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JULY 2012 VOL 3 NO 5

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ASCO 2012 ANNUAL MEETING

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

New Androgen Receptor–Signaling Inhibitor Extends Survival, Improves QOL in Advanced Prostate Cancer By Mark Knight

Photo by © ASCO/Phil McCarten 2012

Chicago, IL—The novel androgen receptor–signaling inhibitor enzalutamide, also known as MDV3100, significantly prolonged overall survival (OS), slowed disease progression, and improved quality-of-life (QOL) measures in men with castration-resistant

Chicago, IL—Canadian researchers reported a finding at the 2012 American Society of Clinical Oncology meeting that runs contrary to what other researchers have observed in the majority of studies. In this study, as oral drug costs increased, so did the likelihood of patients adhering to a prescribed regimen. Low adherence rates have been documented for many oral therapies in various diseases, and medication nonadherence is often the primary cause of treatment failure. “To our knowledge, cost-related adherence to oral therapy in the context of malignancy has not been studied extensively,” said Jalal Continued on page 11

HEALTH POLICY

The Affordable Care Act: The Day of Reckoning Arrives

O

ver the past 2 years, we have written about the impact of accountable care organizations, value-based purchasing, health insurance exchanges, and other programs relevant to the oncology community. These initiatives were all born out of the Affordable Care Act (ACA), which, on June 28, 2012, had its major day of reckoning. In a 5 to 4 decision

authored by Chief Justice John Roberts, the US Supreme Court upheld the ACA’s individual mandate—the requirement that most Americans obtain health insurance that meets the definition of minimum essential coverage. The Court also issued a fractured opinion on Congress’s authority to Continued on page 26

©2012 Engage Healthcare Communications, LLC

Continued on page 15

Defining the Roles of Patient Navigation Can Remove Barriers to Quality Care

Mandi Pratt-Chapman, MA

By Caroline Helwick Houston, TX—Patient navigation assures timely access to care for many patients, especially the medically underserved population, and it will soon become mandated for institutions accredited by the Commission on Cancer, reported Mandi Pratt-

Chapman, MA, Associate Director of the Community Programs, Codirector of the Center for the Advancement of Cancer Survivorship, Navigation and Policy, George Washington Cancer Institute, Washington, DC, at the Continued on page 17

INSIDE

Ross D. Margulies, JD, MPH, and Jayson Slotnik, JD, MPH Mr Margulies is a Health Policy Specialist, Foley Hoag, LLP, and Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

prostate cancer after docetaxel failure, according to results from a large phase 3 clinical trial. In this double-blind, randomized trial, OS improved from 13.6 months in the placebo group to 18.4 months in

IN THE LITERATURE

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Brentuximab vedotin shows high response in relapsed/refractory lymphoma Regorafenib active in advanced GIST ASCO ANNUAL MEETING

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High OOP costs for Medicare patients with cancer QOL drives patient preference for pazopanib vs sunitinib Tivozanib outperforms sorafenib in advanced RCC

CONFERENCE . . .17

Guidelines critical for value-based benefit design in oncology Involving the patient in end-of-life decisions Pathways offer providers true value AMCP ANNUAL MEETING

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Vemurafenib does not impact health plan budget Cost-effective analysis of pemetrexed/platinum in NSCLC

CONTINUING EDUCATION . . . . . . .32

Considerations in multiple myeloma


IV R FO AND D S ON E V OU TI O R NE TRA P AP UTA INIS C M B SU AD

VELCADEHCP.COM


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

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

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

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

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

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

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


In The Literature High Response Rate with Brentuximab Vedotin in Patients with Relapsed/ Refractory Hodgkin Lymphoma Despite significant improvements in the treatment of patients with advanced-stage, newly diagnosed Hodgkin lymphoma (HL) with com-

bined chemotherapy and radiotherapy that have led to durable remission rates of approximately 60% to 80%, a large proportion of patients are not cured and new therapies are needed. Patients with relapsed and/or refractory HL have poor prognosis. Newly reported results of a phase 2 clinical

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.

trial have shown that treatment with the antibody-drug conjugate brentuximab vedotin achieves high response rates in patients with relapsed or refractory HL whose disease has progressed even after receiving autologous stem-cell transplant (auto-SCT) salvage therapy (Younes A, et al. J Clin

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

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

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Oncol. 2012;30:2183-2189). This multinational, open-label study included 102 patients (median age, 31 years) with relapsed (71%) and/or refractory (42%) HL after chemotherapy and auto-SCT. All patients received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks. Those who did not progress or did not have prohibitive adverse events continued with this 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 a complete response (CR) and 96% met the classification of overall disease control (CR plus partial remission plus stable disease). The estimated 12-month survival was 89% (95% CI, 83%-95%). At a median period of 1.5 years (range, 1.823.5 months), 31 of the 102 patients were alive and free of disease progression, and 28 patients died. Adverse events were manageable with standard supportive care, and most were grade 1 or 2. A total of 56 patients had a grade ≥3 event after prolonged use of the drug; most of these events were neutropenia (20%), thrombocytopenia (8%), and anemia (6%). These results have prompted further investigation of brentuximab vedotin for earlier-stage disease and in combination with other therapies. A phase 1 trial is investigating this drug with multiagent chemotherapy in treatment-naïve patients with HL, and a phase 3 clinical trial is evaluating the impact of brentuximab vedotin on progression-free survival and overall survival in high-risk patients with HL after auto-SCT.

Regorafenib Active in Advanced GIST after Failing Standard Therapy The treatment of metastatic gastrointestinal stromal tumor (GIST) was revolutionized with the introduction of imatinib as first-line therapy, with 60% control rates and median progression-free survival (PFS) of 27 weeks with sunitinib in the second-line setting. Nevertheless, resistance to tyrosine kinase inhibitor therapy eventually develops in the majority of patients with advanced GIST; no third-line therapy is yet approved. New data suggest that regorafenib, a unique inhibitor of several kinase-associated cancers, has a wide-range activity in this patient population (George S, et al. J Clin Oncol. 2012;30:2401-2407). This multicenter, phase 2 clinical trial included 34 patients (33 evaluable) with metastatic and/or unreContinued on page 8

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VALUE PROPOSITIONS Precision Diagnostics Currently the True Value of Personalized Medicine According to Genome Health Solutions cofounder Mark S. Boguski, MD, PhD, FCAP, Harvard Medical School’s Center for Biomedical Informatics and Beth Israel Deaconess Medical Center, at this point in time, the promise of genomics lies “not so much in therapeutics or disease prevention, but in precision diagnostics that will really enable personalized medicine.” Dr Boguski and his cofounder Richard Kellner have set the goal for their new company to provide genomic-related management services and technological/biological know-how to the healthcare industry, with the intent “to finally bring the benefits of genomics to patients.” The center’s mission is “to accelerate the translation of genome science and technologies into cost-effective health services.” The center will focus on cancer as the 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 that precision diagnostics will lead to better outcomes. If we can understand in any given tumor which genes are the driver mutations—not just on average for a population, but in that individual patient—we can use advanced multiplex technologies to get that information. That opens up the possibility for more targeted therapy, which you expect would be more effective.” Insight & Intelligence; July 3, 2012

New Biomarker a Promising Development in Ewing’s Sarcoma A team of researchers from the University of Colorado led by Tyler Robin, PhD, Department of OB/GYN, Denver Anschutz Medical Campus, has discovered a new biomarker in Ewing’s sarcoma that explains the lack of disease response to current chemotherapy in some patients with this cancer, who until now have had a very poor prognosis. The identification of EYA3 protein as a novel biomarker—a mediator of chemoresistance—in Ewing’s sarcoma explains the mechanism of EYA3 overexpression as the culprit in the resistance to chemotherapy in this disease. This discovery will be used to direct therapy, by identifying patients with elevated EYA3 levels to either reduce the protein levels directly or to intervene in the EYA3 overproduction process. “First, levels of EYA3 could be a tool in offering accurate prognosis and choosing how aggressively to treat Ewing’s sarcoma, and, second, we hope that by lowering levels of EYA3, we could help increase the effectiveness of existing therapies for Ewing’s sarcoma,” Dr Robin noted. Furthermore, this new understanding will likely lead to the development of new therapies, according to coinvestigator Heide Ford, PhD. “Our next step is to test small-molecule inhibitors against EYA3 to determine which inhibitors best sensitize Ewing’s sarcomas to chemotherapy,” she said. Colorado Cancer Blogs; June 29, 2012

World’s First Pediatric Lymphoma Research Center Launched Texas 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 Center was 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 is sometimes supplemented by radiation. Despite much progress in this area, many patients with lymphoma do not respond to initial treatment, and a significant proportion of patients whose disease responds to available therapies will eventually develop drug resistance, requiring new therapies. The Fayez Sarofim Lymphoma Center will focus on researching the biology of lymphomas to develop new approaches to therapy, including

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new diagnostic methods and targeted therapies. The Texas Children’s Cancer Center has a translational research infrastructure already in place, focusing on rapid translation of laboratory and clinical research into clinical studies. “Our researchers have already developed effective cell-based therapies that have demonstrated extremely exciting clinical results, and we are also evaluating new chemotherapeutic agents with significant clinical promise,” said Catherine Bollard, MD, Director of the Fayez Sarofim Lymphoma Center. Potential advances made at the center will be shared with 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 financial gift “will help expand the number of innovative therapies that will be available to treat our young patients. Our ultimate goal is to find a cure for all children with lymphoma.” Texas Children’s Hospital press release; June 26, 2012

First US Hospital Integrates Psychosocial Support Services in Its Cancer Center Greenville Hospital System (GHS) has launched the Center for Integrative Oncology and Survivorship, which offers emotional services for cancer survivors developed by Cancer Support Community (CSC), an international provider of cancer-related social and emotional services. “Research shows that social and emotional support is as important as medical care in the fact of a cancer diagnosis,” said Larry Gluck, MD, Medical Director, GHS Cancer Center, SC. “Cancer Support Community is a leader in psychosocial oncology, and we are pleased to integrate its evidence-based programs and services into our cancer care delivery model.” This is the first US hospital to offer CSC’s services within the hospital setting itself, including distress screening program, personalized assessment 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 to funding from the Palmetto Peloton Project. Greenville Hospital Services; June 26, 2012

Researchers Highlight Benefits of Exercise for Patients with Cancer Several researchers at the University of Rochester Medical Center have been studying the effects of exercise on patients with cancer for some time 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 it is safe and effective, particularly for relief of treatment side effects,” suggests Karen Mustian, PhD, MPH, Assistant Professor of Radiation Oncology, 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 of nearly 14,900 people. She found that patients with cancer or cancer survivors are less physically active than people without cancer, a reality that has been linked to increased risk for cancer recurrence and reduced survival in this patient population. Dr Sprod notes that it is not clear whether cancer treatment contributes to such reduced physical activity or whether patients with cancer and their physicians are concerned with safety issues for 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 yoga program and were taking aromatase inhibitors reported reduced medication side effects, including less pain, reduced muscle aches, and less overall physical discomfort. These new data reinforce the value of exercise for overall well-being and improved quality of life for patients with cancer. University of Rochester Medical Center newsroom; May 30, 2012

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In This Issue IN THE LITERATURE Brentuximab vedotin has high response rate in relapsed/refractory lymphoma Regorafenib active in advanced GIST Anti–PD-1/PD-L1 antibodies show promising antitumor activity More….

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895

ASCO ANNUAL MEETING High OOP costs for Medicare patients with cancer Quality of life drives patient preference for pazopanib over sunitinib Patients willing to pay out of pocket for genetic testing to assess colon cancer risk Endocrine therapy underutilized in low-income patients with breast cancer Tivozanib outperforms sorafenib in RCC More….

Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896 Associate Publisher Joe Chanley joe@greenhillhc.com Associate Editor Lara J. Lorton Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

VBCC Editorial Board

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

Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL Past President, ACCC Past Chair, NCCN Board of Directors

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

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY

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

Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881

Craig Deligdish, MD Chief Medical Officer Oncology Resource Networks Orlando, FL

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs eviti, Inc

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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CONFERENCE

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

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Evidence-based guidelines critical for value-based benefit design in oncology Collaborate to achieve value in oncology Involving the patient in end-of-life decisions: Aetna’s oncology strategy Tough times for small oncology practices Pathways offer providers a true value proposition More….

AMCP ANNUAL MEETING Vemurafenib does not impact health plan budget Cost-effective analysis of pemetrexed/platinum in NSCLC More….

CONTINUING EDUCATION Considerations in multiple myeloma

Ira Klein, MD, MBA Aetna Hartford, CT

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Crystal Kuntz, MPA Astellas Pharma US Washington, DC John L. Marshall, MD Director, The Ruesch Center for the Cure of GI Cancers Chief, Hematology and Oncology Associate Director, Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

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

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

David Hom, MBA Solucia Farmington, CT

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

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

Naimish Pandya, MD University of Maryland Baltimore, MD

JULY 2012

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY Section Editor Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

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FDA Update New Test for Aiding Biopsy Decision after PSA Test The US Food and Drug Administration (FDA) has approved the Access Hybritech p2PSA (Beckman Coulter) test, which measures a form of prostate-specific antigen (PSA) called [-2]proPSA in the blood and can help men whose PSA test scores are elevated decide whether they should have a biopsy to rule out prostate cancer. The Access Hybritech p2PSA test is approved for use in men aged ≥50 years whose PSA test score is between 4 and 10 ng/mL but a digital rectal examination does not show any signs of cancer. A PSA test score between 4 and 10 ng/mL often prompts physicians to recommend a prostate biopsy. The FDA approval was based on a clinical trial with nearly 660 men, of whom approximately half had prostate cancer. The phi score was better than the PSA score at distinguishing between benign conditions and prostate cancer. In addition, the study showed that the phi score level was a predictor of cancer, with a higher score associated with increased probability of detecting prostate cancer after a biopsy. According to Barry Kramer, MD, Director of the National Cancer Institute Division of Cancer Prevention, the study was not designed to determine 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 a biopsy. According to the FDA, “The choice of an appropriate…phi score to be used in guiding clinical decisionmaking may vary for each patient and may depend in part on other clinically important factors or on family history of disease.” The Access Hybritech p2PSA is expected to be available in the United States this year, according to the manufacturer. (June 14, 2012)

lenalidomide and with bortezomib), resulting in an approximate 22% overall response rate (ORR). However, the toxicity profile was problematic. The side effects seen in this study included serious heart problems, such as cardiac arrest, chest pain, pneumonia, and shortness of breath, including 5

deaths. According to the FDA report, >70% of patients receiving carfilzomib had lung complications. The ODAC report says that because the ORR for carfilzomib was “only 22% in the primary efficacy study, it may not provide an advantage over available therapy. FDA is very concerned

with the severe toxicities, including deaths, that are associated with the use of this agent. The pathogenesis of these toxicities is not understood.” However, the ODAC report states that carfilzomib’s benefits outweigh its risks, and is recommending its approval by the FDA. (June 20, 2012) ■

ODAC Recommends Carfilzomib for Myeloma The FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended in an 11 to 0 vote (and 1 absentee) to approve carfilzomib (Kyprolis; Onyx), a new-generation proteasome inhibitor, for the treatment of patients with refractory and relapsed multiple myeloma who have failed at least 2 other myeloma therapies—the proteasome inhibitor bortezomib (Velcade) and the immunomodulatory drug lenalidomide (Revlimid). The company applied for accelerated approval of this agent based on the results from a phase 2 clinical trial of 266 patients with refractory and relapsed myeloma who had received at least 2 previous treatments (with

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In The Literature Regorafenib Active in Advanced GIST... Continued from page 4

sectable GIST whose disease progressed after therapy with imatinib and sunitinib. The primary end point was a composite of complete response rate, partial response rate, and stable

disease after ≥16 weeks. All patients received oral regorafenib 160 mg daily on days 1 to 21 of a 28-day cycle. After a median followup of 10.9 months, 21 patients continued to receive the drug, and 16 of them remained disease free. In addition, 5 patients continued to receive rego-

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% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

rafenib after disease progression, because of perceived continued benefit. A total of 12 patients discontinued the study because of disease progression. Overall, the clinical benefit rate was 79%; 4 patients achieved partial response, and 22 showed stable disease after ≥16 weeks. The median PFS

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 Mothers It 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 Use Safety 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 (AUC0-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 Use Of 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 Impairment In 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 ADMINISTRATION The 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

was 10.0 months. The most common grade 3 events were hypertension and hand-foot-skin reaction. A phase 3 clinical trial of regorafenib versus placebo in this setting is ongoing.

Anti–PD-1/PD-L1 Antibodies Show Promising Antitumor Activity in Several Cancers The programmed death 1 (PD-1) receptor is expressed by activated T cells and mediates immunosuppression involved in tumor growth. Results from two phase 1 clinical trials—one evaluating an anti–PD-1 antibody (Topalian SL, et al. N Engl J Med. 2012; 366:2443-2454) and the second evaluating an anti–PD-1 ligand (PD-L1) antibody (Brahmer JR, et al. N Engl J Med. 2012;366:2455-2465)—suggest that targeting the PD-1/PD-L1 pathway may be beneficial in treating certain types of solid tumors, including advanced melanoma, non–small-cell lung cancer (NSCLC), and renal-cell cancer. In the first study, 296 patients with advanced melanoma, NSCLC, castration-resistant prostate cancer, renalcell cancer, or colorectal cancer received the anti–PD-1 antibody for up to twelve 8-week treatment/evaluation cycles. Most patients had been heavily pretreated. Among the 236 evaluable patients, dose-related objective responses (partial or complete) were seen in patients with melanoma (range, 19%-41%), NSCLC (range, 6%-32%), and renalcell cancer (range, 24%-31%), but no responses were seen in patients with colorectal or prostate cancer. Objective responses of ≥1 year were seen in small but substantial proportions, ranging from 1 in 5 to 1 in 4 patients with melanoma, NSCLC, or renalcell cancer. The response in patients with NSCLC was unexpected and suggests that that drug’s activity may go beyond immunogenic tumor types. In a secondary analysis of 25 patients with PD-L1–positive tumors, 9 (36%) had an objective response compared with no response among the 17 patients with PD-L1–negative tumors. The adverse event profile seen in this study was consistent with immune-related causes. The incidence of grade 3 or 4 drug-related adverse events was low enough (14% of 296 patients) to suggest potential therapy delivery in an outpatient setting. In the second study, patients with NSCLC, melanoma, colorectal cancer, renal-cell cancer, ovarian cancer, pancreatic cancer, gastric cancer, or breast cancer received an anti–PD-L1 antibody for up to sixteen 6-week treatment cycles. Continued on page 29

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ASCO 2012 Meeting

Unforeseen Hospital Admissions Are Frequent for Patients Receiving Radiotherapy Potential marker of quality of care in cancer therapy By Wayne Kuznar Chicago, IL—Approximately 1 in 5 patients with cancer who are undergoing radiotherapy as part of their treatment can count on unexpected hospital stays—adding an economic and clinical burden on the patient and on the healthcare system, according to an analysis by Nabeel H. Arastu, BS, and colleagues at the Brody School of Medicine at East Carolina University, Greenville, NC, which was presented at the 2012 ASCO meeting. Unanticipated admissions were common among nearly 33% of patients who received radiotherapy to treat symptoms and were also likely in more than 25% of those receiving simultaneous chemoradiation. As part of the analysis, data were collected from the electronic health records of 500 patients with cancer. The patients had received external beam radiotherapy in 2010 at a facility at the University of North Carolina School of Medicine in Chapel Hill. Relevant clinical information and unexpected hospital stays that took place within 90 days of radiotherapy treatment startup were documented. The objective was to find out whether there are any clinical markers pre-radiotherapy to understand if

some patients are more likely than others to be admitted to the hospital unexpectedly. A 20% Unexpected Admissions Rate Of the 500 patients, 101 (20%) had unexpected hospital stays, lasting a mean of 4 days (range, 1-16 days). The mean length of time between a patient beginning radiotherapy and going to the hospital unexpectedly was 32 days (range, 0-86 days). Reasons for hospital admission included: • Pain (19% of cases) • Respiratory issues (15%) • Neurologic conditions (13%) • Malaise (7%) • Fever (5%). Other clinical factors that may influence future unplanned hospital visits include use of pain medicine to control symptoms, weight loss issues, and receipt of intravenous fluid. In addition, 33% of patients who were treated palliatively ended up being admitted to the hospital compared with 16% of curative-focused patients. According to a univariate analysis, 26% of patients who had simultane-

ous radiotherapy and chemotherapy had unplanned hospital admissions compared with 17% of those receiving only radiotherapy. A multivariate examination indicated that unexpect-

It is important to consider preventive approaches in higher-risk patients so that admission rates can be lowered. Unexpected hospital visits may serve as a marker for quality of care in cancer therapy.

ed hospital stays were tied to chemotherapy, treatment goals, and marital status. There were highly inconsistent rates of unexpected hospital visits based on diagnosis— including 37% for metastases; 19% for gastrointestinal, genitourinary, gynecologic, ear, nose, and throat cancers; and 4% for breast cancer.

Patients who were treated with a second or third round of radiotherapy could expect higher admission rates (average, 27%) compared with those who received only 1 treatment round (16%). Furthermore, patients who were undergoing treatment for secondary metastases typically experienced a much higher rate of unexpected hospital visits. According to the researchers, the reason may be that patients undergoing multiple rounds of chemotherapy or treatment for secondary metastases are typically sicker and have more comorbidities than other patients. Preventive Measures Mr Arastu and colleagues note that it is important to consider preventive approaches in higher-risk patients so that admission rates can be lowered. They add that unexpected hospital visits may serve as a marker for quality of care in cancer therapy. To develop measures to trim admission rates and the costs associated with them, the team suggests that it is necessary to understand the frequency of such visits, as well as reliable predictors of why the visits occur in the first place. ■

High OOP Costs for Medicare Patients with Cancer By Mark Knight Chicago, IL—Older patients with cancer and Medicare coverage often incur greater out-of-pocket (OOP) expenses compared with their counterparts without cancer. Factors contributing to the greater expenses for those patients include comorbidities and lack of supplemental insurance. As a result, older patients often hesitate to seek treatment for cancer because of financial concerns, according to a study presented by Amy J. Davidoff, PhD, MS, Assistant Professor, Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, Baltimore, and colleagues at the 2012 American Society of Clinical Oncology meeting. The team used Medicare Current Beneficiary Survey (MCBS) data from 1997 to 2007 that was linked to

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

Medicare claims for their analysis. Patients with a new diagnosis of cancer were chosen based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) codes on claims after a 12month washout period subsequent to the cancer diagnosis. OOP costs

were noted via the patients’ own reporting. The study included 1869 Medicare beneficiaries with cancer and 10,057 without cancer. Those with cancer tended to be older, have more comorbidities, and typically did not have supplemental insurance compared

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with those without cancer. For a patient with cancer, the total OOP spending was $4727 (11.4% of total spending); the OOP difference between patients with and without cancer was $1518. After adjusting for patient characteristics, those with cancer had an incremental increase of $956 in OOP cost. Among patients with cancer, approximately 28% spent ≥20% of their income on OOP expenses compared with 16% of those without cancer who used ≥20% of their income on OOP expenses. Comorbid conditions, undergoing cancer-specific radiation therapy, receiving antineoplastic therapy, and having greater assets led to more OOP expense. Continued on page 10

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

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 one drug over the other because of adverse effects, but “we didn’t ever expect such a big difference between the 2 drugs.”

Photo by © ASCO/Scott Morgan 2012

Chicago, IL—The surprising results of a randomized trial on patient preference for one cancer therapy over another show that patient-reported quality-of-life (QOL) differences influence treatment preference far more than physicians had imagined, suggested researchers at the 2012 American Society of Clinical Oncology meeting. In a double-blind, crossover trial, 168 patients with metastatic renal-cell

—Bernard J. Escudier, MD carcinoma (mRCC) were randomized 1:1 to 10 weeks of 800 mg of pazopanib or 50 mg of sunitinib as first-line cancer treatment; after a 2-week washout period, patients received 10 weeks of the alternate treatment. The primary end point was patient preference, measured at 22 weeks. Because patients with mRCC receive therapies for many months or even years, the team assessed whether the drug toxicity would be significant enough to make patients want to continue treatment with either drug or to switch therapy. A total of 126 patients completed a preference questionnaire. In the primary analysis, 70% of the patients preferred pazopanib, 22% preferred sunitinib, and 8% cited no preference. After adjustments for a modest sequence effect, the difference in preference was

High OOP Costs for Medicare... Supplemental Insurance A separate analysis of the same MCBS database showed that the use of antineoplastic therapy among Medicare recipients is influenced by the availability, but not the type, of supplemental coverage. This analysis—based in large part on data before the addition of Medicare Part D (in 2006)— demonstrated that oral antineoplastic agents were received by many patients with cancer using antineoplastic therapy (non–Part B drugs), yet there was less spending on this therapy than on infused/injected chemotherapy (Part B drugs). There were no notable differences in use or spending on antineoplastic therapy for the post–Part D period relative to the reference period. “With the large number of relatively new oral prescription antineoplastic agents, and with more in the pipeline, monitoring the role of supplemental insurance and particularly the role of

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Part D in access and spending, is a critical area for ongoing research,” said Dr Davidoff. For this retrospective analysis,

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

community-based MCBS participants with new cancer diagnoses were chosen based on ICD-9-CM diagnosis

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49% in favor of pazopanib. All other analyses showed a significant preference for pazopanib.

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

The most common reasons given for pazopanib preference were better QOL and less fatigue. Patients taking pazopanib had fewer dose reductions than those taking sunitinib (13% vs 20%, respectively) and fewer treatment interruptions (6% vs 12%, respectively). Adverse events (AEs) were

compatible with known profiles for both drugs. The researchers, led by Bernard J. Escudier, MD, from the Institut Gustave Roussy, Villejuif, France, said that they expected patients to prefer one drug over the other because of adverse effects, but “we didn’t ever expect such a big difference between the 2 drugs.” Physicians may perceive toxicity differences between 2 different therapies as relatively minor, but to patients, even low-grade toxicities over a long period have a significant effect on QOL, according to Dr Escudier and colleagues. How patients feel when they take a drug over many months is not reflected in traditional AE reporting. A survey on physician therapy preferences, which was a secondary end point in this study, showed some difference in physicians’ drug preferences: 60% preferred pazopanib, 21% preferred sunitinib, and 21% had no preference. Patient-reported outcomes are increasingly being added to traditional efficacy outcomes to better understand the clinical relevance of differences in drug toxicities, Dr Escudier and colleagues noted. ■

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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

codes. A total of 1836 beneficiaries who had a new diagnosis of cancer were enrolled. Of the 559 patients who were treated with antineoplastic therapy, 395 (21.5%) received infused/injected chemotherapy and 254 received oral antineoplastic agents. Patients using antineoplastic therapy spent $7841 (any coverage), $10,364 (Part B coverage), and $1535 (non–Part B coverage). If beneficiaries had supplemental coverage, the antineoplastic therapy rates and spending were greater relative to those who did not have supplemental coverage. After adjustment, patients with supplemental insurance from any source were more likely to receive treatment for cancer. A major predictor of antineoplastic therapy use and spending was the site of the cancer. Also, older age was associated with less spending. ■

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Can Drug Cost Drive Oral Medication... Ebrahim, MD, of St Michael’s Hospital, University of Toronto, Onta-rio, Canada. He and his colleagues conducted a study of 453 patients with cancer at 3 outpatient hematology/oncology clinics. They used a 7-item survey to investigate patient self-reported adher-

The surprising finding in this study suggests that patients with cancer consider more expensive drugs to be more valuable, and should therefore be taken as prescribed.

ence to oral medication, type of coverage, and patients’ perceived cost of the drugs. Of the 453 patients, 50% had a private drug plan, 24% paid for the drug out of pocket, 44% had government funding, and 4% said their physician

had arranged funding for their medication. Approximately 50% of the patients had a drug cost of ≥$100 monthly. Patients paying out of pocket were significantly less likely than all other patients to have oral drug costs of ≥$500 monthly (11% vs 19%, respectively). There was also a significant relationship between drug coverage and oral drug costs. Patients with annual incomes of ≥$70,000 were more likely than those with lower incomes to have monthly drug costs of ≥$1000 (18% vs 9%, respectively). “It is possible that patients are provided with more education regarding newer and more expensive agents than they are for older and cheaper agents, regardless of efficacy,” according to Dr Ebrahim. Strong Adherence to High-Cost Drugs “A strong correlation was observed between monthly oral drug cost and adherence to the regimen,” he said. A low monthly drug cost was not associated with higher adherence rates. The adherence rates related to

Continued from cover

“A strong correlation was observed between monthly oral drug cost and adherence to the regimen.” —Jalal Ebrahim, MD

monthly out-of-pocket costs were: • 55% adherence with ≤$10 • 83% adherence with $10-$100 • 83% adherence with $100-$500 • 75% adherence with $500-$1000 • 85% adherence with ≥$1000. Dr Ebrahim believes that patients consider more expensive drugs to be more valuable, and therefore should not be wasted. This “designer drug” phenomenon may explain the increased adherence rates that were found to be associated with

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

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

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tinal Tumor Risk Assessment Registry, 406 participants (73% female) completed a survey that collected detailed demographic data, cancer history, and psychosocial items related to cancer

“These participants are fearful of a positive result and anticipate benefits afforded by genetic testing in controlling cancer risk.” —Jennifer M. Matro, MD

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

JULY 2012

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

www.ValueBasedCancerCare.com

11


Making

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

TAILORING a PRO tool for myelofibrosis

130TBSFBOJNQPSUBOUNFBOTUPEFNPOTUSBUFUSFBUNFOU benefits in clinical trials. 6TFPGB130JOTUSVNFOUDBO evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. *ODPSQPSBUJOH130TJOUPBDMJOJDBMUSJBMQSPHSBNQSPWJEFTB means for evaluating the impact of therapy from the patientâ&#x20AC;&#x2122;s perspective and helps patients and clinicians make betterinformed decisions.

.ZFMPĂĽCSPTJT .' JTBMJGFUISFBUFOJOH QSPHSFTTJWFEJTFBTF characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, EPVCMFCMJOEQMBDFCPDPOUSPMMFETUVEZ $0.'035* GPS +BLBĂĽ4QMFFOSFEVDUJPO BTNFBTVSFECZJNBHJOH .3*PS$5  was the primary and biologic endpoint, and a reduction in total TZNQUPNTDPSF 544 UIF130NFBTVSF XBTBLFZTFDPOEBSZ endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 5PJODMVEF130TJOUIFUSJBM BOPWFMJOTUSVNFOUIBEUPCF specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version  NPEJĂĽFE.'4"'W XBTĂĽOBMJ[FEBTQBSUPGUIF4QFDJBM 1SPUPDPM"TTFTTNFOUQSJPSUPUIFJOJUJBUJPOPG$0.'035* Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyteâ&#x20AC;&#x2122;s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDAâ&#x20AC;&#x2122;s draft guidance on 130TXBTĂĽOBMJ[FEJO 

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postâ&#x20AC;&#x201C;polycythemia vera myelofibrosis and postâ&#x20AC;&#x201C;essential thrombocythemia myelofibrosis. Important Safety Information t5SFBUNFOUXJUI+BLBĂĽDBODBVTFIFNBUPMPHJDBEWFSTF reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required t5IFUISFFNPTUGSFRVFOUOPOIFNBUPMPHJDBEWFSTF reactions were bruising, dizziness and headache t1BUJFOUTXJUIQMBUFMFUDPVOUT¨9/L at the start of therapy are more likely to develop thrombocytopenia

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


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

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

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patientâ&#x20AC;&#x2122;s response.

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patientâ&#x20AC;&#x2122;s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MFâ&#x20AC;&#x201D;this is an important consideration when evaluating and treating patients.9 5IF'%"BQQSPWBMJODMVEFEQBUJFOUTXJUIJOUFSNFEJBUFSJTLBOEIJHISJTL BTXFMMBTQBUJFOUT with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and BDBEFNJDFYQFSUTUPEFWFMPQSFMFWBOUBOEWBMJEBUFE130JOTUSVNFOUTUIBUDBOCFJODPSQPSBUFEJOUPDMJOJDBMUSJBMT1,8 The approval PG+BLBĂĽNBSLTBTJHOJĂĽDBOUNJMFTUPOFJOXIJDIWBMJEBUFE130JOTUSVNFOUTDBOQSPWJEFTZNQUPNEBUBBOEEFNPOTUSBUF DMJOJDBMCFOFĂĽU5IFFYQFSJFODFXJUI+BLBĂĽNBZQSPWJEFBNPEFMGPSUIFGVUVSFVTFPG130TJONBSLFUJOHBQQMJDBUJPOT8

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

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a â&#x2030;Ľ35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a â&#x2030;Ľ50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms â&#x20AC;&#x153;absentâ&#x20AC;? and 10 representing â&#x20AC;&#x153;worst imaginableâ&#x20AC;? symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

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

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


ASCO 2012 Meeting

Cancer Screening Saves Lives, Is Cost-Effective By Wayne Kuznar Chicago, IL—Improved cancer screening can save lives, and despite the high cost of implementing      such a measure, it was found cost-effective and therefore valuable in a recent analysis using

quality-adjusted life-years (QALYs), said Michael S. Broder, MD, President of Partnership for Health Analytic Research, LLC (PHAR), CA, and colleagues, at the 2012 American Society

of Clinical Oncology meeting. Cancer care spending in the United States has increased from $13.1 billion in 1980 to $104 billion in 2006, but there is much controversy over the suf-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

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VALUE-BASED CANCER CARE

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JULY 2012

ficiency of the benefit of this spending. Cancer screening may reduce cancer-related morbidity, but to study whether such screening is cost-effective, Dr Broder and colleagues from PHAR; the University of California, Los Angeles, Center for Surgical Outcomes and Quality; and RAND Health in Santa Monica, CA, developed a framework for measuring the value of improving compliance with measures for cancer screening compared with other quality measures.

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

Value of Quality Improvement Dr Broder and colleagues used their framework to examine 18 HEDIS 2010 quality measures. Quality improvement (QI)-adjusted incremental costeffectiveness ratios (ICERs) for 3 cancer screening measures—cervical, breast, and colon—were compared to the remaining measures. ICERs were reported for measures representing a tradeoff (ie, between greater cost and greater health, or cost-savings and worse health). To reach 95% compliance on these 3 cancer screening measures would cost $5.1 billion and add 160,000 QALYs— $32,640/QALY. This rate of compliance with all 18 measures would cost $13.4 billion and add 5.8 million QALYs, which translates to $2313/ QALY. That would make QI a good value and very cost-effective compared with most health improvements, which can cost more than $50,000 to $80,000 per QALY, according to Dr Broder. Although these costs were substantial, resulting in an increase of 50% to 200% in the ICER for the cancer screening measures, after incorporating QI costs, the mean QI-adjusted ICER for these 3 measures suggests that improving cancer screening compliance is cost-effective at a $50,000/ QALY willingness-to-pay threshold. “Our analysis shows that complying with cancer screening measures is costeffective, even considering the resources required to change established practices,” said Dr Broder. Addressing overuse of care can save money, he added. ■

VOL. 3

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ASCO 2012 Meeting

the enzalutamide group, for a 37% reduction in the risk of death, said Johann S. de Bono, MB, ChB, MSc, PhD, of the Institute of Cancer Research and the Royal Mardsen National Health Service Foundation Trust, United Kingdom, at the 2012 American Society of Clinical Oncology meeting. “I think these are the best survival data we’ve seen in the postchemotherapy setting,” Dr de Bono said. A total of 1199 patients with castration-resistant prostate cancer who had

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

received docetaxel-based chemotherapy were randomized in a 2:1 ratio to daily enzalutamide or to placebo. Therapy was continued through minor changes in prostate-specific antigen (PSA) level. Treatment with glucocorticoids was allowed but not required. More than 25% of patients had softtissue disease involving the liver or the lung. More than 90% of patients had bone metastases. Approximately 50% of the patients in each arm had ≥3 previous lines of hormonal drug therapy. The trial was unblinded early after the Independent Data Monitoring Committee determined that the riskto-benefit ratio with MDV3100 was favorable; eligible patients in the placebo arm were offered treatment with enzalutamide. With a median follow-up of 14.4 months, enzalutamide conferred a survival advantage across all identified subgroups. “Impressively, enzalutamide had a very high PSA response rate,” said Dr de Bono. With enzalutamide, 25% of patients had a >90% fall in PSA level compared with only 1% with placebo. “I never thought I’d see a 50% and 90% fall in PSA in this population of patients, with 54% of patients having a more than 50% confirmed PSA fall,” Dr de Bono said. All of the secondary end points in

Photo by © ASCO/Silas Crews 2012

New Androgen Receptor–Signaling Inhibitor...

“I think these are the best survival data we’ve seen in the postchemotherapy setting. Impressively, enzalutamide had a very high PSA response rate. I never thought I’d see a 50% and 90% fall in PSA in this population of patients.” —Johann S. de Bono, MB, ChB, MSc, PhD

the study favored the treatment arm. PSA progression-free survival (PFS) was extended from 3.0 months in the

Continued from cover placebo group to 8.3 months in the enzalutamide group. Similarly, the radiographic PFS was 2.9 months in the placebo group and 8.3 months in the enzalutamide group, for a hazard ratio of 0.40 in favor of enzalutamide. Objective response rates (complete and partial) based on the Response Evaluation Criteria in Solid Tumors (RECIST) trial were 3.8% in the placebo arm and 28.9% in the enzalutamide arm. The time to a first skeletal event was again superior in the enzalutamide arm (16.7 months) compared with the placebo arm (13.3 months)—a 38% reduction in the risk of a skeletal-related event. QOL responses as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) were also superior with enzalutamide. In that group, 43.2% had at least a 10-point increase in the overall FACT-P score compared with 18.3% in the placebo group. A smaller proportion of patients treated with enzalutamide had grade ≥3 adverse events (AEs) compared with placebo (45.3% vs 53.1%, respectively). Serious AEs also occurred at a lower rate with enzalutamide than placebo (28.4% vs 33.6%). Seizure rates were 0.6% with enzalutamide and 0% with placebo. ■

Endocrine Therapy Substantially Underutilized Among Low-Income Patients with Breast Cancer By Caroline Helwick Chicago, IL—Researchers from the University of North Carolina in Chapel Hill reported at the 2012 American Society of Clinical Oncology meeting that endocrine therapy is substantially underutilized among the low-income breast cancer population. For women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive disease, endocrine therapy reduces the 5-year recurrence risk by as much as 40%, but this study showed that low income may be an obstacle to receiving this guidelinerecommended treatment. Using Medicaid claims data matched to North Carolina Central Cancer Registry records, the researchers identified factors that predicted the use of guideline-recommended endocrine therapy among low-income women aged 18 to 64 years who were

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diagnosed with in situ stage I or stage II breast cancer between 2004 and 2007. Of the 269 ER- or PR-positive women in this sample, only 49% filled a prescription for endocrine therapy within 15 months of diagnosis, reported Racquel E. Kohler, MSPH, Research Associate at the University of North Carolina, and colleagues. Tamoxifen was the most common therapy among the 132 patients who received adjuvant endocrine therapy (59%). Less common therapies included anastrozole (18%), letrozole (10%), exemestane (2%), and multiple agents (11%). In a multivariate analysis, the only factor significantly associated with receiving guideline-recommended endocrine therapy was involvement in the Breast and Cervical Cancer Control

Program (BCCCP; P = .01). On average, participating in the BCCCP was associated with a 29.9% increase in the

“Our results suggest that endocrine therapy is substantially underutilized in this low-income, vulnerable population, and that intervention efforts to improve its use may be important.” —Racquel E. Kohler, MSPH

likelihood of receiving endocrine treatment compared with women who were not in the BCCCP, controlling for

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other factors, Ms Kohler reported. The BCCCP provides free or lowcost breast and cervical cancer screenings and follow-up to eligible women, mostly through local health departments, community health centers, hospitals, and private physicians’ offices. Other independent variables were not significantly associated in the multivariate analysis; however, in the bivariate analysis, women who received endocrine therapy were more likely 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 underutilized in this low-income, vulnerable population, and that intervention efforts to improve its use may be important,” Ms Kohler pointed out. ■

www.ValueBasedCancerCare.com

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ASCO 2012 Meeting

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

Photo by © ASCO/Silas Crews 2012

By Wayne Kuznar

“Tivozanib should be considered a first-line treatment option for metastatic RCC.” —Robert Motzer, MD

measurable disease, and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomized to tivozanib once daily for 3 weeks (followed by 1 week of rest) or sorafenib twice daily continuously in a 4-week cycle. Patients were either treatment-naive or had received no more than 1 prior systemic therapy for

metastatic disease. Treatment continued until either disease progression or intolerance. Patients randomized to the sorafenib arm were eligible to cross over to tivozanib therapy under a separate protocol after radiographic confirmation of disease progression, and many of them did. No crossover protocol was available for patients randomized to the tivozanib arm. In the overall study population, tivozanib demonstrated a statistically significant improvement in PFS compared with sorafenib (median, 11.9 months vs 9.1 months) when assessed by an independent panel, corresponding to a 21% improvement with tivozanib. When assessed by the investigators, the difference in PFS between the 2 groups was 14.7 months with tivozanib versus 9.6 months for sorafenib, for a 28% improvement. The efficacy advantage of tivozanib was consistent across all subgroups. Among the 70% of treatment-naive patients, median PFS was 12.7 months with tivozanib versus 9.1 months with sorafenib, and the objective response rate was 33% versus 23%, respectively. Tolerability of tivozanib was also

more favorable than sorafenib’s, as evidenced by a low rate of dose interruptions (17% vs 35%, respectively) and reductions (12% vs 43%, respectively); the discontinuation rates were 4% and 5%, respectively. Treatment-emergent adverse events were present in 90% of patients in both groups, although important differences were seen in the safety profile between the 2 drugs. According to Dr Motzer, although hypertension is the predominant adverse event with tivozanib, the development of hypertension is associated with tivozanib’s greater efficacy and potency for the VEGF receptor. The hypertension was treatable, requiring dose reduction in only 2% and dose discontinuation in only 1% of the patients treated with tivozanib. “I think there’s clear evidence that the phase 2 safety profile has indeed been confirmed in phase 3,” said coinvestigator Tim Eisen, MD, Professor of Medical Oncology, Cambridge Research Institute, United Kingdom. The data require more careful evaluation over the next several months to “exclude any hypertension-related complication risk,” he said. ■

Chemotherapy-Related Toxicity Adds to Economic Burden in Metastatic Breast Cancer By Caroline Helwick Chicago, IL—Adverse events (AEs) related to chemotherapy for metastatic breast cancer create a substantial economic burden that is primarily explained by increased inpatient, outpatient, and pharmacy costs, said lead investigator Sara A. Hurvitz, MD, Director of the Oncology Breast Cancer Program at University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center and Assistant Clinical Professor at UCLA School of Medicine, who presented an economic analysis at the 2012 American Society of Clinical Oncology meeting. “An analysis of healthcare costs stratified by the number of AEs reported by patients showed a clear trend: the economic burden of AEs increases with the number of AEs reported,” Dr Hurvitz said. The study is the first to assess costs associated with AEs during treatment for metastatic breast cancer. Patients were selected from the

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PharMetrics Integrated Database, using pharmacy and medical claims from >100 US health plans, representing >70 million lives between 2000 and 2010. The eligible cohort included 3222 patients who used a taxane (ie, docetaxel, paclitaxel) first-line, capecitabine first-line, taxane second-line, or capecitabine second-line. Patients treated with both classes during the same episode were excluded. The list of AEs included almost 2 dozen possibilities. AEs were seen in each of the 4 study cohorts. Incremental Monthly Costs The incremental costs associated with chemotherapy-related complications were estimated by comparing the average costs between the cohorts with and without AEs for the 4 treatment groups: • Taxanes first-line: AEs were associated with a 38.7% increase in monthly costs over patients without

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AEs ($3547). These incremental costs were mainly driven by increased inpatient costs and other drug costs (other than those for chemotherapy) • Taxanes second-line: AEs were associated with a 69.5% increase in monthly costs ($5320). Incremental costs were mainly driven by incremental pharmacy costs for chemotherapy and other drugs • Capecitabine first-line: AEs were associated with a 9% increase in monthly costs ($4933). Incremental costs were mainly driven by inpatient and outpatient costs • Capecitabine second-line: AEs were associated with an 82.9% increase in monthly costs ($4933). Incremental costs were mainly driven by outpatient and inpatient costs. Increasing AEs per Episode Led to Higher Costs The more AEs per episode, the

greater the cost of care, the analysis found. For example, for taxane firstline therapy, the mean cost of a treatment without an AE episode was approximately $10,000, which rose to approximately $11,000 in the setting of 1 or 2 AEs, and to almost $15,000 in the setting of >4 AEs. For second-line capecitabine, treatment without an AE episode cost approximately $6000, but rose to approximately $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 constitutional symptoms with capecitabine, both approaching $16,000 on average. “Further research evaluating the clinical and economic consequences of chemotherapy-related AEs in a prospective manner can further characterize the effects seen here,” Dr Hurvitz concluded. ■

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2nd Conference

Defining the Roles of Patient Navigation... Second Annual Conference of the Association for Value-Based Cancer Care. Patient navigation is a coordinated process that addresses barriers to quality care by providing individualized assistance to patients, survivors, and families, and facilitating timely access to services. Patient navigation is a way to address healthcare disparities, and it serves as an antidote to the fragmented and complex healthcare system, Ms Pratt-Chapman maintained. The goal is to identify and eliminate barriers to care, and to provide culturally competent interventions based on specific population needs. “We know that issues faced by patients with cancer can have devastating consequences, and the healthcare system at large is labyrinthine. Many patients must fight their way through this dysfunctional system, while trying to save their own lives,” she noted. “Navigation is not a cureall, but it is an approach that helps.” Evolution of Patient Navigation Patient navigation was conceived in 1990 by Harold P. Freeman, MD, who observed socioeconomic and racial disparities for cancer care in Harlem. After access to screening and patient navigation, 5-year cancer survival rates improved from 39% to 70% (Freeman HP, et al. Cancer. 1989;63: 2562-2569). These positive results led to an expansion of the concept across the cancer continuum and to the inclusion of families and caregivers.

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

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Continued from cover

Figure GWCI’s Framework for Longitudinal Patient Navigation Longitudinal Patient Navigation Screening Navigation Outreach Education Screening Initial Contact Abnormal results/ diagnosis

Treatment Navigation

Survivorship Navigation

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

Rehabilitation

Eliminate critical delivery gap for populations experiencing disparities Provide seamless transition from screening through treatment and survivorship Diagnosis

Treatment

Survivorship

GWCI indicates George Washington Cancer Institute.

Navigators now include nurses, social workers, trained laypersons, and community health workers who serve in a variety of capacities at various points from screening into survivorship. The roles of navigators and the framework of the program at George Washington Cancer Institute are outlined in the Figure. “Navigation suffers from lack of definition, but we are trying to anchor navigation in meeting each patient’s specific needs,” Ms Pratt-Chapman said. “We are not fixing the system. We are facing the reality of the system and helping patients navigate a system we know is broken.” Navigators educate individuals about screening, diagnosis, and treatment; build partnerships in the community; facilitate access to clinical trials; coordinate appointments with providers; maintain communication between patients and providers; ensure that medical records are available for appointments; arrange for support services (ie, language, financial, transportation, child care, home healthcare); and help patients learn to navigate themselves. Navigators, who are trained to recognize patients with special needs or barriers to care, answer different needs within the various clinical departments. At George Washington Cancer Institute, there are navigators in radiology, in the breast care center, in hematology, and one navigator that is shared by urology and radiation on-

“Many patients must fight their way through this dysfunctional system, while trying to save their own lives. Navigation is not a cure-all, but it is an approach that helps.” —Mandi Pratt-Chapman, MA cology. These individuals meet weekly to discuss cases that may overlap. Ms Pratt-Chapman suggested that attendees at the session focus on barriers specific to their institutions and develop the appropriate navigation structure, with a clear scope of practice for the navigators. “Delineating these roles can be key to your success,” she said. “The determination of who should navigate should be determined by the skill level required.”

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Current Impact, Future Trends More than 30 US sites have been evaluated by research programs funded by the National Cancer Institute, the Centers for Medicare & Medicaid Services, and the Health Resource and Services Administration. These projects showed that navigation significantly shortens the time to definitive diagnosis, reduces stress levels for patients, increases satisfaction, and improves care. There is some indication that time to treatment may be slightly prolonged, although “we believe this may reflect having second opinions and an improved understanding of treatment options,” Ms Pratt-Chapman suggested. As for future trends, Ms PrattChapman noted that institutions accredited through the Commission on Cancer must develop and institute a patient navigation process through a phased-in approach by 2015. “You will be asked to identify a patient navigation process using existing staff or new hires, but you will need to be responsive to the needs of your population, and be regularly evaluated,” she said. This requirement may “fill in gaps” because of the oncology workforce shortage, she added. Policy papers are also in development that should raise awareness on the institutional and national levels, she added, and should provide an evidence basis for moving forward and to inform reimbursement practices. ■

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2nd Conference

Evidence-Based Guidelines/Pathways Critical for Value-Based Benefit Design in Oncology By Caroline Helwick Houston, TX—There is no question that evidence-based guidelines and pathways are critical to the success of value-based oncology, but not all stakeholders have an equal voice, said Craig Deligdish, MD, Chief Medical Officer at Oncology Resource Networks of America at the Second Annual Meeting of the Association for Value-Based Cancer Care. The goals inherent in value-based oncology benefit programs include: • Improving outcomes • Enhancing efficiency for practices and health plans • Reducing the cost of care for practices and health plans • Simplifying and obviating the prior authorization process • Reducing the cost of care at the end of life • Improving care, with a focus on value, outcomes, and fiscal predictability • Sustaining community-based care. “Clearly, we want to improve outcomes and we want to reduce costs, but at the same time we need to think about the patients who are often not represented in meetings such as this,” he said. “The question is, what does the patient have to say about this?” Dr Deligdish continued. “One day, we may all be patients.”

“What we really need to recognize is that the cost of drugs is only about 20% to 23% of the overall spend for the treatment of a patient with cancer.” —Craig Deligdish, MD

The other participant often absent in these conversations, he added, is the government, “which is the elephant in the room.” The future of

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Figure

Pathway Integration

Data integrator

“If stakeholders do not find a way to work together, inclusive of the government, we will be in a much worse situation than the one we have today, and at a much higher cost.”

Broker/consultant/ actuary

EAP provider

Disability administration

Employee satisfaction

Internal data management

EAP data (annually)

STD (quarterly)

Employee satisfaction Employee commitment (annually)

FMLA

LTD (quarterly)

Worker’s compensation Absences Time-keeping system

Productivity Benefit selections

—Craig Deligdish, MD

healthcare is being decided at the federal level through the healthcare reform legislation. And on the state level, changes are also occurring. Many states are unloading the responsibility for healthcare onto the commercial payers, moving healthcare from the traditional Medicaid programs to managed Medicaid. Such changes cannot be ignored, he said. “We all know that chemotherapy is costly, and there have been tremendous advancements in cancer therapies. What we really need to recognize is that the cost of drugs is only about 20% to 23% of the overall spend for the treatment of a patient with cancer. This is a fraction of the $100 billion that is spent annually in the United States on cancer treatment alone,” Dr Deligdish said. Evidence-Based Guidelines and Pathways: Features and Benefits Evidence-based guidelines that have been issued by organizations

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PBM

Pharmacy claims (quarterly)

Employer

Eligibility file (monthly)

Health plan

Benefits administration

Medical claims (quarterly) Wellness information HRA screening (annually) Disease management Complex case management (as needed)

Incentive data (to payroll)

Demographics (weekly)

Satisfaction with wellness offerings (satisfaction assessed but not reported)

Utilization management Provider file

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.

such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology help to ensure standards and predictability in patient care. The goal is not to institute “cookbook medicine” but to “provide some order to what many of you see as a very chaotic approach,” Dr Deligdish said. Evidence-based guidelines offer an established process for reviewing pathways and ensuring appropriateness and relevance. They are used to create evidence-based pathways that aim to provide value, even enhanced value, and generally at a reduced cost. Pathways not only apply to chemotherapy but to supportive care, radiation therapy, molecular diagnostics, advanced illness, and other components of care. The many benefits of evidencebased guidelines and pathways are clear: consistent delivery of appropriate and cost-effective care to patients, more predictable and lower patient care costs, lower administration expenses, less hassle for members and providers, less treatment delay, greater provider and health plan efficiency, and elimination of unnecessary services, according to Dr Deligdish. Although pathway programs may appear relatively straightforward,

their integration is complex, he noted (Figure). The challenge is to take the most promising pilot programs and demonstration projects and implement them in a scalable fashion that makes an impact, Dr Deligdish added. Options for Payers Payers have a variety of options for managing the overall value and cost of cancer treatment: primarily, pharmacy benefit managers, specialty pharmacy benefit managers, radiology benefit managers, oncology benefit managers, and health plans. As medicine becomes more complex and these programs become increasingly common, they become integrated into the hospital setting, where more care is now delivered. “This is probably not the most efficient approach or the optimal place to receive treatment,” he maintained, “because treatment takes longer and costs 3 times as much as when delivered in the community.” The overarching challenge, he said, is for all those who manage patient care and who aim to control costs to collaborate. “If stakeholders do not find a way to work together, inclusive of the government, we will be in a much worse situation than the one we have today, and at a much higher cost,” Dr Deligdish concluded. ■

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2nd Conference

Collaborate, Coordinate to Achieve Value in Oncology AmerisourceBergen taking a tiered approach to value-based care By Caroline Helwick Houston, TX—“Collaboration, coordination, data, and innovation are key to achieving value-based cancer care,” said Loreen M. Brown, MSW, Vice President of Reimbursement and Access Consulting, Xcenda, AmerisourceBergen Consulting Services. Speaking at the Second Annual Conference of the Association for Value-Based Cancer Care, Ms Brown made the following points about the “evolving market” of oncology: • Advances in science are leading to additional, more targeted therapies for smaller population groups • Cost pressures are leading to new and more restrictive coverage and reimbursement policies, although in some states mandates dictate reimbursements • Scrutiny of the value of new therapies is increasing • Cancer is becoming a chronic disease that requires more focus on coordination and planning; cancer survivors will number 18 million by 2020, a 27% increase from 2010.

coverage policies must be founded on value-based decisions that take into account meaningful outcomes, comparative effectiveness, and preferred therapies per treatment pathways or guidelines, Ms Brown noted. The availability of multiple treatment options, oral oncolytics, generics, and eventually biosimilars in addition to standard intravenous (IV) chemotherapy drugs will further complicate the decision-making process.

“Collaboration, coordination, data, and innovation are key to achieving value-based cancer care.” —Loreen M. Brown, MSW

In the past, utilization management mainly centered around prior authorization to ensure appropriate use per the labeled indication. As oncology evolves to a more value-based process,

“Value” Varies by Stakeholder Stakeholders perceive “value” differently within the various components of cancer care (Figure): • For patients, clinical trial data, reflecting efficacy and safety, matter most, followed by out-of-pocket costs • For providers, value is an outgrowth of practice economics • For payers, value is determined by the net price of all aspects of treatment. In the current oncology system, balancing these priorities across stakehold-

Figure Value Varies by Stakeholder

High

Relative perceived value

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

Trial and real-world data relative to comparators in payer-specific setting (effectiveness and safety)

Patient out-of-pocket cost Adherence, dosing, tolerability, convenience

Practice economics

Net price

Patient adherence

Direct cost offsets determined through reliable data

Mechanism of action

Mechanism of action

Net price

Net price

ICER—indirect offsets or external data

ICER

ICER

Mechanism of action

Patient

Physician

US Commercial Payer

Low

Adherence, dosing, convenience

ICER indicates incremental cost-effectiveness ratio.

Table

Hypothetical Treatment Choices

Variable Weekly generic Drug $60/wk reimbursement Administrator $150/wk reimbursement Total payer $1900/12 wk cost

Every-3-week generic

Weekly brand

Every-3-week brand

$95/wk

$1600/wk

$4200/wk

$0

$667/mo

$210/wk

$150/wk

$150/wk

$75/visita

$75/visita

$915/12 wk

RetailIn-office– dispensed oral dispensed oral

$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

9

3

9

3

3

3

Visits, N a

One mid-level evaluation and management code per visit.

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er lines is challenging, Ms Brown said. Today’s system pays providers for volume of services and drugs, lacks the ability to collect and/or capture data for analysis, and offers no real basis for evaluating outcomes or value in a clinical, financial, or quality sense. “Without these things, it is hard to determine outcomes for value,” she said. From the provider’s perspective, reimbursement is diminishing, patient out-of-pocket costs are increasing, shrinking margins are greatly impacting uncompensated services, reimbursement for managing self-administered therapies is lacking, and risk-/case-based reimbursements (ie, Medicare Shared Savings Program) are part of the picture. In a 2011 survey of oncologists, Xcenda researchers asked how route of drug administration influences choice of therapy. Although 38% said it did not influence their selection, 17% preferred IV products because the copay is less for the patient, and 7% preferred IV products because they were economically beneficial to their practices. Oral agents were preferred by 13% as a result of patient convenience. “These were all rational responses, but they were different due to competing priorities,” Ms Brown said. To illustrate this at the conference, she presented hypothetical treatment choices representing different reimbursement, copay, and other cost variables that may be preferred by some stakeholders for different reasons (Table). “Priorities are different, based on numbers like these,” she commented. At the same time, administrative complexity is a growing problem especially for oncology practices. Payers require more management (prior authorizations, treatment pathways, and guidelines), and there is increased use of health information technology resources requiring electronic medical records and e-prescribing, decisionsupport tools, drug inventory cabinets, and data analytics tools. “Practices that lack a skilled administrator are limited in their ability to run an efficient practice,” she observed. “This is increasing the number of mergers, hospital affiliations, and practices that are closing.” Collaborative, Tiered Approach in Oncology AmerisourceBergen, in partnership with IM Solutions and US Bioservices, has developed a collaborative and Continued on page 21

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2nd Conference

Involving the Patient in End-of-Life Care Decisions: Aetna’s Oncology Strategy By Caroline Helwick Houston, TX—Payer-sponsored programs that promote appropriate endof-life care are beneficial to all stakeholders, according to Ira M. Klein, MD, MBA, Chief of Staff to the Chief Medical Officer, Aetna Oncology Strategy. At the Second Annual Conference of the Association for Value-Based Cancer Care, Dr Klein discussed advancedcare directives and emphasized that the patient and family “should be at the center of what you do.” Studies have shown that although 70% of Americans express the wish to die at home, only 25% actually do. And 90% of terminally ill patients with cancer cite their homes as their preferred site of death, yet only 33% actually die there, Dr Klein noted. “It is not a mystery to us when death is approaching. We have more than adequate clinical signals,” he said. “So, what is going on?” Among Aetna members, only 1% generate 33% of its claim costs. When these patients develop terminal conditions, he noted, “We know who they are, their families know, yet they do not end up in the right place.” “Just having a signed advanced-care directive does not mean that all parties have ‘done their duty,’” Dr Klein pointed out. “Unfortunately, discussions with patients and families regarding terminal care and available options happen too late or not at all.” Lacking a more structured approach to end-of-life care, patients are treated within the traditional and expensive framework that is not beneficial, Dr Klein concluded. Aetna’s Approach to End-of-Life Care Aetna offers an “innovative and

Figure 1 Vital Decisions Living Well Program Goal and Strategy Outsourced program Create members who proactively participate in their care by identifying, communicating, and incorporating their priorities into current and future care decisions Identify end-of-life priorities

Integrate priorities into care decisions

Independence, interactivity, comfort Current and future

Care decisions that support priority achievement Current and future

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Ensure effectuation of priorities throughout end of life Integrate with providers

Create an active patient Stage-based behavioral change strategies and activities embedded in process (Prochaska transtheoretical model) Active on current and future scenarios

Create an informed patient Current medical situation Future medical situation scenarios

Current/future care decisions and alternatives Transition points

Communication vehicles and support

Figure 2 Identification of the Most Highly Fragile Members Earlier in the Process

New process: member-centric high-intensity complex case management Algorithm identifies highly fragile members (1-2 per 1000) 12 months

Home visit/ assessment initiated

Current process

Case manager begins to work closely with provider to support member

9 months

Nurse case manager manually identifies member for compassionate care

6 months

3 months

Member enters hospice if chooses 1 month

Compassionate care benefit enhancement (commercial) Opportunity to improve case management for highly fragile members

member-centric” case management program that combines patient support with benefit design. Key components are the use of an outsourced ven-

dor for patient counseling on end-oflife issues, an insourced high-intensity complex case management program, and transition to “compassionate care”

Collaborate, Coordinate to Achieve... tiered approach to oncology care delivery. The program coordinates practice networks in multiple states with national and regional/local payers, and integrates with US Bioservices contracts and capabilities for oral drugs, injectables, and medication therapy management. The first tier, the program’s foundation, includes an innovative compensation program, provider/payer portal, reporting and analysis, and nucleus treatment pathways. The second tier, “value acceleration,” includes an

Develop plan, communicate, and revise

advanced-care planning program, standard nurse triage program, and nucleus data exchange. The third tier, “program enhancements,” features a quality initiative program and a patient portal for educational purposes. The model “pulls together much more data than you see on a claims form,” she said. “The payer and provider forum is useful for exchange of information. It is all implemented electronically, and it interacts with the drug ordering process and practice management software. The innovative

Continued from page 20

compensation program takes the margin out of the drug and gives a management fee. There are variations on this theme, but, in general, this is what we are doing.” Ms Brown concluded that “success” in achieving value in cancer care will require programs such as these that are developed through provider and payer (and even patient) partnerships. “Effective, evidence-based tools that work in concert with key stakeholders do exist,” she said, “and are continuing to evolve.” ■

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that allows patients interventions to improve functional status. The outsourced Vital Decisions Living Well Program was founded on the knowledge that end-of-life interventions increase feelings of empowerment for the patient, reduce hospital admissions and emergency department visits, and reduce costs. “If you employ these services, you do not shorten patients’ lives; you increase patient satisfaction, you improve patients’ attitudes, you resolve conflicts within families, and you use fewer resources,” Dr Klein said. “We knew this, we saw end-of-life discussions as an unmet need, and we decided to do something.” The Vital Decisions Living Well Program acts as a catalyst for planning and decision-making. The vendor, Vital Decisions, is a bioethics services Continued on page 22

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Involving the Patient in End-of-Life Care Decisions... company staffed by highly trained social workers. For Aetna, the goal is to create members who proactively participate in their care by identifying, communicating, and incorporating their priorities into current and future care decisions (Figure 1, page 21). The counselor helps patients become empowered through understanding and choosing among options for care, and developing a plan they can take to their physicians. “Patients are often in the back passenger seat in this journey, and they tell their physicians to ‘just drive.’ When patients have no directions for where the journey is going, they do not always get the best plan for care. Under our program, this changes. The patient says ‘I have a plan,’ and the physician treats in a manner consistent with this.” Physicians as well as patients appreciate the clarity inherent in this process, Dr Klein added. From claims data, patients are identified for the Vital Decisions program on the basis of end-of-life clinical triggers. For patients with cancer, it is usually when metastasis develops that performance status (Eastern Cooperative Oncology Group Performance Status ≥2 or Karnofsky Performance Status ≤70) declines or that patients become dependent in activities of daily living. The timing is such that patients can be engaged in discussions when there is “some certainty about the finality of mortality yet the functional status is still high,” he said. Vital Decisions is given the patient’s name, and the company then obtains the physician’s approval and the patient’s consent to initiate the service. The second component—the highintensity complex case management program—is also part of Aetna’s goal of early identification of fragile members and referral to the compassionate care program (Figure 2, page 21). The program is a member-centric model with high-touch and face-to-face patient assessment by staff with intensive training in motivational interviewing, end-of-life issues, and cultural competency. When appropriate, patients are entered into the compassionate care program, which “gives patients and

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Talking to Patients about End of Life One 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 for Value-Based Cancer Care, Roy A. Beveridge, MD, Chief Medical Officer of US Oncology Network/McKesson Specialty Health; Peter G. Ellis, MD, Deputy Director of Clinical Services and Associate Chief Medical Officer for the University 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.

“Although 70% of Americans express the wish to die at home, only 25% actually do. And 90% of terminally ill patients with cancer cite their homes as their preferred site of death, yet only 33% actually die there.” —Ira M. Klein, MD, MBA

their families a landing place where they do not feel abandoned as they sometimes do going into hospice,” he said. The program provides traditional hospital measures of support, pain management, and symptom control, with psychologic and spiritual support as well. “We now have the right benefit for the right condition. We are matching the solution to the problem,” Dr Klein commented. Results of a 3-year study of program participants show a >70% increase in hospice use, and an almost doubling in the average number of days in hospice; for Medicare patients, an 82% reduction in acute hospitalization days and an 88% reduction in intensive care unit stays; and considerable reductions in emergency department visits for all program participants. Lessons Learned about End-of-Life Care Dr Klein shared lessons learned from Aetna’s experience with structured end-of-life counseling services: • Physicians should direct end-of-life

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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. Physicians don’t like to do it, nurse practitioners don’t like to do it, nurses do not like to do it. To do this properly in terms of scale, the practice has to have a powerful educational methodology built into the information technology infrastructure, 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, perhaps a nurse practitioner. I think it is a team approach. And it is not just one conversation but multiple conversations. In practices that implement this successfully, we find that this does eventually change the global attitude of the 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 some algorithms 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 conversations. There are many different issues involved. Fortunately, there are organizations within the healthcare system that have individuals who are specially 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 and devote the time necessary for this. It is not one conversation, but a series. It is not something we can generally accomplish in the span of 15 minutes. These patients have to be handled in a more sophisticated way by nurses and 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 palliative intent. This begets the entire discussion of end of life with the patient. At the University of Pittsburgh and Via Oncology, whenever a patient with metastatic disease is placed on a chemotherapy regimen that question is asked. 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 or non–small-cell lung cancer you had best have that conversation early. But with breast cancer and myeloma, for example, patients are living years and years with stage IV disease. It has to be individualized.

care, not payers, but payers can facilitate care by providing tools for patients to be “proactive” • Payers should create an environment in which bioethics discussions happen, in an “opt-in” permissive manner • Physicians welcome assistance in engaging patients in end-of-life care discussions • Patients value the availability of skilled and focused bioethics coun-

seling services • The guiding principle for these services is 2-way communication • A dedicated hospice benefit removes barriers and improves the delivery of needed services. “What we are doing is empowering patients, not directing them. When they see their oncologists, they are ready to have these discussions and they value this,” Dr Klein pointed out. ■

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Tough Times for Small Oncology Practices How one Northeast practice views its challenges By Caroline Helwick Houston, TX—Hard times are getting even tougher for small oncology practices, said Leonard Natelson, Chief Executive Officer, Hematology/Oncology Associates, Rockland, NY, at the Second Annual Conference of the Association for Value-Based Cancer Care. Hematology/Oncology Associates is an independent practice of 5 physicians, which in the Northeast region is considered “large,” Mr Natelson said. He cited 5 main challenges facing community oncologists today: • The gridlock in Washington, DC, and the lack of progress in fixing the sustainable growth rate (SGR) • Drug shortages • Implementation of HIPAA (Health Insurance Portability and Accountability Act of 1996) 5010 and ICD-10 (International Classification of Diseases, Tenth Revision) • Reduced reimbursements • Leadership in the transformation of cancer care.

Should the SGR not be “patched” again, providers will be hit with a 30% cut in reimbursement in January 2013. —Leonard Natelson

The inability to settle the SGR continues to plague practices such as Mr Natelson’s. With a “lame duck” Congress around the bend, progress this year seems doubtful, he said. In addition, should the SGR not be “patched” again, providers will be hit

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with a 30% cut in reimbursement in January 2013, and this, compounded by other potential economic difficulties, will worsen the payment delays that continually threaten the fiscal viability of oncology community practices. Mr Natelson suggests that using bundled payments is not the solution to the current fiscal unpredictability, because this approach eliminates flexibility. “With the patients we see, this would be problematic,” he said. Nor is hospital-based cancer care the answer. “Does Congress really believe that pushing physicians to a hospital setting will cut costs for Medicare? Costs are 34% higher in the hospital for the same type of patient visit,” Mr Natelson said. “This was tried 15 years ago, and it did not work” so care was pushed back into the community. “This time, there would be fewer community practices to push back out to.” Further driving practice inefficiency of community practice is the drug shortage crisis. In 2005, 61 drugs were in short supply; this number now approaches 250. The causes include low profit margins for generic drugs, few manufacturers, and poor quality control. “I am chasing my tail all the time,” Mr Natelson said. Conversion difficulties with HIPAA 5010 compliance and the future ICD-10 coding system create additional work, without increasing revenue. “My practice spent $30,000 on information technology infrastructure upgrades, and this does not generate more revenue for me, but it does generate expense. I am also hearing that practices that have converted to 5010 are getting erroneous denials of claims, which is delaying payments,” he said. “Some practices are still waiting for payments from November.”

at a glance

“Two hospitals are after me, as is another large consortium. 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

A decrease in reimbursement is an obvious challenge. Of Mr Natelson’s practice’s drugs, 46% are “under water,” and this makes it “much more challenging to provide the kind of care we want to provide,” he said. “We need wiggle room so that our physicians can spend time with patients.” His practice is also experiencing more denials caused by medically unlikely edits. “Any time we have to pay for a drug up front, and we do not get 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 pertains to leadership in the transformation of cancer care. The question is whether

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➤ 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” community-based oncology will continue to be relevant in the delivery of cancer care, he said. “Two hospitals are after me, as is another large consortium. I do not want to be owned by a hospital. This will only drive up cost, not improve the quality of care I give,” he maintained. Ironically, community oncology is in the best position to operate efficiently and “bend the cost curve,” Mr Natelson said. “We are a small business. It is more real time in community practice. We have to watch what we spend, what we take in, make sure people pay us. We do not have deep pockets like the large institutions that get by if they are not paid for 6 weeks. I would hate to see all oncology practices move to the hospital setting, and then we figure out that it costs more —which is something we already know.” ■

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Pathways Offer Providers a True Value Proposition They can also help prove their value to key stakeholders By Caroline Helwick Houston, TX—“The key question on everyone’s mind is, how do we monetize the value of pathways?” said Peter G. Ellis, MD, Deputy Director of Clinical Services and Associate Chief Medical Officer, University of Pittsburgh Cancer Centers, PA, at the Second Annual Conference of the Association for Value-Based Cancer Care. Clearly, Dr Ellis said, the use of pathways has internal practice value. Pathways: • Drive consistency and quality of care for patients • Lower bad-debt risk by reducing payer denials • Increase practice efficiencies through uniformity of care • Reduce emergency department visits • Have the potential to reduce medical errors • Support clinical trial participation • Serve as marketing tools for practices. Pathways do all this while achieving clinical outcomes that are at least equivalent to off-pathway practices. “We say that pathways are good for patients, good for physicians, and good for the insurance companies. Why isn’t everyone using them?” he asked. Providers make a financial investment in using pathways, and these pathways produce savings that accrue to payers. “So shouldn’t payers have skin in the game?” Dr Ellis asked. He suggested that, “in a perfect world,” payers would increase existing fee schedules or pay management fees to physicians, contract for gain share on savings, steer patients to practices that use pathways through preferred network status, and modify patients’ benefit designs to allow for lower copays or coinsurance for using practices with pathways. Although these things are all possible, they do not happen, mostly because: • The majority of payers’ members are self-insured: new program costs

gested ways that providers can contract with payers to help them stay in community practices.

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

must be approved by their customers; otherwise, savings go straight to the customer, but costs are borne by the plan • Cancer is not a top priority for payers • Some payers think oncologists are already paid too much and should not need more money for providing “quality” • Payers are not accustomed to outsourcing utilization management to the providers themselves • Pathways is a novel program in a politically sensitive area (cancer); payers do not understand it or who in their organization “owns” the pathways or will oversee it • Payers want easily scaled solutions brought to them by companies that offer a suite of products and speak their language. As a practicing oncologist, Dr Ellis pointed out how operating an oncology practice is expensive in ways that payers may not appreciate. He sug-

Opportunities to Recoup the Costs of Practice Providers could try to avoid impending rate cuts or extend their current satisfactory reimbursement rates, by showing payers how they are “doing things better,” he said. They could enlist payers in attempting to reduce their administrative burden by eliminating precertifications and prior authorizations. Providers could try to prevent the payer from pulling drugs out of the practice via specialty pharmacy or infusion centers, and they could try to avoid reverse rate decreases. “But practitioners should be careful what they wish for,” he cautioned. “If payers move forward and contract with third-party vendors for pathways-type programs, is this always a good thing for oncology practices and patients?” he asked.

“If payers move forward and contract with third-party vendors for pathways-type programs, is this always a good thing for oncology practices and patients?” —Peter G. Ellis, MD

The result could be that multiple payers require multiple pathways in a single practice, which would be complicated logistically and ethically, and could lead to the kind of variability within practice that is never beneficial, he said. Practices may be better served to select and implement the pathways program that they want, and use them to preempt payer-imposed programs, Dr Ellis suggested. Physician-

driven pathways are likely to offer a much larger value proposition. Healthcare Reform Trends Will Affect Oncology Practices The healthcare reform is also going to impact oncology practices by: • Shifting responsibility for total cost of care to accountable care organizations (ACOs) • Rewarding medical home practices for managing the entire spectrum of their patient’s care, including costs • Consolidating practices to ensure leverage with payers • Encouraging hospital acquisitions of oncology practices. These situations offer pathways contracting opportunities. Hospital/private practice affiliations will also need pathways, he noted. Physicians who have experience in running their own practices are well equipped for implementing programs (ie, pathways) that will drive quality and savings and that will unite the various groups within the system; they can be financially rewarded for this, he suggested. Pathways can also be used with nonaffiliated oncologists to help develop a clinically integrated network that will be able to contract better with payers. Pathways will also help a patientcentered medical home deliver standardized and efficient care. Medical homes that do not manage patients with cancer will outsource this to the practice that can demonstrate quality of care at the lowest cost. “That is a pathways practice,” Dr Ellis noted. Similarly, oncologists will participate in ACOs, either directly or by referrals, and those practices with pathways will be able to prove quality and will likely “win the bid” to be the preferred oncology providers. Dr Ellis emphasized that pathways will help providers prove their value to key stakeholders and will ensure the viability of their practices for the future. “Take control before someone else does,” he suggested. ■

The most significant value to all attendees was being able to speak, in both public and private forums, with many of the other attendees all in one place. On this theme, we should always seek out diverse stakeholders in the oncology care delivery process and not shy away from controversy. The crowd loves it!

—Ira M. Klein, MD, MBA, FACP

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Newsletter Series

YOUR QUESTIONS ANSWERED

Editor in Chief

Editor in Chief

Sagar Lonial, MD

Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

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

The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Spectrum Pharmaceuticals.

ALL NEW CONTENT FOR 2012 Accreditation These 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.

COEKsize71612AskExperts


Health Policy

The Affordable Care Act... expand Medicaid to a larger portion of the population (and Congress’s authority to penalize states that did not wish to participate in the expansion). Although the Court upheld the authority of Congress to expand the Medicaid program to states that wanted to participate, the Court also held that Congress could not withhold existing Medicaid funds from states in an effort to penalize a state’s refusal to participate in the expansion. What does the decision mean for the oncology community? First and foremost, the path to implementation of the ACA will move forward. Programs that promise to have the most impact on the cost–value debate in oncology will progress: the Independent Payment Advisory Board, the PatientCentered Outcomes Research Institute, and other cost-saving institutions will continue their task of finding the most value in healthcare dollars. Oncologists can expect their patient pools to rise as millions more Americans gain access to health insurance through state health insurance exchanges. The question of the future Medicaid expansion, however, looms large in the wake of the decision. Under the ACA, Medicaid eligibility was expanded and simplified, beginning in 2014, by creating an overarching Medicaid eligibility category for all individuals aged <65 years with incomes less than

Continued from cover to be seen. What is clear, however, is that until the issue of the Medicaid expansion is solidified, oncology

Ross D. Margulies, JD, MPH

Jayson Slotnik, JD, MPH

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 insurance through state health insurance exchanges.

133% of the federal poverty level who meet citizenship/lawful US status and state residency requirements and who do not meet any of the program’s other multiple categorical groupings. Although the Court ruled that Congress is allowed to expand Medicaid to cover the new population under Congress’s spending powers, a majority also ruled that states that do not wish to participate in the Medicaid expansion cannot be penalized for this decision by having their existing

Medicaid funds withheld. It remains unclear whether states will proceed with the planned expansion or opt for a smaller Medicaid population. On the one hand, the direct cost to states in expanding eligibility is limited because the federal government will fund the vast majority of these costs. On the other hand, 6 Republican governors have already publicly stated that they will opt out of the expansion. Whether this is political posturing or a political reality remains

AMCP 2012 Annual Meeting

Should several states begin to opt out of the expansion, this national eligibility system will become a patchwork of different eligibility standards and a headache for oncologists.

providers and manufacturers remain in limbo. The expansion offers an extended patient population (albeit with a lessthan-generous payer) and a more simplified eligibility system. Should several states begin to opt out of the expansion, this national eligibility system will become a patchwork of different eligibility standards and a headache for oncologists. Guidance is expected from the Centers for Medicare & Medicaid Services in the coming months, which will provide answers to many of these questions. The ultimate decision of whether a state will participate in the expansion, however, may not come for some time. ■

See also pages 28, 30

Oncology Genetic Testing: Pharmacists’ Knowledge Gap San Francisco, CA—Knowledge of pharmacogenomics—the genomic factors contributing to individual variability in response to drug therapy (or personalized medicine)—enhances the ability to diagnose, prevent, and treat disease, especially a variety of cancers. The correct application of pharmacogenomics to patient management is essential for providing cost-effective care, but many providers, including physicians and pharmacists, are lacking appropriate knowledge of the science. Other barriers include lack of transparency in clinical utility and inappropriate reimbursement strategies. At the 2012 Academy of Managed Care Pharmacy annual meeting, Angela Luong, PharmD, and colleagues at OPTUMInsight described the results of their survey of pharmacists regarding their knowledge of genetic testing and

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

utilization strategies. A total of 19 pharmacists at 4 different managed care organizations responded to the survey; their responses revealed a basic lack of knowledge of pharmacogenomics. The majority (84%) of respondents agreed or strongly agreed that pharmacogenomics will have an impact on healthcare expenditures and pharmacists should have a good

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knowledge base of related drug therapies and tests; however, they admitted they did not have much education in this area. Overall, 95% of participants scored <60% on a pharmacogenomics test. In addition, knowledge of pharmacogenomics does not appear to immediately have a direct impact on patient care or benefit design. Only 47% of respondents said their plan requires

prior authorization (PA) for the use of the US Food and Drug Administration–approved companion diagnostic test for vemurafenib compared with 58% of respondents whose plans require a PA for the companion test for crizotinib. By contrast, only 16% of respondents said their plans require testing for HER2 mutation before prescribing trastuzumab compared with 58% of respondents whose plans do not require testing and 26% (n = 5) who did not know whether their plans require such testing. Furthermore, the majority of respondents did not know whether their plans had reimbursement policies related to pharmacogenomics. Overall, this survey reveals gaps in pharmacists’ knowledge of personalized medicine utility and its relation to benefit design strategies. ■

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“Managing patients with myeloma means staying current.”

Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

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AMCP 2012 Annual Meeting

Vemurafenib Does Not Impact Health Plan Budget By Caroline Helwick San Francisco, CA—Although the upfront cost of vemurafenib is high, its use to treat patients with metastatic melanoma actually results in a costsavings per health plan member per month (PMPM), according to an analysis presented at the 2012 Academy of Managed Care Pharmacy annual meeting. In a hypothetical health plan of 500,000 enrollees, the use of vemurafenib for the treatment of patients with BRAF V600E mutation is costsaving by $0.04 PMPM, reported William B. Wong, MS, PharmD, of the University of Washington, Seattle. “Overall, our findings imply that providing vemurafenib therapy will have relatively minimal budget impact and may possibly be cost-saving,” Dr Wong said. The BRAF inhibitor vemurafenib is designed to inhibit the V600E-mutated form of the BRAF protein, which plays an important role in progression of this disease. The drug was approved last year for patients with BRAF V600E mutation–positive unresectable or metastatic melanoma. For this study, researchers developed a budget im-

pact model as a tool that can be used by healthcare plans to assess the budgetary impact of covering vemurafenib for treatment-naïve and previously treated patients.

“Overall, our findings imply that providing vemurafenib therapy will have relatively minimal budget impact and may possibly be cost-saving.” —William B. Wong, MS, PharmD

The researchers considered 2 hypothetical scenarios when (1) vemurafenib is not a treatment option for melanoma with BRAF V600E mutation and (2) vemurafenib is a treatment option in treatment-naïve and previously treated patients, and is used until disease progression or unacceptable toxicity for a proportion of eligible patients. The model was based on a health plan with 500,000 enrollees; the estimated annual costs were based on sev-

eral variables of treating this eligible patient population. Patients who tested positive for the mutation received vemurafenib first line and other agents as second and third line on progression. If they tested negative, they never received vemurafenib but did receive alternative treatments. Patients who were not tested received alternative agents but were tested for the mutation after second-line treatments failed. If appropriate, the patients received vemurafenib at that time. Cost data sources included the Analysource drug database and 2011 Centers for Medicare & Medicaid Services national payment rates. Cost Impact The analysis found that 6.6 cases of metastatic melanoma (stage IIIC unresectable and stage IV) were expected in a 500,000-member plan annually, including 4.9 new cases and 1.7 recurrent cases. The total costs and PMPM costs were $1,215,838 for patients in scenario 1 who did not receive vemurafenib and $978,129 for those in scenario 2 who were treated with the drug.

The results were relatively sensitive to the proportion of patients receiving ipilimumab (also recently approved for the first-line treatment of metastatic melanoma), the cost of ipilimumab, the proportion of patients receiving vemurafenib, the percentage of patients positive for the V600E mutation, and the percentage of patients receiving first-line treatment. Dr Wong acknowledged that the model only includes therapies that are approved by the US Food and Drug Administration and are recommended by the National Comprehensive Cancer Network guidelines, but he said that “the effect of excluding some therapies is likely to be minor, since the proportion of patients receiving these treatments is small.” Unresectable stage IIIC patients and patients with recurrence after ≥5 years were not included, because of the small population sizes. The model did not consider efficacy beyond its immediate impact on expenditures, and the distribution of patients estimated to receive these treatment options is based on market research data obtained by surveys of physicians. ■

Does CMS’s Coverage Decision for Sipuleucel-T Herald More Restrictive Policy? San Francisco, CA—In its national coverage decision (NCD) for sipuleucel-T in the treatment of advanced prostate cancer, the Centers for Medicare & Medicaid Services (CMS) left the coverage decision for any off-label use of medications to the discretion of the local Medicare contractors, citing an absence of data on which to make a coverage decision. Charles A. Stevens, JD, MBA, Vice President and General Manager of Commercialization Strategy at Parexel Consulting, Waltham, MA, and colleagues suggested at the 2012 Academy of Managed Care Pharmacy annual meeting that this could be an emerging trend for future expensive therapies. “Budget concerns, the high price of new products, and widespread offlabel use of new therapies have combined to place tremendous pressure on the CMS as it evaluates new drugs and biologics under its NCD process,” observed Mr Stevens and colleagues in a poster presentation. Their goal was to assess how CMS may exercise various NCD options to

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control drug coverage in light of the recent coverage concerns for sipuleucel-T, a high-priced vaccine for castration-resistant prostate cancer that is likely to be used off-label, Mr Stevens noted. The 4 factors that lead to an NCD review by CMS are: • The price of the drug • Lack of the drugmaker’s communication with CMS • Data sharing between the US Food and 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, and no off-label coverage • More restrictive coverage impacting on on-label use • Lack of coverage of the drug. An analysis of NCDs showed that CMS has historically regulated medical devices using the NCD process more often than for drugs or biologics when there has been a concern over unwarranted product utilization that increases costs over existing products

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“Budget concerns, the high price of new products, and widespread off-label use of new therapies have combined to place tremendous pressure on the CMS as it evaluates new drugs and biologics under its NCD process.” —Charles A. Stevens, JD, MBA

without added benefits, Mr Stevens and colleagues noted. These decisions have led to restricted coverage for such products. In the case of sipuleucel-T, the CMS review resulted in an NCD that allowed coverage only for the approved-label use of this drug, reserving off-label coverage decisions for local contractors. Effective for services performed on

or after June 30, 2011, CMS proposed that “the evidence is adequate to conclude that the use of autologous cellular immunotherapy treatment— sipuleucel-T—improves health outcomes for Medicare beneficiaries with asymptomatic or minimally symptomatic metastatic castrateresistant (hormone refractory) prostate cancer, and thus is reasonable and necessary for this on-label indication. Coverage of all offlabel uses…is left to the discretion of the local Medicare Administrative Contractors.” Based on this NCD, it is reasonable to assume that “CMS may continue to make overall coverage decisions regarding on-label indications when adequate data exist to demonstrate value,” noted Mr Stevens. “If the data on treatment value are incomplete, CMS may defer off-label coverage determinations to the local contractors. There is also a strong indication that CMS may strictly limit reimbursement to the labeled indication in the absence of data demonstrating value for other indications.”—CH ■

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In The Literature Anti–PD-1/PD-L1 Antibodies Show Promising Antitumor... Continued from page 8

Durable tumor regression as seen by objective response (range, 6%-17%) and prolonged stabilization of disease at 24 weeks (range, 12%-41%) were achieved in 160 patients, including some who had received extensive previous therapy. As with the first study, there was an unexpected response in patients with NSCLC, but no objective responses were seen in patients with colorectal or prostate cancer. Of the 17 patients with ovarian cancer, 1 had an objective response. Most of the adverse events with the study drug were immune related. Grade 3 or 4 effects were seen in 9% of 207 patients. Although the drugs were not compared directly, these data suggest that the anti–PD-L1 antibody may produce a smaller response than the anti-PD-1 antibody. These early results point to a potential role for this anti-PD-1 antibody as a targeted therapy.

exposed in utero to diethylstilbestrol, or immunocompromised women. The new guidelines are based on a systematic review of the relevant evidence, including the benefits and harms of cervical cancer screening, as well as a computerized decision analysis. The USPSTF points out that for policy and coverage decisions, consid-

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In childhood cancer survivors, subsequent malignant neoplasms are a

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RJ Health Systems — the pharmaceutical specialists that healthcare professionals have turned to since 1983 for their drug information. We work with over 170 Payor organizations that touch approximately 110 million lives.

Cervical cancer remains an important public health issue. The US Preventive Services Task Force (USPSTF) has issued an update to its 2003 cervical cancer screening recommendations based on current evidence (Moyer VA, on behalf of the USPSTF. Ann Intern Med. 2012;156:880-891). The key updated points in the new guidelines include: • Cytology screening should be done every 3 years in women aged 21 to 65 years • Women aged <21 years should not be screened, for lack of evidence for a net benefit • There is no substantial difference in test performance between liquidbased and conventional cytology for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and CIN3+ lesions • Women aged <30 years should not be screened with human papillomavirus (HPV) testing • HPV testing plus cytology every 5 years is an acceptable strategy for women aged 30 to 65 years. In addition, the guidelines recommend against cervical cancer screening in older women (≥65 years) who have had adequate previous screening and are not otherwise at high risk for cervical cancer. These guidelines apply to women who have a cervix, regardless of sexual history, but not to women with highgrade precancerous cervical lesions or cervical cancer, women who were

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Childhood Cancer Survivors at Risk for GI Cancers Later in Life: Screening Recommended

leading cause of premature death, second only to recurrence of the primary cancer. The Childhood Cancer Survivor Study included a cohort of 14,337 childhood cancer survivors (which is believed to be the largest cohort of this type) and assessed the risk for gastrointestinal (GI) malignant

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erations beyond clinical benefits and harms are applicable.

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AMCP 2012 Annual Meeting

In Colorectal Cancer, Treatment Efficacy Is High Among the Elderly By Caroline Helwick San Francisco, CA—The vast majority of published evidence indicates that the relative treatment effect of chemotherapy for stage III colon cancer is as good for elderly patients as it is for younger ones, according to a systematic literature review by Anna Hung, a student in the program, and C. Daniel Mullins, PhD, Professor, Pharmacoeconomics, Pharmaceutical Health Services Research Department, Associate Director, Center on Drugs and Public Policy. The study was presented at the 2012 Academy of Managed Care Pharmacy annual meeting. The effectiveness of chemotherapy in clinical practice may vary from the efficacy demonstrated in clinical trials, particularly for populations that are underrepresented in clinical trials, such as the elderly, Ms Hung noted. “There is limited evidence regarding how chemotherapy impacts the prognosis of elderly patients compared to nonelderly patients.”

The study synthesized the available evidence and examined the relative effectiveness of chemotherapy for stage III colon cancer among elderly versus nonelderly patients through a systematic review of the literature from 2001 to 2011, using the Agency for Healthcare Research and Quality approach.

“Chemotherapy has similar relative effectiveness and safety outcomes in elderly versus nonelderly patients.” —Anna Hung

A total of 24 articles met the eligibility criteria, which were: patients were treated for stage III colon cancer with a

chemotherapy treatment recommended by the National Comprehensive Cancer Network guidelines; studies were clinical trials phase 2, 3, or 4, or observational studies with empirical analyses; studies examined the effectiveness of chemotherapy; studies included patients aged >65 years. The chemotherapy regimens evaluated included FOLFOX (5-fluorouracil [FU], leucovorin, oxaliplatin); CapeOx (capecitabine plus oxaliplatin); capecitabine alone; 5-FU/leucovorin; irinotecan-based treatment with or without 5-FU/leucovorin or capecitabine; bevacizumab with or without 5-FU and oxaliplatin; and multiple regimens based on 5-FU with or without irinotecan, oxaliplatin, bevacizumab, or cetuximab. Among 13 studies that reported overall survival (OS) data, the OS was similar between elderly (aged ≥70 years) and nonelderly (aged <70 years) patients; only 3 studies reported lower

OS in the elderly, 2 that evaluated 5FU/leucovorin and 1 that evaluated multiple chemotherapy regimens. Disease-free survival, time to progression (TTP), and overall response rates (ORRs) were also similar; one sample reported higher TTP and ORR among the elderly. Adverse event rates were similar overall, with a few exceptions. When studies reported higher adverse event rates among elderly patients, the greater toxicities included fatigue, diarrhea, and neutropenia. There were no reports of higher rates for pain, hand-foot syndrome, stomatitis, neuropathy, or nausea and vomiting. “Chemotherapy has similar relative effectiveness and safety outcomes in elderly versus nonelderly patients,” Ms Hung noted. Furthermore, she noted that the findings do not support the concept that elderly patients have lower rates of chemotherapy use. ■

Is Pemetrexed/Platinum Therapy Cost-Effective in NSCLC? By Audrey Andrews San Francisco, CA—In what appears to be the first study to use real-world, non–clinical trial data to evaluate the cost-effectiveness of pemetrexed/platinum (Pem/P) therapy used first line in patients with advanced non–smallcell lung cancer (NSCLC), this combination trended toward being more effective and less costly than carboplatin/paclitaxel plus bevacizumab (C/Pa+B), reported Manan Shah, PharmD, PhD, with Xcenda, Palm Harbor, FL, and colleagues at the 2012 Academy of Managed Care Pharmacy annual meeting. In a second comparison, Pem/P was costlier than C/Pa alone (without bevacizumab), but had a potential incremental clinical benefit, according to this study. “Therefore, depending on society’s or payers’ willingness to pay, Pem/P may be seen as more cost-effective compared to C/Pa due to the fact that Pem/P demonstrated effectiveness at a higher cost,” Dr Shah and colleagues noted. Recent phase 3 trials have shown the effectiveness of certain doublet and triplet first-line combination therapies, such as Pem/P, C/Pa, and C/Pa+B, in advanced nonsquamous NSCLC, but

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the cost-effectiveness of these regimens has not been documented. This retrospective analysis compared the real-world incremental cost-effective-

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

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

ness of the 3 regimens based on data from the International Oncology Network database, which represents 20 large US community oncology practices. The study included data from 2006 to 2010; the index date was when first-line treatment was initiated. Patients were followed for 12 months to assess progression, death, and associated cost of care. Comparator patient cohorts receiving first-line C/Pa or C/Pa+B were matched to patients in the Pem/P cohort based on index year, stage at diagnosis, sex, performance status, and age. A total of 900 patients included 300

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Improved PFS, Lower Costs with Pem/P versus C/Pa+B Patients receiving Pem/P had a significant median progression-free survival (PFS) benefit (134 days) compared with patients receiving C/Pa+B (126 days), with a first event occurring in 86% versus 94% of patients, respectively (hazard ratio [HR], 0.68; P <.001). Overall survival (OS) was higher, although not significantly different, with Pem/P (298 days) than with C/Pa+B (271 days). Patients receiving Pem/P had significantly lower mean costs compared with patients receiving C/Pa+B. Mean PFS costs were $33,745 with Pem/P

and $48,905 with C/Pa+B, for a difference of $15,160. Overall costs were $33,969 with Pem/P versus $53,915 with C/Pa+B, for a $19,946 difference. The probability that Pem/P was more effective and less costly than C/Pa+B was 69.5% for PFS and 85% for OS. Pem/P versus C/Pa Similarly, patients receiving Pem/P had longer PFS (134 days) than those receiving C/Pa (106 days), but also higher costs. The mean PFS costs were $21,841 higher with Pem/P compared with C/Pa, and the overall cost was $19,137 with the former compared with the latter. “Pem/P had a higher probability of being more costly but more effective than C/Pa,” Dr Shah and colleagues noted. OS was 298 days with Pem/P versus 218 days with C/Pa, with events occurring 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 than C/Pa, it nevertheless had a potential cost-effective benefit. The analyses did not evaluate the entire continuum of care in terms of cost, the investigators said. ■

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In The Literature Childhood Cancer Survivors at Risk for GI Cancers... Continued from page 29

neoplasms in this population (Henderson TO, et al. Ann Intern Med. 2012;156:757-766). Results show that survivors of childhood cancer, especially patients who received abdominal radiation, those who survived Hodgkin lymphoma or Wilms’ tumor, and those who took certain chemotherapies (high-dose procarbazine and platinum drugs), are at an increased risk for GI cancers. All participants were diagnosed with cancer before age 21 years, were treated at 1 of 26 centers in the United States and Canada, and survived for at least 5 years after the initial cancer diagnosis; their data were compared with a general population from a national cancer database. The risk for GI cancer later in life was 4.6-fold higher in the childhood cancer survivors than in the general population (95% confidence interval [CI], 3.46.1). The highest risk for GI cancer was associated with abdominal radiation, although survivors who were not exposed to radiation were also at increased risk. Among 11,807 patients with complete data available, the risk for GI cancer later in life was increased with the use of platinum drugs (relative risk [RR], 7.6; CI, 2.3-25.5) and highdose procarbazine (RR, 3.2; CI, 1.1-9.4). One limitation of this study is that most cancer survivors had not yet attained an age when GI cancer typically occurs in the general population, so additional cases and risk factors may yet be identified. These results support the recommendation to consider screening for GI cancers earlier in patients who survive childhood cancer.

New Test May Spare the Need for Surgery to Diagnose Thyroid Cancer Diagnostic surgery is often used to evaluate the 15% to 30% of thyroid nodules that cannot be judged benign or malignant by the use of fine-needle aspiration (FNA). However, such surgery is associated with a 2% to 10% risk of serious complications. A new geneexpression test may soon be used for the diagnosis of such nodules, which could reduce the use of diagnostic surgery in this population (Alexander EK, et al. N Engl J Med. Epub 2012 Jun 25). This prospective, double-blind study involved 4812 FNA samples from 3789 patients over a 19-month period. Of these samples, 577 cytologically indeterminate nodules were further examined to determine their clinical significance. The gene-expression test was performed on the tissue from

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the patients who also had the surgery and therefore had histopathological review results to serve as a reference standard. Of 265 nodules that met the inclusion criteria based on a blinded histopathological review, 85 were malignant. The use of the geneexpression test identified 78 of the 85

malignant nodules, yielding a sensitivity of 92% (95% confidence interval, 84-97). The negative predictive values for “atypia (or follicular lesion) of undetermined clinical significance” and “follicular neoplasm or lesion suspicious for follicular neoplasm” were 95% and 94%, respectively. These values suggest that for aspi-

rates with either of these subtypes and a benign gene-expression test result, the probability of malignancy is as low as that for nodules shown to be benign with FNA. The researchers suggested that routine use of the gene-expression test may potentially offer cost-savings by reducing unnecessary surgery. ■

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CONTINUING EDUCATION JULY 2012 • VOLUME 5 • NUMBER 2

5th Annual

CONSIDERATIONS in

Multiple Myeloma

ASK THE EXPERTS: Maintenance Settings LETTER

FROM THE

EDITOR-IN-CHIEF

Over the past several years, significant progress has been made in the management of multiple myeloma (MM). This is due, in large part, to an accumulating knowledge of the biology of the disease, along with the development and clinical investigation of highly effective therapies. The shift in the paradigm of care for MM has resulted in revised criteria for diagnosing, staging, and risk-stratifying patients; new standards of care; and updated guidelines for the management of comorbidities and treatment-related toxicities. However, more progress is needed and many questions remain regarding the application and interpretation of recent clinical advances. In this fifth annual “Considerations in Multiple Myeloma” newsletter series, we continue to address frequently asked questions related to the diagnosis and treatment of the disease. To provide an interprofessional perspective, questions are answered by physicians, nurses, and pharmacists from leading cancer institutions, who share their insight, knowledge, and professional experience regarding evidence-based care. In this second issue, experts from City of Hope Cancer Center answer questions pertaining to the management of patients in the maintenance setting.

PUBLISHING STAFF President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Director, Medical & Scientific Services Linda M. Ritter, PhD linda@coexm.com

Sincerely,

Editorial Director Susan Berry susan@coexm.com

Sagar Lonial, MD Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine Atlanta, GA

Copyeditor Dana Delibovi

Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

FACULTY

Quality Control Director Barbara Marino

Amrita Y. Krishnan, MD, FACP Director, Multiple Myeloma Program Associate Director, Medical Education and Training Department of Hematology/HCT City of Hope Cancer Center Duarte, CA

Web Coordinator Jose Valentin

Business Manager Blanche Marchitto

Christina Boeckman, RN, ANP-C, AOCNP Nurse Practitioner Department of Hematology/HCT City of Hope Cancer Center Duarte, CA

Sepideh Shayani, PharmD, BCOP Clinical Manager, Pharmacy Services Department of Pharmaceutical Services City of Hope Cancer Center Duarte, CA

Executive Administrator Jackie Luma

Circulation Department circulation@greenhillhc.com

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

Center of Excellence Media, LLC 241 Forsgate Drive Suite 205B Monroe Township, NJ 08831 This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC.

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsor This activity is jointly sponsored by Medical Learning Institute, Inc., and Center of Excellence Media, LLC. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Educational Objectives Upon completion of this activity, the participant will be able to: • Describe recent advances in maintenance therapy that can potentially prolong survival and improve quality of life in patients with MM • Identify specific patient- and disease-related factors that may impact the choice of maintenance therapy in MM • Review recent safety and efficacy data on novel agents used in the maintenance setting for MM Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P12026.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the Certificate for your records. For questions regarding the accreditation of this activity, please contact MLI at 609-333-1693 or cgusack@mlicme.org. Physician Credit Designation The Medical Learning Institute, Inc. (MLI) designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation 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 Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute, Inc. (MLI). Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours. Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.25 contact hours (0.125 CEUs) of continuing education credit. The universal activity number for this activity is 0468-9999-12-024-H01-P. Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by MLI for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Planners’ and Managers’ Disclosures Dana 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 disclosed that her spouse is investigator on a study for Agenix and Lilly; on the data monitoring committee for Infinity; and on the data monitoring committee and principal investigator on a study for Pfizer.

*Amrita Y. Krishnan, MD, FACP, is a consultant for Celgene Corporation, 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 for Genzyme. *Content will include non–FDA-approved uses. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Agenda: 1.25 hours Articles/Commentaries: 60 minutes Evaluation/Posttest: 15 minutes Date of original release: July 12, 2012 Valid for CME/CE credit through: July 12, 2013

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

Recent Advances and Ongoing Controversies in the Maintenance Setting Amrita Y. Krishnan, MD, FACP Director, Multiple Myeloma Program Associate Director, Medical Education and Training, Department of Hematology/HCT City of Hope Cancer Center, Duarte, CA

Introduction Despite 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-

response, as this has been correlated with improved overall survival (OS).1,2 Maintenance therapy with novel agents can contribute to these treatment goals, 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 outweigh benefit in this population. Of course, there are always exceptions, and the approach to therapy must be individualized to the patient. Many questions remain on the optimal use of maintenance therapy, because we do not yet have unequivocal evidence that it prolongs OS in specific MM subgroups.3,4

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

What evidence has influenced your approach to maintenance therapy?

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 patients with MM?

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

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In patients with high-risk cytogenetics who exhibit the translocation t(4;14), I tend to use bortezomib. The HOVON-65/GMMG-HD4 trial showed 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 maintenance that produced this clinical benefit, since patients received bortezomib during induction as well in one arm of the study, whereas the other arm did not receive bortezomib during induction or maintenance (Figure).5 There has also been debate regarding the efficacy of bortezomib maintenance in patients with deletion 17p (del[17p]). A study by Avet-Loiseau and colleagues reported that bortezomib-based therapy could not overcome this chromosomal abnormality. However, patients in this trial received bortezomib short-term (4 cycles) with no maintenance.6 Results of HOVON-

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CONTINUING EDUCATION

Figure. Efficacy results at 36 months of follow-up in the HOVON-65/GMMG-HD4 trial.5 VAD + HDT/ASCT + thalidomide maintenance PAD + HDT/ASCT + bortezomib maintenance

80 70

Patients (%)

60 50 40 30 20 10 0

All pts

t(4;14)

del(17p)

All pts

PFS

t(4;14)

del(17p)

OS

melphalan, prednisone, and lenalidomide (MPR) ± lenalidomide maintenance or melphalan/ASCT ± lenalidomide maintenance. A comparison of all patients given lenalidomide maintenance (after either MPR or ASCT) versus all patients receiving no maintenance showed that maintenance increased PFS but not OS. The recent MM-015 trial evaluated lenalidomide maintenance in older, transplant-ineligible patients with myeloma. The investigators of this study reported that lenalidomide after initial therapy with MPR significantly extended PFS compared with melphalan plus prednisone alone or MPR without maintenance.12 Thalidomide is not used preferentially for maintenance in the United States, largely due to data showing a high incidence of serious adverse events, reduced quality of life, and potentially poorer outcomes in del(17p) patients.13-15 In Europe, however, thalidomide is used more often, because of regulatory limitations on other novel drugs such as lenalidomide. What are some of the key concerns in using maintenance therapy?

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

Table. Efficacy Results at a Median Follow-up of 34 months in the CALGB 100104 Trial9 Lenalidomide Maintenance

Placebo

P Value

46 months

27 months

<.001

3-Year PFS rate

66% (95% CI, 59-73)

39% (95% CI, 33-48)

3-Year OS rate

88% (95 CI, 84-93)

80% (95 CI, 74-86)

Median TTP

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

65/GMMG-HD4 suggested a benefit with bortezomib-based induction plus maintenance,5 as did data from the Total Therapy 3 trial.7 In addition, a recent study by Neben and colleagues reported that patients with del(17p) who received bortezomib before and after ASCT had a median PFS of 26.2 months compared with 12.0 months for patients who did not receive bortezomib (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 treatment for patients with del(17p). For patients with a partial response after ASCT, I generally use lenalidomide maintenance, based on results from the CALGB 100104 and IFM 2005-02 trials.9,10 CALGB 100104 compared single-agent lenalidomide maintenance with placebo in patients with stable disease or better (including patients who achieved CR) following ASCT. This study demonstrated significantly longer time to progression and improved survival in the lenalidomide arm versus the placebo arm (Table).9 IFM 2005-02 also compared singleagent lenalidomide maintenance with placebo post-ASCT (after 2 courses of lenalidomide consolidation in both arms).10 In this study, lenalidomide maintenance improved median PFS to 41 months versus 23 months with placebo (P<.001), with benefit across cytogenetic subgroups. Three-year and 4-year OS 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 induction with lenalidomide and low-dose dexamethasone, followed by either

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The first concern is risk versus benefit. Are we seeing enough clinical benefit to justify the toxicity and added expense of maintenance therapy? Certainly, data suggest benefits in response and PFS when maintenance is used, but a consistent benefit in OS has not been shown.3-8 Adverse events are also an important consideration. With bortezomib maintenance, grade 3 or 4 peripheral neuropathy may be treatment-limiting.3,5 With lenalidomide, trials have reported an increased risk of second primary malignancies with maintenance therapy.9,10,12,16 In CALGB 100104, for example, second cancers were reported in 8% of patients receiving lenalidomide maintenance versus 3% of patients receiving placebo during approximately 3 years of follow-up.9 The investigators of this study have indicated that they will continue to assess risk factors for development of second primary cancers with further follow-up. Factors such as cost and insurance 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 with novel agents?

Currently, there is no consensus regarding the optimal duration of maintenance therapy for myeloma. In HOVON-65/GMMG-HD4, patients received bortezomib maintenance for 2 years.5 In CALGB 100104, lenalidomide maintenance was given until progression.9 The investigators in the IFM 2005-02 trial planned to use lenalidomide until progression but stopped therapy once secondary malignancies arose.10 In the ongoing phase 3 multicenter BMT CTN 0702 trial, we plan to give lenalidomide maintenance therapy for 3 years.17 However, many questions remain unresolved. What is the optimal duration of lenalidomide therapy to improve PFS and possibly OS? Since bortezomib-related neuropathy may shorten maintenance time, can we reduce the incidence and severity of this toxicity and extend the duration of time that 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 define the role of novel agents in the maintenance setting and provide answers to these questions. ◆ References 1. 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-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726.

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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 multiple myeloma. Blood. 2012;119:3003-3015. 4. Rajkumar SV, Gahrton G, Bergsagel PL. Approach to the treatment of multiple myeloma: a clash of philosophies. Blood. 2011;118:3205-3211. 5. 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 by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly 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 improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010;28:4630-4634. 7. Shaughnessey JD, Zhou Y, Haessler J, et al. TP53 deletion is not an adverse feature in multiple myeloma 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 autologous stem 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 for multiple myeloma. N Engl J Med. 2012;366:1770-1781. 10. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation 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 progression 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-ineligible 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 prednisone as maintenance therapy following autologous stem cell transplantation (ASCT) in patients with multiple (MM): the NCIC CTG MY.10 trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 39. 16. Delforge M, Dimopoulos M, Adam Z, et al. Safety profile and management in MM-015 comparing lenalidomide-melphalan-prednisone followed by lenalidomide maintenance (MPR-R) with MP and MPR in newly diagnosed multiple myeloma (NDMM). Presented at: 17th Annual Congress of the European Hematology Association; June 14-17, 2012; Amsterdam, Netherlands. 17. Stem cell transplant with lenalidomide maintenance in patients with multiple myeloma (BMT CTN 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 of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. 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 oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (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 proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033. 22. Kumar S, Bensinger W, Reeder CB, et al. Weekly dosing of the investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed/refractory multiple myeloma (MM): a phase I study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8034.

Improving Patient Outcomes During Maintenance Therapy Christina Boeckman, RN, ANP-C, AOCNP Nurse Practitioner Department of Hematology/HCT, City of Hope Cancer Center Duarte, CA

Introduction Along 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 therapy. As a member of the cancer care team, it is the nurseâ&#x20AC;&#x2122;s responsibility to anticipate which toxicities and complications are likely to occur, to employ the necessary interventions, and to counsel patients

have organ dysfunction (eg, cardiovascular disease, renal impairment) and diabetes, and are more prone to infection and deep vein thrombosis.1 It is crucial to take these factors into account when determining an effective management plan. It is also important to know which agents were used during previous lines of therapy, how patients tolerated these medications, and whether they are experiencing any residual adverse events. In some cases, it may be necessary to avoid the use of specific agents due to preexisting comorbidities or cumulative toxicities. A patientâ&#x20AC;&#x2122;s overall performance status should also be evaluated prior to and during maintenance therapy. Nurses must assess whether an individual is able to perform activities of daily living, such as preparing meals, eating, bathing, and dressing. The goal is to achieve a balance between providing effective therapy and maintaining good quality of life.

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

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

adverse events related to the use of novel agents.

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

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

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

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Table. Bortezomib Dose Modifications Based on Severity of Peripheral Neuropathy5,6 Severity of Peripheral Neuropathy

Modification of Dose and Regimen

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

No action

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

Reduce bortezomib dose from 1.3 to 1.0 mg/m2

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

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

Grade 4 (permanent sensory loss that interferes with function)

Discontinue bortezomib

Grading based on NCI Common Toxicity Criteria CTCAE V 3.0.

recently seen an increase in the use of bortezomib in the maintenance setting, and nurses need to be familiar with its toxicity profile and recommended supportive 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 scales are helpful for these assessments. When patients come to our center for treatment, I ask them if they are experiencing any numbness and tingling in their hands and feet, ringing in their ears, neuropathic pain, or cramping. I also determine if they are having trouble with everyday tasks, such as buttoning their shirts or writing with a pen. Patients must understand the importance of reporting signs and symptoms of PN as soon as they occur, so that the appropriate interventions can be initiated. When bortezomib-related PN develops, the goal is to alleviate symptoms and prevent progression.2 This can be accomplished through recommended dose modifications based on the degree of neurotoxicity (Table).5,6 For example, if a patient develops grade 3 PN while on bortezomib, we typically hold treatment until symptoms resolve, and then reinitiate therapy at a lower dose and schedule. For patients who have neuropathic pain, we prescribe opioids when necessary; the use of nonsteroidal anti-inflammatory drugs is not advisable due to the likelihood of myeloma-related renal dysfunction. Additional medications that may be used in the treatment of PN symptoms include gabapentin, pregabalin, duloxetine hydrochloride, and tricyclic antidepressants.2 We usually recommend that patients start taking B complex vitamins, folic acid, and alpha lipoic acid, as long as they are not contraindicated with other medications. How do you assess and treat hematologic toxicities related to lenalidomide therapy in the maintenance setting?

discontinue lenalidomide. Treatment can usually be resumed when platelet counts return to 30,000/mcL, but it may be necessary to restart them at a reduced dose.7,8 We usually do not initiate transfusion unless platelet counts decline to <20,000/mcL. If the patient’s absolute neutrophil count (ANC) is <1000/mcL, lenalidomide treatment should also be halted until counts return to baseline. In some cases, we may initiate granulocyte colony-stimulating factor 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 and symptoms at home. We tell them to notify us immediately if they experience bleeding that does not stop, frequent bruising, or fever. It is important to instruct patients on effective strategies for infection control, including routine hand washing and the avoidance of crowds, when their blood counts are low. If patients develop signs of infection, we may also need to hold lenalidomide treatment until symptoms resolve. What is the nurse’s role in helping patients continue with maintenance therapy?

Prior to the initiation of maintenance, it is important to discuss with patients both the risks and benefits of prolonged therapy with novel agents. Some individuals do not understand why they need to undergo further treatment if they have responded well to initial chemotherapy and/or transplantation. It is important to remind these patients that continued use of effective agents may help to delay relapse and disease progression. Although patients will typically be familiar with the toxicity profiles of agents they have already received during frontline therapy, we review this information again prior to the start of maintenance. We also inform patients about the increased risk for secondary malignancies related to prolonged duration of therapy, and encourage them to be diligent about routine health screenings, including mammograms and colonoscopies. We ensure them that we will also monitor for secondary malignancies through 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 rather receive oral lenalidomide, so they do not have to travel back and forth to the center every week for treatment. If we determine that a patient can be compliant with an oral regimen, and they do not have comorbidities or other characteristics that 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 is prescribed during maintenance, oncology nurses play an important role in improving patient outcomes by establishing good communication with patients, carefully monitoring for signs and symptoms of toxicities, and being prepared to initiate effective supportive care strategies when needed. ◆ References

Hematologic toxicities are commonly associated with the use of lenalidomide.7 To effectively manage these adverse events, it is important for myeloma patients to have their blood counts monitored regularly, with the most frequent monitoring performed early in their treatment cycles. We see patients at least every 2 weeks during the first and second cycles of maintenance to assess how they are responding to treatment and to evaluate the need to make dose or schedule adjustments based on their counts. Depending on their performance status and laboratory results, we may lessen the frequency of these evaluations to once per month. When platelet counts fall to <30,000/mcL, we may need to temporarily

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1. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy 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 neuropathy associated with novel therapies in patients with multiple myeloma: consensus statement 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 survival in patients with multiple myeloma. Blood. 2006;108:3289-3294. 4. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple 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 multiple 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 the IMF Nurse Leadership Board. Clin J Oncol Nurs. 2008;12(suppl 3):13-20. 8. Revlimid [package insert]. Summit, NJ: Celgene Corporation; October 2010.

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Dosing and Administration of Novel Agents in the Maintenance Setting Sepideh Shayani, PharmD, BCOP Clinical Manager, Pharmacy Services Department of Pharmaceutical Services City of Hope Cancer Center Duarte, CA

Introduction Over the past decade, maintenance therapy has become an increasingly important component of treatment for patients with multiple myeloma (MM). Recent evidence has shown that newer target-

age or comorbidities, the schedule of bortezomib (1.3 mg/m2) used for induction was reduced from twice weekly to once weekly. In addition, both the VMPT 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 schedule of bortezomib lowered discontinuation rates and prolonged time on therapy. This finding has important clinical implications, especially for the treatment of older patients who may have difficulty tolerating a standard regimen. The schedule adjustment used in this study also significantly reduced the incidence of severe sensory PN from 16% to 3% (P<.001).

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, conventional therapies used for this indication. In this article, Sepideh Shayani, PharmD, BCOP, discusses recent advances in the maintenance setting, and answers questions related to the administration of

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.

novel agents.

Has a standard dose and schedule been established for bortezomib as maintenance therapy?

To date, a standard dose and schedule has yet to be established for bortezomib maintenance; however, data from recent clinical trials can be helpful in guiding therapeutic decisions. As in the frontline and relapsed/refractory settings, 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. In the phase 3 HOVON-65/GMMG-HD4 trial, transplant-eligible patients with MM were randomly assigned to induction therapy with vincristine, doxorubicin, and dexamethasone (VAD) or bortezomib, doxorubicin, and dexamethasone (PAD).1 This was followed by high-dose melphalan and autologous stem cell transplant (ASCT). Patients started on VAD received thalidomide maintenance at a dose of 50 mg/day for 2 years (arm A) and those randomized to PAD received bortezomib maintenance at a 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% at 36 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 started maintenance therapy, and 64% and 47% of those patients, respectively, went off 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, and thalidomide (VMPT) followed by 2 years of maintenance with bortezomib (1.3 mg/m2 every 14 days) plus thalidomide (50 mg/day) (VT) or to nine 6-week cycles of VMP induction without maintenance.2 Early in this trial, which enrolled patients who were not eligible for transplant due to advanced

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Both of these maintenance trials reported encouraging clinical activity with bortezomib. In GIMEMA, once-weekly dosing was more tolerable than twice-weekly dosing, but maintained good clinical activity.2 In this trial, bortezomib maintenance administered bimonthly also appeared to be an effective strategy. Investigators continue to evaluate various bortezomib dosing and schedule protocols. Hopefully, data from new trials will help to determine a standard of care. In the meantime, following established dosing adjustment guidelines for bortezomib3,4 to reduce toxicities such as PN is essential to ensure optimal outcomes. Additionally, subcutaneous administration of bortezomib may improve the adverse event profile associated with this agent. In a recent trial of relapsed/refractory MM, this mode of administration resulted in similar overall response rates but significantly less PN than traditional intravenous dosing.5 The increased tolerability seen with subcutaneous bortezomib in this population of patients may translate to the maintenance setting. What dosing and administration schedules are being used for lenalidomide as maintenance?

In the phase 3 IFM 2005-02 trial, patients with MM who had single or double 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 tolerated).6 Treatment was continued until disease progression or development

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

Progression

Other

Overall

Thalidomide

31%

31%

2%

64%

Bortezomib

9%

29%

9%

47%

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Table 2. Select Grades 3 and 4 Hematologic Toxicities in the MM-015 Trial8 MP (Gr 3/4)

MPR (Gr 3/4)

MPR-R (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.

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

We are seeing RVD used more frequently as induction therapy in MM, so data from this study should be relevant to clinical practice. The phase 3 MM-015 trial randomized elderly, transplant-ineligible MM patients to 9 cycles of melphalan, prednisone, and lenalidomide followed by lenalidomide maintenance (MPR-R), or to 9 cycles of MPR or MP without maintenance.7,8 In this study, the scheduled dose of lenalidomide (during induction and maintenance) was 10 mg/day, given on days 1 to 21. Patients could receive maintenance until disease progression or development of intolerance. After a median follow-up of 27 months, PFS was significantly longer with 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 hematologic toxicities in this study are shown in Table 2. However, during the maintenance phase of MPR-R, the incidence of new or worsening toxicities was low. Discontinuation due to adverse events in the MPR-R, MPR, and MP arms was observed in 16%, 14%, and 5%, respectively. These rates were higher in patients >75 years of age than in those 65 to 75 years of age, as was the need for dose reductions. Incidence of second primary malignancies was low, 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

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and efficacy of lenalidomide maintenance in 3 cohorts of patients.9 Following ASCT, participants will proceed to either second transplant, consolidation with lenalidomide, dexamethasone, and bortezomib (RVD), or maintenance with lenalidomide. Patients undergoing second transplant and consolidation will also receive maintenance therapy, which will start at 10 mg/day for 3 months and increase to 15 mg/day. We are seeing RVD used more frequently as induction therapy in MM, so data from this study should be relevant to clinical practice. What strategies are important to ensure optimal outcomes in the maintenance setting?

Certainly, it is important to consider safety and efficacy data from recent studies in the decision-making process. Beyond that, factors such as convenience, cost, reimbursement, and, of course, toxicity profiles of specific agents must be considered so that therapy can be tailored to a patientâ&#x20AC;&#x2122;s needs. The treatment landscape for MM is constantly evolving; therefore, clinicians must also stay informed of new agents that are being investigated in clinical trials. For example, early data from phase 1/2 trials were recently released on the use of the oral proteasome inhibitor MLN9708 in MM. In both newly diagnosed and relapsed/refractory patients, treatment with this agent resulted in encouraging response rates with good tolerability, especially low rates of PN.10,11 Based on these results, phase 3 trials are under way to further evaluate the safety and efficacy of this agent in myeloma. â&#x2014;&#x2020;

References 1. 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 by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with 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 followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalanprednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28:5101-5109. 3. Mohty B, El-Cheikh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatments for multiple 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-inferiority study. Lancet Oncol. 2011;12:431-440. 6. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stem-cell transplantation 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 diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 8. Palumbo A, Hajek R, Kropff M, et al. Continuous lenalidomide treatment for transplant-ineligible 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. 9. ClinicalTrials.gov Web site. Stem cell transplant with lenalidomide maintenance in patients with 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 investigational oral proteasome inhibitor MLN9708 in patients (pts) with relapsed and/or refractory multiple myeloma (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 investigational proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma (MM): a phase I/II study. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012;30(suppl):Abstract 8033.

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