October 2012, Vol 5, No 7 by The Oncology Pharmacist

OCTOBer 2012

www.TheOncologyPharmacist.com

VOl 5, NO 7

OVARIAN CANCER

CANCER CENTER PROFILE

Bevacizumab in the Treatment of Advanced Ovarian Cancer

Cancer Institute of New Jersey The Changing Paradigm of Cancer Care

By Quan Li, PharmD, BCOP Department of Pharmacy, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University

By Alice Goodman

Photo from the Cancer Institute of New Jersey.

varian cancer is the fifth leading cause of cancer-related death in females in the United States.1 There will be an estimated 22,280 new cases and 15,500 deaths related to ovarian cancer in 2012.1 The prognosis of advanced ovarian cancer is poor, with a 5-year survival rate of 5% to 20%. A platinum-based doublet chemotherapy

post cytoreductive surgery has been the standard of care for the past decade. A breakthrough came when vascular endothelial growth factor (VEGF) and angiogenesis were found to be associated with prognosis and overall survival.2 Previous phase 2 trials have shown positive efficacy data for bevacizumab, a humanized monoclonal antibody of VEGF, Continued on page 12

BEST PRACTICES Michael P. Kane, RPh, BCOP; Ashley Finamore, PharmD, CGP; and Pulkita Patel, PharmD (left to right), of the Cancer Institute of New Jersey.

he Cancer Institute of New Jersey (CINJ) is 1 of 41 National Cancer Institute‒designated Comprehensive Cancer Centers in the United States. CINJ delivers advanced comprehensive care to adults and children, and CINJ investigators are heavily involved in research. Basic scientists and physicians work together to transform laboratory discoveries so that they can be applicable to clinical practice. CINJ provides education and outreach regarding cancer prevention, detection, and treatment. The CINJ network includes 15 hospitals in New Jersey, with Robert Wood Johnson University Hospital as its flagship hospital. The network provides care to more than one-third Continued on page 36 of people with cancer who live in that state.

Weight-Based Dosing Is Appropriate for Obese Patients Meta-Analysis Actually Shows Fewer Serious Adverse Events By Caroline Helwick

meta-analysis reported at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) supports the new guidelines that recommend weight-based chemotherapy dosing for obese cancer patients.1,2

“We found that grade 3/4 toxicities— hematologic and overall—are actually less in obese patients versus normalweight patients, which is not what people predict,” said Kathryn C. Hourdequin, MD, of the Norris Cotton Cancer

NEWS BRIEFS

Continued on page 25

By Alice Goodman

Missing Gene May Account for 25% or More Breast Cancers

lthough preliminary, a recent experimental study published online in the journal Genetics (Wallace MD, et al. Genetics. 2012;192: 385-396) found that lack of the neurofibromin 1 (NF1) gene was observed in more than 1 of every 4 experimentally induced breast cancers. The study findings also suggest that tamoxifen will not be effective in cancers that lack the NF1 gene.

This research—if borne out in humans—will have huge implications for the estimated 60,000 new cases of breast cancer that will be diagnosed in the United States and the 383,000 cases that will be diagnosed worldwide in 2012. In the study, the NF1 gene was missing in about 28% of breast cancers. Previous studies have shown that NF1 depletion

INSIDE ConferenCe news

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Highlights From ASCO 2012 Breast Cancer Symposium side effeCt ManageMent

Preventing CIPN Remains Elusive . . . . . . . . . . . . . . . . . . . . . . . . . . . . .21 Severe Diarrhea Associated With Molecularly Targeted Agents Can Impact Quality of Life and Healthcare Resource Utilization . . .40

Breast CanCer

Continued Benefit for Everolimus in Updated Results of BOLERO-2 . . . . . . . . . . . . 26 Zoledronic Acid: Less Frequent Dosing May Be Just as Good . . . . 38 CoMpliMentary Ce

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Considerations in Multiple Myeloma— Ask the Experts: Transplant-Eligible and -Ineligible Patients

IV R FO AND ED US ION V T O O A PR ANE ST R P A UT INI 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.

News Briefs Missing Gene... Continued from cover

causes tamoxifen resistance, and patients with tumors that have low NF1 levels had worse outcomes on tamoxifen. The NF1 gene has negative effects on the RAS oncogene, which is involved in intracellular signaling that controls cell growth. When NF1 is lacking, RAS becomes hyperactivated and can lead to tumor proliferation.

The study employed a mouse model with elevated mutation rates that led to breast cancers in 80% of the animals. When the researchers looked at the genomes of mice that developed mammary tumors, nearly all were missing the NF1 gene, explained senior author of the paper, John Schimenti, PhD, professor of genetics at the College of Veterinary Medicine, Cornell University, Ithaca, New York. Human breast cancers have many

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.

causes, and each patient’s tumor has a unique set of gene variants as well as new mutations, making it extremely difficult to identify individual genes that drive the cancer, explained Schimenti in a press release from Cornell. The mouse model used in the study is inbred, and the mice get exactly the same type of tumor every time, eliminating “noise” and allowing the researchers to identify NF1 as a driver of these mutations, according to the press release.

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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RAS is hyperactivated in the mouse model for breast cancer. Chemotherapy agents that interrupt the RAS pathway are available for the treatment of breast cancer, and it is possible that these drugs will be effective in breast cancers that have low levels of NF1 or cancers with a missing NF1 gene. The Cornell researchers plan to study whether insertion of a replacement NF1 gene can reverse tumor growth in mice lacking the gene. They are also studying whether RAS inhibitors can slow the growth of breast cancer in the mouse model. In the paper, the researchers stated that RAS inhibitors could slow tumor cell growth in vitro. Marsha Wallace, a graduate student at Cornell, was lead author of the paper. The authors note that the loss of NF1 may trigger activation of other pathways in addition to RAS, and it will be important to understand these effects as well.

Study Tracks risk of Heart Failure With Trastuzumab The incidence of heart failure and cardiomyopathy were significantly increased in women with breast cancer treated with trastuzumab either alone or in combination with anthracyclinebased chemotherapy, according to the results of a recent large, populationbased, retrospective cohort study (Bowles EJ, et al. J Natl Cancer Inst. 2012;104: 1293-1305). An adjusted analysis found that the risk of heart failure and/or cardiomyopathy was 4 times greater among women treated with trastuzumab alone and 7 times greater in women treated with trastuzumab plus anthracycline versus women who did not receive any chemotherapy. The study was based on data from 8 integrated Cancer Research Network health maintenance systems. Overall, the risk of anthracycline-associated heart failure/cardiomyopathy in women under the age of 65 years was similar in this study as in previously reported randomized clinical trials, but the risk associated with trastuzumab alone or when combined with an anthracycline was higher than in previous reports. Lead author Erin J. Aiello Bowles noted that this study shows that findings of clinical trials may not be generalizable to individual patients treated in real-world settings. The study included 12,500 women, with a mean age of 60 years, diagnosed with invasive breast cancer from January 1, 1999, through December 31, 2007. Women with preexisting heart failure/ cardiomyopathy were excluded. At a median follow-up of 4.4 years, 46.5% had not been treated with chemotherapy, about 30% had received an-

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OCTOBER 2012 I VOL 5, NO 7

www.TheOncologyPharmacist.com

Editorial Board EDITOR-IN-CHIEF

Patrick Medina, PharmD, BCOP

Anjana Elefante, PharmD, BSc, BSc Pharm, RPh

Dwight Kloth, PharmD, FCCP, BCOP

Oklahoma University College of Pharmacy Tulsa, OK

Roswell Park Cancer Institute Buffalo, NY

Fox Chase Cancer Center Philadelphia, PA

ASSOCIATE EDITOR-IN-CHIEF

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN

Jim Koeller, MS

Steve Stricker, PharmD, MS, BCOP Samford University McWhorter School of Pharmacy Birmingham, AL

University of Texas at Austin San Antonio, TX

Cleveland Clinic Taussig Cancer Institute Cleveland, OH

Timothy G. Tyler, PharmD, FCSHP Desert Regional Medical Center Palm Springs, CA

John M. Valgus, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

Christopher Fausel, PharmD

Christopher J. Lowe, PharmD

Indiana University Simon Cancer Center Indianapolis, IN

Indiana University Hospital Indianapolis, IN

David Baribeault, RPh, BCOP

Rebecca S. Finley, PharmD, MS

Emily Mackler, PharmD, BCOP

Burt Zweigenhaft, BS

Boston Medical Center Boston, MA

Jefferson School of Pharmacy Philadelphia, PA

University of Michigan Health System & College of Pharmacy Ann Arbor, MI

BioPharma Partners LLC New York, NY

Betty M. Chan, PharmD, BCOP

David C. Gammon, BSPh

USC/Norris Cancer Hospital Los Angeles, CA

OncologyPharmacist.net Warwick, RI

Laura Boehnke Michaud, PharmD, BCOP, FASHP

John F. Aforismo, BSc Pharm, RPh, FASCP RJ Health Systems International, LLC Wethersfield, CT

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska College of Pharmacy Omaha, NE

Marlo Blazer, PharmD, BCOP

The University of Texas MD Anderson Cancer Center Houston, TX

James Cancer Hospital & Solove Research Institute Columbus, OH

Heidi D. Gunderson, PharmD, BCOP Mayo Clinic Cancer Center Rochester, MN

Steven L. Dâ&#x20AC;&#x2122;Amato, RPh, BCOP

Lew Iacovelli, BS, PharmD, BCOP, CPP

LeAnn Best Norris, PharmD, BCPS, BCOP

Maine Center for Cancer Medicine Scarborough, ME

Moses H. Cone Health System Greensboro, NC

South Carolina College of Pharmacy Columbia, SC

www.TheOncologyPharmacist.com

Kamakshi V. Rao, PharmD, BCOP University of North Carolina Hospitals and Clinics Chapel Hill, NC

OCTOBER 2012 I VOL 5, NO 7

From the Editors PUBLISHING STAFF Senior Vice President, Sales & Marketing Philip Pawelko phil@greenhillhc.com Publisher John W. Hennessy john@greenhillhc.com Associate Publisher Joe Chanley joe@greenhillhc.com

Patrick Medina, PharmD, BCOP Editor-in-Chief

Associate Publisher Cris Pires cris@engagehc.com

n this month’s issue of The Oncology Pharmacist (TOP), we continue our coverage of the news from the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) by addressing the topic of chemotherapy dosing for patients who are obese. In our reader survey poll, we ask you about your experiences in determining the appropriate chemotherapy dose for these patients. Go to www.TheOncologyPharmacist.com and tell us about your experiences with this patient population. With all the news coming from the ASCO Breast Cancer Symposium, held in September in San Francisco, California, we present our summary of abstracts of interest to TOP

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The Oncology Pharmacist®, ISSN 1944-9607 (print); ISSN 1944-9593 (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2012 by Green Hill Healthcare Communications, LLC. All rights reserved. The Oncology Pharmacist® logo is a registered trademark of Green Hill 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. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, The Oncology Pharmacist®, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues, $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in The Oncology Pharmacist® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mention in The Oncology Pharmacist® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. BPA Worldwide membership applied for April 2011.

OCTOBER 2012 I VOL 5, NO 7

readers. These studies help us keep current about the status of some of the latest research. This is something that Michael P. Kane, RPh, BCOP, of the Cancer Institute of New Jersey, points out when he talks about how quickly the field of oncology pharmacy is changing: “The standard of care is a rapidly moving target, day to day, month to month, and from ASCO to ASCO.” Be sure to read what else Michael has to say in this month’s Cancer Center Profile. As always, we want to know what you think about TOP. Tell us what topics you want us to cover and give us your feedback—positive and negative. Contact us at editorial@ greenhillhc.com. ●

Recent FDA News

Executive Administrator Jackie Luma

™

Steve Stricker, PharmD, MS, BCOP Associate Editor-in-Chief

regorafenib Approved to Treat Metastatic Colorectal Cancer The US Food and Drug Administration (FDA) approved regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Regorafenib approval was granted on September 27, 2012. The FDA approval was based on the results of Study 14387, an international, randomized, double-blind, placebo-controlled trial that enrolled 760 patients who had been previously treated for mCRC. All the patients in the trial had received treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and with bevacizumab. Of the patients with KRAS wild-type tumors, all but 1 received panitumumab or cetuximab. Patients randomized to the regorafenib arm received regorafenib 160 mg orally once daily for the first 21 days of each 28-day cycle plus best supportive care. Patients in the control group received matching placebo with best supportive care. Patients in the regorafenib arm had a statistically significant prolongation in overall survival (hazard ratio [HR] 0.77; 95% confidence interval [CI]: 0.64, 0.94; P=.0102). The median survival time was 6.4 months (95% CI: 5.8, 7.3) in the regorafenib arm and 5.0 months (95% CI: 4.4, 5.8) in the placebo arm. There was also a statistically significant improvement in progression-free survival (HR 0.49; 95% CI: 0.42, 0.58; P <.0001). In the regorafenib arm, the median progressionfree survival was 2.0 months (95% CI: 1.9, 2.3). Median progression-free survival was 1.7 months (95% CI: 1.7, 1.8) in the placebo arm. No difference in overall response rate was observed. Partial responses were experienced by 5 patients (1%) in the regorafenib arm and by 1 patient (0.4%) in the placebo arm. Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia were the most frequently observed adverse drug reactions (≥30%) in patients receiving regorafenib. The most serious adverse drug reactions in patients receiving regorafenib were hepatotoxicity, hemorrhage, and gastrointestinal perforation. Regorafenib

was approved with a boxed warning describing the risk of hepatotoxicity. Regorafenib was reviewed under the FDA’s priority review program that provides an expedited 6-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists. Regorafenib was approved 1 month ahead of the product’s prescription drug user fee goal date of October 27, 2012, the date the FDA was scheduled to complete review of the drug application. Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research, noted that regorafenib “is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with colorectal cancer in the past two months.” Potentially Contaminated Medication From NeCC On October 4, 2012, the FDA and the US Centers for Disease Control and Prevention (CDC) recommended that all healthcare professionals cease use and remove from pharmaceutical inventory any product produced by the New England Compounding Center (NECC). The FDA and CDC issued the health advisory after a multistate outbreak of Aspergillus meningitis among patients who received an epidural steroid injection of preservative-free methylprednisolone acetate suspension prepared by NECC. On October 6, NECC announced a voluntary recall of all products currently in circulation that were compounded at and distributed from its facility in Framingham, Massachusetts, stating that it was taking this action “out of an abundance of caution due to the potential risk of contamination, and in cooperation with an investigation being conducted by the U.S. Food and Drug Administration, the Centers for Disease Control and Prevention and the Massachusetts Board of Registration in Pharmacy.” The situation with NECC has focused attention on the regulation of pharmaceutical compounding companies. Currently, the FDA has limited authority over the operations of compounding pharmacies, which are mainly regulated at the state level. According to the International Academy of Compounding Pharmacists, there are approximately 7500 pharmacies in the United States that specialize in advanced compounding services, with approximately 3000 providing sterile compounding. ●

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Conference News

Highlights From ASCO 2012 Breast Cancer Symposium By Caroline Helwick

he American Society of Clinical Oncology 2012 Breast Cancer Symposium, held September 13-15 in San Francisco, California, offered all members of the cancer team an upfront view of new data and an opportunity for one-on-one interaction with experts. The following are a few research items of interest to oncology pharmacists.

Palonosetron Most effective in Preventing Treatment Delays Among early-stage breast cancer patients initiating a highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC) regimen, palonosetron was associated with a significantly reduced risk for chemotherapy-induced nausea and vomiting (CINV). It also was associated with a lower rate of delayed therapy with MEC (equal to HEC) and higher adherence to MEC regimens (equal to HEC), compared with other 5-HT3 receptor antagonists in a comparison led by Hope S. Rugo, MD, of the University of California San Francisco (Abstract 75).1 The study was an observational case-control study that employed medical and pharmacy administrative claims data from the HealthCore Integrated Research Database. Patients were treated according to National Comprehensive Cancer Network guidelines between 2002 and 2010.

Patients receiving palonosetron for MEC had a 39% reduced risk of having 1 or more CINV events, compared with those receiving other 5-HT3 agents. Patients received palonosetron, dolasetron, granisetron, or ondansetron at the start of chemotherapy and for 5 days during their index treatment. Outcomes with palonosetron were compared with outcomes pooled together from all other antiemetics. Follow-up was defined as the duration of time between the index data and the earliest occurrence of any of the following: switching from a single-day HEC/ MEC regimen to a multiday index HEC/ MEC regimen, augmenting the index regimen with nonindex drugs, death, end of health plan eligibility, and end of available data stream. CINV was defined as having at least 1 acute (on chemotherapy start date) or delayed (at 5+ days) CINV event.

Patients receiving palonosetron for MEC had a 39% reduced risk of having 1 or more CINV events, compared with those receiving other 5-HT3 agents (P <.0001), and a 49% reduced risk when they received HEC (P

<.0001). No statistically significant difference in treatment delays due to CINV was found for palonosetron versus other agents in the HEC cohort. Among the MEC cohort, however, the need to delay therapy was reduced by

63% with palonosetron (P = .0005). Adherence to treatment also was significantly higher with palonosetron, versus other agents, in the MEC cohort (P = .02) but not in the HEC cohort. Continued on page 8

Announcing: J-code for YERVOY™ (ipilimumab) J9228 Indication YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma.1

Replaces J9999, J3490, J3590, and C9284.

Product Description

50-mg/10 mL (5 mg/mL), single-use vial of YERVOY

200-mg/40 mL (5 mg/mL), single-use vial of YERVOY

NDC Number 10-digit

0003-2327-11

0003-2328-22

11-digit

00003-2327-11

00003-2328-22

The accurate completion of reimbursement- or coverage-related documentation is the responsibility of the healthcare provider and patient. Bristol-Myers Squibb and its agents make no guarantee regarding reimbursement for any service or item. This coding guidance is not intended to provide specific directions on requesting prior authorization or submitting claims for YERVOY and does not provide a guarantee of receiving prior authorization or reimbursement. Oncology practices need to make coding decisions based on the diagnosis and treatment of each patient and the specific insurer requirements. Access Support™, the Bristol-Myers Squibb Oncology reimbursement services program, offers patient assistance support, benefits investigation, prior authorization support and appeals assistance. Program counselors are available Monday through Friday, from 8:00 A.M. to 8:00 P.M. ET at 1-800-861-0048, to support the oncology offices’ reimbursement services needs of their insured and uninsured patients. You can also find information online at www.bmsaccesssupport.com

Important Safety Information WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests (LFTs) and thyroid function tests at baseline and before each dose. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions.

Please see Important Safety Information, including Boxed WARNING regarding immune-mediated adverse reactions, continued on the following pages. REFERENCES 1. YERVOY (ipilimumab) [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011. 2. Alpha-numeric HCPCS. Centers for Medicare & Medicaid Services Web site. http://www.cms.gov/ HCPCSReleaseCodeSets/Downloads/12anweb.zip. Accessed November 1, 2011.

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Conference News Highlights From Breast Cancer Symposium... Continued from page 7 Vascular Toxicities Do Not lead to endocrine Therapy Discontinuations A large retrospective cohort study of 629 postmenopausal women treated with endocrine therapy found a high incidence of vascular toxicities, but a low rate of treatment discontinuations because of this (Abstract 68).2 The vascu-

lar toxicities were consistent with those described in published reports: with aromatase inhibitors, an increase in cardiovascular events and hypercholesterolemia; and with tamoxifen, a higher incidence of thrombosis. Vascular toxicities were observed in 37% of patients receiving tamoxifen

and 25% to 35% of patients on aromatase inhibitors. The most common toxicities seen with tamoxifen were peripheral edema (23.2%) and thromboembolic events (7.1%). Patients on aromatase inhibitors were also likely to have peripheral edema (19%), as well as hypercholesterolemia (5.4%), ar-

rhythmia (5.2%), and cardiovascular events (4.8%). Preexisting vascular comorbidities significantly increased the risk of developing a new vascular toxicity if the patients were taking letrozole or tamoxifen. Treatment was discontinued due to vascular toxicity 3 times more often

Important Safety Information (cont) Recommended Dose Modifications Withhold dose for any moderate immune-mediated adverse reactions or for symptomatic endocrinopathy until return to baseline, improvement to mild severity, or complete resolution, and patient is receiving <7.5 mg prednisone or equivalent per day. Permanently discontinue YERVOY for any of the following: t Persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5 mg prednisone or equivalent per day t Failure to complete full treatment course within 16 weeks from administration of first dose t Severe or life-threatening adverse reactions, including any of the following – Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency (≥7 over baseline), stool incontinence, need for intravenous hydration for >24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation – AST or ALT >5 × the upper limit of normal (ULN) or total bilirubin >3 × the ULN – Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full-thickness dermal ulceration or necrotic, bullous, or hemorrhagic manifestations – Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis – Severe immune-mediated reactions involving any organ system – Immune-mediated ocular disease which is unresponsive to topical immunosuppressive therapy Immune-mediated Enterocolitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal (diarrhea of ≥7 stools above baseline, fever, ileus, peritoneal signs; Grade 3-5) immune-mediated enterocolitis occurred in 34 (7%) and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) patients t Across all YERVOY-treated patients (n=511), 5 (1%) developed intestinal perforation, 4 (0.8%) died as a result of complications, and 26 (5%) were hospitalized for severe enterocolitis t Infliximab was administered to 5 of 62 (8%) patients with moderate, severe, or life-threatening immunemediated enterocolitis following inadequate response to corticosteroids t Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms t Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). Upon improvement to ≤Grade 1, initiate corticosteroid taper and continue over at least 1 month. In clinical trials, rapid corticosteroid

tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients t Withhold YERVOY for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for >1 week, initiate systemic corticosteroids (0.5 mg/kg/day prednisone or equivalent) Immune-mediated Hepatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations >5x the ULN or total bilirubin elevations >3x the ULN; Grade 3–5) occurred in 8 (2%) patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% t 13 (2.5%) additional YERVOY-treated patients experienced moderate hepatotoxicity manifested by LFT abnormalities (AST or ALT elevations >2.5x but ≤5x the ULN or total bilirubin elevation >1.5x but ≤3x the ULN; Grade 2) t Monitor LFTs (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of LFT monitoring until resolution t Permanently discontinue YERVOY in patients with Grade 3-5 hepatotoxicity and administer systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent). When LFTs show sustained improvement or return to baseline, initiate corticosteroid tapering and continue over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients with persistent severe hepatitis despite high-dose corticosteroids t Withhold YERVOY in patients with Grade 2 hepatotoxicity Immune-mediated Dermatitis: t In the pivotal Phase 3 study in YERVOY-treated patients, severe, life-threatening or fatal immune-mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3–5) occurred in 13 (2.5%) patients – 1 (0.2%) patient died as a result of toxic epidermal necrolysis – 1 additional patient required hospitalization for severe dermatitis t There were 63 (12%) YERVOY-treated patients with moderate (Grade 2) dermatitis t Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated t Permanently discontinue YERVOY in patients with severe, life-threatening, or fatal immune-mediated dermatitis (Grade 3-5). Administer systemic corticosteroids (1-2 mg/ kg/day of prednisone or equivalent). When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY in patients with moderate to severe signs and symptoms

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Conference News Highlights From Breast Cancer Symposium with tamoxifen (11%) than with an aromatase inhibitor (3%), mostly due to thromboembolic events (7.1% vs 2.9%). “These results are encouraging and suggest that the risk of vascular toxicities should not preclude selection of the optimal endocrine strategy,” said Susan

F. Dent, MD, of the Ottawa Hospital Cancer Centre in Canada. Metformin May reduce risk of Developing Breast Cancer A meta-analysis of published studies found that metformin use in women with diabetes is associated with a 17% lower

risk of developing invasive breast cancer (Abstract 25).3 The analysis identified 443 studies, of which 7 (all observational) met study criteria. Diabetic women taking metformin experienced an overall 17% reduction in the risk of breast cancer. The risk reduction was 25% for those taking the drug for more than 3 years,

and 6% when exposure was 3 years or less. Older studies (prior to 1997) also found a greater association. “Because this finding is based upon observational studies, it may reflect bias or confounding,” acknowledged Rowan T. Chlebowski, MD, PhD, of the David Continued on page 10

Important Safety Information (cont) t Treat mild to moderate dermatitis (e.g., localized rash and pruritus) symptomatically. Administer topical or systemic corticosteroids if there is no improvement within 1 week Immune-mediated Neuropathies: t In the pivotal Phase 3 study in YERVOY-treated patients, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported t Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported t Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-Barré–like syndromes t Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe neuropathies. Withhold YERVOY in patients with moderate neuropathy (not interfering with daily activities) Immune-mediated Endocrinopathies: t In the pivotal Phase 3 study in YERVOY-treated patients, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3-4) occurred in 9 (1.8%) patients – All 9 patients had hypopituitarism, and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism – 6 of the 9 patients were hospitalized for severe endocrinopathies t Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) YERVOY-treated patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and 1 case each of hyperthyroidism and Cushing’s syndrome t Median time to onset of moderate to severe immunemediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY t Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism – Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms should be considered immune-mediated

– Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland t Withhold YERVOY in symptomatic patients. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) and initiate appropriate hormone replacement therapy. Long-term hormone replacement therapy may be necessary Other Immune-mediated Adverse Reactions, Including Ocular Manifestations: t In the pivotal Phase 3 study in YERVOY-treated patients, clinically significant immune-mediated adverse reactions seen in <1% were: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia t Across the clinical development program for YERVOY, immune-mediated adverse reactions also reported with <1% incidence were: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis t Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids (1-2 mg/kg/day of prednisone or equivalent) for severe immune-mediated adverse reactions t Administer corticosteroid eye drops for uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease unresponsive to local immunosuppressive therapy Pregnancy & Nursing: t YERVOY is classified as pregnancy category C. There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus t Human IgG1 is known to cross the placental barrier and YERVOY is an IgG1; therefore, YERVOY has the potential to be transmitted from the mother to the developing fetus t It is not known whether YERVOY is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY Common Adverse Reactions: t The most common adverse reactions (≥5%) in patients who received YERVOY at 3 mg/kg were fatigue (41%), diarrhea (32%), pruritus (31%), rash (29%), and colitis (8%)

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Conference News Highlights From Breast Cancer Symposium Continued from page 9 Geffen School of Medicine at the University of California Los Angeles. â&#x20AC;&#x153;But the finding of a stronger effect size associated with studies of longer duration of metformin use and those that had longer observation periods suggest that the finding may be real. If the result is confirmed in prospective studies with

a large number of breast cancer events, clinical trials should assess whether metformin can reduce breast cancer risk.â&#x20AC;? Statin Use Ameliorates risk of Bone Metastasis The use of statins was associated with a reduced risk of bone metastases in

breast cancer and improved disease-free survival (Abstract 40).4 The study, by investigators from Albert Einstein Medical Center in Philadelphia, Pennsylvania, was a retrospective review of 841 stage I to III breast cancer patients, stratified according to the use of statins for 3 months or longer. Patients who used statins had

YERVOYâ&#x201E;˘ (ipilimumab) Injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert. WARNING: IMMUNE-MEDIATED ADVERSE REACTIONS YERVOY (ipilimumab) can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of YERVOY. Permanently discontinue YERVOY and initiate systemic high-dose corticosteroid therapy for severe immune-mediated reactions. [See Dosage and Administration (2.2) in Full Prescribing Information] Assess patients for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and evaluate clinical chemistries including liver function tests and thyroid function tests at baseline and before each dose. [See Warnings and Precautions] INDICATIONS AND USAGE YERVOY (ipilimumab) is indicated for the treatment of unresectable or metastatic melanoma. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS YERVOY can result in severe and fatal immune-mediated reactions due to T-cell activation and proliferation. [See Boxed Warning] Immune-mediated Enterocolitis In Study 1, severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3â&#x20AC;&#x201C;5) immune-mediated enterocolitis occurred in 34 (7%) YERVOY-treated patients, and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 (5%) YERVOY-treated patients. Across all YERVOY-treated patients (n=511), 5 (1%) patients developed intestinal perforation, 4 (0.8%) patients died as a result of complications, and 26 (5%) patients were hospitalized for severe enterocolitis. The median time to onset was 7.4 weeks (range 1.6â&#x20AC;&#x201C;13.4) and 6.3 weeks (range 0.3â&#x20AC;&#x201C;18.9) after the initiation of YERVOY for patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis and with Grade 2 enterocolitis, respectively. Twenty-nine patients (85%) with Grade 3â&#x20AC;&#x201C;5 enterocolitis were treated with high-dose (â&#x2030;Ľ40 mg prednisone equivalent per day) corticosteroids, with a median dose of 80 mg/day of prednisone or equivalent; the median duration of treatment was 2.3 weeks (ranging up to 13.9 weeks) followed by corticosteroid taper. Of the 28 patients with moderate enterocolitis, 46% were not treated with systemic corticosteroids, 29% were treated with <40 mg prednisone or equivalent per day for a median duration of 5.1 weeks, and 25% were treated with high-dose corticosteroids for a median duration of 10 days prior to corticosteroid taper. Infliximab was administered to 5 of the 62 patients (8%) with moderate, severe, or life-threatening immune-mediated enterocolitis following inadequate response to corticosteroids. Of the 34 patients with Grade 3â&#x20AC;&#x201C;5 enterocolitis, 74% experienced complete resolution, 3% experienced improvement to Grade 2 severity, and 24% did not improve. Among the 28 patients with Grade 2 enterocolitis, 79% experienced complete resolution, 11% improved, and 11% did not improve. Monitor patients for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus). In symptomatic patients, rule out infectious etiologies and consider endoscopic evaluation for persistent or severe symptoms. Permanently discontinue YERVOY in patients with severe enterocolitis and initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least one month. In clinical trials, rapid corticosteroid tapering resulted in recurrence or worsening symptoms of enterocolitis in some patients. Withhold YERVOY dosing for moderate enterocolitis; administer anti-diarrheal treatment and, if persistent for more than one week, initiate systemic corticosteroids at a dose of 0.5 mg/kg/day prednisone or equivalent. [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Hepatitis In Study 1, severe, life-threatening, or fatal hepatotoxicity (AST or ALT elevations of more than 5 times the upper limit of normal or total bilirubin elevations more than 3 times the upper limit of normal; Grade 3â&#x20AC;&#x201C;5) occurred in 8 (2%) YERVOY-treated patients, with fatal hepatic failure in 0.2% and hospitalization in 0.4% of YERVOY-treated patients. An additional 13 (2.5%) patients experienced moderate hepatotoxicity manifested by liver function test abnormalities (AST or ALT elevations of more than 2.5 times but not more than 5 times the upper limit of normal or total bilirubin elevation of more than 1.5 times but not more than 3 times the upper limit of normal; Grade 2). The underlying pathology was not ascertained in all patients but in some instances included immune-mediated hepatitis. There were insufficient numbers of patients with biopsyproven hepatitis to characterize the clinical course of this event.

Seven (54%) YERVOY-treated patients with severe dermatitis received high-dose corticosteroids (median dose 60 mg prednisone/day or equivalent) for up to 14.9 weeks followed by corticosteroid taper. Of these 7 patients, 6 had complete resolution; time to resolution ranged up to 15.6 weeks. Of the 63 patients with moderate dermatitis, 25 (40%) were treated with systemic corticosteroids (median of 60 mg/day of prednisone or equivalent) for a median of 2.1 weeks, 7 (11%) were treated with only topical corticosteroids, and 31 (49%) did not receive systemic or topical corticosteroids. Forty-four (70%) patients with moderate dermatitis were reported to have complete resolution, 7 (11%) improved to mild (Grade 1) severity, and 12 (19%) had no reported improvement. Monitor patients for signs and symptoms of dermatitis such as rash and pruritus. Unless an alternate etiology has been identified, signs or symptoms of dermatitis should be considered immune-mediated. Permanently discontinue YERVOY in patients with Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations. Administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When dermatitis is controlled, corticosteroid tapering should occur over a period of at least 1 month. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. [See Dosage and Administration (2.2) in Full Prescribing Information] For mild to moderate dermatitis, such as localized rash and pruritus, treat symptomatically. Administer topical or systemic corticosteroids if there is no improvement of symptoms within 1 week. Immune-mediated Neuropathies In Study 1, one case of fatal Guillain-BarrĂŠ syndrome and one case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-BarrĂŠ syndrome have been reported. Monitor for symptoms of motor or sensory neuropathy such as unilateral or bilateral weakness, sensory alterations, or paresthesia. Permanently discontinue YERVOY in patients with severe neuropathy (interfering with daily activities) such as Guillain-BarrĂŠ-like syndromes. Institute medical intervention as appropriate for management of severe neuropathy. Consider initiation of systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe neuropathies. Withhold YERVOY dosing in patients with moderate neuropathy (not interfering with daily activities). [See Dosage and Administration (2.2) in Full Prescribing Information] Immune-mediated Endocrinopathies In Study 1, severe to life-threatening immune-mediated endocrinopathies (requiring hospitalization, urgent medical intervention, or interfering with activities of daily living; Grade 3â&#x20AC;&#x201C;4) occurred in 9 (1.8%) YERVOY-treated patients. All 9 patients had hypopituitarism and some had additional concomitant endocrinopathies such as adrenal insufficiency, hypogonadism, and hypothyroidism. Six of the 9 patients were hospitalized for severe endocrinopathies. Moderate endocrinopathy (requiring hormone replacement or medical intervention; Grade 2) occurred in 12 (2.3%) patients and consisted of hypothyroidism, adrenal insufficiency, hypopituitarism, and one case each of hyperthyroidism and Cushingâ&#x20AC;&#x2122;s syndrome. The median time to onset of moderate to severe immune-mediated endocrinopathy was 11 weeks and ranged up to 19.3 weeks after the initiation of YERVOY. Of the 21 patients with moderate to life-threatening endocrinopathy, 17 patients required long-term hormone replacement therapy including, most commonly, adrenal hormones (n=10) and thyroid hormones (n=13). Monitor patients for clinical signs and symptoms of hypophysitis, adrenal insufficiency (including adrenal crisis), and hyper- or hypothyroidism. Patients may present with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific symptoms which may resemble other causes such as brain metastasis or underlying disease. Unless an alternate etiology has been identified, signs or symptoms of endocrinopathies should be considered immune-mediated. Monitor thyroid function tests and clinical chemistries at the start of treatment, before each dose, and as clinically indicated based on symptoms. In a limited number of patients, hypophysitis was diagnosed by imaging studies through enlargement of the pituitary gland. Withhold YERVOY dosing in symptomatic patients. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent, and initiate appropriate hormone replacement therapy. [See Dosage and Administration (2.2) in Full Prescribing Information] Other Immune-mediated Adverse Reactions, Including Ocular Manifestations The following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients in Study 1: nephritis, pneumonitis, meningitis, pericarditis, uveitis, iritis, and hemolytic anemia. Across the clinical development program for YERVOY, the following likely immune-mediated adverse reactions were also reported with less than 1% incidence: myocarditis, angiopathy, temporal arteritis, vasculitis, polymyalgia rheumatica, conjunctivitis, blepharitis, episcleritis, scleritis, leukocytoclastic vasculitis, erythema multiforme, psoriasis, pancreatitis, arthritis, and autoimmune thyroiditis. Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immunemediated adverse reactions. Administer corticosteroid eye drops to patients who develop uveitis, iritis, or episcleritis. Permanently discontinue YERVOY for immune-mediated ocular disease that is unresponsive to local immunosuppressive therapy. [See Dosage and Administration (2.2) in Full Prescribing Information]

Permanently discontinue YERVOY in patients with Grade 3â&#x20AC;&#x201C;5 hepatotoxicity and administer systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent. When liver function tests show sustained improvement or return to baseline, initiate corticosteroid tapering and continue to taper over 1 month. Across the clinical development program for YERVOY, mycophenolate treatment has been administered in patients who have persistent severe hepatitis despite high-dose corticosteroids. Withhold YERVOY in patients with Grade 2 hepatotoxicity. [See Dosage and Administration (2.2) in Full Prescribing Information]

ADVERSE REACTIONS

In Study 1, severe, life-threatening, or fatal immune-mediated dermatitis (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; Grade 3â&#x20AC;&#x201C;5) occurred in 13 (2.5%) YERVOY-treated patients. One (0.2%) patient died as a result of toxic epidermal necrolysis and one additional patient required hospitalization for severe dermatitis. There were 63 (12%) patients with moderate (Grade 2) dermatitis.

OCTOBER 2012 I VOL 5, NO 7

The median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3.1 weeks and ranged up to 17.3 weeks from the initiation of YERVOY (ipilimumab).

Monitor liver function tests (hepatic transaminase and bilirubin levels) and assess patients for signs and symptoms of hepatotoxicity before each dose of YERVOY. In patients with hepatotoxicity, rule out infectious or malignant causes and increase frequency of liver function test monitoring until resolution.

Immune-mediated Dermatitis

a 51% reduction in metastasis to the bone, but not to other sites. Their median disease-free survival was 63.6 months versus 53.9 months among nonusers. Gentry T. King, MD, explained that the mevalonic acid pathway has been implicated in the promotion of a microenvironment for bony metastasis

The following adverse reactions are discussed in greater detail in other sections of the labeling.

t *NNVOF NFEJBUFE FOUFSPDPMJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE IFQBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE EFSNBUJUJT [see Warnings and Precautions].

t *NNVOF NFEJBUFE OFVSPQBUIJFT [see Warnings and Precautions].

t *NNVOF NFEJBUFE FOEPDSJOPQBUIJFT [see Warnings and Precautions].

t 0 UIFS JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT JODMVEJOH PDVMBS NBOJGFTUBUJPOT [see Warnings and Precautions].

Pub:

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Conference News Highlights From Breast Cancer Symposium from breast cancer. The statins, which act on this pathway, have in vitro antineoplastic and antiosteoclast activity against breast cancer through interference with this pathway. â&#x20AC;&#x153;I would not yet prescribe a statin for the purpose of reducing bone metastasis risk,â&#x20AC;? he said, â&#x20AC;&#x153;but if patients are al-

ready on them, because of the possible protective effect, I would certainly not take the patient off the statin.â&#x20AC;? â&#x2014;? references 1. Rugo HS, Palli S, Grabner M, et al. The impact of 5HT3RA antiemetics on the incidence of chemotherapy-induced nausea and vomiting (CINV), treatment adherence, and delay of therapy in early-stage breast

cancer (BC) patients treated with moderately/highly emetogenic chemotherapy (MEC/HEC). Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 75. 2. Dent SF, Crawley FL, Graham NA, et al. Vascular toxicities of endocrine therapy in early-stage breast cancer: encouraging observations in a nontribal setting. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 68.

Clinical Trials Experience

Immunogenicity

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared with rates in other clinical trials or experience with therapeutics in the same class and may not reflect the rates observed in clinical practice.

In clinical studies, 1.1% of 1024 evaluable patients tested positive for binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay. This assay has substantial limitations in detecting anti-ipilimumab antibodies in the presence of ipilimumab. Infusion-related or peri-infusional reactions consistent with hypersensitivity or anaphylaxis were not reported in these 11 patients nor were neutralizing antibodies against ipilimumab detected.

The clinical development program excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation. Exposure to YERVOY (ipilimumab) 3 mg/kg for four doses given by intravenous infusion in previously treated patients with unresectable or metastatic melanoma was assessed in a randomized, double-blind clinical study (Study 1). [See Clinical Studies (14) in Full Prescribing Information] One hundred thirty-one patients (median age 57 years, 60% male) received YERVOY as a single agent, 380 patients (median age 56 years, 61% male) received YERVOY with an investigational gp100 peptide vaccine (gp100), and 132 patients (median age 57 years, 54% male) received gp100 peptide vaccine alone. Patients in the study received a median of 4 doses (range 1 to 4 doses). YERVOY was discontinued for adverse reactions in 10% of patients. The most common adverse reactions (â&#x2030;Ľ5%) in patients who received YERVOY at 3 mg/kg were fatigue, diarrhea, pruritus, rash, and colitis. Table 1 presents selected adverse reactions from Study 1, which occurred in at least 5% of patients in the YERVOY-containing arms and with at least 5% increased incidence over the control gp100 arm for all-grade events and at least 1% incidence over the control group for Grade 3â&#x20AC;&#x201C;5 events. Table 1:

Percentage (%) of YERVOY 3 mg/kg n=131

Gastrointestinal Disorders Diarrhea Colitis Skin and Subcutaneous Tissue Disorders Pruritus Rash General Disorders and Administration Site Conditions Fatigue a

YERVOY 3 mg/kg+gp100 n=380

gp100 n=132

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

Any Grade

Grade 3â&#x20AC;&#x201C;5

32 8

5 5

37 5

4 3

20 2

1 0

31 29

0 2

21 25

<1 2

11 8

0 0

No formal drug-drug interaction studies have been conducted with YERVOY (ipilimumab). USE IN SPECIFIC POPULATIONS Pregnancy

In a combined study of embryo-fetal and peri-postnatal development, severe toxicities including increased incidences of third-trimester abortion, stillbirth, premature delivery, low birth weight, and infant mortality occurred following intravenous administration of ipilimumab to pregnant cynomolgus monkeys every 21 days from the onset of organogenesis through parturition at doses of 2.6 or 7.2 times the recommended human dose of 3 mg/kg (by AUC). [See Nonclinical Toxicology (13.2) in Full Prescribing Information] In genetically engineered mice in which the gene for CTLA-4 has been deleted (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?), offspring lacking CTLA-4 were born apparently healthy, but died within 3â&#x20AC;&#x201C;4 weeks due to multi-organ infiltration and damage by lymphocytes. Human IgG1 is known to cross the placental barrier and ipilimumab is an IgG1; therefore, ipilimumab has the potential to be transmitted from the mother to the developing fetus.

Have you had experience in determining the appropriate chemotherapy dose for patients who are obese?

Nursing Mothers

Table 2 presents the per-patient incidence of severe, life-threatening, or fatal immune-mediated adverse reactions from Study 1. Severe to Fatal Immune-mediated Adverse Reactions in Study 1 Percentage (%) of Patients

Any Immune-mediated Adverse Reaction Enterocolitisa,b Hepatotoxicitya Dermatitisa Neuropathya Endocrinopathy Hypopituitarism Adrenal insufficiency Other Pneumonitis Meningitis Nephritis Eosinophiliac Pericarditisa,c

YERVOY 3 mg/kg n=131

YERVOY 3 mg/kg+gp100 n=380

15 7 1 2 1 4 4 0

12 7 2 3 <1 1 1 1

0 0 1 1 0

<1 <1 0 0 <1

It is not known whether ipilimumab is secreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from YERVOY, a decision should be made whether to discontinue nursing or to discontinue YERVOY, taking into account the importance of YERVOY to the mother.

Safety and effectiveness of YERVOY have not been established in pediatric patients. Geriatric Use Of the 511 patients treated with YERVOY at 3 mg/kg, 28% were 65 years and over. No overall differences in safety or efficacy were reported between the elderly patients (65 years and over) and younger patients (less than 65 years). Renal Impairment No formal studies of YERVOY in patients with renal impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] Hepatic Impairment No formal studies of YERVOY in patients with hepatic impairment have been conducted. [See Clinical Pharmacology (12.3) in Full Prescribing Information] OVERDOSAGE There is no information on overdosage with YERVOY. PATIENT COUNSELING INFORMATION See MEDICATION GUIDE in Full Prescribing Information. t *OGPSN QBUJFOUT PG UIF QPUFOUJBM SJTL PG JNNVOF NFEJBUFE BEWFSTF SFBDUJPOT t "EWJTF QBUJFOUT UP SFBE UIF :&370: .FEJDBUJPO (VJEF CFGPSF FBDI :&370: JOGVTJPO t "EWJTF XPNFO UIBU :&370: NBZ DBVTF GFUBM IBSN t "EWJTF OVSTJOH NPUIFST OPU UP CSFBTU GFFE XIJMF UBLJOH :&370:

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

Including fatal outcome. b Including intestinal perforation. c Underlying etiology not established. Across clinical studies that utilized YERVOY doses ranging from 0.3 to 10 mg/kg, the following adverse reactions were also reported (incidence less than 1% unless otherwise noted): urticaria (2%), large intestinal ulcer, esophagitis, acute respiratory distress syndrome, renal failure, and infusion reaction. Based on the experience in the entire clinical program for melanoma, the incidence and severity of enterocolitis and hepatitis appear to be dose dependent.

TRIM 7.25" x 9.75"

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r Yes r No

Pediatric Use

Reader Poll

DRUG INTERACTIONS

There are no adequate and well-controlled studies of YERVOY in pregnant women. Use YERVOY during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Patientsa

Incidences presented in this table are based on reports of adverse events regardless of causality.

Table 2:

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to YERVOY with the incidences of antibodies to other products may be misleading.

Pregnancy Category C

Selected Adverse Reactions in Study 1

System Organ Class/ Preferred Term

Because trough levels of ipilimumab interfere with the ECL assay results, a subset analysis was performed in the dose cohort with the lowest trough levels. In this analysis, 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg dose, tested positive for binding antibodies against ipilimumab.

3. Col N, Ochs L, Springmann V, et al. Metformin and breast cancer risk: a meta-analysis and critical literature review. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 25. 4. King GT, Yun JH, Chae YK, et al. Statin use and the development of bone metastasis in breast cancer patients. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 40.

1281558A2

IP-B0001A-03-11

Issued: March 2011

Pub:

Go to www.TheOncology Pharmacist.com to cast your vote and add your comments. Please tell us about your experiences with obese patients and how you determine appropriate chemotherapy dosing. OCTOBER 2012 I VOL 5, NO 7

Ovarian Cancer Bevacizumab in the Treatment of Advanced Ovarian Cancer Continued from cover in the treatment of recurrent and/or refractory ovarian cancer.3,4 In 2011, results were published from 2 large phase 3 randomized trials (GOG 2185 and ICON76) exploring bevacizumab as first-line therapy. Around the same time, a cost-benefit study involving bevacizumab was reported. This article reviews these latest advances in managing ovarian cancer.

In 2011, results were published from 2 large phase 3 randomized trials (GOG 218 and ICON7) exploring bevacizumab as first-line therapy.

Clinical Trials

GOG 218 Trial5 The Gynecologic Oncology Group 218 (GOG 218) trial was a doubleblind, placebo-controlled, randomized phase 3 trial in patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian, primary peritoneal, or fallopian tube cancer. Additional eligibility criteria included maximal debulking surgery within 12 weeks, a GOG performance score of 0 to 2, and no history of clinically significant vascular events or evidence of intestinal obstruction. A total of 1873 patients post surgical debulking were randomized into 3 groups. Group 1 (control group, n = 625) received IV paclitaxel 175 mg/m2 and carboplatin AUC 6 every 3 weeks in cycles 1 through 6, plus placebo in cycles 2 through 22. Table

ICON7 Trial6 The International Collaboration on Ovarian Neoplasms 7 (ICON7) trial, conducted by the Gynecologic Cancer InterGroup, was a randomized trial in patients with newly diagnosed, highrisk, early-stage or advanced epithelial ovarian, primary peritoneal, or fallopi-

counts for 30% of this patient population, revealed statistically significant differences of OS between the bevacizumab group and the chemotherapy group (HR, 0.64; CI, 0.48-0.85; P = .002). As in the GOG 218 trial, QOL was improved in both groups, but the difference was not significant.

At 36 months after randomization, progression-free survival in the bevacizumab group was 21.8 months, significantly longer than the 20.3 months in the chemotherapy group. an tube cancer. Unlike the GOG 218 study, this study did not use a placebo or double-blind approach. Patients were randomized to receive IV paclitaxel 175 mg/m2 and carboplatin AUC 5 or 6 every 3 weeks for 6 cycles (n = 764), or chemotherapy with concurrent bevacizumab 7.5 mg/kg every 3 weeks for 5 or 6 cycles, followed by another 12 cycles or until disease progression (n = 764). The primary end point was PFS; 70% of patients were stage IIIC or IV. More than 90% of patients in both groups completed chemotherapy, and those patients in the bevacizumab group who began chemotherapy more than 4 weeks after surgery received a median of 17 cycles of bevacizumab. After disease progression, only 3% of patients received further antiangiogenic treatment. At 36 months after randomization, PFS in the bevacizumab group was 21.8 months, significantly longer than the 20.3 months in the chemotherapy group (HR, 0.81; CI, 0.70-0.94; P = .004). The median OS was not reached. However, an updated subgroup analysis of patients at high risk for progression, which ac-

Cost-effectiveness Analysis7 Bevacizumab is a high-cost drug, currently priced at $2801.52/400 mg.8 Based on preliminary results, Cohn and colleagues conducted a cost-effectiveness analysis comparing the 3 treatment arms of the GOG 218 study. Actual and estimated costs of treatment and the potential cost of complications in each arm were included for analysis. The incremental cost-effectiveness ratio (ICER) per progression-free life-year saved (PF-LYS) was estimated. For 600 patients evaluated on each arm, the cost of chemotherapy alone was $2.5 million, which was significantly increased to $78.3 million when bevacizumab was added to chemotherapy for 16 cycles. These costs resulted in an ICER of $401,088 per PF-LYS for patients in the bevacizumab-throughout group. Sensitivity analysis revealed that if the cost of bevacizumab were decreased by 25%, the ICER per PF-LYS dropped to below $100,000 for the bevacizumab-throughout arm. The authors concluded that in the GOG 218 trial, adding bevacizumab to chemotherapy in the treatment of Continued on page 16

Comparison Between GOG 218 and ICON7 Trials

Study GOG 218

ICON7

Group 2 (bevacizumab-initiation group, n = 625) received the same chemotherapy plus bevacizumab 15 mg/kg in cycles 2 through 6, plus placebo in cycles 7 through 22. Group 3 (bevacizumab-throughout group, n = 623) received chemotherapy plus bevacizumab in cycles 2 through 22. The primary end point, initially overall survival (OS), was modified to progression-free survival (PFS). Only 19% of patients overall completed the planned treatment (16%, 17%, and 24% in the control, bevacizumab-initiation, and bevacizumab-throughout groups, respectively). After a median follow-up of 17.4 months, the median PFS was 10.3 months in the control group, 11.2 months in the bevacizumab-initiation group, and 14.1 months in the bevacizumab-throughout group. The difference in progression or death was statistically significant between the bevacizumabthroughout group and the control group (hazard ratio [HR], 0.717; 95% confidence interval [CI], 0.625-0.824; P <.001) but not between the bevacizumab-initiation group and the control group (HR, 0.908; 95% CI, 0.7951.040; P = .16). The OS was 39.3 months, 38.7 months, and 39.7 months for the control group, bevacizumabinitiation group, and bevacizumabthroughout group, respectively; there was no significant difference between either of the bevacizumab-treated groups and the control group. Updated data analyses of PFS and OS after 47% of the patients had died were consistent with those from original analyses. Quality of life (QOL) was similar among different groups. Hypertension requiring therapy was more often seen in the bevacizumab-initiation group (16.5%) and bevacizumab-throughout group (22.9%) than in the control group (7.2%).

Study Sample Treatment Design Size Double-blind, 1873 Control: placeboPAC + CAR × 6 cycles AND controlled, placebo × 21 cycles; randomized trial BEV-initiation: PAC + CAR × 6 cycles PLUS BEV × 5 cycles, followed by placebo × 16 cycles; BEV-throughout: PAC + CAR × 6 cycles PLUS BEV × 21 cycles

OCTOBER 2012 I VOL 5, NO 7

7.5 mg/kg Control: every 3 weeks PAC + CAR × 6 cycles; BEV: PAC + CAR × 6 cycles PLUS BEV × 18 cycles or until progression

Primary End Point OS initially, changed to PFS

Results PFS: 10.3, 11.2, and 14.1 mo for control, BEV-initiation and BEV-throughout groups, respectively. HR of progression or death in the BEV-throughout group significantly lower vs control (HR, 0.717; P <.001). OS: 39.3, 38.7, and 39.7 mo for control, BEVinitiation and BEV-throughout groups, respectively. (Did not reach statistical significance.)

PFS: 20.3 vs 21.8 mo for control and BEV groups. (HR, 0.81; P = .004) OS: not yet reached High risk for progression group: PFS: 14.5 vs 18.1 mo (control vs BEV) (HR, 0.73; P = .002) OS: 28.8 vs 36.6 mo (HR, 0.64; P = .002) Abbreviations: BEV, bevacizumab; CAR, carboplatin; HR, hazard ratio; mo, month; OS, overall survival; PAC, paclitaxel; PFS, progression-free survival.

Randomized trial 1528

Bevacizumab Dose 15 mg/kg every 3 weeks

PFS

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For appropriate patients receiving highly emetogenic chemotherapy who are at risk of chemotherapy-induced nausea and vomiting (CINV)

PREVENTION BEGINS WHERE TRIPLE THERAPY STARTS

On Cycle 1, Day 1, start with Triple Therapy—EMEND® (fosaprepitant dimeglumine) for Injection, a 5-HT3 antagonist, and a corticosteroid—for first-line prevention of CINV. EMEND for Injection, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. EMEND for Injection has not been studied for treatment of established nausea and vomiting. Chronic continuous administration of EMEND for Injection is not recommended.

Selected Important Safety Information t EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions. t Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor. Because fosaprepitant is rapidly converted to aprepitant, neither drug should be used concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions. t EMEND for Injection should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND for Injection could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND for Injection is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND for Injection is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant. t Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND® (aprepitant) was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine. t Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

Selected Important Safety Information (continued) t There have been isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. It is not recommended to reinitiate the infusion in patients who have experienced these symptoms during first-time use. t Coadministration of EMEND for Injection with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND for Injection with each chemotherapy cycle. t The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND for Injection. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND for Injection. t Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. t In clinical trials of EMEND® (aprepitant) in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence of 1% or greater were hiccups (4.6% EMEND vs 2.9% standard therapy), asthenia/fatigue (2.9% vs 1.6%), increased ALT (2.8% vs 1.5%), increased AST (1.1% vs 0.9%), constipation (2.2% vs 2.0%), dyspepsia (1.5% vs 0.7%), diarrhea (1.1% vs 0.9%), headache (2.2% vs 1.8%), and anorexia (2.0% vs 0.5%). t In a clinical trial evaluating safety of the 1-day regimen of EMEND for Injection 150 mg compared with the 3-day regimen of EMEND, the safety profile was generally similar to that seen in prior highly emetogenic chemotherapy studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients who received fosaprepitant (3.0%) than in those who received aprepitant (0.5%). Those infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. Please see the adjacent Brief Summary of the Prescribing Information.

An antiemetic regimen including

INDICATIONS AND USAGE EMEND for Injection is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in adults for use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) including high-dose cisplatin. Limitations of Use: EMEND for Injection has not been studied for the treatment of established nausea and vomiting. Chronic continuous administration is not recommended [see Warnings and Precautions].

EMENDÂŽ (fosaprepitant dimeglumine) for Injection

Brief Summary of the Prescribing Information for

CONTRAINDICATIONS Hypersensitivity: EMEND for Injection is contraindicated in patients who are hypersensitive to EMEND for Injection, aprepitant, polysorbate 80, or any other components of the product. Known hypersensitivity reactions include flushing, erythema, dyspnea, and anaphylactic reactions [see Adverse Reactions]. Concomitant Use With Pimozide or Cisapride: Aprepitant, when administered orally, is a moderate cytochrome P450 isoenzyme 3A4 (CYP3A4) inhibitor following the 3-day antiemetic dosing regimen for CINV. Since fosaprepitant is rapidly converted to aprepitant, do not use fosaprepitant concurrently with pimozide or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions [see Drug Interactions]. WARNINGS AND PRECAUTIONS CYP3A4 Interactions: Fosaprepitant is rapidly converted to aprepitant, which is a moderate inhibitor of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Fosaprepitant should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by aprepitant or fosaprepitant could result in elevated plasma concentrations of these concomitant medications. When fosaprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When aprepitant is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant [see Drug Interactions]. Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, the oral aprepitant regimen was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, no clinically significant change in docetaxel or vinorelbine pharmacokinetics was observed when the oral aprepitant regimen was coadministered. Due to the small number of patients in clinical studies who received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied [see Drug Interactions]. Hypersensitivity Reactions: Isolated reports of immediate hypersensitivity reactions including flushing, erythema, dyspnea, and anaphylaxis have occurred during infusion of fosaprepitant. These hypersensitivity reactions have generally responded to discontinuation of the infusion and administration of appropriate therapy. Reinitiation of the infusion is not recommended in patients who experience these symptoms during first-time use. Coadministration With Warfarin (a CYP2C9 substrate): Coadministration of fosaprepitant or aprepitant with warfarin may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle [see Drug Interactions]. Coadministration With Hormonal Contraceptives: Upon coadministration with fosaprepitant or aprepitant, the efficacy of hormonal contraceptives may be reduced during and for 28 days following the last dose of either fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant [see Drug Interactions]. Chronic Continuous Use: Chronic continuous use of EMEND for Injection for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use. ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Since EMEND for Injection is converted to aprepitant, those adverse reactions associated with aprepitant might also be expected to occur with EMEND for Injection. The overall safety of fosaprepitant was evaluated in approximately 1,100 individuals and the overall safety of aprepitant was evaluated in approximately 6,500 individuals. Oral Aprepitant: Highly Emetogenic Chemotherapy (HEC): In 2 well-controlled clinical trials in patients receiving highly emetogenic cancer chemotherapy, 544 patients were treated with aprepitant during Cycle 1 of chemotherapy and 413 of these patients continued into the multiple-cycle extension for up to 6 cycles of chemotherapy. Oral aprepitant was given in combination with ondansetron and dexamethasone. In Cycle 1, adverse reactions were reported in approximately 17% of patients treated with the aprepitant regimen compared with approximately 13% of patients treated with standard therapy. Treatment was discontinued due to adverse reactions in 0.6% of patients treated with the aprepitant regimen compared with 0.4% of patients treated with standard therapy. The most common adverse reactions reported in patients treated with the aprepitant regimen (n=544) with an incidence of >1% and greater than with standard therapy (n=550), respectively, are listed below: Respiratory system: hiccups 4.6 vs 2.9 Body as a whole/Site unspecified: asthenia/fatigue 2.9 vs 1.6 Investigations: increased ALT 2.8 vs 1.5, increased AST 1.1 vs 0.9 Digestive system: constipation 2.2 vs 2.0, dyspepsia 1.5 vs 0.7, diarrhea 1.1 vs 0.9 Nervous system: headache 2.2 vs 1.8 Metabolism and nutrition: anorexia 2.0 vs 0.5 A listing of adverse reactions in the aprepitant regimen (incidence <1%) that occurred at a greater incidence than with standard therapy are presented in the Less Common Adverse Reactions subsection below. In an additional active-controlled clinical study in 1,169 patients receiving aprepitant and HEC, the adverseexperience profile was generally similar to that seen in the other HEC studies with aprepitant. Less Common Adverse Reactions: Adverse reactions reported in either HEC or moderately emetogenic chemotherapy (MEC) studies in patients treated with the aprepitant regimen with an incidence of <1% and greater than with standard therapy are listed below. Infection and infestations: candidiasis, staphylococcal infection Blood and lymphatic system disorders: anemia, febrile neutropenia Metabolism and nutrition disorders: weight gain, polydipsia Psychiatric disorders: disorientation, euphoria, anxiety Nervous system disorders: dizziness, dream abnormality, cognitive disorder, lethargy, somnolence Eye disorders: conjunctivitis Ear and labyrinth disorders: tinnitus Cardiac disorders: bradycardia, cardiovascular disorder, palpitations

Vascular disorders: hot flush, flushing Respiratory, thoracic, and mediastinal disorders: pharyngitis, sneezing, cough, postnasal drip, throat irritation Gastrointestinal disorders: nausea, acid reflux, dysgeusia, epigastric discomfort, obstipation, gastroesophageal reflux disease, perforating duodenal ulcer, vomiting, abdominal pain, dry mouth, abdominal distension, hard feces, neutropenic colitis, flatulence, stomatitis Skin and subcutaneous tissue disorders: rash, acne, photosensitivity, hyperhidrosis, oily skin, pruritus, skin lesion Musculoskeletal and connective tissue disorders: muscle cramp, myalgia, muscular weakness Renal and urinary disorders: polyuria, dysuria, pollakiuria General disorders and administration site conditions: edema, chest discomfort, malaise, thirst, chills, gait disturbance Investigations: increased alkaline phosphatase, hyperglycemia, microscopic hematuria, hyponatremia, decreased weight, decreased neutrophil count In another chemotherapy-induced nausea and vomiting (CINV) study, Stevens-Johnson syndrome was reported as a serious adverse reaction in a patient receiving aprepitant with cancer chemotherapy. The adverse-experience profiles in the multiple-cycle extensions of HEC studies for up to 6 cycles of chemotherapy were similar to that observed in Cycle 1. Fosaprepitant: In an active-controlled clinical study in patients receiving HEC, safety was evaluated for 1,143 patients receiving the 1-day regimen of EMEND for Injection 150 mg compared with 1,169 patients receiving the 3-day regimen of EMEND. The safety profile was generally similar to that seen in prior HEC studies with aprepitant. However, infusion-site reactions occurred at a higher incidence in patients in the fosaprepitant group (3.0%) compared with those in the aprepitant group (0.5%). The reported infusion-site reactions included infusion-site erythema, infusion-site pruritus, infusion-site pain, infusion-site induration, and infusion-site thrombophlebitis. The following additional adverse reactions occurred with fosaprepitant 150 mg and were not reported with the oral aprepitant regimen in the corresponding section above: General disorders and administration site conditions: infusion-site erythema, infusion-site pruritus, infusion-site induration, infusion-site pain Investigations: increased blood pressure Skin and subcutaneous tissue disorders: erythema Vascular disorders: thrombophlebitis (predominantly infusion-site thrombophlebitis) Other Studies: Angioedema and urticaria were reported as serious adverse reactions in a patient receiving aprepitant in a non-CINV/non-PONV study. Postmarketing Experience: The following adverse reactions have been identified during postapproval use of fosaprepitant and aprepitant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the drug. Skin and subcutaneous tissue disorders: pruritus, rash, urticaria, rarely Stevens-Johnson syndrome/toxic epidermal necrolysis Immune system disorders: hypersensitivity reactions including anaphylactic reactions DRUG INTERACTIONS Drug interactions following administration of fosaprepitant are likely to occur with drugs that interact with oral aprepitant. Aprepitant is a substrate, a moderate inhibitor, and an inducer of CYP3A4 when administered as a 3-day antiemetic dosing regimen for CINV. Aprepitant is also an inducer of CYP2C9. Fosaprepitant 150 mg, given as a single dose, is a weak inhibitor of CYP3A4 and does not induce CYP3A4. Fosaprepitant and aprepitant are unlikely to interact with drugs that are substrates for the P-glycoprotein transporter. The following information was derived from data with oral aprepitant, 2 studies conducted with fosaprepitant and oral midazolam, and 1 study conducted with fosaprepitant and dexamethasone. Effect of Fosaprepitant/Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 Substrates: Aprepitant, as a moderate inhibitor of CYP3A4, and fosaprepitant 150 mg, as a weak inhibitor of CYP3A4, can increase plasma concentrations of concomitantly coadministered oral medications that are metabolized through CYP3A4 [see Contraindications]. 5-HT3 antagonists: In clinical drug interaction studies, aprepitant did not have clinically important effects on the pharmacokinetics of ondansetron, granisetron, or hydrodolasetron (the active metabolite of dolasetron). Corticosteroids: Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0â&#x20AC;&#x201C;24hr of dexamethasone, administered as a single 8-mg oral dose on Days 1, 2, and 3, by approximately 2-fold on Days 1 and 2. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg I.V. on Day 1. An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 through 5, coadministered with 20-mg oral dexamethasone on Day 1 and 8-mg oral dexamethasone on Days 2 through 5, increased the AUC of dexamethasone by 2.2-fold on Days 1 and 5. The oral dexamethasone doses should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Methylprednisolone: An oral aprepitant regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3 increased the AUC of methylprednisolone by 1.34-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3. The intravenous methylprednisolone dose should be reduced by approximately 25% and the oral methylprednisolone dose should be reduced by approximately 50% when coadministered with a regimen of fosaprepitant 115 mg followed by aprepitant. Chemotherapeutic agents: Docetaxel: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of docetaxel [see Warnings and Precautions]. Vinorelbine: In a pharmacokinetic study, oral aprepitant (CINV regimen) did not influence the pharmacokinetics of vinorelbine to a clinically significant degree [see Warnings and Precautions]. Oral contraceptives: When oral aprepitant, ondansetron, and dexamethasone were coadministered with an oral contraceptive containing ethinyl estradiol and norethindrone, the trough concentrations of both ethinyl estradiol and norethindrone were reduced by as much as 64% for 3 weeks posttreatment. The coadministration of fosaprepitant or aprepitant may reduce the efficacy of hormonal contraceptives (these can include birth control pills, skin patches, implants, and certain IUDs) during and for 28 days after administration of the last dose of fosaprepitant or aprepitant. Alternative or backup methods of contraception should be used during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. Midazolam: Interactions between aprepitant or fosaprepitant and coadministered midazolam are listed below (increase is indicated as K, decrease as L, no change as ): Fosaprepitant 150 mg on Day 1, oral midazolam 2 mg on Days 1 and 4: AUC K 1.8-fold on Day 1 and AUC on Day 4 Fosaprepitant 100 mg on Day 1, oral midazolam 2 mg: oral midazolam AUC K 1.6-fold Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 to 5, oral midazolam 2 mg SD on Days 1 and 5: oral midazolam AUC K 2.3-fold on Day 1 and K 3.3-fold on Day 5 Oral aprepitant 125 mg on Day 1 and 80 mg on Days 2 and 3, intravenous midazolam 2 mg prior to 3-day

EMEND® (fosaprepitant dimeglumine) for Injection regimen of aprepitant and on Days 4, 8, and 15: intravenous midazolam AUC K 25% on Day 4, AUC L 19% on Day 8, and AUC L 4% on Day 15 Oral aprepitant 125 mg, intravenous midazolam 2 mg given 1 hour after aprepitant: intravenous midazolam AUC K 1.5-fold A difference of less than 2-fold increase of midazolam AUC was not considered clinically important. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant. CYP2C9 Substrates (Warfarin, Tolbutamide): Warfarin: A single 125-mg dose of oral aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S(–) warfarin determined on Day 3, there was a 34% decrease in S(–) warfarin trough concentration accompanied by a 14% decrease in the prothrombin time (reported as INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that inhibit CYP3A4 activity may result in increased plasma concentrations of aprepitant. Consequently, concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir) should be approached with caution. Because moderate CYP3A4 inhibitors (eg, diltiazem) result in a 2-fold increase in plasma concentrations of aprepitant, concomitant administration should also be approached with caution. Aprepitant is a substrate for CYP3A4; therefore, coadministration of fosaprepitant or aprepitant with drugs that strongly induce CYP3A4 activity (eg, rifampin, carbamazepine, phenytoin) may result in reduced plasma concentrations and decreased efficacy. Ketoconazole: When a single 125-mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant or aprepitant with strong CYP3A4 inhibitors should be approached cautiously. Rifampin: When a single 375-mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant or aprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy. Additional Interactions: Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant with diltiazem 120 mg 3 times daily resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure (mean [SD] of 24.3 [±10.2] mmHg with fosaprepitant vs 15.6 [±4.1] mmHg without fosaprepitant) and resulted in a small further maximum decrease in systolic blood pressure (mean [SD] of 29.5 [±7.9] mmHg with fosaprepitant vs 23.8 [±4.8] mmHg without fosaprepitant), which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval beyond those changes induced by diltiazem alone. In the same study, administration of aprepitant once daily as a tablet formulation comparable to 230 mg of the capsule formulation, with diltiazem 120 mg 3 times daily for 5 days, resulted in a 2-fold increase of aprepitant AUC and a simultaneous 1.7-fold increase of diltiazem AUC. These pharmacokinetic effects did not result in clinically meaningful changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. Paroxetine: Coadministration of once-daily doses of aprepitant as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic effects: Pregnancy Category B: In the reproduction studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Reproduction studies performed in rats at oral doses of aprepitant of up to 1000 mg/kg twice daily (plasma AUC0–24hr of 31.3 mcgshr/mL, about 1.6 times the human exposure at the recommended dose) and in rabbits at oral doses of up to 25 mg/kg/day (plasma AUC0–24hr of 26.9 mcgshr/mL, about 1.4 times the human exposure at the recommended dose) revealed no evidence of impaired fertility or harm to the fetus due to aprepitant. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers: Aprepitant is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for possible serious adverse reactions in nursing infants from aprepitant and because of the potential for tumorigenicity shown for aprepitant in rodent carcinogenicity studies, 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: Safety and effectiveness of EMEND for Injection in pediatric patients have not been established. Geriatric Use: In 2 well-controlled CINV clinical studies, of the total number of patients (N=544) treated with oral aprepitant, 31% were 65 and over, while 5% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Greater sensitivity of some older individuals cannot be ruled out. Dosage adjustment in the elderly is not necessary. Patients With Severe Hepatic Impairment: There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh score >9). Therefore, caution should be exercised when fosaprepitant or aprepitant is administered in these patients. OVERDOSAGE There is no specific information on the treatment of overdosage with fosaprepitant or aprepitant. In the event of overdose, fosaprepitant and/or oral aprepitant should be discontinued and general supportive treatment and monitoring should be provided. Because of the antiemetic activity of aprepitant, drug-induced emesis may not be effective. Aprepitant cannot be removed by hemodialysis. Thirteen patients in the randomized controlled trial of EMEND for Injection received both fosaprepitant 150 mg and at least one dose of oral aprepitant, 125 mg or 80 mg. Three patients reported adverse reactions that were similar to those experienced by the total study population. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in Sprague-Dawley rats and in CD-1 mice for 2 years. In the rat carcinogenicity studies, animals were treated with oral doses ranging from 0.05 to 1000 mg/kg twice daily. The highest dose produced a systemic exposure to aprepitant (plasma AUC0–24hr) of 0.7 to 1.6 times the human exposure (AUC0–24hr=19.6 mcgshr/mL) at the recommended dose of 125 mg/day. Treatment with aprepitant at doses of 5 to 1000 mg/kg twice daily caused an increase in the incidences of thyroid follicular cell adenomas and carcinomas in male rats. In female rats, it produced hepatocellular adenomas at 5 to 1000 mg/kg twice daily and hepatocellular carcinomas and thyroid follicular cell adenomas at 125 to 1000 mg/kg twice daily. In the mouse carcinogenicity studies, the animals

were treated with oral doses ranging from 2.5 to 2000 mg/kg/day. The highest dose produced a systemic exposure of about 2.8 to 3.6 times the human exposure at the recommended dose. Treatment with aprepitant produced skin fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. Carcinogenicity studies were not conducted with fosaprepitant. Aprepitant and fosaprepitant were not genotoxic in the Ames test, the human lymphoblastoid cell (TK6) mutagenesis test, the rat hepatocyte DNA strand break test, the Chinese hamster ovary (CHO) cell chromosome aberration test and the mouse micronucleus test. Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant. Oral aprepitant did not affect the fertility or general reproductive performance of male or female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (providing exposure in male rats lower than the exposure at the recommended human dose and exposure in female rats at about 1.6 times the human exposure). PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling]: Physicians should instruct their patients to read the patient package insert before starting therapy with EMEND for Injection and to reread it each time the prescription is renewed. Patients should follow the physician’s instructions for the regimen of EMEND for Injection. Allergic reactions, which may be sudden and/or serious, and may include hives, rash, itching, redness of the face/skin, and may cause difficulty in breathing or swallowing, have been reported. Physicians should instruct their patients to stop using EMEND and call their doctor right away if they experience an allergic reaction. In addition, severe skin reactions may occur rarely. Patients who develop an infusion-site reaction such as erythema, edema, pain, or thrombophlebitis should be instructed on how to care for the local reaction and when to seek further evaluation. EMEND for Injection may interact with some drugs, including chemotherapy; therefore, patients should be advised to report to their doctor the use of any other prescription or nonprescription medication or herbal products. Patients on chronic warfarin therapy should be instructed to have their clotting status closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle. Administration of EMEND for Injection may reduce the efficacy of hormonal contraceptives. Patients should be advised to use alternative or backup methods of contraception during treatment with and for 1 month following the last dose of fosaprepitant or aprepitant. For detailed information, please read the Prescribing Information. Rx only

Ovarian Cancer Bevacizumab in the Treatment of Advanced Ovarian Cancer Continued from page 12 advanced ovarian cancer was not costeffective, and maintenance with bevacizumab was associated with significant direct and indirect costs. Discussion These phase 3 trials demonstrated that only extended use, but not the short-term use of bevacizumab, in combination with chemotherapy, improved PFS in patients with newly diagnosed ovarian cancer. However, the GOG 218 trial failed to demonstrate statistically significant OS benefit. The ICON7 trial showed no improved median OS but did show a substantial OS benefit in a subgroup analysis. Based on the results, bevacizumab was approved in Europe as first-line treatment with chemotherapy in the treatment of advanced ovarian cancer. In the United States, it is unknown if the Food and Drug Administration (FDA) will grant approval of bevacizumab in the treatment of advanced ovarian cancer without OS benefit. The current National Comprehensive Cancer Network (NCCN) guidelines have not included a bevacizumab-based regimen as first-line therapy.9

The optimal bevacizumab dose and treatment duration remain unclear, based on the results of these 2 large trials.

It is not clear why the PFS difference was not transformed to OS benefit in the GOG 218 trial, especially since the patient population in the GOG 218 trial is similar to the subgroup of patients who had improved OS upon treatment in the ICON7 trial. Crossover effect cannot be ruled out. The percentage of patients in the GOG 218 trial receiving postprogression antiangiogenic therapy has not been determined, while it is known that 3% of pa-

tients in the ICON7 trial received subsequent antiangiogenic therapy.10 It is possible that if a significant number of patients in the chemotherapy-only group of the GOG 218 trial received postprogression antiangiogenic therapy, the OS benefit of bevacizumab treatment could be masked.

into treatment. For most patients, the financial hurdles must be cleared before treatment can be initiated. It is also unknown if efficacy of bevacizumab-based IV chemotherapy is comparable to the current standard of care as intraperitoneal (IP) therapy in advanced ovarian cancer especially for

The European Commission approved the new indication of bevacizumab to be used as the first-line therapy for untreated advanced ovarian cancer. However, it is not clear whether the FDA will grant approval of bevacizumab in the treatment of advanced ovarian cancer.

The optimal bevacizumab dose and treatment duration remain unclear, based on the results of these 2 large trials. In the ICON7 trial, the dose of bevacizumab was 7.5 mg/kg every 3 weeks for 5 or 6 cycles, and patients received bevacizumab for an additional 12 cycles postchemotherapy or until disease progression. In contrast, patients in the GOG 218 trial received 15 mg/kg bevacizumab every 3 weeks, and patients were allowed an additional 16 cycles of bevacizumab after chemotherapy completion. Despite the dosing difference of bevacizumab, the absolute PFS gain from bevacizumab in the GOG 218 trial (3.8 months) was close to that of patients with high risk for progression in the ICON7 trial (3.5 months). These findings suggest that the 7.5 mg/kg bevacizumab dose may achieve efficacy similar to the efficacy of the 15 mg/kg dose. The dose change could make a significant difference in terms of cost. A recent pharmacoeconomic analysis demonstrated that the bevacizumabthroughout approach was not cost-effective based on the GOG 218 trial. It is important for patients and providers to give serious consideration to the high cost of bevacizumab before they make decisions to incorporate bevacizumab

patients with optimal reduction. To address this question, the ongoing GOG 252 clinical trial randomized patients with advanced ovarian cancer to either IV carboplatin/paclitaxel with bevacizumab, IV paclitaxel plus IP carboplatin with bevacizumab, or IV paclitaxel plus IP carboplatin/paclitaxel with bevacizumab. All patients receive bevacizumab 15 mg/kg with chemotherapy and additional 16 cycles.11 Another ongoing trial, GOG 262, repeats dose-intense paclitaxel with IV carboplatin, but allows bevacizumab 15 mg/kg as an option, to be combined with chemotherapy to treat stage II through IV ovarian cancer patients.12 Summary Recent results from the GOG 218 and ICON7 trials demonstrated that adding maintenance bevacizumab to chemotherapy improved PFS among patients with newly diagnosed advanced ovarian cancer. However, there was no significant difference in OS between the bevacizumab group and chemotherapy group in the GOG 218 trial, and the final results of OS from the ICON7 trial are still pending. Based on these findings, the European Commission approved the new indication of

bevacizumab to be used as the first-line therapy for untreated advanced ovarian cancer. However, it is not clear whether the FDA will grant approval of bevacizumab in the treatment of advanced ovarian cancer. Recently, a pharmacoeconomic analysis concluded that the use of bevacizumab was not cost-effective based on the GOG 218 study. The 2012 NCCN guidelines have not yet included bevacizumab as first-line therapy for patients with advanced ovarian cancer. Oncologists and clinical pharmacists need to take this information into careful consideration before incorporating bevacizumab with chemotherapy. Future studies are focusing on including bevacizumab in IP therapy for patients with advanced ovarian cancer and discovering potential markers to identify individuals most likely to achieve clinical benefit. â&#x2014;? references 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10-29. 2. Xu L, Yoneda J, Herrera C, et al. Inhibition of malignant ascites and growth of human ovarian carcinoma by oral administration of a potent inhibitor of the vascular endothelial growth factor receptor tyrosine kinases. Int J Oncol. 2000;16:445-454. 3. Burger RA, Sill MW, Monk BJ, et al. Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007;25:5165-5171. 4. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25:5180-5186. 5. Burger RA, Brady MF, Bookman MA, et al. Incorporation of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med. 2011;365:2473-2483. 6. Perren TJ, Swart AM, Pfisterer J, et al. A phase 3 trial of bevacizumab in ovarian cancer. N Engl J Med. 2011;365:2484-2496. 7. Cohn DE, Kim KH, Resnick KE, et al. At what cost does a potential survival advantage of bevacizumab make sense for the primary treatment of ovarian cancer? A cost-effectiveness analysis. J Clin Oncol. 2011;29:1247-1251. 8. RED BOOK for Windows version 61144. Vol 063. Greenwood Village, CO: Thomson Healthcare; c2012. 9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer Including Fallopian Tube Cancer and Primary Peritoneal Cancer. Version 3.2012. http://www.nccn. org/professionals/physician_gls/pdf/ovarian.pdf. Accessed April 18, 2012. 10. Burger RA. Bevacizumab in ovarian cancer. N Engl J Med. 2012;366:1257-1258. 11. Gynecologic Oncology Group. https://gogmember. gog.org/documents/protocols/pdf/0252.pdf. Accessed April 18, 2012. 12. Gynecologic Oncology Group. https://gogmember. gog.org/documents/protocols/pdf/0262.pdf. Accessed April 18, 2012.

Get involved: have you ever wanted to write an article for TOP? Weâ&#x20AC;&#x2122;re interested in articles about the everyday issues that affect pharmacistsâ&#x20AC;&#x201D; everything from chemotherapy safe handling to supportive care for patients to challenging cases.

Contact editorial@greenhillhc.com for more information. 16

OCTOBER 2012 I VOL 5, NO 7

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THE AFINITOR® (everolimus) TABLETS DUAL BENEFIT CO-PAY CARD FROM NOVARTIS PHARMACEUTICALS CORPORATION Designed to help make treatment more affordable for your eligible AFINITOR patients h The AFINITOR Dual Benefit Co-Pay Card With this co-pay assistance card, most eligible patients will pay $25 per 28-day prescription of AFINITOR® (everolimus) Tablets when they visit their pharmacy. The card also provides up to $50 off their co-pay for generic exemestane when prescribed with AFINITOR.

601341 RxBIN: OHCP RxPCN: RxGrp: [OHXXXXXXX] RxID: [000000000000] 01 Suf:

THE AFINITOR DUAL BENEFIT CO-PAY CARD

Novartis Pharmaceuticals Corporation will pay the balance of your eligible patient’s out-of-pocket expenses, up to a maximum of $1200 per month for the AFINITOR prescription and up to $50 per month for generic exemestane when prescribed with AFINITOR. Not valid for prescriptions for which payment may be made in whole or in part under federal or state healthcare programs, including, but not limited to, Medicare or Medicaid. The exemestane offer is not valid in Michigan. Patients can obtain the co-pay card at their physician’s office or at www.AFINITOR.com. This program will expire on June 30, 2014.

Helping make access to AFINITOR easier Novartis Oncology shares your commitment to helping patients living with cancer receive the medicines they need. Patient Assistance Now Oncology offers quick and easy access to information about the broad array of support and reimbursement programs available for patients. For more information about AFINITOR access services, please visit www.AFINITOR.com.

Please see accompanying Important Safety Information and Brief Summary of Prescribing Information for AFINITOR on the following pages.

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

9/12

AFB-1046627

AFINITOR速 (everolimus) Tablets is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Important Safety Information AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. The use of corticosteroids may be indicated. For grade 4 cases, discontinue AFINITOR. Corticosteroids may be indicated until symptoms resolve. For grade 3 cases, interrupt AFINITOR until resolution to ) grade 1. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered, depending on the individual clinical circumstances. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections: AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Treatment of preexisting invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate antifungal treatment. Oral Ulceration: Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44% to 86% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. In such cases, topical treatments are recommended, but alcohol-, peroxide-, iodine-, or thyme-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. Geriatric Patients: In the randomized advanced hormone receptorpositive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients * 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent discontinuation occurred in 33% of patients * 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended. Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets, have been reported. Renal function (including measurement of blood urea nitrogen, urinary protein, or serum creatinine), blood glucose, lipids,

and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Drug-Drug Interactions: Avoid coadministration with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if coadministration with a moderate CYP3A4 and/or PgP inhibitor is required (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid coadministration with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if coadministration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5-mg increments. Hepatic Impairment: Exposure of everolimus was increased in patients with hepatic impairment. For patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Embryo-Fetal Toxicity: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use a highly effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment. Adverse Reactions: The most common adverse reactions (incidence * 30%) were stomatitis (67%), infections (50%), rash (39%), fatigue (36%), diarrhea (33%) and decreased appetite (30%). The most common grade 3/4 adverse reactions (incidence * 2%) were stomatitis (8%), infections (5%), hyperglycemia (5%), fatigue (4%), dyspnea (4%), pneumonitis (4%) and diarrhea (2%). Laboratory Abnormalities: The most common laboratory abnormalities (incidence * 50%) were hypercholesterolemia (70%), hyperglycemia (69%), increased aspartate transaminase (AST) concentrations (69%), anemia (68%), leukopenia (58%), thrombocytopenia (54%), lymphopenia (54%), increased alanine transaminase (ALT) concentrations (51%), and hypertriglyceridemia (50%). The most common grade 3/4 laboratory abnormalities (incidence * 3%) were lymphopenia (12%), hyperglycemia (9%), anemia (7%), decreased potassium (4%), increased AST (4%), increased ALT (4%), and thrombocytopenia (3%). Please see accompanying Brief Summary of Prescribing Information for AFINITOR on the following pages.

AFINITOR (everolimus) tablets for oral administration Initial U.S. Approval: 2009 Brief Summary of Prescribing Information. See full prescribing information for complete product information. 1 INDICATIONS AND USAGE AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptorpositive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. 4 CONTRAINDICATIONS Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. 5 WARNINGS AND PRECAUTIONS Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2) in the full prescribing information]. If toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported even at a reduced dose. Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions]. Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR [see Laboratory Tests and Monitoring]. Geriatric Patients In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended [see Dosage and Administration (2.2) in the full prescribing information, Use in Specific Populations] . Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematologic Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5) in the full prescribing information]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP inhibitor [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Drug Interactions]. Hepatic Impairment Exposure to everolimus was increased in patients with hepatic impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B)

hepatic impairment, a dose reduction is recommended [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. For SEGA patients with severe hepatic impairment, AFINITOR is not recommended. For SEGA patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed; however subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and Administration (2.4, 2.5) in the full prescribing information]. Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus therapy. Embryo-fetal Toxicity There are no adequate and well-controlled studies of AFINITOR in pregnant women; however, based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations]. 6 ADVERSE REACTIONS The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone-receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased AST, anemia, leukopenia, thrombocytopenia, lymphopenia, increased ALT, and hypertriglyceridemia. The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). Table 3 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Table 3: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC* AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Any adverse reaction 100 41 9 90 22 5 Gastrointestinal disorders 67 8 0 11 0.8 0 Stomatitisb Diarrhea 33 2 0.2 18 0.8 0 Nausea 29 0.2 0.2 28 1 0 Vomiting 17 0.8 0.2 12 0.8 0 Constipation 14 0.4 0 13 0.4 0 Dry mouth 11 0 0 7 0 0 General disorders and administration site conditions Fatigue 36 4 0.4 27 1 0 Edema peripheral 19 1 0 6 0.4 0 Pyrexia 15 0.2 0 7 0.4 0 Asthenia 13 2 0.2 4 0 0 Infections and infestations 50 4 1 25 2 0 Infectionsc Investigations Weight decreased 25 1 0 6 0 0 Metabolism and nutrition disorders Decreased appetite 30 1 0 12 0.4 0 Hyperglycemia 14 5 0.4 2 0.4 0 Musculoskeletal and connective tissue disorders Arthralgia 20 0.8 0 17 0 0 Back pain 14 0.2 0 10 0.8 0 Pain in extremity 9 0.4 0 11 2 0 Nervous system disorders Dysgeusia 22 0.2 0 6 0 0 Headache 21 0.4 0 14 0 0 Psychiatric disorders Insomnia 13 0.2 0 8 0 0 Respiratory, thoracic and mediastinal disorders Cough 24 0.6 0 12 0 0 Dyspnea 21 4 0.2 11 0.8 0.4 Epistaxis 17 0 0 1 0 0 19 4 0.2 0.4 0 0 Pneumonitisd Skin and subcutaneous tissue disorders Rash 39 1 0 6 0 0 Pruritus 13 0.2 0 5 0 0 Alopecia 10 0 0 5 0 0 Vascular disorders Hot flush 6 0 0 14 0 0 Median Duration of Treatmente 23.9 weeks 13.4 weeks CTCAE Version 3.0 *160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks) a Exemestane (25 mg/day) b Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration c Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis (<1%), and sepsis (<1%), and hepatitis C (<1%). d Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis e Exposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 4. Table 4: Key Laboratory Abnormalities Reported in â&#x2030;Ľ 10% of Patients with Advanced HR+ BC Laboratory parameter AFINITOR (10 mg/day) Placebo + exemestanea + exemestanea N=482 N=238 All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 % % % % % % Hematologyb Hemoglobin decreased 68 6 0.6 40 0.8 0.4 WBC decreased 58 1 0 28 5 0.8 Platelets decreased 54 3 0.2 5 0 0.4 Lymphocytes decreased 54 11 0.6 37 5 0.8 Neutrophils decreased 31 2 0 11 0.8 0.8 Clinical Chemistry Glucose increased 69 9 0.4 44 0.8 0.4 Cholesterol increased 70 0.6 0.2 38 0.8 0.8 Aspartate transaminase (AST) increased 69 4 0.2 45 3 0.4 Alanine transaminase (ALT) increased 51 4 0.2 29 5 0 Triglycerides increased 50 0.8 0 26 0 0 Albumin decreased 33 0.8 0 16 0.8 0 Potassium decreased 29 4 0.2 7 1 0 Creatinine increased 24 2 0.2 13 0 0 CTCAE Version 3.0 a Exemestane (25 mg/day) b Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: O >8GB6BA4MB?8 4 FGEBA: 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

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Concomitant strong inhibitors of CYP3A4 should not be used [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Use caution when AFINITOR is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose [see Dosage and Administration (2.2, 2.4) in the full prescribing information and Warnings and Precautions]. Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers "A ;84?G;L FH5=86GF 6B 47@<A<FGE4G<BA B9 "'",(* J<G; E<94@C<A 4 FGEBA: <A7H68E B9 CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared GB 8I8EB?<@HF GE84G@8AG 4?BA8 BA F<78E 4 7BF8 <A6E84F8 B9 "'",(* J;8A 6B 47@<A<FG8E87 J<G; FGEBA: 0) <A7H68EF <9 4?G8EA4G<I8 treatment cannot be administered. St. Johnâ&#x20AC;&#x2122;s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2, 2.4) in the full prescribing information]. Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions 58GJ88A "'",(* 4A7 G;8 !& B E87H6G4F8 <A;<5<GBEF 4GBEI4FG4G<A 4 0) FH5FGE4G8 4A7 CE4I4 FG4G<A 4 ABA 0) FH5FGE4G8 4A7 CBCH?4G<BA C;4E@46B kinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. FGH7L <A ;84?G;L FH5=86GF 78@BAFGE4G87 G;4G 6B 47@<A<FGE4G<BA B9 4A BE4? 7BF8 B9 @<7 4MB?4@ F8AF<G<I8 0) FH5FGE4G8 J<G; 8I8EB?<@HF E8FH?G87 <A 4 <A6E84F8 <A @<7 4MB?4@ max and a 30% increase in @<74MB?4@ - <A9 . Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse 8I8AGF E8?4G87 GB 8K8@8FG4A8 J4F B5F8EI87 <A C4G<8AGF J<G; ;BE @BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 47I4A687 5E84FG 64A68E E868<I<A: G;8 6B@5<A4G<BA Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. 8 USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions]. ,;8E8 4E8 AB 478DH4G8 4A7 J8?? 6BAGEB??87 FGH7<8F B9 "'",(* <A CE8:A4AG JB@8A ;BJ8I8E 54F87 BA the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. I8EB?<@HF 64HF87 8@5ELB 98G4? GBK<6<G<8F <A 4A<@4?F 4G @4G8EA4? 8KCBFHE8F G;4G J8E8 ?BJ8E G;4A ;H@4A exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the 7EH: G;8 C4G<8AG F;BH?7 58 4CCE<F87 B9 G;8 CBG8AG<4? ;4M4E7 GB 4 98GHF /B@8A B9 6;<?7584E<A: CBG8AG<4? should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. In animal reproductive studies, oral administration of everolimus to female rats before mating and G;EBH:; BE:4AB:8A8F<F <A7H687 8@5ELB 98G4? GBK<6<G<8F <A6?H7<A: <A6E84F87 E8FBECG<BA CE8 <@C?4AG4G<BA 4A7 CBFG <@C?4AG4G<BA ?BFF 786E84F87 AH@58EF B9 ?<I8 98GHF8F @4?9BE@4G<BA 8 : FG8EA4? 6?89G 4A7 retarded skeletal development. These eff86GF B66HEE87 <A G;8 45F8A68 B9 @4G8EA4? GBK<6<G<8F @5ELB 98G4? toxicities in rats occurred at doses â&#x2030;Ľ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC ;) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

"A 4 CE8 4A7 CBFG A4G4? 78I8?BC@8AG FGH7L <A E4GF 4A<@4?F J8E8 7BF87 9EB@ <@C?4AG4G<BA G;EBH:; ?46G4 tion. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or F<:AF B9 @4G8EA4? GBK<6<GL ;BJ8I8E G;8E8 J8E8 E87H6G<BAF <A 5B7L J8<:;G HC GB E87H6G<BA 9EB@ G;8 6BAGEB? 4A7 <A FHEI<I4? B9 B99FCE<A: N 7<87 BE @<FF<A: ,;8E8 J8E8 AB 7EH: E8?4G87 89986GF BA G;8 developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 AFINITOR is recommended for use only in patients with SEGA who are aged â&#x2030;Ľ 3 years. CEBFC86G<I8 BC8A ?458? F<A:?8 4E@ GE<4? J4F 6BA7H6G87 GB 8I4?H4G8 G;8 F498GL 4A7 899<646L B9 "'",(* <A C4G<8AGF J<G; + 4FFB6<4G87 J<G; ,+ "A GBG4? C4G<8AGF E868<I87 GE84G@8AG J<G; "'",(* @87<4A 4:8 J4F L84EF E4A:8 "'",(* ;4F ABG 588A FGH7<87 <A C4G<8AGF J<G; + L84EF B9 4:8

Geriatric Use "A G;8 E4A7B@<M87 47I4A687 ;BE@BA8 E868CGBE CBF<G<I8 ! * A8:4G<I8 5E84FG 64A68E FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 years of age, while 15% were 75 and over. No overall differences in effectiveness were observed between elderly and younger subjects. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients â&#x2030;Ľ 65 years of age compared to 2% in C4G<8AGF L84EF B9 4:8 7I8EF8 E846G<BAF ?847<A: GB C8E@4A8AG GE84G@8AG 7<F6BAG<AH4G<BA B66HEE87 <A 33% of patients â&#x2030;Ľ L84EF B9 4:8 6B@C4E87 GB <A C4G<8AGF L84EF B9 4:8 [see Warnings and Precautions]. "A GJB BG;8E E4A7B@<M87 GE<4?F 47I4A687 E8A4? 68?? 64E6<AB@4 4A7 47I4A687 A8HEB8A7B6E<A8 GH@BEF B9 pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and LBHA:8E FH5=86GF "A G;8 E4A7B@<M87 47I4A687 * FGH7L B9 "'",(* GE84G87 C4G<8AGF J8E8 â&#x2030;Ľ 65 L84EF B9 4:8 J;<?8 J8E8 4A7 BI8E "A G;8 E4A7B@<M87 47I4A687 )' , FGH7L B9 "'",(* treated patients were â&#x2030;Ľ 65 years of age, while 7% were 75 and over. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out 1F88 ?<A<64? );4E macology (12.3) in the full prescribing information]. 'B 7BF4:8 47=HFG@8AG <A <A<G<4? 7BF<A: <F E8DH<E87 <A 8?78E?L C4G<8AGF 5HG 6?BF8 @BA<GBE<A: 4A7 4CCEBCE< ate dose adjustments for adverse reactions is recommended. [see Dosage and Administration (2.2), Clinical Pharmacology (12.3) in the full prescribing information]. Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal <@C4<E@8AG <F ABG 8KC86G87 GB <A9?H8A68 7EH: 8KCBFHE8 4A7 AB 7BF4:8 47=HFG@8AG B9 8I8EB?<@HF <F E86 ommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information]. Hepatic Impairment The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose FGH7L B9 8I8EB?<@HF <A FH5=86GF J<G; <@C4<E87 ;8C4G<6 9HA6G<BA E8?4G<I8 GB FH5=86GF J<G; ABE@4? ;8C4G<6 9HA6 tion. KCBFHE8 J4F <A6E84F87 <A C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF @B78E4G8 ;<?7 )H:; 6?4FF 4A7 F8I8E8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 1F88 ?<A<64? );4E@46B?B:L <A G;8 9H?? CE8 scribing information]. For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the E<F> BE C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 4 dose reduction is recommended [see Dosage and Administration (2.2) in the full prescribing information]. BE + C4G<8AGF J<G; F8I8E8 ;8C4G<6 <@C4<E@8AG ;<?7 )H:; 6?4FF "'",(* <F ABG E86B@@8A787

BE + C4G<8AGF J<G; @<?7 ;<?7 )H:; 6?4FF BE @B78E4G8 ;<?7 )H:; 6?4FF ;8C4G<6 <@C4<E@8AG 47=HFG@8AG GB G;8 FG4EG<A: 7BF8 @4L ABG 58 A88787 ;BJ8I8E FH5F8DH8AG 7BF<A: F;BH?7 58 <A7<I<7H4? <M87 54F87 BA G;8E4C8HG<6 7EH: @BA<GBE<A: [see Dosage and Administration (2.4 <A G;8 9H?? CE8F6E<5 ing information]. 10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. Manufactured by: Novartis Pharma Stein AG +G8<A +J<GM8E?4A7 Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ÂŠ Novartis , July 2012

News Briefs Heart Failure... Continued from page 4

thracycline-based chemotherapy alone, 0.9% had received trastuzumab with no anthracycline, 3.5% had received anthracycline plus trastuzumab, and about 20% had received other chemotherapy. Baseline characteristics were different among the groups. Women who received anthracycline alone or in combination with trastuzumab were younger, had been diagnosed at later stages, had fewer comorbidities, and were slightly more likely to be treated with radiation therapy, compared with women who did not receive any chemotherapy or who received other chemotherapy. With increasing follow-up, the inci-

dence of heart failure/cardiomyopathy increased in all groups, but the greatest increase was seen in the trastuzumabtreated patients. In the group treated with anthracyclines, the cumulative incidence of heart failure/cardiomyopathy increased from 1.2% at year 1 to 4.3% at year 5; this increase was similar to that for patients treated with other chemotherapies (from 1.3% to 4.5%). Patients who did not receive any chemotherapy had a cumulative incidence of heart failure/cardiomyopathy of 0.9% at year 1 and 3.1% at year 5. The greatest increase was observed in patients treated with anthracycline plus trastuzumab: from 6.2% at year 1 to 20.1% by year 5. At 5 years, the cumulative incidence of heart failure/cardiomyopathy was greater

in older women for all treatment groups, but as women aged, the hazard ratio for heart failure/cardiomyopathy decreased. The investigators noted that the study demonstrates the importance of observational comparative safety and effectiveness studies to complement data from clinical trials. These observational studies provide an estimate of risks and benefits in community practices that treat patients who often are not eligible for clinical trials but who still receive treatments based on clinical trial data. In an accompanying editorial (Geiger AM. J Natl Cancer Inst. 2012;104:12691270), Ann Geiger, PhD, Wake Forest University, Winston-Salem, North Carolina, acknowledged the important survival benefits of trastuzumab in wom-

en with HER2-positive breast cancer, but she stated that there are still safety concerns related to risks of heart failure/cardiomyopathy. These risks, shown in the current study as well as in other studies, justify long-term surveillance for congestive heart failure in women treated with trastuzumab and for women enrolled in trials. Also, Geiger expressed concern that about 25% of women in this study had received trastuzumab as adjuvant therapy before it was proven to be of benefit in randomized clinical trials in the adjuvant setting. This was probably based on data from the metastatic setting. She advocated longer follow-up on the risks of new treatments to justify their continued use. ●

Side Effect Management

Preventing Chemotherapy-Induced Peripheral Neuropathy remains elusive By Alice Goodman

dentifying agents that can prevent chemotherapy-induced peripheral neuropathy (CIPN) is a work in progress. Studies of some interventions suggest modestly encouraging findings, but research on prevention has been hampered by a poor understanding of the different mechanisms of this toxicity with the various chemotherapy agents that induce CIPN.1 “We still have much work to do. We are getting better at trial design, finding the best outcome measures, and including homogeneous populations in clinical trials. We need better preclinical models and better biomarkers,” stated Dawn Hershman, MD, of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center in New York City. “One problem in studying CIPN is that numerous anti-cancer drugs cause these symptoms, and the mechanism for each drug may be different. Our approach to treating one symptom can be problematic. We may miss signals that one drug works for one type of CIPN but not another,” she explained. Hershman reviewed completed clinical trials for the prevention of CIPN at the 2012 Multinational Association of Supportive Care in Cancer International Symposium.1 She emphasized that a drug that works for prevention may not be effective for treatment of CIPN, and vice versa. Vitamin E has been studied in neuropathic pain, based on positive pilot and phase 2 studies suggesting a neuroprotective effect when given with platinum or taxanes. However, a phase 3 placebo-

www.TheOncologyPharmacist.com

controlled study found no effect of vitamin E 300 mg twice daily on any CIPN parameters in patients treated with adjuvant platinum or taxane therapy.2 “Think twice about recommending vitamin E to your patients for prevention of CIPN,” Hershman said. Calcium/magnesium has been studied in patients with colon cancer undergoing adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) therapy.3 The study of 104 patients had a primary end point of development of grade 2 or higher CIPN. The intervention appeared to be beneficial, but the study was closed prematurely because of concern that calcium/magnesium could decrease treatment efficacy; further analysis showed that this concern was false. “Even with a smaller sample size, there is a likely benefit of calcium/magnesium in this setting, with a suggestion of significant improvement in objective and patient-reported outcomes,” she stated. Acetyl-L-carnitine is a supplement that improves neuropathy in patients with diabetes and HIV infection and is also reported to improve fatigue and cognition, with toxicity limited to mild nausea.1 Based on positive results of a small phase 2 trial showing improvement in sensory and motor neuropathy, the Southwest Oncology Group mounted a phase 3 trial in approximately 400 patients with breast cancer treated with taxanes.4 No effect of acetyl-L-carnitine was observed at 12 weeks, but at 24 weeks worsening neuropathy was observed in the group treated with the supplement. “This is a big surprise. After control-

ling for age and regimen, the odds ratio for worsening neuropathy was 1.57. This study shows that we have to be careful when we give agents to patients. Not everything we give is benign, and this is a good reason to study these agents,” Hershman said.

Prevention of CIPN remains the ideal rather than the reality.

tion of cisplatin- or paclitaxel-induced neuropathy due to insufficient data.6 Ongoing clinical trials of prevention of CIPN include phase 3, placebo-controlled trials of alpha lipoic acid and of erythropoietin. A separate 12-week, single-blind study at Hershman’s institution is looking at electroacupuncture given weekly with paclitaxel chemotherapy in 50 patients with stage I to III breast cancer.7 Results of these studies are awaited, she said, but prevention of CIPN remains the ideal rather than the reality. ● references

Glutamine has also been studied in CIPN in a small trial of 86 patients with colon cancer and oxaliplatin-induced peripheral neuropathy.5 The study found a reduction in grades 1 and 2 neuropathy as well as a significantly lower incidence of grades 3 and 4 neuropathy in the glutamine-treated group, according to patient-reported outcomes, but no difference in electrophysiological abnormalities with glutamine. Hershman commented that electrophysiologic exam may not be the right end point to study. With these equivocal results in a small trial, glutamine is not a strong recommendation. Although 4 clinical trials of amifostine conducted in patients treated with cisplatin found that pretreatment with amifostine reduced, prevented, or provided some protection against cumulative neurotoxicity, in the ASCO 2008 clinical practice guideline update, amifostine is not recommended for preven-

1. Hershman D. Cancer induced perpheral neuropathy: prevention. Presented at: 2012 Multinational Association of Supportive Care in Cancer International Symposium; June 28-30, 2012; New York, NY. 2. Kottschade LA, Sloan JA, Mazurczak MA, et al. The use of vitamin E for the prevention of chemotherapyinduced peripheral neuropathy: results of a randomized phase III clinical trial. Support Cancer Care. 2011;19:1769-1777. 3. Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and magnesium for oxaliplatininduced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2011;29:421-427. 4. Hershman DL, Unger JM, Crew KD, et al. SWOG S0715: randomized placebo-controlled trial of acetylL-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy. Presented at: 2012 American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago, IL. Abstract 9018. 5. Wang WS, Lin JK, Lin TC, et al. Oral glutamine is effective for preventing oxaliplatin-induced neuropathy in colorectal cancer patients. Oncologist. 2007; 12:312-319. 6. Hensley ML, Hagerty KL, Kewalramani T, et al. American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy or radiation therapy protectants. J Clin Oncol. 2009;27: 127-145. 7. Hershman DL. Acupuncture study for the prevention of taxane induced myalgias and neuropathy. Clinical Trials.gov Web site. http://clinicaltrials.gov/ct2/show/ NCT01163682?term=electroacupuncture&rank=31. Updated October 27, 2011. Accessed September 5, 2012.

OCTOBER 2012 I VOL 5, NO 7

TREANDA速 (bendamustine HCI) for Injection is his chemo.

This is his therapy.

Single-agent TREANDA tripled median PFS* TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). EfďŹ cacy relative to ďŹ rst-line therapies other than chlorambucil has not been established. PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Survival distribution function

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HRâ&#x20AC; =0.27 (95% CIâ&#x20AC;Ą: 0.17, 0.43)

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). â&#x20AC; HR=hazard ratio. â&#x20AC;Ą CI=confidence interval.

s 42%!.$! WAS COMPARED WITH CHLORAMBUCIL IN A RANDOMIZED OPEN LABEL PHASE TRIAL IN TREATMENT NAĂ&#x2022;VE PATIENTS WITH "INET STAGE " OR # 2AI STAGES ) )6 #,, WHO REQUIRED TREATMENT . s 42%!.$! IS ADMINISTERED WITH A CONVENIENT DOSING SCHEDULE n 4HE RECOMMENDED DOSE FOR 42%!.$! IS MG M2 ADMINISTERED INTRAVENOUSLY OVER MINUTES ON $AYS AND OF A DAY TREATMENT CYCLE UP TO CYCLES n )N THE PHASE TRIAL PATIENTS RECEIVED CHLORAMBUCIL AT A DOSE OF MG KG ORALLY ON $AYS AND N OF A DAY TREATMENT CYCLE UP TO CYCLES s )N THE PIVOTAL PHASE TRIAL THE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FREQUENCY â&#x2030;Ľ WERE PYREXIA NAUSEA AND VOMITING N 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ WERE ANEMIA THROMBOCYTOPENIA NEUTROPENIA LYMPHOPENIA AND LEUKOPENIA N Important Safety Information s 3ERIOUS ADVERSE REACTIONS INCLUDING MYELOSUPPRESSION INFECTIONS INFUSION REACTIONS AND ANAPHYLAXIS TUMOR LYSIS SYNDROME SKIN REACTIONS INCLUDING 3*3 4%. OTHER MALIGNANCIES AND EXTRAVASATION HAVE BEEN ASSOCIATED WITH 42%!.$! 3OME REACTIONS SUCH AS MYELOSUPPRESSION INFECTIONS AND 3*3 4%. WHEN 42%!.$! WAS ADMINISTERED CONCOMITANTLY WITH ALLOPURINOL AND OTHER MEDICATIONS KNOWN TO CAUSE 3*3 4%. HAVE BEEN FATAL 0ATIENTS SHOULD BE MONITORED CLOSELY FOR THESE REACTIONS AND TREATED PROMPTLY IF ANY OCCUR s !DVERSE REACTIONS MAY REQUIRE INTERVENTIONS SUCH AS DECREASING THE DOSE OF 42%!.$! OR WITHHOLDING OR DELAYING TREATMENT s 42%!.$! IS CONTRAINDICATED IN PATIENTS WITH A KNOWN HYPERSENSITIVITY TO BENDAMUSTINE OR MANNITOL 7OMEN SHOULD BE ADVISED TO AVOID BECOMING PREGNANT WHILE USING 42%!.$! s 4 HE MOST COMMON NON HEMATOLOGIC ADVERSE REACTIONS FOR #,, FREQUENCY â&#x2030;Ľ ARE PYREXIA NAUSEA AND VOMITING 4HE MOST COMMON HEMATOLOGIC ABNORMALITIES FREQUENCY â&#x2030;Ľ ARE ANEMIA THROMBOCYTOPENIA NEUTROPENIA LYMPHOPENIA AND LEUKOPENIA

Discover the elements of efficacy and safety LEARN MORE AT WWW.TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be â&#x2030;Ľ 1 x 109/L and the platelet count should be â&#x2030;Ľ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naĂŻve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in â&#x2030;Ľ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant â&#x2030;ĽÂ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to â&#x2030;¤Â Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) â&#x2030;ĽÂ 1 x 109/L, platelets â&#x2030;ĽÂ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Reconstitution/Preparation for Intravenous Administration. t Aseptically SFDPOTUJUVUF FBDI 53&"/%" WJBM BT GPMMPXT t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP t NH 53&"/%" WJBM "EE N- PG POMZ Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be VTFE t "TFQUJDBMMZ XJUIESBX UIF WPMVNF OFFEFE GPS UIF SFRVJSFE EPTF CBTFE PO NH N- DPODFOUSBUJPO BOE immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2â&#x20AC;&#x201C;0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The BENJYUVSF TIPVME CF B DMFBS BOE DPMPSMFTT UP TMJHIUMZ ZFMMPX TPMVUJPO t 6TF 4UFSJMF 8BUFS GPS *OKFDUJPO 641 GPS reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride *OKFDUJPO 641 GPS EJMVUJPO BT PVUMJOFE BCPWF /P PUIFS EJMVFOUT IBWF CFFO TIPXO UP CF DPNQBUJCMF t 1BSFOUFSBM drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8Â°C or 36-47Â°F) or for 3 hours when stored at room temperature (15-30Â°C or 59-86Â°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber singleuse vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25Â°C (77Â°F) with excursions permitted up to 30Â°C (86Â°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. 50

Distributed by: Cephalon, Inc. Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. All rights reserved. ÂŠ2008-2012 Cephalon, Inc., or its affiliates. TRE-2500 TRE-2511a (Label Code: 00016287.06) This brief summary is based on TRE-2527 TREANDAfull fullPrescribing PrescribingInformation. Information. TRE-006 TREANDA

April 2012 August

Best Practices

Weight-Based Dosing Is Appropriate for Obese Patients Continued from cover Center at Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. “We should not be reducing chemotherapy doses in obese patients, which is what’s still happening in up to 40% of patients at this point.” Hourdequin and colleagues earned an ASCO Merit Award for their study. While chemotherapy dosing should be weight-based, it is not always done in clinical practice when the patient is obese. The problem is that with weight-based dosing, obese patients can receive doses of chemotherapy that seem inappropriately large, she said. “As a result, many oncologists fear there will be excess toxicity, and they respond by reducing the doses in obese patients,” she said. “Up to 40% of obese patients receive reduced doses, and evidence suggests that reducing chemotherapy doses or dose-intensities from the recommended standards may negatively impact survival.” Hourdequin and her team conducted a systematic review of the literature and identified studies that compared outcomes of obese versus normalweight adults receiving chemotherapy dosed according to actual body weight. The studies followed subjects for at least 1 cycle of chemotherapy and reported at least 1 prespecified outcome. Study Details Of 3921 studies, 5 met the inclusion criteria, for a total of 6877 subjects treated between 1995 and 2012. The review included 21 chemotherapy agents and 13 different cancers, suggesting the results have broad applicability among many commonly used chemotherapy agents. The majority of studies concluded that when chemotherapy was dosed by actual body weight, toxicity was lower or no different in obese versus normalweight patients. This was true for any grade 3/4 toxicity, for grade 3/4 hematologic toxicity, and by leukocyte nadir, Hourdequin said. In 3 studies, any grade 3/4 toxicity was observed in 556 of 1310 obese patients and in 1527 of 3847 normalweight patients, which produced an odds ratio of 0.74 favoring obese patients (P <.0001). In 3 studies, there were 182 grade 3/4 hematologic adverse events among 1480 obese patients and 493 events among 2873 normal-weight patients, for an odds ratio of 0.73 favoring the obese patients (P = .04). A study that compared leukocyte nadirs had variable results, depending on the regimen, dosing, and patient comorbidities. Three studies reported other toxicities (change in platelets,

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change in white blood cell counts, documented infections, and so forth), with variable findings. Three of 4 studies reported reduced overall survival in obese patients, though none of the studies reported a statistically significant difference.

“It would be a jump to recommend higher doses, but at a minimum we should not be reducing dosing in these patients,” Hourdequin concluded. ● references 1. Hourdequin KC, Schpero WL, Piazik BL, et al. Tox-

icity of chemotherapy dosing using actual body weight in obese versus normal-weight patients: a systematic review and meta-analysis. Poster presented at: 2012 ASCO Annual Meeting; June 1-5, 2012; Chicago, IL. 2. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2012;30(13): 1553-1561.

NOW AVAILABLE

KYPROLIS.com OCTOBER 2012 I VOL 5, NO 7

Breast Cancer

Continued Benefit for everolimus in Updated results of BOlerO-2 New Data Show Positive Effect on Bone By Caroline Helwick

Photo © ASCO/Todd Buchanan 2012.

pdated results from the pivotal phase 3 BOLERO-2 trial uphold, and even add to, the previous benefits reported for the addition of everolimus to exemestane in advanced breast cancer, including a positive effect on bone markers.1,2 The 18-month data from BOLERO-2 were reported at the American Society of Clinical Oncology 2012 Breast Cancer Symposium, held in San Francisco, California.

“Everolimus is the first and only treatment that boosts the effectiveness of endocrine therapy,” he said. “This approval redefines the treatment and management of advanced hormone receptor-positive breast cancer.” 18-Month Update Shows 55% reduction in risk At the Breast Cancer Symposium, Hope S. Rugo, MD, of the University of California San Francisco, reported,

“Patients who took everolimus not only had less bone loss but actually seemed to improve from baseline. This is an unusual finding.” —Hope S. Rugo, MD

BOLERO-2 is a phase 3, doubleblind, randomized, international trial comparing treatment with the aromatase inhibitor exemestane (25 mg once daily) plus the mammalian target of rapamycin (mTOR) inhibitor everolimus (10 mg once daily) or placebo in 724 postmenopausal women with advanced estrogen receptor-positive breast cancer who progressed or recurred after treatment with letrozole or anastrozole. In the previous 12-month analysis, the combination was associated with more than a doubling in disease-free survival, which led to the recent US Food and Drug Administration approval of the regimen after treatment with letrozole or anastrozole. The incorporation of an mTOR inhibitor into an endocrinebased regimen is a novel approach and represents a milestone in treating this disease, said Gabriel Hortobagyi, MD, chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, Houston, and the principal investigator of the pivotal trial.

“The progression-free survival [PFS] at the 18-month follow-up confirms the benefits observed at the 6.5-month and 12.5-month follow-ups, and the PFS benefits were consistent in all subgroups.” The study’s lead author was Francis P. Arena, MD.1 By local assessment, PFS was 7.8 months with everolimus/exemestane versus 3.2 months with exemestane alone, for a 55% reduction in risk. By central review, PFS was 11.0 months with the combination and 4.1 months with exemestane, for a 62% reduction in risk. The differences in each analysis were highly significant (P <.0001). Overall survival differences, however, have yet to emerge, although the difference between the arms is widening, she said. Mortality rates are 25.4% with the combination and 32.2% in the control arm, for an absolute difference of 6.8% favoring the everolimus arm. A post hoc analysis showed that, in addition to significantly improving PFS, everolimus plus exemestane does not compromise health-related quality of

life (Abstract 125).3 Whereas the combination resulted in higher rates of grade 3/4 toxicity, especially stomatitis and fatigue, and more patients discontinued treatment in the experimental arm, the analysis consistently showed that time to deterioration according to the 30-item EORTC QLQ-C30 score was actually longer, not shorter, with the combination, Rugo reported. Positive effects on Bone Markers and Progression in Bone In addition to delaying progression, an exploratory analysis of BOLERO-2 suggested that everolimus reduces bone turnover and reverses the increase in bone resorption associated with endocrine therapy, reported Lowell L. Hart, MD, of Florida Cancer Specialists in Fort Myers.2 Bone turnover markers analyzed at 6 and 12 weeks after treatment initiation included bone-specific alkaline phosphatase, amino-terminal propeptide of type 1 collagen, and C-terminal crosslinking telopeptide of type 1 collagen. Progressive disease in bone was defined as worsening of a preexisting bone lesion or a new bone lesion. In the placebo arm, bone-marker levels increased over baseline by more than 30%, but in the everolimus arm they actually decreased by more than 30%, for an absolute difference of 66%, Hart reported. At day 60, progressive disease in the bone was observed in 3.03% of the combination arm versus 6.16% of the control arm (P = .0263), and this trend was sustained beyond 6 months. Hart reported that the delay in bone progression was seen in patients with and without bone metastases at baseline, and regardless of the use of bisphosphonates. Fractures were observed in 2.3% of patients receiving the combination versus 3.8% on single-agent exemestane. The positive bone effects occurred in addition to the reported increase in PFS, and “data suggest favorable bone health clinical benefits,” Hart said. “The boneprotective effect with everolimus sug-

gests the potential for using everolimus in the adjuvant breast cancer setting for this purpose.” This hypothesis, in fact, will be tested in a trial by SWOG (Southwest Oncology Group). Rugo elaborated on these findings. “Patients who took everolimus not only had less bone loss but actually seemed to improve from baseline. This is an unusual finding,” she said, noting that it is in keeping with preclinical models that suggest that mTOR inhibitors alter the effect of exemestane on bone. “You are actually getting some buildup of the bone,” she pointed out, “which suggests that there is a site-specific effect with this targeted agent. This is exciting. It is not something we have seen much with other targeted agents.” Future Trials of everolimus BOLERO-4, an open-label, international, single-arm phase 2 study, will evaluate everolimus plus letrozole in 200 patients, who will also receive everolimus plus exemestane upon progression. The phase 2 BOLERO-6 trial will evaluate everolimus, with and without exemestane, versus capecitabine in 300 patients. The phase 2 PrECOG trial will evaluate fulvestrant plus everolimus in 132 patients. SWOG 2107 will move everolimus into the adjuvant setting, evaluating 5 years of endocrine therapy with and without everolimus in high-risk early breast cancer patients. ● references 1. Arena FP, Noguchi S, Pritchard KI, et al. Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 99. 2. Hart LL, Baselga J, Rugo HS, et al. Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets). Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 102. 3. Rugo HS, Beck JT, Baselga J, et al. BOLERO-2: Health-related quality-of-life (HRQoL) in metastatic breast cancer patients treated with everolimus and exemestane versus exemestane. Presented at: American Society of Clinical Oncology 2012 Breast Cancer Symposium; September 13-15, 2012; San Francisco, CA. Abstract 125.

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CONTINUING EDUCATION OCTOBER 2012 • VOLUME 5 • NUMBER 3

5th Annual

CONSIDERATIONS in

Multiple Myeloma

™

ASK THE EXPERTS: Transplant-Eligible and -Ineligible Patients LETTER

FROM THE

EDITOR-IN-CHIEF

PUBLISHING STAFF

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

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 third issue, experts from Washington University answer questions pertaining to the management of transplant-eligible and -ineligible patients.

Sincerely, Director, Production and Manufacturing Alaina Pede

Director, Creative and Design Robyn Jacobs

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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

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FACULTY

Web Coordinator Jose Valentin

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Bookkeeper Teresa Torgersen

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Ravi Vij, MD Associate Professor of Medicine Washington University School of Medicine Section of Stem Cell Transplant and Leukemia Division of Medical Oncology St. Louis, MO

Maggie Kavanaugh, ANP-BC Adult Nurse Practitioner Bone Marrow Transplant, Leukemia and Lymphoma Barnes-Jewish Hospital Washington University School of Medicine St. Louis, MO

Lindsay Hladnik, PharmD, BCOP Clinical Pharmacist, Hematologic Malignancies/SCT Barnes-Jewish Hospital/Washington University Department of Pharmacy St. Louis, MO

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

Circulation Department circulation@greenhillhc.com Center of Excellence Media, LLC 1249 South River Road Suite 202B Cranbury, NJ 08512

OCTOBER 2012 I VOL 5, NO 7

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

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CONSIDERATIONS IN MULTIPLE MYELOMA Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Celgene Corporation and Millennium: The Takeda Oncology Company. Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with multiple myeloma (MM). Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of MM. Physician Credit Designation The Medical Learning Institute Inc 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 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 Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours. Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-12-026-H01-P. Learning Objectives Upon completion of this activity, the participant will be able to: • Describe the impact of novel regimens for MM as they relate to

improved patient outcomes prior to and following transplantation • Evaluate the efficacy and safety of newer therapies for patients with MM who are ineligible for transplant • Review evidence-based strategies for preventing and managing adverse events commonly seen with novel agents used in the transplant and nontransplant settings for MM 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 offlabel discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc 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, ImClone, and Lilly; on the data monitoring committee for Infinity; on the Advisory Committee for Boehringer Ingelheim; and on the data monitoring committee and principal investigator on a study for Pfizer. Faculty Disclosures *Sagar Lonial, MD, is Consultant to Bristol-Myers Squibb, Celgene Corporation, Merck, Millennium: The Takeda Oncology Company, Novartis, and Onyx. *Ravi Vij, MD, is a consultant for Celgene Corporation and Onyx Pharmaceuticals, has received grant support from Celgene, and is on the speakers’ bureau for Celgene Corporation and Millennium: The Takeda Oncology Company. Maggie Kavanaugh, ANP-BC, is on the speakers’ bureau for Celgene Corporation. Lindsay Hladnik, PharmD, BCOP, has nothing to disclose. *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/CPE/CE activity for any amount during the past 12 months. Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the indepen dent 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. Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/ CPE/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/P12027.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 Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org. Estimated time to complete activity: 1.25 hours Date of initial release: October 12, 2012 Valid for CME/CPE/CE credit through: October 12, 2013

SCAN HERE to Download the PDF or Apply for Credit. To use 2D barcodes, download the ScanLife app: • Text “scan” to 43588 • Go to www.getscanlife.com on your smartphone’s Web browser, and select “Download” • Visit the app store for your smartphone

Frontline Therapy for Transplant-Eligible and -Ineligible Patients Ravi Vij, MD Associate Professor of Medicine, Washington University School of Medicine Section of Stem Cell Transplant and Leukemia Division of Medical Oncology, St. Louis, MO

Introduction The use of novel targeted therapies has significantly improved outcomes in multiple myeloma (MM). The impact of these agents has been especially impressive in the frontline setting, both for pretransplant induction regimens, as well as for the initial treatment of patients not eligible for transplant. In this article, Ravi Vij, MD, discusses recent data from key clinical trials of newer combination regimens for myeloma and provides insights regarding the selection of therapeutic approaches in the era of novel agents.

How has the use of novel frontline therapies improved outcomes in transplant-eligible patients with MM?

There is no doubt that the incorporation of thalidomide, bortezomib, and lenalidomide into frontline combinations has greatly improved complete response (CR) rates, especially when these therapies are used in triplet regimens. Follow-up data from phase 3 clinical trials extending 1 to 2 years or longer are showing a progression-free survival (PFS) advantage with many newer combinatioms. Our hope is that with extended followup, this will translate into an overall survival (OS) advantage, as CR has been shown to be a surrogate for this end point in numerous clinical trials.

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In the Total Therapy 2 trial, incorporation of thalidomide not only improved CR and very good partial response (VGPR) rates following autologous stem cell transplant (ASCT), but it also translated into better PFS and OS in specific subsets of patients with MM.1-3 Prolonged 5-year OS was reported in younger patients (<65 years of age), with longer 5-year eventfree survival (EFS) and OS reported in complete responders to therapy.1 Trials that compared thalidomide-based combinations with vincristine, doxorubicin, and dexamethasone have reported improvements in response and PFS in patients treated with thalidomide as part of induction therapy.4,5 In a 2012 meta-analysis,6 which included 2 randomized trials of thalidomide,2,5 the use of this agent was shown to improve CR and PFS (but not OS) compared with chemotherapy. In a seminal group of clinical trials, bortezomib-based therapies improved response rates and PFS versus comparator regimens in the transplant setting (Table 1).7-10 The 2012 meta-analysis mentioned above,6 which included 3 randomized trials of bortezomib,7,8,11 reported improved CR and PFS with regimens using this agent. Though not yet studied in a randomized clinical trial, the 3-drug combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) is also a commonly used pretransplant induction regimen. There are no randomized studies of lenalidomide specifically in the pretransplant setting. The best data on this agent as induction come from the ECOG E4A03 trial of lenalidomide plus dexamethasone in a patient population that could choose between transplant or continuing with the initial regimen.12 In this trial, lenalidomide plus low-dose dexamethasone (Rd) was associated with better OS at 1 year versus lenalidomide plus high-dose dexa-

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CONTINUING EDUCATION

Table 1. Bortezomib-Based Induction Prior to Transplant7-10

Trial

Regimen

CR + VGPR Postinduction (%)

CR + VGPR Post-ASCT (%)

PFS

VTD vs TD

236

62a

82a

68% at 3 yr

238

56% at 3 yr

VD vs VAD

223

37.7a

67.7a

Median 36 mo

218

15.1

46.7

Median 29.7 mo

PAD vs VAD

308

42a

76b

Median 36 mo

305

Median 27 mo

VD vs vTD

Median 30 mo

100

49c

74d

Median 26 mo

Cavo et al7

Harousseau et al IFM 2005-018

Sonneveld et al HOVON-659

Moreau et al IFM 2007/0210

P Value

.0057

.063

.005

.22

a P<.001; bP=.001; cP=.05; dP=.02. ASCT indicates autologous stem cell transplant; CR, complete response; PAD, bortezomib, doxorubicin, and dexamethasone; PFS, progression-free survival; TD, thalidomide and dexamethasone; VAD, vincristine, doxorubicin, and dexamethasone; VD, bortezomib and dexamethasone; VGPR, very good partial response; vTD, reduced-dose bortezomib, thalidomide, and dexamethasone; VTD, bortezomib, thalidomide, and dexamethasone.

Table 2. RD Plus ASCT versus Rd: Results from the ECOG E4A03 Trial12,13

1-Year Survival Probability

3-Year Survival Probability

All patients

141

.94

.78

RD patients

.89

.79

Rd patients

.97

.78

All patients

1.0

.94

RD patients

1.0

.95

Rd patients

1.0

.93

Treatment No Early Transplant

bination.14 In patients with renal insufficiency, which requires lenalidomide dose reduction,15 I often substitute cyclophosphamide for lenalidomide and treat patients with CyBorD.16 In this population, bortezomib-based regimens may offer the best chance of reversing renal dysfunction.17 In addition, there is evidence from several trials that including bortezomib as part of the initial treatment regimen overcomes certain high-risk cytogenetics in MM.7,9,14 Over the past 18 months, we have been administering bortezomib as a subcutaneous injection, based on data showing that subcutaneous dosing offers equivalent response to treatment and reduced peripheral neuropathy compared with intravenous dosing.18

Early Transplant

ASCT indicates autologous stem cell transplant; Rd, lenalidomide plus low-dose dexamethasone; RD, lenalidomide plus high-dose dexamethasone.

methasone (RD) (96% vs 87%, respectively; P=.0002), which was attributed to a greater incidence of toxicity-related deaths during the first 4 cycles in the high-dose dexamethasone group. Subsequent analysis of patients who survived the first 4 cycles in this trial showed that those patients treated with either regimen who had undergone early ASCT had superior survival at 1 and 3 years posttransplant compared with those who did not undergo early ASCT (Table 2). This advantage for postinduction ASCT was observed in both younger and older age groups.12,13 In a recent phase 1/2 trial of newly diagnosed patients, treatment with lenalidomide, bortezomib, and dexamethasone (RVD) led to favorable results, with 100% of patients in the phase 2 population achieving a partial response or better and 74% achieving VGPR, with good tolerability.14 Three-drug regimens such as this, which combine 2 novel agents plus 1 conventional drug, may be an optimal choice for induction as long as there are no contraindications. What is your approach to selecting induction therapy for transplanteligible patients?

In my practice, I tend to favor triplet regimens over doublet regimens. We commonly use RVD, given the impressive response data seen with this com-

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Do you think that the improved efficacy seen with newer induction regimens will allow patients to delay transplant?

Expert opinions vary widely regarding this topic. Certainly, the Group Myelome-Autogreffe trial showed that ASCT produced a median OS exceeding 5 years in younger patients with symptomatic MM, whether performed early (as frontline therapy) or late (as rescue treatment). However, median EFS, average time without symptoms, treatment, and treatment-related toxicity (TWiSTT) analysis favored early transplant.19 Patients in this trial received 3 or 4 treatments with vincristine, doxorubicin, and methylprednisone pretransplant.19 Unfortunately, there are no prospective studies designed to replicate this trial in the age of thalidomide, bortezomib, and lenalidomide. However, a retrospective analysis did show that, among patients who received immunomodulatory drugs (ie, lenalidomide or thalidomide) in frontline therapy, followed by early stem-cell mobilization, delaying ASCT resulted in an OS similar to that observed with early ASCT.20 In my practice, I do continue to advocate taking patients to transplant early in the course of the disease. I may delay ASCT in specific situations, such as for a patient with a poor performance status after induction or an individual who is extremely reluctant to undergo transplant. However, I do strongly urge these patients to undergo ASCT at first progression, if they are able. There are no data to suggest that delaying transplant beyond first progression provides the same benefits and survival as early transplant. Some oncologists suggest delaying ASCT in patients who achieve CR during induction with novel therapies. This is a rational argument, but not an

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CONSIDERATIONS IN MULTIPLE MYELOMA

approach I have personally adopted, as ASCT is likely to provide more durability to the response even in these patients.

Figure. Median Progression-Free Survival in a Comparative Trial of MPR-R, MPR, and MP27

Which newer frontline therapies are effective for transplant-ineligible patients?

Conclusion

Today, there are numerous effective frontline regimens available for transplant-eligible and -ineligible patients. Choosing an appropriate therapy requires a thorough evaluation of patient-related factors, including performance

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MPR-R

* 30

MPR

Months

In the nontransplant setting, most randomized trials have evaluated the safety and efficacy of adding a novel agent to melphalan plus prednisone (MP). Five such trials were conducted using thalidomide plus MP (MPT); all showed superior PFS. However, only 2 trials showed an OS advantage.21 The VISTA trial compared bortezomib plus MP (VMP) with MP alone in newly diagnosed, transplant-ineligible patients.22-24 Results of this trial, after 5 years of follow-up, showed a sustained OS advantage with the 3-drug regimen.24 Mateos and colleagues recently compared VMP with bortezomib, thalidomide, and prednisone (VTP) in patients who were 65 years of age. Results showed essentially equivalent overall response rates after induction with these 2 therapies (80% with VMP vs 81% with VTP), and similar 1-year OS rates (92% and 89%, respectively).25 However, it is important to note that investigators in this trial incorporated 2 different maintenance strategies after initial therapy: bortezomib plus prednisone and bortezomib plus thalidomide. The use of these maintenance regimens made it more difficult to analyze the effect of frontline therapy on outcomes. In the community-based, open-label UPFRONT study, older transplantineligible patients received 24 weeks of induction therapy with 1 of 3 regimens: bortezomib plus dexamethasone (VD), bortezomib, thalidomide, and dexamethasone (VTD), or VMP.26 Regardless of the frontline regimen assigned, all patients were treated with bortezomib maintenance therapy for 25 weeks. Overall, the investigators concluded that the 3 regimens were relatively similar in efficacy and yielded encouraging results for this population. Lenalidomide-based therapy for transplant-ineligible patients was recently investigated in the randomized MM-015 trial, which compared melphalan, prednisone, and lenalidomide (MPR) versus MPR followed by lenalidomide maintenance (MPR-R) versus MP alone.27 In this trial, there was a significant PFS advantage seen with MPR-R (Figure), but the benefit was limited to patients who were between 65 and 75 years of age. None of the arms showed an OS advantage. In all of these trials, MP was used as both the comparator and a component of the study regimen, which was necessary for drug approval by the US Food and Drug Administration. However, few would accept MP as a clinical standard. Melphalan is a slow-acting drug with potential to cause substantial myelosuppression and is being used less frequently in the frontline setting. Certainly, early follow-up from the UPFRONT study suggests that nonâ&#x20AC;&#x201C;melphalan-containing bortezomib combinations provide similar CR and OS rates.26 Currently, we are eagerly awaiting results from the multicenter, phase 3 MM-020 study (also known as the FIRST trial), which is evaluating the safety and efficacy of Rd given until disease progression versus Rd for 18 4-week cycles versus MPT for 12 6-week cycles.28 Another important fact to keep in mind is that the definition of transplantineligible continues to evolve. Today we are performing more and more transplants in patients who are 65 years of age. In my view, the truly transplantineligible population is older than 75 years of age. For this elderly population, we do not have sufficient data on the tolerability of regimens such as VMP, MPT, or MPR, and more studies are needed.21-23

20 15 10

5 0 All Patients

*Median progression-free survival significantly longer in MPR-R group than in MP or MPR groups ( <.001). MP indicates melphalan plus prednisone; MPR, melphalan, prednisone, and lenalidomide; MPR-R, melphalan, prednisone, lenalidomide, followed by continuous lenalidomide maintenance.

status, comorbidities, and disease-related features. It is also important to consider the efficacy and toxicity profiles of specific agents and combination regimens so that therapy can be tailored to the individual needs of each patient. Patient preference, based on factors such as route of administration and affordability, may play a role in determining the choice of therapy. Deciding when to initiate ASCT in eligible candidates is also a complex decision that involves careful consideration of risks, benefits, and patient preferences.

References 1. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030. 2. Barlogie B, Pineda-Roman M, van Rhee F, et al. Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112:3115-3121. 3. Barlogie B, Attal M, Crowley J, et al. Long-term follow-up of autotransplantation trials for multiple myeloma: update of protocols conducted by the Intergroupe Francophone du Myelome, Southwest Oncology Group, and University of Arkansas for Medical Sciences. J Clin Oncol. 2010;28:1209-1214. 4. Macro M, Divine M, Uzunhan Y, et al. Dexamethasone + thalidomide (Dex/Thal) compared to VAD as a pre-transplant treatment in newly diagnosed multiple myeloma (MM): a randomized trial. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 57. 5. Lockhorst HM, van der Holt B, Zweegman S, et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010;115:1113-1120. 6. Wang L, Ran X, Wang B, Sheng Z, Liu L. Novel agents-based regimens as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: a metaanalysis of randomized controlled clinical trials. Hematol Oncol. 2012;30:57-61. 7. Cavo M, Tacchetti P, Patriarca F, et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376:2075-2085. 8. Harousseau J-L, Attal M, Avet-Loiseau H, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial. J Clin Oncol. 2010;28:4621-4629. 9. Sonneveld P, Schmidt-Wolf I, ven 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. 10. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood. 2011;118:5752-5758. 11. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al. First analysis of HOVON-65/GMMGHD4 randomized phase III trial comparing bortezomib, adriamycin, dexamethasone (PAD) vs VAD as induction treatment prior to high dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2008;112:Abstract 653. 12. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 13. Siegel DS, Jacobus S, Rajkumar SV, et al; on behalf of the Eastern Cooperative Oncology Group. Outcome with lenalidomide plus dexamethasone followed by early autologous stem cell trans-

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CONTINUING EDUCATION

plantation in the ECOG E4A03 randomized clinical trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 38. 14. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 15. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012. 16. Reeder CB, Reece DE, Kukreti V, et al. Cyclophosphamide, bortezomib and dexamethasone (CyBorD) induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 17. Dimopoulos MA, Terpos E, Chanan-Kahn A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 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. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood. 1998;92:3131-3136. 20. Kumar SK, Lacy MQ, Dispenzieri A, et al. Early versus delayed autologous transplantation after immunomodulatory agents-based induction therapy in patients with newly diagnosed multiple myeloma. Cancer. 2012;118:1585-1592. 21. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. Leukemia. 2011;25:689-696. 22. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone or ini-

tial treatment of multiple myeloma. N Engl J Med. 2008;359:906-917. 23. 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; 28:2259-2266. 24. San Miguel JF, Schlag R, Khuageva NK, et al. Continued overall survival benefit after 5 years’ follow-up with bortezomib-melphalan-prednisone (VMP) versus melphalan-prednisone (MP) in patients with previously untreated multiple myeloma, and no increased risk of second primary malignancies: final results of the phase 3 VISTA trial. Blood (ASH Annual Meeting Abstracts). 2011;118:Abstract 476. 25. Mateos M-V, Oriol A, Teruel A-I, et al. Maintenance therapy with bortezomib plus thalidomide (VT) or bortezomib plus prednisone (VP) in elderly myeloma patients included in the GEM 2005MAS65 Spanish randomized trial. Blood (ASH Annual Meeting Abstracts). 2011;118: Abstract 477. 26. Niesvizky R, Flinn IW, Rifkin R, et al. Efficacy and safety of three bortezomib-based combinations in elderly, newly diagnosed multiple myeloma patients: results from all randomized patients in the community-based, phase 3b UPFRONT study. Blood (ASH Annual Meeting Abstracts). 2011; 118:Abstract 478. 27. Palumbo A, Hajek R, Delforge M, et al; MM-015 Investigators. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:1759-1769. 28. Study to determine efficacy and safety of lenalidomide plus low-dose dexamethasone versus melphalan, prednisone, thalidomide in patients with previously untreated multiple myeloma (FIRST) (NCT00689936). http://www.clinicaltrials.gov/ct2/show/NCT00689936?term=nct00689936& rank=1. Accessed September 26, 2012.

Nursing Considerations in the Frontline Treatment Setting Maggie Kavanaugh, ANP-BC Adult Nurse Practitioner Bone Marrow Transplant, Leukemia and Lymphoma Barnes-Jewish Hospital Washington University School of Medicine, St. Louis, MO

Introduction In the frontline setting for multiple myeloma (MM), multidrug regimens based on novel agents can generate a range of adverse events (AEs) that require nursing intervention. Transplant-eligible patients must cope with the effects of induction followed by the impact of autologous stem cell transplant (ASCT). Patients ineligible for transplant—typically, the elderly or those compromised by comorbidities—face elevated drug toxicity risks. In this article, Maggie Kavanaugh, ANP-BC, discusses the nurse’s role in navigating such risks,

receive adequate hydration, and we offer nutritional counseling. The advent of subcutaneous dosing of bortezomib also has reduced the GI toxicity associated with use of this agent.5 We monitor hepatic function in patients scheduled to receive bortezomib, since dosing must be adjusted when a patient experiences hepatic impairment.2 With lenalidomide administration, doses need to be reduced in patients with renal dysfunction, so monitoring of serum creatinine and creatinine clearance must be performed routinely (Table 1).3 The use of bortezomib has been shown to affect blood glucose control in patients with comorbid diabetes.2 When bortezomib is combined with dexamethasone—a corticosteroid that can induce hyperglycemia6—blood glucose levels must be watched closely. All 3 of these novel agents can cause peripheral neuropathy (PN), although our experience is that both the risk and the severity of PN may be greater with bortezomib and thalidomide than with lenalidomide. Now that we have the ability to administer bortezomib subcutaneously, we are able to reduce the risk and severity of PN associated with this agent.5 Baseline assess-

so as to balance treatment efficacy with patient comfort.

How do you manage common AEs associated with frontline regimens in the transplant-eligible patient?

Many drugs used in frontline regimens for MM are associated with hematologic toxicities—neutropenia, anemia, thrombocytopenia. Compounding the problem is the anemia associated with the myeloma disease process itself.1 For these reasons, weekly monitoring of blood counts is an essential part of patient care. Monitoring enables us to make adjustments to dosing and to determine whether the initiation of treatment is improving an individual’s myeloma-related anemia. We also need to monitor metabolic, hepatic, renal, and gastrointestinal (GI) function on a regular basis. Bortezomib, lenalidomide, and thalidomide are associated with diarrhea, nausea, and constipation,2-4 all of which can, in turn, impact quality of life and nutritional status. We ensure that patients

OCTOBER 2012 I VOL 5, NO 7

Table 1. Suggested Lenalidomide Dose Reductions for Renal Impairment3 Degree of Renal Dysfunction

Renal Function (Cockcroft-Gault CrCl)

Moderate

30-60 mL/min

10 mg orally every 24 hours

Severe (not on dialysis)

<30 mL/min

15 mg orally every 48 hours

End-stage renal disease (on dialysis)

<30 mL/min

5 mg orally every 24 hoursa

Dose for MM

CrCl indicates creatinine clearance; MM, multiple myeloma. a Doses that fall on dialysis days should be given after dialysis.

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CONSIDERATIONS IN MULTIPLE MYELOMA

ment of neuropathy, with follow-up evaluation at every visit, is the best way to ensure that we detect developing PN early. We are then able to modify or discontinue a patient’s dose before symptoms erode his or her functional status. An important part of the neurologic assessment is a review of all medications the patient takes for comorbid conditions, since some of these drugs may also cause or exacerbate PN. These would include certain antihypertensives and anticonvulsants, as well as drugs used to treat rheumatoid arthritis and gout. Some prophylactic treatment is required with novel therapies. Since herpes zoster virus reactivation is a risk associated with bortezomib use,2 we administer antiviral prophylaxis. When a patient is also treated with dexamethasone, we sometimes provide chemoprophylaxis for fungal and Pneumocystis jirovecii pneumonia infections.7

Table 2. Risk Assessment for VTE Prophylaxis in Patients Treated with Immunomodulatory Agents10-13 Individual Risk Factors

Treatment-Related Risk Factors High-dose dexamethasone ( 480 mg/month or 120 mg/week)

Obesity (BMI 30 kg/m ) Previous VTE Central venous catheter or pacemaker Chronic renal disease (CrCl <40 mL/min)

Doxorubicin Combination chemotherapy

Diabetes Medications (erythropoietin, estrogen) Immobility General surgery Trauma (major or lower extremity)

How do you counsel patients and their families before and after ASCT?

In the pretransplant phase, patients need to undergo testing of major organ systems to verify transplant eligibility. It is the nurse’s responsibility to explain the need for these tests. We also discuss the process by which stem cells will be collected and educate patients on the goal of ASCT: to deliver very high doses of chemotherapy, safely, by collecting blood cells ahead of time and then reinfusing them later. Considerable confusion surrounds the word “transplant,” so it is imperative that we explain the ASCT process very carefully to both patients and their families. Prior to transplantation, a social worker from our team will conduct a psychosocial evaluation of the patient. This assessment is designed to identify patient needs for emotional support, caregiving, housing, financial assistance, and any other matter that could affect recovery. At this time, we may discover that a patient is experiencing anxiety or depression, and we will refer that person for the necessary psycho/oncology services. We may also ascertain that the caregiver needs some support to navigate through these services. Because we are now performing more transplants in patients aged 65 to 70 years, we must remember to focus on needs related to elderly patients, including psychosocial issues associated with aging, Medicare reimbursement, or the lack of a spouse/caregiver. Once the transplantation process has begun, nurses must continue counseling and educating patients appropriately. A major issue posttransplant is securing insurance coverage for supportive medications, such as prophylactic antibiotics, antiemetics, or proton pump inhibitors. We work with families to help them manage reimbursement and costs. We also follow patients to ensure that they start the recommended reimmunization process 6 months posttransplant.8 In patients who are ineligible for transplant because of age or comorbidities, what strategies do you use to balance the need for efficacy with the need to prevent AEs?

The nontransplant population today consists mainly of patients who are quite elderly, with poor performance status and marked comorbidities such as cardiac problems, poorly controlled hypertension or diabetes, pulmonary issues, and renal impairment with dialysis. Obviously, any pharmacologic treatment in these patients can be risky. We try to tailor the regimen to the patient’s specific comorbidity in order to manage risk. For example, when renal impairment is present, we will consider a bortezomib-based regimen, because strong evidence suggests that this agent can reverse renal dysfunction in patients with MM.9 In patients receiving immunomodulatory drugs in combination with steroids, it is imperative to provide effective venous thromboembolism prophylaxis when recommended (Table 2).10-13 In the elderly population, an all-oral regimen, such as lenalidomide plus

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Blood-clotting disorders Number of Risk Factors

Prophylaxis

0-1

Aspirin 81-325 mg daily

LMWH (enoxaparin 40 mg SC daily, or equivalent) Warfarin (INR 2-3)

BMI indicates body mass index; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; SC, subcutaneously; VTE, venous thromboembolism.

dexamethasone, may be advantageous. Oral therapy means less travel to and from the center for treatments, which is helpful in older patients who may be dependent on family members for transportation. With the use of oral regimens, however, we need to ensure that no factors are present that will predispose a patient to nonadherence, such as dementia or lack of a live-in caregiver. We always provide medication diaries for patients to help support compliance. Conclusion

Although current frontline therapies for MM have improved patient outcomes, they require close monitoring and timely action to minimize AEs. Active, prompt nursing intervention is needed to manage the toxicities associated with the use of multidrug regimens, reduce the impact of ASCT, and minimize risks among elderly or vulnerable patients. References 1. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-23. 2. Velcade [package insert]. Cambridge, MA: Millennium Pharmaceuticals, Inc; June 2012. 3. Revlimid [package insert]. Summit, NJ: Celgene Corporation; May 2012. 4. Thalomid [package insert]. Summit, NJ: Celgene Corporation; August 2010. 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. Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. Endocr Pract. 2009;15:469-474. 7. Worth LJ, Dooley MJ, Seymour JF, Mileshkin L, Slavin MA, Thursky KA. An analysis of the utilisation of chemoprophylaxis against Pneumocystis jirovecii pneumonia in patients with malignancy receiving corticosteroid therapy at a cancer hospital. Br J Cancer. 2005;92:867-872. 8. Centers for Disease Control and Prevention; Infectious Diseases Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation. MMWR Recomm Rep. 2000;49(RR10):1-128. 9. Dimopoulos MS, Terpos E, Chanan-Kahn A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984. 10. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomideassociated thrombosis in myeloma. Leukemia. 2008;22:414-423. 11. Klein U, Kosely F, Hillengass J, et al. Effective prophylaxis of thromboembolic complications with low molecular weight heparin in relapsed multiple myeloma patients treated with lenalidomide and dexamethasone. Ann Hematol. 2009;88:67-71. 12. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S-453S. 13. Palumbo A, Cavo M, Bringhen S, et al. Aspirin, warfarin, or enoxaparin prophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;29:983-993.

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Pharmacologic Considerations in the Frontline Treatment Setting Lindsay Hladnik, PharmD, BCOP Clinical Pharmacist, Hematologic Malignancies/SCT Barnes-Jewish Hospital/Washington University Department of Pharmacy St. Louis, MO

Introduction The management of multiple myeloma (MM) is rapidly changing, with novel agents and combination regimens providing improved rates of response and survival. However, to provide optimal benefits for patients, it is imperative to consider factors such as medical comorbidities, treatment-related toxicities, and the inherent, myelomarelated risks of bone disease and thromboembolism. In this article, Lindsay Hladnik, PharmD, BCOP, describes the role of the pharmacist in identifying and addressing the needs of each patient, to individualize drug selection and dosing strategies.

What is the impact of newer dosing forms or schedules on frontline MM treatment?

61% after 4 cycles of treatment.3 In this study, oral cyclophosphamide 300 mg/m2 was given weekly on days 1, 8, 15, and 22; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11; and oral dexamethasone 40 mg on days 1 to 4, 9 to 12, and 17 to 20, in a 28-day cycle. A second cohort of patients were administered a modified regimen in hopes of reducing toxicity while maintaining dose delivery.4 This cohort received the same weekly cyclophosphamide schedule; weekly bortezomib 1.5 mg/m2 IV on days 1, 8, 15, and 22; and the same dexamethasone schedule for cycles 1 and 2, then 40 mg once weekly for cycles 3 and 4. The modified schedule of once-weekly bortezomib demonstrated comparable efficacy, with an ORR of 93%, and a VGPR rate of 60% after 4 cycles of therapy. The once-weekly bortezomib cohort experienced less grade 3/4 toxicities compared with the twice-weekly bortezomib cohort (37%/3% vs 48%/12%). There were also fewer dose reductions of bortezomib (13% vs 21%) and dexamethasone (20% vs 30%). Neuropathy rates were similar (57% once-weekly vs 64% twice-weekly) although the total bortezomib dose per cycle was higher in the once-weekly cohort (6 mg/m2) versus the twice-weekly cohort (5.2 mg/m2). This modified dosing schedule of CyBorD was reported in a small cohort of patients (N=30), but seems to maintain efficacy while offering a more convenient option for patients, possibly increasing therapy compliance, and with less adverse events. Low-dose dexamethasone plus lenalidomide

Subcutaneous bortezomib

In January 2012, the US Food and Drug Administration approved subcutaneous (SC) administration of bortezomib for the treatment of MM. One of the studies leading to the approval was the MMY-3021 trial, which compared the safety and efficacy of SC versus intravenous (IV) administration of the drug.1 This was an international, multicenter, phase 3, open-label trial that randomized patients with relapsed MM to receive up to 8 21-day cycles of bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11, administered by SC injection or IV push. SC administration was noninferior to IV when assessed for the primary efficacy endpointâ&#x20AC;&#x201D;overall response rate (ORR) after 4 cycles of single-agent treatment (42% in each arm). Rates of complete response (CR), near-complete response, and very good partial response (VGPR) after 4 cycles; ORR after 8 cycles (with or without the addition of dexamethasone); time to response; duration of response; time to progression (TTP); progression-free survival (PFS); and 1-year overall survival (OS) were similar between treatment arms. However, the SC route demonstrated improved tolerability compared with the IV route, especially in terms of peripheral neuropathy (PN) (Table).1 Guidelines for the treatment of MM set forth by the National Comprehensive Cancer Network recognize SC bortezomib as an option for patients with preexisting or high-risk PN.2 This route of administration may also offer a more convenient means of drug delivery for certain patients who have poor venous access, or it may decrease the need for repeated access of a central venous catheter.

Lenalidomide combined with low-dose dexamethasone is an acceptable induction option in newly diagnosed MM. The phase 3 open-label, noninferiority ECOG E4A03 trial randomized patients to receive either lenalidomide plus high-dose dexamethasone (RD; oral lenalidomide 25 mg/day on days 1-21 plus oral dexamethasone 40 mg/day on days 1-4, 9-12, and 17-20 of each 28-day cycle) or lenalidomide plus low-dose dexamethasone (Rd; same schedule of lenalidomide plus oral dexamethasone 40 mg/day on days 1, 8, 15, and 22 of each 28-day cycle).5 Despite the fact that the ORR rate (CR + partial response) after 4 cycles was higher with RD versus Rd (79% vs 68%; P=.008), this did not translate into an improvement in TTP, PFS, or OS in the RD arm. The trial was stopped early, and patients were allowed to cross over from the high-dose to low-dose dexamethasone arm because OS was significantly higher with Rd than with RD (1-year OS: 96% vs 87%; P=.0002). This difference was thought to be related to increased toxicities seen with RD versus Rd, including deep vein thrombosis/pulmonary embolism (26% vs 12%; P=.0003) and infections (16% vs 9%; P=.04). The

Table. Incidence of Peripheral Neuropathy in the Phase 3 MMY-3021 Trial1 SC Bortezomib (N=147), N (%)

IV Bortezomib (N=74), N (%)

P Value

Any peripheral neuropathy

56 (38%)

39 (53%)

.044

Once-weekly bortezomib

Grade 2

35 (24%)

30 (41%)

.012

One of the induction regimens we use at our institution is the combination of cyclophosphamide, bortezomib, and dexamethasone (CyBorD), based on results from a phase 2 study showing an ORR of 88%, with a VGPR rate of

Grade 3

9 (6%)

12 (16%)

.026

OCTOBER 2012 I VOL 5, NO 7

IV indicates intravenous; SC, subcutaneous.

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CONSIDERATIONS IN MULTIPLE MYELOMA

incidence of early mortality within the first 4 months was 5% with RD and 0.5% with Rd (P=.003). Rd may be preferred over RD for induction in patients 65 years of age, given the fact that the inferior survival outcome with high-dose dexamethasone was greater in this age group. What are your strategies for initiating bisphosphonate support for patients with MM?

Bone involvement is common in myeloma, and it is extremely important to prevent skeletal-related events in this patient population, in hopes of maintaining quality of life and performance status. Bisphosphonate therapy is recommended for all MM patients with lytic destruction of bone or compression fracture of the spine from osteopenia detected on plain radiographs or imaging studies.6 It is reasonable to initiate therapy in patients with osteopenia but without evidence of documented lytic bone involvement.6 Acceptable options for therapy include pamidronate 90 mg IV over at least 2 hours or zoledronic acid 4 mg IV over at least 15 minutes, every 3 to 4 weeks. Therapy may be continued for a 2-year duration. Further use should be at the physician’s discretion and on an individualized basis.6 The initiation of bisphosphonate therapy is not recommended in patients with a solitary plasmacytoma, smoldering/indolent myeloma, or with monoclonal gammopathy of undetermined significance.6 Patients must have their renal function monitored during bisphosphonate therapy, including a serum creatinine prior to each dose, as zoledronic acid and pamidronate have both been associated with renal deterioration.6 The dose of zoledronic acid should be adjusted in patients with mild-to-moderate renal impairment (creatinine clearance [CrCl]) 30-60 mL/min) per the manufacturer’s package insert.7 With pamidronate, no dosing guidelines are available for patients with preexisting renal impairment.8 Guidelines published by the American Society of Clinical Oncology (ASCO) recommend that healthcare professionals consider a dose reduction of the initial pamidronate dose in this setting.6 Neither the package labeling for zoledronic acid nor pamidronate recommend the use of these agents in patients with severe renal impairment.7,8 Patients with a serum creatinine >3 mg/dL were excluded in studies and limited pharmacokinetic data exist in patients with a CrCl <30 mL/min.7,8 However, in this population, ASCO guidelines state that pamidronate 90 mg IV over 4 to 6 hours may be administered to patients with extensive bone disease in the setting of existing severe renal impairment.6 In the setting of renal deterioration, bisphosphonate therapy should be withheld and further work-up initiated. Other considerations during bisphosphonate therapy include the risk of developing osteonecrosis of the jaw. Prior to initiating bisphosphonate therapy, it is recommended that patients undergo a comprehensive dental examination and preventive dentistry.6 Active oral infections should be appropriately treated and areas at high risk for infection should be eliminated.6 During therapy, patients should maintain good oral hygiene and invasive dental procedures should be avoided, if possible. What is the pharmacist’s role within the interdisciplinary team in ensuring the safety and efficacy of treatment?

The oncology pharmacist has an integral role among the interdisciplinary team to ensure therapies are being administered in the most safe and efficacious manner possible. The treatment of MM is complex, and therapies continue to evolve as new data become available. It is important for us to help prevent and manage complications and toxicities that are associated with

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treatment. Supportive care issues such as bone health, as previously discussed, along with others such as venous thromboembolism (VTE) prophylaxis and medication dose adjustments for renal dysfunction, are just a few of the issues that need to be addressed by our team. There are several risk factors, both patient and therapy related, that must be considered when evaluating VTE risk in MM. The International Myeloma Working Group (IMWG) has published guidelines on risk assessment and prophylaxis of VTE in this population.9 These recommendations take into account certain antimyeloma therapies, such as the combination of immunomodulators (thalidomide and lenalidomide) with high-dose steroids, which increase the risk of VTE and warrant prophylaxis, provided contraindications do not exist. Renal impairment (serum creatinine 2 mg/dL) is common in MM, occurring in approximately 20% of newly diagnosed patients, and in more than 50% of patients some time during the course of their disease.10 Several management strategies have been recommended for MM patients with renal impairment, including hydration; management of hypercalcemia and/or hyperuricemia; avoidance of nonsteroidal anti-inflammatory drugs, loop diuretics, IV contrast, and other potentially nephrotoxic medications.10 When systemic therapy for MM is initiated, however, it is important to evaluate the need for dose adjustment based upon renal dysfunction. Dose adjustments for renal impairment are necessary for agents such as lenalidomide and melphalan. The IMWG has published guidelines for the management of MM patients with renal impairment11 and addresses these issues. Of course, it is also important to evaluate the patient’s entire medication profile and adjust accordingly for the degree of renal impairment. Conclusion

Advances in frontline therapies for MM have led to improved response rates and survival. Working with the interdisciplinary team to ensure safe and efficacious administration of these therapies is vital to optimize outcomes. Additionally, the management of supportive care issues are crucial to maintain the best quality of life for our patients.

References 1. 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. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed October 1, 2012. 3. Reeder C, Reece D, Kukreti V, et al. Cyclophosphamide, bortezomib, and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009;23:1337-1341. 4. Reeder CB, Reece DE, Kukreti V, et al. Once- versus twice-weekly bortezomib induction therapy with CyBorD in newly diagnosed multiple myeloma. Blood. 2010;115:3416-3417. 5. Rajkumar SV, Jacobus S, Callander NS, et al; for the Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29-37. 6. Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472. 7. Zometa [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. March 2012. 8. Aredia [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008. 9. Palumbo A, Rajkumar SV, Dimopolous MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:414-423. 10. Gaballa MR, Laubach JP, Schlossman RL, et al. Management of myeloma-associated renal dysfunction in the era of novel therapies. Expert Rev Hematol. 2012;5:51-68. 11. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:4976-4984.

OCTOBER 2012 I VOL 5, NO 7

Cancer Center Profile Cancer Institute of New Jersey Continued from cover The Oncology Pharmacist spoke with Michael P. Kane, RPh, BCOP, director of Oncology Pharmacy Services at CINJ, about care at CINJ and the evolving role of the oncology pharmacist.

What approach does your institution take to treating people with cancer?

Michael P. Kane (MPK): We have a well-rounded model of multidisciplinary care, with the patient at the center of the paradigm respected as equally important in decision making. This model gives the patient access to all disciplines involved in cancer treatment along the trajectory of care. Overlaying this paradigm, we recognize

that participation in a clinical trial represents the best care option when available.

How does this model translate to better outcomes for your patients? MPK: As pharmacists and the pharmacy department play a strong role in that paradigm, we resolve all clinical

Individualizing Treatment for DCIS of the Breast: New Molecular Approaches LOG ON TODAY TO PARTICIPATE

www.coexm.com/ace09 TARGET AUDIENCE This initiative will target medical oncologists, hematologists, breast surgeons, radiation oncologists, oncology nurses, advanced practice nurses, nurse practitioners, physician assistants, oncology pharmacists, managed care professionals, and others with clinical research and management interest in treatment of ductal carcinoma in situ (DCIS) and early-stage breast cancer.

STATEMENT OF NEED Ability to detect DCIS has dramatically improved in recent decades, and the current incidence of DCIS is several-fold higher than in the 1970s and 1980s, largely due to increased use of mammography screening.1,2 However, attempts to identify subsets of DCIS women who may be spared radiotherapy and perhaps treated with surgery alone have heretofore been unsuccessful. This inability to predict which patients will develop recurrent DCIS or invasive disease has complicated DCIS management. Many clinicians and other healthcare professionals dealing with patients diagnosed with DCIS are unaware or incompletely knowledgeable about the most recent results from a clinical trial examining the ability of the 12-gene assay, using a prespecified DCIS algorithm, to predict recurrence risk, and the implications these findings may have for management of their patients with DCIS. 1. Kerlikowske K. Epidemiology of ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010:139-141. 2. Virnig BA, Tuttle TM, Shamliyan T, Kane RL. Ductal carcinoma in situ of the breast: a systematic review of incidence, treatment, and outcomes. J Natl Cancer Inst. 2010;102:170-178.

EDUCATIONAL OBJECTIVES After completion of this activity, participants will be better able to: • Identify approaches currently available or in development to predict recurrence risk in DCIS patients • Explain how the 12-gene expression assay for DCIS was developed and how it compares with the 21-gene assay for early invasive breast cancer • Describe the design and findings of the ECOG 5194 validation study • Apply the 12-gene assay for DCIS into clinical decision-making • Explain relevant information about the 12-gene DCIS assay and DCIS score to patients

Release Date: May 8, 2012 Expiration Date: May 7, 2013

FACULTY Chair: Lawrence J. Solin, MD, FACR, FASTRO Chairman Department of Radiation Oncology Albert Einstein Medical Center Philadelphia, PA

E. Shelley Hwang, MD, MPH Professor and Chief, Breast Surgery Duke University Medical Center Durham, NC

Kathy D. Miller, MD Associate Professor Department of Medicine IU School of Medicine Indianapolis, IN This activity is supported by an educational grant from Genomic Health, Inc.

ACCREDITATION Physicians: Creative Educational Concepts, Inc. (CEC) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. CEC designates this enduring educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: CEC is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC) Commission on Accreditation. CEC provides this activity for 1.0 contact hour. Learners are advised that accredited status does not imply endorsement by the provider or ANCC of any commercial products displayed in conjunction with an activity. Case Managers: This activity has been approved for 1.0 clock hour through 12/31/12 by the Commission for Case Manager Certification. Case Managers number 790005057.

OCTOBER 2012 I VOL 5, NO 7

questions by including the patient in the discussion and learning firsthand about problems, comorbidity factors, and the patient’s goals. By the time we have these discussions, the patient’s and physician’s goals should be aligned. We consider whether the goals are heroic, palliative, or curative and whether patients are willing to tolerate side effects of therapy or the complexity of managing the regimen. Our model provides pharmacists with the opportunity to meet with the patient, educate him or her about treatments, and improve adherence, especially to oral drugs, as well as to drugs that address common comorbidities and supportive care. I can’t think of a better outcome than helping patients manage their side effects and comorbidities and therefore improve their adherence to treatment, whether in our infusion center or at home.

I am particularly excited about the shift from injectable to oral targeted therapies for specific cancer types. What are you excited about in the field of oncology right now? MPK: This is tied to the previous question. I am particularly excited about the shift from injectable to oral targeted therapies for specific cancer types. This is an opportunity for oncology pharmacists to step away from the traditional role of preparing injectable medications to provide direction and education to patients about oral therapies so they understand optimal timing, frequency, and dosage, as well as expected and unexpected side effects and how they are to be managed. Investigational therapies constitute a large portion of our treatment offerings at CINJ—40% of our clinical trials involve oral therapies. The new oral therapies are a superior option to injectable therapies due to different mechanisms of action and the ability to self-medicate; however, the new oral therapies won’t replace injectable therapy, but rather it appears that most will be used in conjunction with it. The addition of oral targeted therapy to current injectable regimens has improved survival in many cancers. Some oral targeted therapies are used as maintenance therapy; for example, gefitinib in lung cancer, while others (eg, lenalidomide, dasatinib) are used as adjuncts to chemotherapy to improve response and survival in certain heme malignancies.

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Cancer Center Profile Cancer Institute of New Jersey Additionally, new oral therapies are being approved to treat malignancies that historically have had very few options (eg, vemurafenib).

How has the role of the oncology pharmacist changed in the past 5 years? MPK: The decision-making process has changed to include the oncology pharmacist in the discussions about selection and dosing of therapies. We discuss side effects of new oral therapies, and we participate in medication reconciliation to prevent drug-drug interactions from occurring, as well as drug-comorbidities contraindications. Additionally, patients often have comorbidities and preexisting end-organ dysfunctions that necessitate the input of a pharmacist to determine the best dosing options.

treatments and what to expect. Then I got another opportunity to move to CINJ 18 years ago, and with this position I could use all the knowledge and experience from the previous job, working at an institution with a strong research agenda. I could participate in taking an idea from the bench to the

bedside to improve outcomes for cancer patients. I enjoy my job. Every day is a different day. The standard of care is a rapidly moving target, day to day, month to month, and from ASCO to ASCO. I’ve seen leaps and bounds in treating cancers happen within a small time frame. For example, patients with

metastatic colorectal cancer used to have a survival measured in months, and now patients live from 2 to 5 years with good quality of life. This is happening across several solid tumors, and our involvement in hematologic cancers and transplantation at CINJ has Continued on page 38

Newsletter Series

YOUR QUESTIONS ANSWERED

™

The standard of care is a rapidly moving target, day to day, month to month, and from ASCO to ASCO. What inspired you to become an oncology pharmacist? MPK: I’ve read a lot of editorials about this in pharmacy publications. Many people describe a key event that led them to their careers. For me, it was serendipity. I started with a job at a local hospital and applied for an opening as an oncology pharmacist. It didn’t take long for me to fall in love with this job, partly because of the opportunity to help patients with best supportive care and consulting at the bedside prior to discharge about their

™

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.

Photo from the Cancer Institute of New Jersey.

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OCTOBER 2012 I VOL 5, NO 7

Cancer Center Profile Cancer Institute of New Jersey Continued from page 37 also been optimistic. There is also great excitement in the area of cancer prevention. Whether it’s helping the public with smoking cessation or the effort put forth in developing vaccine therapies, prevention will be far more satisfying than treatment.

What advice would you give to pharmacists just entering the field? MPK: Get your hands and your brain dirty. Keep current with the fastmoving target of standard of care. You

Whether it’s helping the public with smoking cessation or the effort put forth in developing vaccine therapies, prevention will be far more satisfying than treatment.

need to be engrossed in the changing paradigm of cancer care. I am an advocate of board certification and board recertification for oncology pharmacists. This is not a requirement, but I recommend it to remain competitive for job opportunities. Follow and participate in clinical research!

What would you be if you weren’t an oncology pharmacist? MPK: While evaluating colleges, I was originally attracted to the semi-

nary but I decided on a different path. Now I would say that I would stay in clinical medicine in some capacity. I enjoy patient contact and hands-on care, but I would have liked to do benchtop research. I find patient contact extremely rewarding; it’s another form of religious work. Also, I think that the business education component of medical care is missing in much of our education. In my silver years, I will look to either pursue a business education or a teaching position. ●

Breast Cancer

Zoledronic Acid: less Frequent Dosing May Be Just as Good By Caroline Helwick

n women with metastatic breast cancer, less frequent dosing of zoledronic acid (ZA) may be as protective as the standard monthly infusion, according to 2 studies presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO).

The studies address an important issue that has implications for patient convenience and cost of care. The Italian ZOOM trial was a phase 3 prospective randomized study of 425 women with stage IV breast cancer and bone metastases. After 1 year of standard ZA treatment (4 mg every 4 weeks), patients were randomized to continue with monthly infusions or to receive ZA every 3 months (4 mg every 12 weeks). The study concluded that an every12-week infusion was not inferior to the standard monthly infusion. The mean skeletal morbidity rate (number of skeletal-related events per patient per year) was 0.26 and 0.22, respectively, which indicated statistical noninferiori-

ty of the less frequent dosing schedule. Toxicities were also similar between the arms, reported Dino Amadori, MD, of the Istituto Scientifico Romagnolo in Meldola, Italy. Bone Turnover remains Suppressed After a Single Dose A Canadian study looked at 1 turnover following a single dose of ZA and found that after a single 4-mg dose, bone turnover remained suppressed at 12 weeks in 73% of patients. The study involved 26 patients with metastatic breast cancer to the bone and no prior ZA treatment. Patients received a single dose of ZA, and biomarkers of bone turnover (serum carboxy-terminal collagen crosslinks [CTX]) were collected every 2 weeks subsequently. Patients remained on study if their biomarkers remained suppressed but came off study as soon as they escaped from suppression (rise >50% of baseline). At 12 weeks, 73% of patients had continued suppression of bone turnover by serum CTX. The patients who escaped suppression did so at a median of 8 weeks after the first infusion. “Biomarkers of bone turnover have been found to correlate with the risk of developing a skeletal-related event,

and with response to bisphosphonate therapy,” noted Christine E. Simmons, MD, of the University of Toronto. The magnitude of suppression of serum CTX at week 4 was significantly greater in those who had continued suppression compared with those who escaped suppression before 12 weeks (75% vs 58%; P = .02). The absolute baseline value of CTX was significantly lower in patients who maintained suppression (507 ng/L vs 745 ng/L; P = .04). Quality-of-life scores and pain medication use did not change appreciably during this period. “Our study suggests that ZA does not need to be given at conventional dosing frequency in the majority of patients, and can be withheld without increased morbidity or effect on quality of life,” Simmons said. “We think that baseline serum CTX (<600 ng/L) and magnitude of suppression of CTX (>70%) may predict for those who can wait 12 weeks between doses.” Studies Address an Important Issue Teresa Gilewski, MD, of Memorial Sloan-Kettering Cancer Center, New York, who discussed the findings at the Best of ASCO meeting in Boston, Massachusetts, said the studies address an important issue that has implications

for patient convenience and cost of care. While confirmation is needed, she said, it is possible that some patients may fare as well with less frequent infusions. ASCO guidelines state that bonemodifying agents should be continued until the patient’s performance status substantially declines; however, the optimal schedule and duration of ZA have not been widely established. Gilewski questioned whether some patients may be doing well enough—having significant reductions in the volume of bone destruction—that long-term ZA treatment may be unnecessary. “The biggest strength of the Italian study is that it raises an incredibly important clinical question, in terms of patient compliance and economic issues,” she said. While the study did not assess the extent of bone destruction, she believes that such data might help guide the dosing interval. “In patients with a lot of destruction, we may be less likely to change the infusion schedule, compared to patients with just 1 or 2 sites. But if patients are doing well, we may be more willing to consider the change,” Gilewski said. Currently, however, she said the data are preliminary and should not yet be clinically applied. Studies are under way that may validate the findings. ●

THIRD ANNUAL CONFERENCE Influencing the Patient-Impact Factor

May 2-5, 2013 Westin Diplomat Hollywood, Florida

OCTOBER 2012 I VOL 5, NO 7

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Breast Cancer

Chemotherapy-related Adverse events Add to economic Burden in Metastatic Breast Cancer By Caroline Helwick

dverse events (AEs) related to chemotherapy for metastatic breast cancer (MBC) create a substantial economic burden that is primarily explained by increased inpatient, outpatient, and pharmacy costs, said Sara A. Hurvitz, MD, of the University of California Los Angeles, who presented an economic analysis at the 2012 Annual Meeting of the American Society of Clinical Oncology. “In addition, 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,” she added. The study is the first to assess costs associated with AEs that occur during treatment for MBC, she said. Hurvitz led a study sponsored by Genentech that aimed to quantify the economic impact of AEs reported in patients with MBC receiving first- or second-line therapy with taxanes or capecitabine for at least 30 days per treatment episode. Patients were selected from the PharMetrics Integrated Database. The data elements included pharmacy and medical claims from more than 100 healthcare plans in the United States, covering more than 70 million lives between 2000 and 2010. The eligible cohort included 3222 patients who used a taxane (docetaxel, paclitaxel) first-line (n = 1866), capecitabine first-line (n = 812), taxane second-line (n = 715), or capecitabine second-line (n = 369). Patients treated with both classes during the same episode were excluded. The AE list included almost 2 dozen possible AEs. AEs were commonly seen in each of the 4 study cohorts. With taxanes, 94.6% of first-line patients and 94.4% of secondline patients experienced at least 1 event during treatment. With capecitabine, 83.7% and 84.0%, respectively, experienced at least 1 AE. Nausea/vomiting was the most common complication with either agent, Hurvitz reported. In general, patients who experienced no AEs in the study were relatively younger and had fewer comorbidities at baseline. Incremental Monthly Costs Associated With Aes The incremental costs associated with chemotherapy-related complications were estimated by comparing the average costs between the cohorts with AEs and without AEs for the 4 treatment groups. The analysis revealed the following:

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• Taxanes first-line: AEs were associated with a 38.7% increase in monthly costs, over patients without AEs ($3547). These incremental costs were mainly driven by increased inpatient costs and other drug costs (other than 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 inpatient and outpatient costs.

Increasing Aes per episode led to Higher Costs The more AEs per episode, the greater the cost of care, the analysis further found. For example, for taxane first-line therapy, the mean cost for 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 more than 4 AEs.

The more AEs per episode, the greater the cost of care, the analysis further found.

For second-line capecitabine, treatment without an AE episode cost approximately $6000, but rose to approx-

imately $14,000 in the setting of more than 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. Hurvitz cautioned that the study has limitations: cause-and-effect associations cannot be confirmed and the reported rates are restricted to duration of an episode of treatment and did not take into account complications occurring after treatment ended. It is also a retrospective observational study based on claims data, though this also has the advantage of being a valid, large sample-source of clinical practice data, she pointed out. “Further research evaluating the clinical and economic consequences of chemotherapy-related AEs in a prospective manner can further characterize the effects seen here,” she said. ●

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July 26-28, 2013 Hyatt Regency La Jolla at Aventine 3777 La Jolla Village Drive San Diego, California Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma Squamous Cell Carcinoma • Merkel Cell Carcinoma

OCTOBER 2012 I VOL 5, NO 7

Breast Cancer

No Association Between Taxane-Induced Neuropathy and Clinical Outcomes in early Breast Cancer By Alice Goodman

ccording to an analysis of the Eastern Cooperative Oncology Group trial ECOG-E1199 by Schneider and colleagues, the development of grade 2 to 4 peripheral neuropathy in patients with operable breast cancer who received taxanes does not appear to affect clinical outcome.1 “We found that, although neuropathy was a common complication that was associated with necessary dose reductions [of taxanes], it was not associated with a higher risk of recurrence or inferior survival,” wrote Bryan P. Schneider, MD, and colleagues. Schneider is affiliated with ECOG at the Indiana University School of Medicine, Indianapolis. The investigators of this study previously identified several single nucleotide polymorphisms that were significantly associated with an increased risk for developing grade 2 to 4 peripheral neuropathy in patients with breast cancer treated with taxane-containing chemotherapy. The present study suggests that this biomarker will not be useful for identifying patients who will

derive preferential benefit from taxane therapy. “This finding provides reassurance that biomarkers predictive for neuropathy will likely not enrich for patients who are more likely to benefit from taxane therapy and may also be useful for the identification of patients who are most likely to benefit from adjunctive therapies to mitigate neuropathy,” wrote the authors.

and then randomized to 1 of 4 treatment arms: 4 cycles of paclitaxel 175 mg/m2 every 3 weeks (arm P3), 12 cycles of paclitaxel 80 mg/m2 every week (arm P1), 4 cycles of docetaxel 100 mg/m2 every 3 weeks (arm D3), or 12 cycles of docetaxel 35 mg/m2 every week (arm D1). Grade 2 to 4 peripheral neuropathy was evaluated using the National Cancer Institute Common Toxicity Criteria (version 2.0) grading scale. End points

The risk of neuropathy was decreased in premenopausal patients compared with postmenopausal patients, and the risk of neuropathy was higher in blacks than in other races and in obese patients versus nonobese patients.

The study population included 4554 women with operable breast cancer—either axillary node-positive or high-risk node-negative breast cancer. They were treated with up to 4 cycles of doxorubicin/cyclophosphamide every 3 weeks

were overall survival, disease-free survival, and recurrence-free survival. Grade 2 to 4 neuropathy developed in 18%, 22%, 15%, and 13% of patients in the P3, P1, D3, and D1 treatment arms, respectively. In a model adjusted

for age, race, obesity, menopausal status, tumor size, nodal status, treatment arm, neuropathy, and hyperglycemia, no significant relationship was observed between neuropathy and the 3 end points. The risk of neuropathy was decreased in premenopausal patients compared with postmenopausal patients, and the risk of neuropathy was higher in blacks than in other races and in obese patients versus nonobese patients. The association between hyperglycemia and neuropathy was significant and remained significant after adjusting for age, race, obesity, and menopausal status. Hyperglycemia was also associated with inferior outcomes, but only in the P3 arm. “These findings must…be interpreted with caution because treatment-associated hyperglycemia may be multifactorial and not reflect patients with a formal diagnosis of diabetes,” the authors wrote. ● reference 1. Schneider BP, Zhao F, Wang M, et al. Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer. J Clin Oncol. 2012;30:3051-3057.

Side Effect Management

Severe Diarrhea Associated With Molecularly Targeted Agents Can Impact Quality of Life and Healthcare Resource Utilization

preliminary report of a metaanalysis of clinical trials of molecularly targeted therapies shows that they are not benign and can add to the toxicity of standard chemotherapy. In particular, increased rates of oral mucositis and diarrhea are reported with several US Food and Drug Administration (FDA)-approved agents. Increased mucositis seen with bevacizumab and erlotinib does not appear to be clinically significant, but severe diarrhea occurs with a number of targeted agents and has a potential impact on quality of life (QOL) and healthcare resource utilization. The meta-analysis provides some perspective on toxicities associated with molecularly targeted agents, and preliminary findings were presented at the 2012 Multinational Association of Supportive Care in Cancer International Symposium, held in New York City.

OCTOBER 2012 I VOL 5, NO 7

“We know oral and gastrointestinal mucositis reduce quality of life, increase healthcare resource utilization and costs, and can lead to treatment delays and dose reductions, which interfere with treatment efficacy. There are no systematic reviews of toxicities of targeted agents, and trials are inadequately powered to look at toxicity. We get around this with meta-analysis to come up with more precise estimates of toxicities,” explained Linda Elting, DrPH, of the MD Anderson Cancer Center in Houston, Texas. Elting and colleagues searched the literature for molecularly targeted therapies, limiting the search to randomized, controlled phase 2 or 3 clinical trials of FDA-approved targeted drugs and approved indications for those drugs. The 78 studies they included compared current standard of care with standard of care plus a molecularly targeted drug. The studies had different

designs, treatment regimens, and dose differences. All studies listed all-grade toxicity as well as grades 3, 4, and 5 separately. “We included only drugs for which at least 3 papers were published,” she explained. Bevacizumab was associated with an increase in all-grade oral mucositis, and the risk of grades 3 and 4 was increased 5-fold compared with standard therapy alone. The risk increases with higher doses. Elting remarked that the absolute risk of grades 3 and 4 mucositis was low, only around 3%, with the addition of bevacizumab-targeted therapy. “The risk of [severe] mucositis with bevacizumab is very low and does not appear to be a clinically significant finding,” she stated. A 5-fold increase in all-grade oral mucositis was found with erlotinib, but no increase in grades 3 and 4 was observed

compared with standard therapy alone. “As with bevacizumab, this is not clinically significant and is limited to low-grade oral mucositis,” she said. “Diarrhea is a hallmark of targeted therapy, so don’t be surprised by high rates,” she told listeners. With both trastuzumab and lapatinib, all grades of diarrhea are increased when added to standard therapy. A 10fold increase in grades 3 and 4 diarrhea is reported with trastuzumab, with an absolute increased risk of 12%. “This could be important for clinical care and resource utilization,” Elting commented. “Lapatinib, erlotinib, cetuximab, gefitinib, and sorafenib are also associated with increased risk of diarrhea, including a 2- to 5-fold increase in grades 3 and 4 diarrhea, which is clinically significant and has a clear impact on quality of life and resource utilization,” she stated.—AG ●

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