent MM-015 trial evaluated lenalidomidemaintenance in older, transplant-ineligible patients with myeloma. Theinvestigators of this study reported that lenalidomide after initial therapywith MPR significantly extended PFS compared with melphalan plus pred-nisone alone or MPR without maintenance.12

Thalidomide is not used preferentially for maintenance in the UnitedStates, largely due to data showing a high incidence of serious adverseevents, reduced quality of life, and potentially poorer outcomes in del(17p)patients.13-15 In Europe, however, thalidomide is used more often, because ofregulatory limitations on other novel drugs such as lenalidomide.

What are some of the key concerns in using maintenance therapy?

The first concern is risk versus benefit. Are we seeing enough clinicalbenefit to justify the toxicity and added expense of maintenance therapy?Certainly, data suggest benefits in response and PFS when maintenance isused, but a consistent benefit in OS has not been shown.3-8

Adverse events are also an important consideration. With bortezomibmaintenance, grade 3 or 4 peripheral neuropathy may be treatment-limit-ing.3,5 With lenalidomide, trials have reported an increased risk of secondprimary malignancies with maintenance therapy.9,10,12,16 In CALGB 100104,for example, second cancers were reported in 8% of patients receivinglenalidomide maintenance versus 3% of patients receiving placebo duringapproximately 3 years of follow-up.9 The investigators of this study haveindicated that they will continue to assess risk factors for development ofsecond primary cancers with further follow-up. Factors such as cost andinsurance coverage may also affect the choice of maintenance therapy.These issues can influence patient preference, which we always consider.

How long should patients remain on maintenance therapy withnovel agents?

Currently, there is no consensus regarding the optimal duration of main-tenance therapy for myeloma. In HOVON-65/GMMG-HD4, patientsreceived bortezomib maintenance for 2 years.5 In CALGB 100104, lenalido-mide maintenance was given until progression.9 The investigators in theIFM 2005-02 trial planned to use lenalidomide until progression but stoppedtherapy once secondary malignancies arose.10 In the ongoing phase 3 multi-center BMT CTN 0702 trial, we plan to give lenalidomide maintenancetherapy for 3 years.17

However, many questions remain unresolved. What is the optimal dura-tion of lenalidomide therapy to improve PFS and possibly OS? Since bor -tezomib-related neuropathy may shorten maintenance time, can we reducethe incidence and severity of this toxicity and extend the duration of timethat patients can stay on maintenance by using subcutaneous bortezomib18

or an alternate proteasome inhibitor such as carfilzomib or MLN9708?19-22

Hopefully, emerging clinical data and ongoing research will better definethe role of novel agents in the maintenance setting and provide answers tothese questions. �

References1. Harousseau J-L, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response

is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dosetherapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

Figure. Efficacy results at 36 months of follow-up in the HOVON-65/GMMG-HD4 trial.5

Pati

ents

(%

)

80

70

60

50

40

30

20

10

0

HDT/ASCT indicates high-dose therapy/autologous stem cell transplant; OS, overall survival; PAD,bortezomib, doxorubicin, dexamethasone; PFS, progression-free survival; VAD, vincristine, doxoru-bicin, dexamethasone.

All pts t(4;14) del(17p) All pts t(4;14) del(17p)

PFS OS

VAD + HDT/ASCT + thalidomidemaintenancePAD + HDT/ASCT + bortezomibmaintenance

Table. Efficacy Results at a Median Follow-up of 34 months inthe CALGB 100104 Trial9

LenalidomideMaintenance Placebo P Value

Median TTP 46 months 27 months <.001

3-Year PFS rate 66% 39% —(95% CI, 59-73) (95% CI, 33-48)

3-Year OS rate 88% 80% —(95 CI, 84-93) (95 CI, 74-86)

OS indicates overall survival; PFS, progression-free survival; TTP, time to progression.

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2. Harousseau J-L, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma.Blood. 2009;114:3139-3146.

3. Ludwig H, Duries BGM, McCarthy P, et al. IMWG consensus on maintenance therapy in multi-ple myeloma. Blood. 2012;119:3003-3015.

4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clashof philosophies. Blood. 2011;118:3205-3211.

5. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomizedphase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed byhigh-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients withnewly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 40.

6. Avet-Loiseau H, Leleu X, Roussel M, et al. Bortezomib plus dexamethasone induction improvesoutcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J ClinOncol. 2010;28:4630-4634.

7. Shaughnessey JD, Zhou Y, Haessler J, et al. TP53 deletion is not an adverse feature in multiplemyeloma treated with total therapy 3. Br J Haematol. 2009;147:347-351.

8. Neben K, Lokhorst HM, Jauch A, et al. Administration of bortezomib before and after autologousstem cell transplantation improves outcome in multiple myeloma patients with deletion 17p.Blood. 2012;119:940-948.

9. McCarthy PL, Owzar K, Hofmeister CG, et al. Lenalidomide after stem-cell transplantation formultiple myeloma. N Engl J Med. 2012;366:1770-1781.

10. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplan-tation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

11. Cavallo F, Hardan I, Gay F, et al. Lenalidomide maintenance significantly reduces the risk of pro-gression in newly diagnosed young multiple myeloma patients enrolled in RV-MM-PI-209 trial.Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012;Amsterdam, Netherlands.

12. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligi-ble newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled in MM-015.Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012;Amsterdam, Netherlands.

13. Hicks LK, Haynes AE, Reece DE, et al. A meta-analysis and systematic review of thalidomide

for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34:442-452.14. Morgan GJ, Jackson GH, Davies FE, et al. Maintenance thalidomide may improve progression

free but not overall survival: results from the Myeloma IX maintenance randomisation. Blood(ASH Annual Meeting Abstracts). 2008;112:Abstract 656.

15. Stewart AK, Trudel S, Bahlis NJ, et al. A randomized phase III trial of thalidomide and pred-nisone as maintenance therapy following autologous stem cell transplantation (ASCT) inpatients with multiple (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual MeetingAbstracts). 2010;116:Abstract 39.

16. Delforge M, Dimopoulos M, Adam Z, et al. Safety profile and management in MM-015 compar-ing lenalidomide-melphalan-prednisone followed by lenalidomide maintenance (MPR-R) withMP and MPR in newly diagnosed multiple myeloma (NDMM). Presented at: 17th AnnualCongress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands.

17. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMTCTN 0702). ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT01109004.Updated March 28, 2012. Accessed June 30, 2012.

18. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration ofbortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

19. Jakubowiak AJ, Griffith KA, Dytfeld D, et al. Stringent complete response (sCR) in patients (pts)with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide(LEN), and dexamethasone (DEX). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8011.

20. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigational oralproteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myelo-ma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017.

21. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigational pro-teasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) withpreviously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO AnnualMeeting Abstracts). 2012;30(suppl):Abstract 8033.

22. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasomeinhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase Istudy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8034.

IntroductionAlong with the clinical benefits seen with maintenance regimens for

multiple myeloma (MM), new challenges have arisen, due to the

increased risk of adverse events associated with prolonged use of ther-

apy. As a member of the cancer care team, it is the nurse’s responsi-

bility to anticipate which toxicities and complications are likely to

occur, to employ the necessary interventions, and to counsel patients

accordingly. In this article, Christina Boeckman, RN, ANP-C, AOCNP,

discusses effective nursing strategies in the maintenance setting, and

shares her perspectives on preventing and managing common

adverse events related to the use of novel agents.

Which patient-related factors need to be considered in the main-tenance setting?

Age, comorbidities, and performance status must all be considered when apatient is scheduled to receive maintenance therapy. Elderly MM patientsfrequently have age-related comorbid conditions that can make managingtheir disease especially challenging.1 These individuals are more likely to

have organ dysfunction (eg, cardiovascular disease, renal impairment) anddiabetes, and are more prone to infection and deep vein thrombosis.1 It is cru-cial to take these factors into account when determining an effective man-agement plan. It is also important to know which agents were used duringprevious lines of therapy, how patients tolerated these medications, andwhether they are experiencing any residual adverse events. In some cases, itmay be necessary to avoid the use of specific agents due to preexisting comor-bidities or cumulative toxicities. A patient’s overall performance status should also be evaluated prior to

and during maintenance therapy. Nurses must assess whether an individual isable to perform activities of daily living, such as preparing meals, eating,bathing, and dressing. The goal is to achieve a balance between providingeffective therapy and maintaining good quality of life.

What strategies do you use to minimize peripheral neuropathy (PN)in patients receiving bortezomib as maintenance therapy?

Neuropathy is a well-known adverse event associated with the use of novelagents such as bortezomib and thalidomide.2 Symptoms may include tran-sient numbness and tingling, paresthesias, and muscle cramping or weakness,or in severe cases, burning pain, organ dysfunction, and paralysis.2 High ratesof thalidomide-induced PN have been observed during maintenance thera-py.2-4 If treatment with this agent is not interrupted quickly, symptoms maybecome irreversible.5 As a result, thalidomide is being used less frequently asmaintenance. Bortezomib-induced PN, on the other hand, is generallyreversible with dose reduction and treatment discontinuation.2 We have

Improving Patient Outcomes DuringMaintenance Therapy

Christina Boeckman, RN, ANP-C, AOCNPNurse PractitionerDepartment of Hematology/HCT, City of Hope Cancer CenterDuarte, CA

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recently seen an increase in the use of bortezomib in the maintenance set-ting, and nurses need to be familiar with its toxicity profile and recommendedsupportive care strategies.Assessing PN prior to the start of maintenance and throughout the course

of therapy is essential.2,5 Verbal and nonverbal questionnaires and pain scalesare helpful for these assessments. When patients come to our center for treat-ment, I ask them if they are experiencing any numbness and tingling in theirhands and feet, ringing in their ears, neuropathic pain, or cramping. I alsodetermine if they are having trouble with everyday tasks, such as buttoningtheir shirts or writing with a pen. Patients must understand the importanceof reporting signs and symptoms of PN as soon as they occur, so that theappropriate interventions can be initiated. When bortezomib-related PN develops, the goal is to alleviate symptoms

and prevent progression.2 This can be accomplished through recommendeddose modifications based on the degree of neurotoxicity (Table).5,6 For exam-ple, if a patient develops grade 3 PN while on bortezomib, we typically holdtreatment until symptoms resolve, and then reinitiate therapy at a lower doseand schedule. For patients who have neuropathic pain, we prescribe opioidswhen necessary; the use of nonsteroidal anti-inflammatory drugs is not advis-able due to the likelihood of myeloma-related renal dysfunction. Additionalmedications that may be used in the treatment of PN symptoms includegabapentin, pregabalin, duloxetine hydrochloride, and tricyclic antidepres-sants.2 We usually recommend that patients start taking B complex vitamins,folic acid, and alpha lipoic acid, as long as they are not contraindicated withother medications.

How do you assess and treat hematologic toxicities related to lena -lidomide therapy in the maintenance setting?

Hematologic toxicities are commonly associated with the use of lenalido-mide.7 To effectively manage these adverse events, it is important for myelo-ma patients to have their blood counts monitored regularly, with the mostfrequent monitoring performed early in their treatment cycles. We seepatients at least every 2 weeks during the first and second cycles of mainte-nance to assess how they are responding to treatment and to evaluate theneed to make dose or schedule adjustments based on their counts. Dependingon their performance status and laboratory results, we may lessen the frequen-cy of these evaluations to once per month. When platelet counts fall to <30,000/mcL, we may need to temporarily

discontinue lenalidomide. Treatment can usually be resumed when plateletcounts return to 30,000/mcL, but it may be necessary to restart them at areduced dose.7,8 We usually do not initiate transfusion unless platelet countsdecline to <20,000/mcL. If the patient’s absolute neutrophil count (ANC) is<1000/mcL, lenalidomide treatment should also be halted until counts returnto baseline. In some cases, we may initiate granulocyte colony-stimulatingfactor if a patient’s ANC remains low for an extended period of time.Patients also need to be evaluated for bleeding, bruising, dyspnea, fatigue,

and infection, and should be educated on how to monitor for these signs andsymptoms at home. We tell them to notify us immediately if they experiencebleeding that does not stop, frequent bruising, or fever. It is important toinstruct patients on effective strategies for infection control, including rou-tine hand washing and the avoidance of crowds, when their blood counts arelow. If patients develop signs of infection, we may also need to hold lenalido-mide treatment until symptoms resolve.

What is the nurse’s role in helping patients continue with mainte-nance therapy?

Prior to the initiation of maintenance, it is important to discuss with patientsboth the risks and benefits of prolonged therapy with novel agents. Some indi-viduals do not understand why they need to undergo further treatment if theyhave responded well to initial chemotherapy and/or transplantation. It isimportant to remind these patients that continued use of effective agents mayhelp to delay relapse and disease progression. Although patients will typicallybe familiar with the toxicity profiles of agents they have already received duringfrontline therapy, we review this information again prior to the start of main-tenance. We also inform patients about the increased risk for secondary malig-nancies related to prolonged duration of therapy, and encourage them to bediligent about routine health screenings, including mammograms and colon -oscopies. We ensure them that we will also monitor for secondary malignanciesthrough laboratory tests and other procedures.To provide optimal care, nurses must consider patient preferences as well as

psychosocial factors in the maintenance setting. Some individuals would ratherreceive oral lenalidomide, so they do not have to travel back and forth to the cen-ter every week for treatment. If we determine that a patient can be compliantwith an oral regimen, and they do not have comorbidities or other characteristicsthat would preclude the use of lenalidomide, we will most likely use this therapy.For other patients, intravenous or subcutaneous bortezomib may be preferential,based on patient- or disease-related factors. Regardless of which type of therapy isprescribed during maintenance, oncology nurses play an important role inimproving patient outcomes by establishing good communication with patients,carefully monitoring for signs and symptoms of toxicities, and being prepared toinitiate effective supportive care strategies when needed. �

References1. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of ther-

apy or sequencing. Hematology Am Soc Hematol Educ Program. 2009:566-577.2. Tariman JD, Love G, McCullagh E, Sandifer S; IMF Nurse Leadership Board. Peripheral neu-

ropathy associated with novel therapies in patients with multiple myeloma: consensus state-ment of the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):29-36.

3. Attal M, Harousseau JL, Leyvraz S, et al. Maintenance therapy with thalidomide improves sur-vival in patients with multiple myeloma. Blood. 2006;108:3289-3294.

4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation formultiple myeloma. N Engl J Med. 2006;354:1021-1030.

5. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for mul-tiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319.

6. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012.7. Miceli T, Colson K, Gavino M, Lilleby K; IMF Nurse Leadership Board. Myelosuppression

associated with novel therapies in patients with multiple myeloma: consensus statement of theIMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20.

8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.

Table. Bortezomib Dose Modifications Based on Severity ofPeripheral Neuropathy5,6

Severity of Peripheral Neuropathy Modification of Dose and Regimen

Grade 1 (paresthesia or loss of reflex) without pain or loss of function

Grade 1 with pain or grade 2 (interferes with function but not with activities of daily living)

Grade 2 with pain or grade 3 (interferes with activities of daily living)

Grade 4 (permanent sensory loss that interferes with function)

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

No action

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

Withhold bortezomib until toxicity resolves, then reinitiate at a dose of 0.7 mg/m2 once weekly

Discontinue bortezomib

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Dosing and Administration of Novel Agents in the Maintenance Setting

IntroductionOver the past decade, maintenance therapy has become an

increasingly important component of treatment for patients with mul-

tiple myeloma (MM). Recent evidence has shown that newer target-

ed agents, such as bortezomib and lenalidomide, have the potential

to extend duration of response following frontline therapy, and are

generally better tolerated and more effective than older, conven-

tional therapies used for this indication. In this article, Sepideh

Shayani, PharmD, BCOP, discusses recent advances in the mainte-

nance setting, and answers questions related to the administration of

novel agents.

Has a standard dose and schedule been established for bortez -omib as maintenance therapy?

To date, a standard dose and schedule has yet to be established for bortez -omib maintenance; however, data from recent clinical trials can be helpful inguiding therapeutic decisions. As in the frontline and relapsed/refractory set-tings, it is essential to strike a balance between efficacy and safety when usingnovel agents as maintenance, especially since patients will be on therapy foran extended period of time.In the phase 3 HOVON-65/GMMG-HD4 trial, transplant-eligible pa -

tients with MM were randomly assigned to induction therapy with vin-cristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxoru-bicin, and dexamethasone (PAD).1 This was followed by high-dosemelphalan and autologous stem cell transplant (ASCT). Patients started onVAD received thalidomide maintenance at a dose of 50 mg/day for 2 years(arm A) and those randomized to PAD received bortezomib maintenance ata dose of 1.3 mg/m2 biweekly for 2 years (arm B).In this trial, progression-free survival (PFS) was lower with VAD/

ASCT/thalidomide compared with PAD/ASCT/bortezomib (42% vs 46% at36 months, P=.047). Overall survival was significantly higher in arm B(P=.048). A total of 67% of patients in arm A and 57% in arm B startedmaintenance therapy, and 64% and 47% of those patients, respectively, wentoff protocol due to various factors (Table 1). Grade 3/4 peripheral neuropathy(PN) was observed in 7% of patients in arm A and 16% of patients in arm B.In the phase 3 GIMEMA trial, patients with MM were randomized to nine

6-week cycles of induction with bortezomib, melphalan, prednisone, andthalidomide (VMPT) followed by 2 years of maintenance with bortezomib(1.3 mg/m2 every 14 days) plus thalidomide (50 mg/day) (VT) or to nine6-week cycles of VMP induction without maintenance.2 Early in this trial,which enrolled patients who were not eligible for transplant due to advanced

age or comorbidities, the schedule of bortezomib (1.3 mg/m2) used for induc-tion was reduced from twice weekly to once weekly. In addition, both theVMPT and VMP schedules were changed to nine 5-week cycles. Results showed a benefit with VMPT/VT compared with VMP alone, in

terms of complete response rates (38% vs 24%; P<.001), PFS (56% vs 41%,P=.008), and time to next treatment. Importantly, the once-weekly scheduleof bortezomib lowered discontinuation rates and prolonged time on therapy.This finding has important clinical implications, especially for the treatmentof older patients who may have difficulty tolerating a standard regimen. Theschedule adjustment used in this study also significantly reduced the inci-dence of severe sensory PN from 16% to 3% (P<.001).

Both of these maintenance trials reported encouraging clinical activitywith bortezomib. In GIMEMA, once-weekly dosing was more tolerable thantwice-weekly dosing, but maintained good clinical activity.2 In this trial,bortezomib maintenance administered bimonthly also appeared to be aneffective strategy. Investigators continue to evaluate various bortezomib dos-ing and schedule protocols. Hopefully, data from new trials will help to deter-mine a standard of care. In the meantime, following established dosingadjustment guidelines for bortezomib3,4 to reduce toxicities such as PN isessential to ensure optimal outcomes. Additionally, subcutaneous adminis-tration of bortezomib may improve the adverse event profile associated withthis agent. In a recent trial of relapsed/refractory MM, this mode of adminis-tration resulted in similar overall response rates but significantly less PN thantraditional intravenous dosing.5 The increased tolerability seen with subcuta-neous bortezomib in this population of patients may translate to the mainte-nance setting.

What dosing and administration schedules are being used forlenalidomide as maintenance?

In the phase 3 IFM 2005-02 trial, patients with MM who had single ordouble ASCT were treated with 2 cycles of consolidation with lenalidomide(25 mg/day, days 1-21) followed by placebo or lenalidomide maintenance(given at 10 mg/day for the first 3 months and increased to 15 mg/day if tol-erated).6 Treatment was continued until disease progression or development

Sepideh Shayani, PharmD, BCOPClinical Manager, Pharmacy ServicesDepartment of Pharmaceutical ServicesCity of Hope Cancer CenterDuarte, CA

Table 1. Discontinuation Rates in the Maintenance Phase of theHOVON-65/GMMG-HD4 Trial1

Toxicity Progression Other Overall

Thalidomide 31% 31% 2% 64%

Bortezomib 9% 29% 9% 47%

It is essential to strike a balance between efficacy and safety when using novel agents as maintenance, especially since patients will be on therapy for an extended period of time.

� ��



of intolerance. After a median follow-up of 2 years postrandomization tomaintenance, there was a significant improvement in PFS in the lenalido-mide arm (41 months vs 23 months, P<.001). The rates of grade 3/4 PN weresimilar in both groups. Grade 3/4 hematologic events were reported in 58%of patients on lenalidomide versus 23% on placebo, but these were manage-able with dose adjustments (down to 5 mg/day). The incidence of second pri-mary cancers was higher in the lenalidomide arm (3.1 vs 1.2 per 100 patient-years, P=.002). Overall, 21% of patients in the lenalidomide arm and 15% inthe placebo arm discontinued therapy due to toxicity.6

The phase 3 MM-015 trial randomized elderly, transplant-ineligible MMpatients to 9 cycles of melphalan, prednisone, and lenalidomide followed bylenalidomide maintenance (MPR-R), or to 9 cycles of MPR or MP withoutmaintenance.7,8 In this study, the scheduled dose of lenalidomide (duringinduction and maintenance) was 10 mg/day, given on days 1 to 21. Patientscould receive maintenance until disease progression or development of intol-erance. After a median follow-up of 27 months, PFS was significantly longerwith lenalidomide maintenance (31 vs 14 vs 13 months for MPR-R, MPR,and MP, respectively; MPR-R vs MP, P<.001).The most common adverse events were hematologic; these occurred more

frequently in patients who received lenalidomide. Grades 3 and 4 hemato-logic toxicities in this study are shown in Table 2. However, during themaintenance phase of MPR-R, the incidence of new or worsening toxicitieswas low. Discontinuation due to adverse events in the MPR-R, MPR, andMP arms was observed in 16%, 14%, and 5%, respectively. These rates werehigher in patients >75 years of age than in those 65 to 75 years of age, as wasthe need for dose reductions. Incidence of second primary malignancies waslow, corresponding to 3.04, 2.57, and 0.98 per 100 patient-years for MPR-R,MPR, and MP, respectively.8

BMT CTN-0702, a new phase 3 multicenter trial, will evaluate the safety

and efficacy of lenalidomide maintenance in 3 cohorts of patients.9 FollowingASCT, participants will proceed to either second transplant, consolidationwith lenalidomide, dexamethasone, and bortezomib (RVD), or maintenancewith lenalidomide. Patients undergoing second transplant and consolidationwill also receive maintenance therapy, which will start at 10 mg/day for 3months and increase to 15 mg/day. We are seeing RVD used more frequentlyas induction therapy in MM, so data from this study should be relevant toclinical practice.

What strategies are important to ensure optimal outcomes in themaintenance setting?

Certainly, it is important to consider safety and efficacy data from recentstudies in the decision-making process. Beyond that, factors such as conven-ience, cost, reimbursement, and, of course, toxicity profiles of specific agentsmust be considered so that therapy can be tailored to a patient’s needs. Thetreatment landscape for MM is constantly evolving; therefore, cliniciansmust also stay informed of new agents that are being investigated in clinicaltrials. For example, early data from phase 1/2 trials were recently released onthe use of the oral proteasome inhibitor MLN9708 in MM. In both newlydiagnosed and relapsed/refractory patients, treatment with this agent resultedin encouraging response rates with good tolerability, especially low rates ofPN.10,11 Based on these results, phase 3 trials are under way to further evaluatethe safety and efficacy of this agent in myeloma. �

References1. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMG-HD4 randomized

phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed byhigh-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patientswith newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts).2010;116:Abstract 40.

2. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalidomide fol-lowed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J ClinOncol. 2010;28:5101-5109.

3. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for mul-tiple myeloma: background and practical recommendations. Haematologica. 2010;95:311-319.

4. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals; January 2012.5. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of

bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferioritystudy. Lancet Oncol. 2011;12:431-440.

6. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell trans-plantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791.

7. Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diag-nosed multiple myeloma. N Engl J Med. 2012;366:1759-1769.

8. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-inel-igible newly diagnosed multiple myeloma: update on patients aged 65-75 years enrolled inMM-015. Presented at: 17th Annual Congress of the European Hematology Association; June14-17, 2012; Amsterdam, Netherlands.

9. ClinicalTrials.gov Web site. Stem cell transplant with lenalidomide maintenance in patientswith multiple myeloma (BMT CTN 0702). http://clinicaltrials.gov/ct2/show/NCT01109004.Updated March 28, 2012. Accessed July 3, 2012.

10. Lonial S, Baz RC, Wang M, et al. Phase I study of twice-weekly dosing of the investigationaloral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiplemyeloma (MM). J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8017.

11. Richardson PGG, Berdeja JG, Niesvizky R, et al. Oral weekly MLN9708, an investigationalproteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts)with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCOAnnual Meeting Abstracts). 2012;30(suppl):Abstract 8033.

Table 2. Select Grades 3 and 4 Hematologic Toxicities in theMM-015 Trial8

MP MPR MPR-R(Gr 3/4) (Gr 3/4) (Gr 3/4)

Neutropenia (%) 29/8 64/32 67/35

Thrombocytopenia (%) 12/4 38/12 35/11

Anemia (%) 14/1 26/3 24/3

MP indicates melphalan plus prednisone; MPR, melphalan, prednisone, lenalidomide;MPR-R, melphalan, prednisone, lenalidomide plus lenalidomide maintenance.

We are seeing RVD used more frequently as induction therapy in MM, so data from this studyshould be relevant to clinical practice.

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