VBCC October 2012, VOL 3, NO 7

OCTOBER 2012 VOL 3 NO 7

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com ESMO 2012

Crizotinib Superior to Chemotherapy, Extends Median Survival in First Head-to-Head Trial May be a new standard in ALK-positive NSCLC

Photo © European Society for Medical Oncology

By Audrey Andrews

Updated Data Confirm Survival Benefits with T-DM1 in Breast Cancer and with Regorafenib in Colon Cancer

By Phoebe Starr Vienna, Austria—The updated analyses of 2 major studies of drugs that were recently approved by the US Food and Drug Administration (FDA) confirm the benefits of trastuzumab emtansine (T-DM1) in patients with advanced HER2-positive breast cancer and of regorafenib (Stivarga) in patients with metastatic colorectal cancer (mCRC). Both studies were presented at the 2012 European Society for Medical On-

cology (ESMO) Congress. Regorafenib was approved by the FDA for the treatment of mCRC during the ESMO meeting (see page 7).

EMILIA Trial The latest findings from the EMILIA clinical trial that were presented at the meeting showed that T-DM1 prolonged survival versus treatment with lapatinib (Tykerb) plus capContinued on page 17

2nd Annual Conference

Vienna, Austria—In the first head-to-head phase 3 clinical trial, the anaplastic lymphoma kinase (ALK) inhibitor crizotinib (Xalkori) proved more effective than standard chemotherapy with pemetrexed (Alimta) or docetaxel (Taxotere) as a second-line treatment for patients with non–small-cell lung cancer (NSCLC) and the ALK genetic abnormality.

Continued on page 11

BREAST CANCER SYMPOSIUM

Indirect Costs of Metastatic Breast Cancer Are Substantial

By Caroline Helwick San Francisco, CA—The indirect costs of metastatic breast cancer are substantial and are much higher than the costs of early breast cancer, according to what may be the first study to compare costs related to lost productivity in the population with breast cancer.

The study was reported at the 2012 Breast Cancer Symposium by Yin Wan, MS, of Pharmerit International, Bethesda, MD. The senior researcher was Lee Schwartzberg, MD, Medi-

cal Director of the West Clinic in Memphis, TN. “Breast cancer is mostly prevalent in women of working age, and the breast cancer–related indirect costs, such as productivity loss, cannot be overlooked,” noted Ms Wan. The aim of the study was to estimate indirect costs (ie, sick leave and short-term disability) associated with metastatic breast cancer compared Continued on page 24

©2012 Engage Healthcare Communications, LLC

Many Emerging Biomarkers, but Few Are Clinically Applicable Oncologists need to consider the evidence carefully

By Caroline Helwick Houston, TX—Despite much talk about biomarkers and a field that is exploding, only a few biomarkers can be reliably and routinely used to improve patient care at this time, according to Peter G. Ellis, MD,

Deputy Director of Clinical Services, Associate Chief Medical Officer, University of Pittsburgh Medical Center Cancer Centers.

A biomarker is any measure (ie, gene Continued on page 34

INSIDE FDA UPDATE . . . . . . . . . . . . . . . . . . .4 Regorafenib for colorectal cancer Marqibo new option for ALL

BREAST CANCER SYMPOSIUM . .24 Fewer women undergo mammography since new recommendations

VALUE PROPOSITIONS . . . . . . . . . .5 New payer-oncologist collaboration Genome-based drug development

CONFERENCE . . .32 Health plans need policies for off-label drug use

IN THE LITERATURE . . . . . . . . . . . . .8 Enzalutamide prolongs OS Cetuximab beneficial in KRAS G13D

DRUG UPDATE . . . . . . . . . . . . . . . .40 Pertuzumab a new option for HER2positive metastatic breast cancer

ESMO 2012 CONFERENCE . . . . . . .9 Novel drugs for prostate cancer Is personalized medicine affordable?

CONTINUING EDUCATION . . . . .44 Considerations in multiple myeloma

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

VELCADEHCP.COM

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

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

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

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

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

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

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, Option 2 (1-866-835-2233). *Melphalan+prednisone. † VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

Updated analyses were performed.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

FDA Update Regorafenib Latest Therapy Approved for Metastatic Colorectal Cancer Using its priority review process, the US Food and Drug Administration (FDA) approved the oral multikinase inhibitor regorafenib (Stivarga; Bayer

HealthCare Pharmaceuticals) for the treatment of patients with metastatic colorectal cancer (mCRC).

“Stivarga is the latest colorectal cancer treatment to demonstrate an ability to extend patients’ lives and is the second drug approved for patients with

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.

colorectal cancer in the past 2 months,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Colorectal cancer (CRC) is the third most common cancer and the third

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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leading cause of cancer-related death among US adults; an estimated 51,690 people will die from CRC in 2012.

The approval of regorafenib was based on the safety and efficacy data in a single clinical trial of 760 patients with previously treated mCRC. The patients were randomized to regorafenib best supportive care (BSC) or to placebo plus BSC until disease progression or until side effects became unacceptable.

Regorafenib plus BSC was associated with a significantly longer overall survival (OS) versus placebo plus BSC (hazard ratio [HR] 0.77; 95% confidence interval [CI], 0.64-0.94; P = .010); median OS was 6.4 months versus 5.0 months, respectively. Progression-free survival (PFS) was also significantly improved with regorafenib; HR 0.49 (CI, 0.42-0.58; P <.001). The median PFS was 2.0 months with regorafenib versus 1.7 months with placebo.

The most frequently reported (≥30%) adverse events (AEs) with regorafenib were asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, and dysphonia; the most serious AEs were hepatotoxicity, hemorrhage, and gastrointestinal perforation.

The recommended dosing for regorafenib is 160 mg (ie, 4 tablets of 40 mg each) once daily for the first 21 days of a 28-day cycle.

Regorafenib carries a Boxed Warning potential for severe and fatal liver toxicity that had occurred in patients using this drug. (September 27, 2012)

FDA Approves Neutroval for Severe Neutropenia The FDA approved tbo-filgrastim (Neutroval; Sicor Biotech UAB, a member of Teva Corporation) to reduce the duration of severe neutropenia in patients with cancer receiving chemotherapy.

Tbo-filgrastim is a short-acting recombinant human granulocyte colonystimulating factor that is indicated for use in patients with cancer, except blood or bone marrow cancers, who are receiving chemotherapies that cause febrile neutropenia. Tbo-filgrastim is administered as a subcutaneous injection, 5 mcg/kg, 24 hours after chemotherapy treatment.

The manufacturer submitted a Biologics License Application for this agent, which in the European Union is licensed as a biosimilar (ie, Tevagrastim) to Neupogen (filgrastim).

The FDA approval of tbo-filgrastim was based on 1 clinical trial evaluating effectiveness and 3 studies evaluating safety. Effectiveness was established in patients with metastatic breast cancer Continued on page 7

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VALUE PROPOSITIONS Ovarian Cancer Therapy Moving Toward Personalized Medicine The recent discovery of 3 subtypes of high-grade serous ovarian cancer (HGSOC) by researchers at Dana-Farber Cancer Institute will soon enable oncologists to determine which of their patients with HGSOC—the most common type of ovarian cancer—are most likely to benefit from a certain class of drugs.

HGSOC cells have a high level of genomic “instability,” meaning that their nuclei have large or extra chromosomes or are missing chromosomes or fragments of chromosomes, which leads to a process known as loss of heterozygosity (LOH). “Patients with the greatest burden of LOH had the longest progression-free survival….This is the group that stands to derive the most from certain classes of drugs,” said lead researcher Zhigang C. Wang, PhD, Assistant Professor, Department of Surgery, Harvard Medical School, and Assistant Professor, Cancer Biology, Dana-Farber Cancer Institute, Boston, MA. “Our findings suggest that, for the most part, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer,” said coinvestigator Ursula A. Matulonis, MD, Associate Professor, Department of Medicine, Harvard Medical School, and Director of Medical Gynecologic Oncology, Department of Medical Oncology at Dana-Farber. “For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward.” Dana-Farber Cancer Institute Newsroom; September 19, 2012

The IOM Considers the Economics of GenomeBased Targeted Drug Development The Institute of Medicine (IOM) recently held a roundtable discussion on the status of genome-based drug development. In its summary of the meeting, the IOM stated, “The number of new drug approvals has remained steady for the last 50 years while spending on health-related research and development has tripled since 1990. This trajectory is not economically sustainable for the businesses involved, and, in response, many companies are turning toward collaborative models of drug development. Introducing greater efficiency and knowledge into these new models and aligning incentives among participants may help to increase efficiency and lower costs, while producing more effective drugs in the process. Genomic information has significantly increased our understanding of disease and...has resulted in the recent successful development of a number of new targeted therapeutics. However, there remains skepticism over how useful genomic information will be to the larger drug development process, requiring examination of the impact of and challenges for incorporating genome-based strategies.” Institute of Medicine; September 5, 2012

New Payer-Oncologist Collaboration to Curb Cancer Care Costs, Improve Quality, Launched in Michigan In September, Cardinal Health Specialty Solutions announced the launch of a new collaboration initiative with Health Alliance Plan (HAP) and Physician Resource Management to establish an evidence-based clinical pathways program aimed at reducing the costs of cancer care while improving quality of care. “We’re committed to partnering with community oncologists and innovative insurance companies like HAP to develop new models for delivering highly effective, well-coordinated cancer care,” said Bruce Feinberg, MD, Vice President and Chief Medical Officer, Oncology, Cardinal Health Specialty Solutions. “Physician-driven clinical pathways programs like this one can play an integral role in defining a more sustainable model for caring for patients with cancer, by increasing

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the quality, consistency, and predictability of the care they receive.”

Cardinal Health Specialty Solutions will work directly with medical oncologists who contract with HAP to identify and implement evidencebased treatment regimens for breast, lung, and colon cancers. “I believe it’s critical for oncologists, patients, and payers to work together to develop a balanced set of quality and financial outcome goals that improve cancer care,” said Phillip Stella, MD, President of Physician Resource Management. Cardinal Health Specialty Solutions Press Release; September 11, 2012

Novel Best Test to Guide Therapy in Children with Acute Myeloid Leukemia Early treatment response is a strong predictor of long-term outcomes in children with acute myeloid leukemia (AML); it can further help to determine whether an aggressive treatment approach is needed.

Researchers at St. Jude Children’s Research Hospital have identified the best test to measure early response to treatment in children with AML. The test uses a technique called “flow cytometry,” which helps to identify a single cancer cell among 1000 normal cells after the initial weeks of intensive chemotherapy. This new test identifies patients with AML who have minimal residual disease after chemotherapy and would therefore benefit from more intensive therapy, including bone marrow transplantation.

The use of flow cytometry proved better than 2 other common methods used to identify minimal residual disease and predict patient survival.

“These results will help establish flow cytometry testing for minimal residual disease as a routine tool for guiding therapy of acute myeloid leukemia and identifying patients early who are at risk of treatment failure,” said lead investigator Hiroto Inaba, MD, PhD, Pediatric Hematologist/Oncologist, Department of Oncology, Division of Leukemia/Lymphoma, St. Jude Hospital. St. Jude Children’s Research Hospital Press Release; September 10, 2012

Two Genetic Signatures Can Help Identify Patients with Aggressive Prostate Cancer The search for better diagnostic tools for prostate cancer continues, with current test modalities leaving much room for improvement.

Researchers in the United Kingdom have identified 2 new genetic “signatures” for prostate cancer that could help oncologists to identify patients with prostate cancer whose tumor is aggressive and to implement a more intensive therapy than might otherwise seem warranted. The test, which has been developed from these 2 blood signatures, is quite promising and may prove very valuable for identifying those high-risk patients, experts suggest.

“Prostate cancer is a very diverse disease—some people live with it for years without symptoms, but for others it can be aggressive and lifethreatening,” said lead investigator Johann de Bono, MD, PhD, MSc, FRCP, Professor of Experimental Cancer Medicine, Honorary Consultant Medical Oncologist, Royal Marsden Hospital and Institute of Cancer Research, London, England. “So it’s vital we develop reliable tests to tell the different types apart.”

According to Dr de Bono, studying these blood signatures has the potential to be more accurate than the prostate cancer tests that are currently available on the market; furthermore, this new test does not require a follow-up biopsy, as in the case of the prostate-specific antigen test. “Our test reads the pattern of genetic activity like a barcode, picking up signs that a patient is likely to have a more aggressive cancer. Doctors should then be able to adjust the treatment they give accordingly,” Dr de Bono said. Lancet Oncology; October 9, 2012

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In This Issue

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1882 Associate Publisher American Health & Drug Benefits Maurice Nogueira maurice@engagehc.com 732-992-1895

FDA UPDATE

BREAST CANCER SYMPOSIUM

Regorafenib for metastatic colorectal cancer Neutroval for severe neutropenia Marqibo for acute lymphoblastic leukemia

Fewer women undergo mammography Disparities in treatment a cause of cancer death Fewer therapy delays with palonosetron More….

IN THE LITERATURE

Associate Publisher Cristopher Pires cris@engagehc.com 732-992-1896

Health plans need policies for off-label drug use Evolving strategies for cost-effective cancer management More….

ESMO

ECONOMIC ISSUES IN ONCOLOCY

Novel drugs for prostate cancer More….

Associate Publisher Joe Chanley joe@greenhillhc.com Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536

Personalized oncology care marches forward, but issues remain Is personalized cancer care affordable?

Quality Control Director Barbara Marino Business Manager Blanche Marchitto

VBCC Editorial Board

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments.

This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

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

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

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

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

Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 8 times a year by Engage Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved.

Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

Craig Deligdish, MD Chief Medical Officer Oncology Resource Networks Orlando, FL Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs eviti, Inc

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher.

Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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Integrative medicine cuts inpatient costs in oncology care unit More….

PERSONALIZED MEDICINE

National Accounts Manager Zach Ceretelle Director, Creative & Design Robyn Jacobs

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CONFERENCE

Adding cetuximab to chemotherapy improves outcomes in KRAS G13D mutation Soy isoflavone consumption reduces breast cancer recurrence risk More….

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

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DRUG UPDATE Pertuzumab for HER2-positive breast cancer

Ira Klein, MD, MBA Aetna Hartford, CT

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

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

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

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

David Hom, MBA Solucia Farmington, CT

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

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

Naimish Pandya, MD University of Maryland Baltimore, MD

OCTOBER 2012

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

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FDA Update FDA Approves Neutroval...

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who were receiving treatment with doxorubicin and docetaxel. A total of 348 patients were randomized to tbofilgrastim, to placebo, or to a non–FDAapproved filgrastim product. Patients receiving tbo-filgrastim recovered from severe neutropenia in 1.1 days compared with 3.8 days for those patients receiving placebo.

The safety of tbo-filgrastim was established based on 3 clinical studies with 680 patients who had breast cancer, lung cancer, or non-Hodgkin lymphoma who received high-dose chemotherapy that reduces bone marrow cells.

The most common side effect with tbo-filgrastim was bone pain. (August 29, 2012)

sure, respiratory distress, and cardiac arrest, were reported in 76% of the patients. The most common AEs during the trials were constipation, nausea, low blood-cell counts, fever, nerve damage, fatigue, diarrhea, decreased appetite, and insomnia.

Vincristine sulfate liposome carries a Boxed Warning that it must be administered intravenously, because this drug is deadly if it is administered in other ways (eg, into the spinal fluid). The warnings also state that the dosing recommendations for vincristine sulfate

liposome are different from those for vincristine sulfate alone. To avoid overdose, it is important to verify the drug’s name and its dose before administration. The label lists special requirements for preparation of the drug. (August 9, 2012) ■

Marqibo New Option for Acute Lymphoblastic Leukemia The FDA accelerated the approval of vincristine sulfate liposome injection (Marqibo; Talon Therapeutics) for the treatment of patients with Philadelphia chromosome–negative acute lymphoblastic leukemia (ALL), a rare type of leukemia, with a second or greater relapse after treatment with ≥2 antileukemia therapies. The drug is designated as an orphan product.

“Marqibo’s approval demonstrates the FDA’s commitment to the development and approval of drugs that address serious, unmet medical needs,” said Dr Pazdur. Some 1440 patients with ALL are estimated to die from this disease in 2012.

Marqibo contains vincristine, a common anticancer drug, encased within a liposome, which is a drug-delivery vehicle composed of material similar to cell membranes. Marqibo is injected once weekly by a healthcare professional.

The FDA approval of vincristine sulfate liposome was based on 1 clinical trial evaluating effectiveness and 2 studies evaluating safety. The safety trial included 65 patients who were in second relapse or greater; of these, 10 showed complete remission or complete remission with an incomplete blood count recovery with the active drug. The median duration of remission with vincristine sulfate liposome was 28 days, and the median time to a first event—including relapse, death, or next therapy—was 56 days.

The 2 safety trials were single-arm studies of 83 patients who received vincristine sulfate liposome. Of these, 28% of the patients discontinued the drug because of AEs, including peripheral neuropathy and tumor lysis syndrome.

Serious AEs, such as low white blood– cell counts with fever, low blood pres-

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In The Literature Enzalutamide Prolongs Overall Survival after Chemotherapy in Prostate Cancer The once-daily oral androgen-receptor–signaling inhibitor enzalutamide (Xtandi) differs from current antiandrogen therapies by its ability to inhib-

it nuclear translocation of the androgen receptor, its DNA binding activity, and its coactivator recruitment, in addition to other clinical benefits in the context of prostate cancer. This novel agent is administered without the need for concomitant prednisone, which has been postulated to activate

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other.

Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia.

Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation.

System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim.

Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim.

The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading.

Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta.

• Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity.

Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice.

Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

androgen-receptor signaling. In this phase 3, double-blind, placebo-controlled clinical trial, enzalutamide significantly prolonged survival in patients with castration-resistant prostate cancer (CRPC) after standard chemotherapy (Scher HI, et al. N Engl J Med. 2012;367:1187-1197).

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred.

Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area).

Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll.

Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk.

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

Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11).

The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain.

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

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

DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy.

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed.

NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product.

This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2012 Amgen Inc. All rights reserved. www.neulastaHCP.com 1-800-77-AMGEN (1-800-772-6436) v 13.0

65481-R1-V1

A total of 1199 men with CRPC who had received chemotherapy were randomized in a 2:1 ratio to oral enzalutamide 160 mg daily or to placebo. The study primary end point was overall survival (OS). According to the study design, the trial was stopped when 520 deaths occurred, and an interim analysis was conducted; by that point, the OS was not reached with enzalutamide. The median OS was 18.4 months in the group receiving enzalutamide (confidence interval [CI], 18.3not reached) compared with 13.6 months with placebo (CI, 11.3-15.8).

Enzalutamide was significantly (P <.001) superior to placebo in all of the secondary end points as well. These secondary measures showed that 54% of patients who received enzalutamide had reduced prostate-specific antigen (PSA) levels by more than 50% versus by 2% in the placebo group; the quality-of-life response rate was 43% with enzalutamide versus 18% with placebo; time to PSA progression was 8.3 months versus 3.0 months, respectively; radiographic progression-free survival (PFS) was 8.3 months versus 2.9 months (hazard ratio [HR], 0.40), respectively; and time to first skeletalrelated event was 16.7 months versus 13.3 months (HR, 0.69), respectively.

The rates of adverse events (AEs) were similar in the 2 groups, with the exception of higher rates of fatigue, diarrhea, and hot flashes reported with enzalutamide than with placebo. In addition, 5 patients (0.6%) had seizures while taking enzalutamide. Of note, AEs of grade ≥3 occurred 8.4 months earlier with placebo than with enzalutamide—the median time to such events was 4.2 months with placebo and 12.6 months with enzalutamide.

These results confirm that androgen-receptor signaling is a significant target for therapy in men with prostate cancer. Enzalutamide is currently being investigated in clinical trials of men with earlier-stage prostate cancer.

Adding Cetuximab to Chemotherapy Improves Outcomes in Patients with KRAS G13D Mutation Although epidermal growth factor receptor (EGFR) monoclonal antibodies were initially indicated for the treatment of EGFR-expressing metastatic colorectal cancer (mCRC), studies conducted in patients with mCRC have failed to show benefits of the EGFR monoclonal antibodies cetuximab (Erbitux) and panitumumab (Vectibix) for patients with KRAS mutations.

However, approximately 40% of patients with CRC have one of the KRAS gene mutations, with the most Continued on page 14

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ESMO 2012 Conference

Head-to-Head Comparison: Pazopanib versus Sunitinib in Metastatic Renal-Cell Carcinoma Vienna, Austria—In a head-to-head comparison of 2 treatments for metastatic renal-cell carcinoma (mRCC), pazopanib (Votrient) showed similar efficacy to sunitinib (Sutent), with a 1month survival advantage for sunitinib, which was associated with fewer side effects and an increased quality of life (QOL), suggested Robert J. Motzer, MD, Professor of Medicine, Weill Medical College of Cornell University, and an attending physician at Memorial Sloan-Kettering Cancer Center, New York. Dr Motzer presented the results of the COMPARZ trial at the 2012 European Society for Medical Oncology Congress.

The choice of treatment is a “complicated situation” that requires individualization, “but, in general, this trial tips the scale for the preferred treatment from sunitinib to pazopanib, based on its better tolerability,” Dr Motzer said at a press briefing.

The objective of the phase 3, randomized, open-label COMPARZ trial was to show noninferiority in progression-free survival (PFS). The noninferiority limits were set to exclude a more than 25% difference in the hazard for progression.

“We aimed this phase 3 trial to provide a direct comparison of the efficacy, safety, and tolerability for pazopanib and sunitinib,” Dr Motzer noted.

Among 1110 patients with clear-cell mRCC who were randomized to receive pazopanib or sunitinib, patients receiving pazopanib achieved a median PFS of 8.4 months compared with 9.5 months for patients receiving

Photo © European Society for Medical Oncology

By Caroline Helwick

“This trial tips the scale for the preferred treatment from sunitinib to pazopanib, based on its better tolerability.”

—Robert J. Motzer, MD

sunitinib (hazard ratio, 1.047). This was a nonsignificant difference that fell within the prespecified statistical findings for noninferiority, Dr Motzer reported.

Overall response rates were 31% for pazopanib and 25% for sunitinib.

Pazopanib was associated with less fatigue than sunitinib (55% vs 63%, respectively), less hand-foot syndrome (29% vs 50%, respectively), less alteration in taste (26% vs 36%, respectively), and less thrombocytopenia (10% vs 34%, respectively).

However, pazopanib was associated with more transaminase elevation than sunitinib (31% vs 18%, respectively) and more hair color changes (30% vs 10%, respectively; a significant difference), Dr Motzer reported.

The study also showed a significant outcome in favor of pazopanib for approximately a dozen QOL domains, including fatigue, mouth and throat

soreness, and foot soreness. “All domains achieving a statistical significance favored pazopanib,” Dr Motzer pointed out.

Equal Efficacy, but Quality-of-Life Comparison Questionable The invited discussant of the study at the Presidential Symposium, Tim Eisen, MD, PhD, FRCP, Director of the Cambridge Cancer Centre at the University of Cambridge, United Kingdom, said that the study had “an acceptable statistical plan,” and he suggested that, “In the context of other trials, I would say the drugs are comparable in efficacy.” However, he also added that the new tyrosine kinase inhibitor tivozanib is superior to both pazopanib and sunitinib.

Regarding toxicity, he suggested that “pazopanib does score” in terms of side effects that “matter to patients.”

He questioned, however, the suggestion that QOL was better with pazopanib, suggesting that the timing of the assessment might have led to the differences that were observed.

Although pazopanib is administered continuously, sunitinib is used for 4 weeks on, 1 week off, and “patients can feel better in the ‘off’ week,” Dr Eisen said. The timing of the disease assessment intervals at day 28 “favored pazopanib,” he maintained.

“The quality-of-life data are not as convincing as the efficacy data,” Dr Eisen concluded.

Robin Wiltshire, MD, Global Medical Affairs Lead at Pfizer in the United Kingdom, commented to Value-

Based Cancer Care that the 2 drugs actually have “overlapping side effects to some extent, and both have some tolerability issues.”

He said the elevation in liver enzymes with pazopanib can be serious. “Patients don’t feel this, but it can be silent and life-threatening,” Dr Wiltshire said.

“In the context of other trials, I would say the drugs are comparable in efficacy.

The quality-of-life data are not as convincing as the efficacy data.”

—Tim Eisen, MD, PhD “There are tolerability issues with either, and each patient has a different journey,” he said. “Sunitinib has been around for 6 years, and physicians have gained experience in working through the side effects for an extremely positive outcome. This heritage of experience is very important, especially given the efficacy results with sunitinib.”

Dr Wiltshire further noted that the noninferiority design allows for a 25% difference between the agents, and maintained the “PFS difference [of 1 month favoring sunitinib] is important.

With pazopanib, there is an unknown as to where it lies on the efficacy scale.

The study does not demonstrate equivalent efficacy.” ■

High Economic Burden Associated with Thromboembolism in Patients with Cancer Vienna, Austria—A review of 34,000 patients with cancer in an insurance claims database showed that during the first 12 months after the diagnosis of cancer, the overall cost of developing venous thromboembolism (VTE) was approximately $100,000 per patient, reported Duke University researchers at the 2012 European Society for Medical Oncology.

“VTE development is associated with a significant economic burden in terms of healthcare expenditures,” said Nicole M. Kuderer, MD, a medical instructor of hematology/oncology at

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Duke University School of Medicine, Durham, NC. Dr Kuderer and colleagues calculated the economic impact of VTE on 34,144 patients with breast or prostate cancer based on claims in the US IMPACT database. The index date was defined as the first day of chemotherapy after being diagnosed with cancer.

Patients with at least 12 months of continuous medical coverage before the index date and at least 3.5 months of coverage during follow-up were included. Patients with a previous VTE event within 12 months before the index date

“VTE development is associated with a significant economic burden in terms of healthcare expenditures. The cumulative rate of VTE in prostate and breast cancer patients almost doubled at 12 months.”

—Nicole M. Kuderer, MD

were excluded from the analysis.

Patients who developed VTE had more comorbid conditions and more metastatic disease compared with those who did not develop VTE, but they were otherwise similar at baseline. The incidence of VTE was assessed at 3.5 months and 12 months after the index date, and costs were evaluated 12 months after the initiation of chemotherapy.

High Rates of VTE The rates of VTE after 3.5 months of Continued on page 10

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ESMO 2012 Congress

New Drugs for the Treatment of Prostate Cancer ODM-201 and OGX-427 show promising results

By Phoebe Starr Vienna, Austria—Promising preliminary results for 2 novel prostate cancer drugs—ODM-201 and OGX-427— were reported at the 2012 European Society for Medical Oncology Congress. Both drugs were studied for the treatment of castration-resistant prostate cancer (CRPC).

ODM-201 ODM-201 (Orion Pharmaceuticals, Endo Pharmaceuticals) is a novel androgen receptor antagonist. In a proof-of-concept, first-in-man study, ODM-201 reduced levels of prostatespecific antigen (PSA) in men with progressive metastatic CRPC. In this doseescalation trial, 87% (N = 15) of patients experienced a decrease in PSA level at 12 weeks. All 6 patients who were pretreated with docetaxel achieved a decrease in PSA at 12 weeks. All evaluable patients had a partial response or stable disease at 12 weeks.

“These early results are promising.

ODM-201 may prove to be a new hormonal treatment option, and its efficacy and safety profile seems to be very promising in prostate cancer patients,” said lead author Christophe Massard, MD, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, Paris, France. “Of course, this will

need to be confirmed in larger trials.”

Preclinical data with this novel androgen receptor antagonist showed that the drug does not penetrate the brain and does not have partial agonist activity, as is observed with another hormonal agent, bicalutamide. The tolerability of ODM-201 was good.

The formal discussant of this poster, Joan Carles, MD, PhD, of Vall d’Hebron University Hospital, Barcelona, Spain, said that, compared with enzalutamide (also known as MDV3100), ODM-201 achieved better PSA responses and was associated with less toxicity, including less diarrhea and asthenia. In addition, ODM201 does not appear to carry any risk of seizure.

“The weakness of this study is that there are few patients, and the recommended dose for phase 2 and 3 trials is not clear,” Dr Carles noted.

“ODM-201 may prove to be a new hormonal treatment option, and its efficacy and safety profile seems to be very promising in prostate cancer patients.”

—Christophe Massard, MD

OGX-427 Results from the phase 1 portion of a planned phase 1/2 trial focused on OGX-427 (OncoGenex Pharmaceuticals), a heat shock protein inhibitor, according to a poster by Kim N. Chi, MD, Senior Scientist and Clinical Associate Professor of Medicine at BC Cancer Agency, Vancouver, Canada,

and colleagues. The phase 2 component of this trial is ongoing. OGX-427 is also in other ongoing phase 2 studies, one in combination with abiraterone for patients with CRPC and one in combination with gemcitabine

High Economic Burden Associated with...

at a glance ➤ The development of VTE in a patient with cancer is associated with a significant economic burden ➤ Claims data from a large health insurance database reveals that the rate of VTE in patients with prostate or breast cancer almost doubled at 12 months ➤ The annual adjusted costs 12 months after initiating chemotherapy increase from approximately $56,000 in a patient without VTE to approximately $91,000 in a patient with VTE

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months, these rates were 8.1% and 7.1%, respectively.

“The cumulative rate of VTE in prostate and breast cancer patients almost doubled at 12 months,” Dr Kuderer said. For both cancer types, more than 70% of VTE events were deep-vein thromboses, and more than 60% occurred in the outpatient setting.

Healthcare Costs A comparison of patients who did and did not develop VTE by 12 months after receiving chemotherapy showed that the cost of VTE was $7744 in the average patient with breast cancer and $8498 in the average patient with prostate cancer. However, the adjusted annual costs for the average patient with cancer and VTE rose to $90,690 compared with $56,142 for patients with cancer who did not have VTE (P <.001) during the 12 months after initiating chemotherapy, Dr Kuderer reported.

At the end of the 12-month period,

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the costs were higher for patients with breast cancer ($109,825) than for those with prostate cancer ($80,584).

Before being diagnosed with either type of cancer, the baseline

Photo © European Society for Medical Oncology

chemotherapy initiation were 3.6% in patients with prostate cancer and 3.9% in patients with breast cancer; after 12

and cisplatin for patients with bladder cancer.

Patients with metastatic CRPC were randomized to OGX-427 plus prednisone (n = 17) or to prednisone alone (n = 16). Crossover at disease progression was allowed.

Treatment with OGX-427 demonstrated antitumor activity, with a response rate of 25% versus 12% for prednisone alone. Decreases in PSA of ≥50% were observed in 47% of patients treated with OGX-427 plus prednisone versus in 21% of patients who received prednisone alone.

The drug achieved a delay in disease progression and was generally well tolerated, with adverse events predominantly seen as grades 1 and 2 infusion-related reactions. Grades 1 and 2 diarrhea, fatigue, and nausea were also observed. Most adverse events were reported during the first or second administration of the drug.

Dr Carles pointed out that ODM-201 and OGX-427 represent potential new agents for the treatment of CRPC. Going forward, the challenge will be to choose the best treatment option and to determine the optimal combinations and sequencing of several new, effective drugs that have become available in the past few years. ■

studies are needed. “The decision to use thromboprophylaxis in cancer patients undergoing chemotherapy should be based on the balance between the potential benefit and

“The cumulative rate of VTE in prostate and breast cancer patients almost doubled at 12 months.” For both cancer types, more than 70% of VTE events were deep-vein thromboses, and more than 60% occurred in the outpatient setting.

—Nicole M. Kuderer, MD costs for the patients with VTE were approximately $5000 greater than for those who did not subsequently develop VTE. The analysis did not consider the cost-effectiveness of thromboprophylaxis in these patients, but such

harm, including any bleeding risk,” Dr Kuderer suggested.

Cost-effectiveness and cost-utility studies of VTE prevention in patients with cancer are needed, especially in the outpatient cancer setting, Dr Kuderer added.—CH ■

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ESMO 2012 Conference

Crizotinib Superior to Chemotherapy...

Alice Tsang Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital in Boston reported the results of the global PROFILE 1007 trial at the 2012 European Society for Medical Oncology (ESMO) Congress. In this trial, crizotinib was compared with pemetrexed or with docetaxel in 347 patients with ALKpositive stage IIIB or stage IV NSCLC who had been treated with chemotherapy.

Crizotinib was superior to standard single-agent chemotherapy in objective response, progression-free survival (PFS), and quality of life (QOL) in ALK-positive patients who progressed after first-line, platinum-based chemotherapy. “These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC,” Dr Shaw reported.

Rearrangements of the ALK gene are found in approximately 5% of patients

“These results establish crizotinib as the standard of care for patients with advanced, previously treated, ALK-positive NSCLC.” —Alice Tsang Shaw, MD, PhD

If abstracts presented at the 2012 ESMO Congress were any indication, the FDA approval of crizotinib opened the door to a virtual roomful of nextgeneration ALK inhibitors. Although crizotinib targets only the 5% of patients with NSCLC who have the ALK genetic translocation, it makes a huge impact on this subset, doubling the time that patients with advanced disease spend in remission.

“Crizotinib is the poster child for precision medicine,” according to Mace Rothenberg, Senior Vice President of Clinical Development and Medical Affairs at Pfizer Oncology. At a press briefing, Mr Rothenberg said that the robust responses with crizotinib observed in phase 1 clinical trials of ALKpositive patients have led to a “rapid reduction of our clinical development program.”

Data from phase 1 and 2 clinical trials presented at ESMO suggest that these next-generation ALK inhibitors currently in development may follow in the footsteps of crizotinib: ➤ AP26113, an oral agent that also targets mutations in the epidermal growth factor receptor (EGFR). A study of 29 patients with NSCLC showed activity in the first-line and the resistant cohorts ➤ LDK378, a potent, oral, small-molecule ALK inhibitor, showed a high level of activity in patients who progressed after having received crizotinib ➤ CH5424802, an oral agent, produced 3 complete responses and 36 partial responses among 46 patients with NSCLC who had no previous ALK therapy; 40 patients remain on treatment ➤ AUY922, a heat shock protein 90 inhibitor that is delivered by weekly infusion, was highly active in 121 patients with previously treated NSCLC who had ALK or EGFR mutations. Responses were observed in 32% of ALK-positive patients and 20% of EGFR-mutated patients.

Investigators of NSCLC who were at the meeting emphasized that new ALK inhibitors will be needed for treating patients who will inevitably become resistant to crizotinib despite its initial efficacy. They added that next-generation ALK inhibitors appear to be even better tolerated than crizotinib.

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with NSCLC. In previous studies, crizotinib was shown to induce significant clinical responses in patients with advanced ALK-positive NSCLC, but this is the first phase 3 study to directly compare this novel agent with standard chemotherapy.

Crizotinib the Poster Child of Precision Medicine?

VOL. 3

See also Personalized Medicine

Survival Rates At a median follow-up of 12 months, crizotinib prolonged the median PFS to 7.7 months compared with 3.0 months with chemotherapy, a significant 51% reduction in progression risk (P <.001). The objective response rate was also significantly higher with crizotinib at 65% versus 20% with chemotherapy (P <.001).

All subgroups showed a PFS benefit with crizotinib, with the greatest advantages seen in patients with nonadenoma histology (hazard ratio [HR], 0.12).

At this point, the survival analysis is immature, with only 40% of events occurring; therefore, overall survival (OS) differences have not yet been observed. Also, 87% of the chemotherapy-treated patients have crossed over to receive crizotinib on progression, which would dilute any OS differences, Dr Shaw said.

The median OS at this point is approximately 22 months in each arm.

When the results were adjusted for confounding by crossovers, a 17% reduced mortality risk was still seen for the patients who received the ALK inhibitor, she noted.

Adverse Events Side effects were more frequent with crizotinib, but Dr Shaw pointed out that crizotinib-treated patients received an average of 11 cycles compared with 4 cycles with pemetrexed or docetaxel, which partly explains the differences. Toxicities with crizotinib are, however, distinct from those seen with chemotherapy, but are “generally tolerable and manageable,” said Dr Shaw.

The most adverse events (AEs) associated with crizotinib were diarrhea (60%), vision disturbance (60%), nausea (55%), and vomiting (47%).

Patients receiving chemotherapy had more fatigue, alopecia, dyspnea, and rash. Grade 3 or 4 toxicity rates were similar between the groups, except for an increased rate of elevated transaminases (16%) in the crizotinib arm.

Of note, 10% of patients in the pemetrexed/docetaxel arm discontinued the trial because of treatmentrelated AEs compared with 6% in the crizotinib arm.

OCTOBER 2012

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Improved Quality of Life with Crizotinib Patients taking crizotinib reported improved QOL compared with chemotherapy. “They reported greater improvement from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain with crizotinib,” Dr Shaw said, “and all of these were statistically significant.”

The patients showed significant improvement from baseline in global QOL, and “time to deterioration in lung cancer symptoms” was also significantly extended with crizotinib treatment, to 5.6 months compared with 1.4 months with chemotherapy (HR, 0.54; P <.001).

“Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with a median OS now of 22 months versus 9 months in the past, and this is accomplished with very mild toxicity.”

—Jean-Charles Soria, MD, PhD

Crizotinib “Changes the Natural History” of Lung Cancer Discussing the study at ESMO 2012, Jean-Charles Soria, MD, PhD, Professor of Medicine and Medical Oncology at South-Paris University, and a cancer specialist at Institut Gustave Roussy in Villejuif, Paris, France, noted that 2 months of extended survival with advanced NSCLC is essentially “unheard of” in the general population of patients with NSCLC. “Comparison with historical data suggests that crizotinib has changed the natural history of the disease, with Continued on page 17

www.ValueBasedCancerCare.com

11

In Advanced Renal Cell Carcinoma (RCC)...

INDICATION VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

IMPORTANT SAFETY INFORMATION WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. See â&#x20AC;&#x153;Warnings and Precautions,â&#x20AC;? Section 5.1, in complete Prescribing Information. s Hepatic Toxicity and Hepatic Impairment: Severe and fatal hepatotoxicity has occurred. Increases in serum transaminase levels (ALT, AST) and bilirubin were observed.

Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks). In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced to 200 mg per day or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with severe hepatic impairment. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution [see Drug Interactions].

Before the initiation of treatment and regularly during treatment, monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. s QT Prolongation and Torsades de Pointes: Prolonged QT intervals and arrhythmias, including torsades de pointes, have occurred. Use with caution in patients with a history of QT interval prolongation, patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. Baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes within the normal range should be performed.

s Cardiac Dysfunction: Cardiac dysfunction, such as congestive heart failure and decreased left ventricular ejection fraction (LVEF), has occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 4/586 patients (0.6%). Monitor blood pressure and manage promptly using a combination of anti-hypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment).

Carefully monitor patients for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction, including previous anthracycline exposure. s Hemorrhagic Events: Fatal hemorrhagic events were reported in 0.9% (5/586) of patients in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT compared to 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). VOTRIENT should not be used in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months. s Arterial Thrombotic Events: Arterial thrombotic events have been observed, including fatal events (0.3%, 2/586) in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident, and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. Use with caution in patients who are at increased risk for these events and do not use in patients who have had an arterial thrombotic event in the past 6 months. s Venous Thromboembolic Events: Venous thromboembolic events have occurred, including venous thrombosis and fatal pulmonary emboli. In the randomized RCC trial, venous thromboembolic events were reported

in 1% of patients treated with VOTRIENT and in 1% of patients treated with placebo. Monitor for signs and symptoms. s Gastrointestinal Perforation and Fistula: In RCC trials, gastrointestinal perforation or fistula were reported in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforation events occurred in 0.3% (2/586) of these patients. Use with caution in patients at risk for these events and monitor for signs and symptoms. s Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS has been reported and may be fatal. Permanently discontinue VOTRIENT in patients developing RPLS. s Hypertension: Hypertension, including hypertensive crisis, has occurred. Hypertension occurs early in the course of treatment (approximately 40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks).

Blood pressure should be well-controlled prior to initiating VOTRIENT, monitored early after starting treatment (no longer than one week), and frequently thereafter. Treat increased blood pressure promptly with standard antihypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. Discontinue VOTRIENT if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction of VOTRIENT. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension. s Wound Healing: VOTRIENT may impair wound healing.

Interruption of therapy is recommended in patients undergoing surgical procedures; treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. VOTRIENT should be discontinued in patients with wound dehiscence. s Hypothyroidism: Hypothyroidism was reported in 7% (19/290) of patients treated with VOTRIENT in the

Move Forward With VOTRIENT In a Phase 3, randomized, double-blind, placebo-controlled trial, VOTRIENT provided significant improvement in progression-free survival (PFS) in both treatment-naïve and cytokine-pretreated patients with advanced RCC of clear cell or predominant clear cell histology1,2

All patients

Treatment-naïve patients

Cytokine-pretreated patients

9.2 months (95% CI, 7.4-12.9)

11.1 months (95% CI, 7.4-14.8)

7.4 months (95% CI, 5.6-12.9)

overall median PFS with VOTRIENT (n=290) vs 4.2 months (95% CI, 2.8-4.2) with placebo (n=145) (P<0.001) 1,3

median PFS with VOTRIENT (n=155) vs 2.8 months (95% CI, 1.9-5.6) with placebo (n=78) (P<0.001) 1,3

median PFS with VOTRIENT (n=135) vs 4.2 months (95% CI, 2.8-5.6) with placebo (n=67) (P<0.001) 1,3

NCCN Guidelines® Category 1 recommendation4 s As a first-line therapy for relapsed or Stage IV unresectable RCC of predominant clear cell histology. These Guidelines also include therapies other than pazopanib (VOTRIENT) as first-line treatment options

Once-daily oral dosing1

VOTRIENT: Adverse events profile included1:

s The recommended starting dose of VOTRIENT is 800 mg once daily without food (1 hour before or 2 hours after a meal). Daily dose should not exceed 800 mg s Do not crush tablets due to the potential for increased rate of absorption s If a dose is missed, it should not be taken if it is less than 12 hours until the next dose s In RCC, initial dose reduction should be 400 mg; additional dose decrease or increase should be in 200-mg steps based on individual tolerability s Dose modifications, interruptions, and discontinuations may be required in patients with hepatic impairment, drug interactions, and following adverse events

s Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended

s Forty-two percent of patients on VOTRIENT required a dose interruption; 36% of patients on VOTRIENT were dose-reduced

randomized RCC trial and in no patients receiving placebo.

Monitoring of thyroid function tests is recommended. s Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT, leading to discontinuation of treatment in 2 patients. There were no reports of proteinuria in patients receiving placebo. Monitor urine protein. Interrupt treatment for 24-hour urine protein *3 grams and discontinue for repeat episodes despite dose reductions.

s Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound healing, hypothyroidism, proteinuria, infection, increased toxicity with other cancer therapies, and fetal harm s Most common adverse events (>20%) observed in patients with advanced RCC taking VOTRIENT were diarrhea, hypertension, hair color changes (depigmentation), nausea, anorexia, and vomiting s See below and accompanying Brief Summary for additional Important Safety Information, including warnings and precautions

s Pneumothorax: Two of 290 patients treated with VOTRIENT and no patients on the placebo arm in the randomized RCC trial developed a pneumothorax. s Drug Interactions: Coadministration with strong CYP3A4 Inhibitors (eg, ketoconazole, ritonavir, clarithromycin) increases concentrations of pazopanib and should be avoided, but, if warranted, reduce the dose of VOTRIENT. Avoid grapefruit and grapefruit juice.

s Infection: Serious infections (with or without neutropenia), some with fatal outcomes, have been reported. Monitor for signs and symptoms and treat active infection promptly.

Consider interruption or discontinuation of VOTRIENT.

Concomitant use of strong CYP3A4 inducers (eg, rifampin) should be avoided due to the potential to decrease concentrations of pazopanib. VOTRIENT should not be used in patients who cannot avoid chronic use of CYP3A4 inducers.

s Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Increased toxicity and mortality have been observed in clinical trials administering VOTRIENT in combination with lapatinib or with pemetrexed. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens.

CYP Substrates: Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized

by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events.

s Pregnancy Category D: VOTRIENT can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant while taking VOTRIENT. s Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact. s Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients.

In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients.

Laboratory abnormalities occurring in >10% of patients and more commonly (*5%) in patients taking VOTRIENT versus placebo included increases in ALT (53% vs 22%), AST (53% vs 19%), glucose (41% vs 33%), and total bilirubin (36% vs 10%); decreases in phosphorus (34% vs 11%), sodium (31% vs 24%), magnesium (26% vs 14%), and glucose (17% vs 3%); and leukopenia (37% vs 6%), neutropenia (34% vs 6%), thrombocytopenia (32% vs 5%), and lymphocytopenia (31% vs 24%).

Please see Brief Summary of Prescribing Information for VOTRIENT, including BOXED WARNING, on adjacent pages.

References: 1. VOTRIENT® (pazopanib) Tablets [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. 2. Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068. 3. Data on file, GlaxoSmithKline.

4. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology® for Kidney Cancer V.2.2012. ©National Comprehensive Cancer Network, Inc. 2012. All rights reserved. Accessed June 1, 2012. To view the most recent and complete version of the guideline, go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. If a patient develops ALT elevations, follow dosing guidelines for VOTRIENT, consider alternatives to VOTRIENT, or consider discontinuing simvastatin. There are insufficient data to assess the risk of concomitant administration of alternative statins and VOTRIENT. s Adverse Reactions in the Randomized RCC Trial: Forty-two percent of patients on VOTRIENT required a dose interruption. Thirty-six percent of patients on VOTRIENT were dose reduced.

The most common adverse reactions (>20%) for VOTRIENT versus placebo were diarrhea (52% vs 9%), hypertension (40% vs 10%), hair color changes (depigmentation) (38% vs 3%), nausea (26% vs 9%), anorexia (22% vs 10%), and vomiting (21% vs 8%).

VOTRIENT.com

B:22.25 T:21” S:19.25

In The Literature Adding Cetuximab to Chemotherapy...

Continued from page 8

frequent mutations seen with G12D (13%), G12V (9%), or G13D (8%). A recent analysis of previously published data indicates that adding cetuximab to first-line therapy benefits patients with the KRAS G13D mutation (Tejpar S, et

al. J Clin Oncol. 2012;30:3570-3577).

This study evaluated PFS, OS, and response to therapy using pooled data from 1378 patients in the 2 randomized clinical trials, CRYSTAL and OPUS. Among the 533 patients (39%) with KRAS mutations, 83 (16%) had the G13D mutation, 125 (23%) had the G12V mutation, and 325 (61%) had

BRIEF SUMMARY VOTRIENT® (pazopanib) tablets The following is a brief summary only; see full prescribing information for complete product information.

WARNING: HEPATOTOXICITY Severe and fatal hepatotoxicity has been observed in clinical trials.

Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended. [See Warnings and Precautions (5.1).]

1 INDICATIONS AND USAGE VOTRIENT is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosing: The recommended starting dose of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) [see Clinical Pharmacology (12.3) of full prescribing information]. The dose of VOTRIENT should not exceed 800 mg. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3) of full prescribing information]. If a dose is missed, it should not be taken if it is less than 12 hours until the next dose. 2.2 Dose Modification Guidelines: In RCC, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200 mg steps based on individual tolerability. Hepatic Impairment: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to VOTRIENT should be considered. If VOTRIENT is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. VOTRIENT is not recommended in patients with severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. Concomitant Strong CYP3A4 Inhibitors: The concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. If coadministration of a strong CYP3A4 inhibitor is warranted, reduce the dose of VOTRIENT to 400 mg.

Further dose reductions may be needed if adverse effects occur during therapy.

This dose is predicted to adjust the pazopanib AUC to the range observed without inhibitors. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors [see Drug Interactions (7.1)]. Concomitant Strong CYP3A4 Inducer: The concomitant use of strong CYP3A4 inducers (e.g., rifampin) may decrease pazopanib concentrations and should be avoided.

VOTRIENT should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers [see Drug Interactions (7.1)].

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatic Toxicity and Hepatic Impairment: In clinical trials with VOTRIENT, hepatotoxicity, manifested as increases in serum transaminases (ALT, AST) and bilirubin, was observed. This hepatotoxicity can be severe and fatal. Transaminase elevations occur early in the course of treatment (92.5% of all transaminase elevations of any grade occurred in the first 18 weeks) [see Dosage and Administration (2.2)]. In the randomized RCC trial, ALT >3 X ULN was reported in 18% and 3% of the VOTRIENT and placebo groups, respectively. ALT >10 X ULN was reported in 4% of patients who received VOTRIENT and in <1% of patients who received placebo. Concurrent elevation in ALT >3 X ULN and bilirubin >2 X ULN in the absence of significant alkaline phosphatase >3 X ULN occurred in 2% (5/290) of patients on VOTRIENT and 1% (2/145) on placebo. Two-tenths percent of the patients (2/977) from trials that supported the RCC indication died with disease progression and hepatic failure. Monitor serum liver tests before initiation of treatment with VOTRIENT and at least once every 4 weeks for at least the first 4 months of treatment or as clinically indicated. Periodic monitoring should then continue after this time period. Patients with isolated ALT elevations between 3 X ULN and 8 X ULN may be continued on VOTRIENT with weekly monitoring of liver function until ALT return to Grade 1 or baseline. Patients with isolated ALT elevations of >8 X ULN should have VOTRIENT interrupted until they return to Grade 1 or baseline. If the potential benefit for reinitiating treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then reintroduce VOTRIENT at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks [see Dosage and Administration (2.2)].

Following reintroduction of VOTRIENT, if ALT elevations >3 X ULN recur, then VOTRIENT should be permanently discontinued. If ALT elevations >3 X ULN occur concurrently with bilirubin elevations >2 X ULN, VOTRIENT should be permanently discontinued. Patients should be monitored until resolution. VOTRIENT is a UGT1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome [see Clinical Pharmacology (12.5) of full prescribing information]. Patients with only a mild indirect hyperbilirubinemia, known Gilbert’s syndrome, and elevation in ALT >3 X ULN should be managed as per the recommendations outlined for isolated ALT elevations. Concomitant use of VOTRIENT and simvastatin increases the risk of ALT elevations and should be undertaken with caution and close monitoring [see Drug Interactions (7.3)].

Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT. In patients with pre-existing moderate hepatic impairment, the starting dose of VOTRIENT should be reduced or alternatives to VOTRIENT should be considered. Treatment with VOTRIENT is not recommended in patients with pre-existing severe hepatic impairment, defined as total bilirubin >3 X ULN with any level of ALT [see Dosage and Administration (2.2), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) of full prescribing information]. 5.2 QT Prolongation and Torsades de Pointes: In the RCC trials

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other mutations.

Even though previous comparisons between patients with KRAS wildtype tumors and patients with KRAS mutations have not differentiated between subtypes of KRAS mutations, this new analysis of pooled data from previously published studies shows significant variations in treatment

effects in terms of the response rate and duration of PFS in patients with the KRAS G13D mutation compared with all the other mutations (including KRAS G12V).

In the subgroups of patients with the KRAS G13D mutation, PFS improved significantly by adding cetuximab to standard chemotherapy, leading to a

of VOTRIENT, QT prolongation (≥500 msec) was identified on routine electrocardiogram monitoring in 2% (11/558) of patients. Torsades de pointes occurred in <1% (2/977) of patients who received VOTRIENT in the monotherapy studies. In the randomized RCC trial, 1% (3/290) of patients who received VOTRIENT had post-baseline values between 500 to 549 msec. None of the 145 patients receiving placebo had post-baseline QTc values ≥500 msec. VOTRIENT should be used with caution in patients with a history of QT interval prolongation, in patients taking antiarrhythmics or other medications that may prolong QT interval, and those with relevant pre-existing cardiac disease. When using VOTRIENT, baseline and periodic monitoring of electrocardiograms and maintenance of electrolytes (e.g., calcium, magnesium, potassium) within the normal range should be performed. 5.3 Cardiac Dysfunction: In clinical trials with VOTRIENT, events of cardiac dysfunction such as decreased left ventricular ejection fraction (LVEF) and congestive heart failure have occurred. In the overall safety population for RCC (N=586), cardiac dysfunction was observed in 0.6% (4/586) of patients without routine on-study LVEF monitoring. Blood pressure should be monitored and managed promptly using a combination of antihypertensive therapy and dose modification of VOTRIENT (interruption and re-initiation at a reduced dose based on clinical judgment) [see Warnings and Precautions (5.9)]. Patients should be carefully monitored for clinical signs or symptoms of congestive heart failure. Baseline and periodic evaluation of LVEF is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure. 5.4 Hemorrhagic Events: Fatal hemorrhage occurred in 0.9% (5/586) in the RCC trials. In the randomized RCC trial, 13% (37/290) of patients treated with VOTRIENT and 5% (7/145) of patients on placebo experienced at least 1 hemorrhagic event. The most common hemorrhagic events in the patients treated with VOTRIENT were hematuria (4%), epistaxis (2%), hemoptysis (2%), and rectal hemorrhage (1%). Nine of 37 patients treated with VOTRIENT who had hemorrhagic events experienced serious events including pulmonary, gastrointestinal, and genitourinary hemorrhage. One percent (4/290) of patients treated with VOTRIENT died from hemorrhage compared with no (0/145) patients on placebo. In the overall safety population in RCC (N=586), cerebral/intracranial hemorrhage was observed in <1% (2/586) of patients treated with VOTRIENT. VOTRIENT has not been studied in patients who have a history of hemoptysis, cerebral, or clinically significant gastrointestinal hemorrhage in the past 6 months and should not be used in those patients. 5.5 Arterial Thrombotic Events: Fatal arterial thromboembolic events were observed in 0.3% (2/586) of patients in the RCC trials. In the randomized RCC trial, 2% (5/290) of patients receiving VOTRIENT experienced myocardial infarction or ischemia, 0.3% (1/290) had a cerebrovascular accident and 1% (4/290) had an event of transient ischemic attack. No arterial thrombotic events were reported in patients who received placebo. VOTRIENT should be used with caution in patients who are at increased risk for these events or who have had a history of these events. VOTRIENT has not been studied in patients who have had an arterial thrombotic event within the previous 6 months and should not be used in those patients. 5.6 Venous Thromboembolic Events: In trials of VOTRIENT, venous thromboembolic events including venous thrombosis and fatal pulmonary embolus have occurred. In the randomized RCC trial, the rate of venous thromboembolic events was 1% in both arms. There were no fatal pulmonary emboli in the RCC trial. Monitor for signs and symptoms of VTE and PE. 5.7 Gastrointestinal Perforation and Fistula: In the RCC trials, gastrointestinal perforation or fistula occurred in 0.9% (5/586) of patients receiving VOTRIENT. Fatal perforations occurred in 0.3% (2/586) of these patients in the RCC trials. Monitor for signs and symptoms of gastrointestinal perforation or fistula. 5.8 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been reported in patients receiving VOTRIENT and may be fatal. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances.

Mild to severe hypertension may be present. The diagnosis of RPLS is optimally confirmed by magnetic resonance imaging. Discontinue VOTRIENT in patients developing RPLS. 5.9 Hypertension: Hypertension (systolic blood pressure ≥150 or diastolic blood pressure ≥100 mm Hg) and hypertensive crisis were observed in patients treated with VOTRIENT. Blood pressure should be well-controlled prior to initiating VOTRIENT. Hypertension occurs early in the course of treatment (40% of cases occurred by Day 9 and 90% of cases occurred in the first 18 weeks). Blood pressure should be monitored early after starting treatment (no longer than one week) and frequently thereafter to ensure blood pressure control. Approximately 40% of patients who received VOTRIENT experienced hypertension. Grade 3 hypertension was reported in 4% to 7% of patients receiving VOTRIENT [see Adverse Reactions (6.1)]. Increased blood pressure should be treated promptly with standard anti-hypertensive therapy and dose reduction or interruption of VOTRIENT as clinically warranted. VOTRIENT should be discontinued if there is evidence of hypertensive crisis or if hypertension is severe and persistent despite anti-hypertensive therapy and dose reduction. Approximately 1% of patients required permanent discontinuation of VOTRIENT because of hypertension [see Dosage and Administration (2.2)]. 5.10 Wound Healing: No formal trials on the effect of VOTRIENT on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as pazopanib may impair wound healing, treatment with VOTRIENT should be stopped at least 7 days prior to scheduled surgery. The decision to resume VOTRIENT after surgery should be based on clinical judgment of adequate wound healing. VOTRIENT should be discontinued in patients with wound dehiscence. 5.11 Hypothyroidism: Hypothyroidism, confirmed based on a simultaneous rise of TSH and decline of T4, was reported in 7% (19/290) of patients treated with VOTRIENT in the randomized RCC trial. No patients on the placebo arm had hypothyroidism.

In RCC trials of VOTRIENT, hypothyroidism was reported as an adverse reaction in 4% (26/586) of patients. Proactive monitoring of thyroid function tests is recommended. 5.12 Proteinuria: In the randomized RCC trial, proteinuria was reported as an adverse reaction in 9% (27/290) of patients receiving VOTRIENT and in no patients receiving placebo. In 2 patients, proteinuria led to discontinuation of treatment with VOTRIENT. Baseline and periodic urinalysis

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5” ” 5”

In The Literature median PFS of 7.4 months with the combination compared with 6.0 months with placebo (HR, 0.47; P = .039); similarly, tumor response rate was 40.5% versus 22.0%, respectively (odds ratio [OR], 3.38; P = .042). However, there was no significant difference in OS; median OS was 15.4 months with the combination versus 14.7 months with

chemotherapy alone (HR, 0.89; P = .68) in patients with the G13D mutation.

Patients with the G12V mutation and other mutations did not benefit from the combination. Of note, patients with the KRAS G13D mutation who received chemotherapy alone had worse outcomes than those with other mutations receiving chemotherapy alone (response

during treatment is recommended with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt VOTRIENT and dose reduce for 24-hour urine protein ≥3 grams; discontinue VOTRIENT for repeat episodes despite dose reductions [see Dosage and Administration (2.2)]. 5.13 Infection: Serious infections (with or without neutropenia), including some with fatal outcome, have been reported. Monitor patients for signs and symptoms of infection.

Institute appropriate anti-infective therapy promptly and consider interruption or discontinuation of VOTRIENT for serious infections. 5.14 Increased Toxicity with Other Cancer Therapy: VOTRIENT is not indicated for use in combination with other agents. Clinical trials of VOTRIENT in combination with pemetrexed and lapatinib were terminated early due to concerns over increased toxicity and mortality. The fatal toxicities observed included pulmonary hemorrhage, gastrointestinal hemorrhage, and sudden death. A safe and effective combination dose has not been established with these regimens. 5.15 Pregnancy: VOTRIENT can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, VOTRIENT is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. There are no adequate and wellcontrolled studies of VOTRIENT in pregnant women. 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT [see Use in Specific Populations (8.1)].

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience: 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. Potentially serious adverse reactions with VOTRIENT included hepatotoxicity, QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial and venous thrombotic events, gastrointestinal perforation and fistula, Reversible Posterior Leukoencephalopathy Syndrome (RPLS), hypertension, infection, and increased toxicity with other cancer therapies [see Warnings and Precautions (5.1-5.9, 5.13-5.14)]. Renal Cell Carcinoma: The safety of VOTRIENT has been evaluated in 977 patients in the monotherapy trials which included 586 patients with RCC at the time of NDA submission. With a median duration of treatment of 7.4 months (range 0.1 to 27.6), the most commonly observed adverse reactions (≥20%) in the 586 patients were diarrhea, hypertension, hair color change, nausea, fatigue, anorexia, and vomiting. The data described below reflect the safety profile of VOTRIENT in 290 RCC patients who participated in a randomized, double-blind, placebo-controlled trial [see Clinical Studies (14.1) of full prescribing information]. The median duration of treatment was 7.4 months (range 0 to 23) for patients who received VOTRIENT and 3.8 months (range 0 to 22) for the placebo arm. Forty-two percent (42%) of patients on VOTRIENT required a dose interruption. Thirty-six percent (36%) of patients on VOTRIENT were dose reduced. Table 1 presents the most common adverse reactions occurring in ≥10% of patients who received VOTRIENT. Table 1. Adverse Reactions Occurring in ≥10% of Patients with RCC who Received VOTRIENT VOTRIENT

Placebo

(N=290)

(N=145)

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4

% % % % % % Adverse Reactions Diarrhea 52 3 <1 9 <1 0 Hypertension 40 4 0 10 <1 0 Hair color changes 38 <1 0 3 0 0 Nausea 26 <1 0 9 0 0 Anorexia 22 2 0 10 <1 0 Vomiting 21 2 <1 8 2 0 Fatigue 19 2 0 8 1 1 Asthenia 14 3 0 8 0 0 Abdominal pain 11 2 0 1 0 0 Headache 10 0 0 5 0 0 a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Other adverse reactions observed more commonly in patients treated with VOTRIENT than placebo and that occurred in <10% (any grade) were alopecia (8% versus <1%), chest pain (5% versus 1%), dysgeusia (altered taste) (8% versus <1%), dyspepsia (5% versus <1%), dysphonia (4% versus <1%), facial edema (1% versus 0%), palmar-plantar erythrodysesthesia (hand-foot syndrome) (6% versus <1%), proteinuria (9% versus 0%), rash (8% versus 3%), skin depigmentation (3% versus 0%), and weight decreased (9% versus 3%).

Table 2 presents the most common laboratory abnormalities occurring in >10% of patients who received VOTRIENT and more commonly (≥5%) in patients who received VOTRIENT versus placebo.

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rate, 22.0% vs 43.2%; OR, 0.40; P = .032).

This analysis of first-line chemotherapy with or without cetuximab provides evidence for significant heterogeneous treatment effects in patients with different KRAS mutations: adding cetuximab to first-line chemotherapy for patients with improved PFS and the KRAS G13D mutation is

associated with improved clinical outcomes, including prolonged tumor response rate.

Soy Isoflavone Intake Significantly Reduces Risk of Breast Cancer Recurrence, May Improve Survival Continued on page 16

Table 2. Selected Laboratory Abnormalities Occurring in >10% of Patients with RCC who Received VOTRIENT and More Commonly (≥5%) in Patients who Received VOTRIENT Versus Placebo Placebo (N=145)

VOTRIENT (N=290)

Parameters

All All Gradesa Grade 3 Grade 4 Gradesa Grade 3 Grade 4 % % % % % %

Hematologic 37 0 0 6 0 0 Leukopenia 34 1 <1 6 0 0 Neutropenia 32 <1 <1 5 0 <1 Thrombocytopenia 31 4 <1 24 1 0 Lymphocytopenia Chemistry ALT increased 53 10 2 22 1 0 53 7 <1 19 <1 0 AST increased Glucose 41 <1 0 33 1 0 increased Total bilirubin 3 <1 10 1 <1 36 increased Phosphorus 34 4 0 11 0 0 decreased Sodium 31 4 1 24 4 0 decreased Magnesium <1 1 14 0 0 26 decreased Glucose 17 0 <1 3 0 0 decreased a National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.

Diarrhea: Diarrhea occurred frequently and was predominantly mild to moderate in severity in the clinical trials. Patients should be advised how to manage mild diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs so appropriate management can be implemented to minimize its impact.

Lipase Elevations: In a single-arm RCC trial, increases in lipase values were observed for 27% (48/181) of patients. Elevations in lipase as an adverse reaction were reported for 4% (10/225) of patients and were Grade 3 for 6 patients and Grade 4 for 1 patient. In the RCC trials of VOTRIENT, clinical pancreatitis was observed in <1% (4/586) of patients. Pneumothorax: Two of 290 patients treated with VOTRIENT and no patient on the placebo arm in the randomized RCC trial developed a pneumothorax. 6.2 Postmarketing Experience: The following adverse reactions have been identified during post approval use of VOTRIENT. Because these reactions are reported voluntarily from a population of uncertain size it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure. Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.8)].

7 DRUG INTERACTIONS 7.1 Drugs That Inhibit or Induce Cytochrome P450 3A4 Enzymes: In vitro studies suggested that the oxidative metabolism of pazopanib in human liver microsomes is mediated primarily by CYP3A4, with minor contributions from CYP1A2 and CYP2C8. Therefore, inhibitors and inducers of CYP3A4 may alter the metabolism of pazopanib. CYP3A4 Inhibitors: Coadministration of pazopanib with strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin) increases pazopanib concentrations and should be avoided. Reduce the dose of VOTRIENT when it must be coadministered with strong CYP3A4 inhibitors [see Dosage and Administration (2.2)]. Grapefruit juice should be avoided as it inhibits CYP3A4 activity and may also increase plasma concentrations of pazopanib.

CYP3A4 Inducers: CYP3A4 inducers such as rifampin may decrease plasma pazopanib concentrations. VOTRIENT should not be used if chronic use of strong CYP3A4 inducers cannot be avoided [see Dosage and Administration (2.2)].

7.2 Effects of Pazopanib on CYP Substrates: Results from drug-drug interaction studies conducted in cancer patients suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, and CYP2D6 in vivo, but had no effect on CYP1A2, CYP2C9, or CYP2C19 [see Clinical Pharmacology (12.3) of full prescribing information].

Concomitant use of VOTRIENT with agents with narrow therapeutic windows that are metabolized by CYP3A4, CYP2D6, or CYP2C8 is not recommended.

Coadministration may result in inhibition of the metabolism of these products and create the potential for serious adverse events [see Clinical Pharmacology (12.3) of full prescribing information]. 7.3 Effect of Concomitant use of VOTRIENT and Simvastatin: Concomitant use of VOTRIENT and simvastatin increases the incidence of ALT elevations. Across monotherapy studies with VOTRIENT, ALT >3 X ULN was reported in 126/895 (14%) of patients who did not use statins, compared with 11/41 (27%) of patients who had concomitant use of simvastatin.

If a patient receiving concomitant simvastatin develops ALT elevations, follow dosing guidelines for VOTRIENT or consider alternatives to VOTRIENT [see Warnings and Precautions (5.1)]. Alternatively, consider discontinuing simvastatin [see Warnings and Precautions (5.1)]. Insufficient data are available to assess the risk of concomitant administration of alternative statins and VOTRIENT.

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In The Literature Soy Isoflavone Intake Significantly Reduces Risk...

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It has been suggested in previous studies that soy isoflavones have anticancer properties; however, it is also known that soy-based foods possess estrogen-like properties and can there-

fore present complications rather than benefits for patients with breast cancer, potentially even playing a role in the genesis of breast cancer or its progression. Now 2 new studies indicate that daily consumption of soy-based foods may confer benefits for patients with breast cancer.

10 OVERDOSAGE Pazopanib doses up to 2,000 mg have been evaluated in clinical trials.

Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively. Treatment of overdose with VOTRIENT should consist of general supportive measures. There is no speciďŹ c antidote for overdosage of VOTRIENT. Hemodialysis is not expected to enhance the elimination of VOTRIENT because pazopanib is not signiďŹ cantly renally excreted and is highly bound to plasma proteins.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with pazopanib have not been conducted. However, in a 13-week study in mice, proliferative lesions in the liver including eosinophilic foci in 2 females and a single case of adenoma in another female was observed at doses of 1,000 mg/kg/day (approximately 2.5 times the human clinical exposure based on AUC). Pazopanib did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay. Pazopanib may

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impair fertility in humans. In female rats, reduced fertility including increased pre-implantation loss and early resorptions were noted at dosages â&#x2030;Ľ30 mg/kg/day (approximately 0.4 times the human clinical exposure based on AUC). Total litter resorption was seen at 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC). Post-implantation loss, embryolethality, and decreased fetal body weight were noted in females administered doses â&#x2030;Ľ10 mg/kg/day (approximately 0.3 times the human clinical exposure based on AUC). Decreased corpora lutea and increased cysts were noted in mice given â&#x2030;Ľ100 mg/kg/day for 13 weeks and ovarian atrophy was noted in rats given â&#x2030;Ľ300 mg/kg/day for 26 weeks (approximately 1.3 and 0.85 times the human clinical exposure based on AUC, respectively). Decreased corpora lutea was also noted in monkeys given 500 mg/kg/day for up to 34 weeks (approximately 0.4 times the human clinical exposure based on AUC). Pazopanib did not affect mating or fertility in male rats. However, there were reductions in sperm production rates and testicular sperm concentrations at doses â&#x2030;Ľ3 mg/kg/day, epididymal sperm concentrations at doses â&#x2030;Ľ30 mg/kg/day, and sperm motility at â&#x2030;Ľ100 mg/kg/day following 15 weeks of dosing. Following 15 and 26 weeks of dosing, there were decreased testicular and epididymal weights at doses of â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC); atrophy and degeneration of the testes with aspermia, hypospermia and cribiform change in the epididymis was also observed at this dose in the 6-month toxicity studies in male rats.

17 PATIENT COUNSELING INFORMATION See Medication Guide. The Medication Guide is contained in a separate leaďŹ&#x201A;et that accompanies the product. However, inform patients of the following: t 5IFSBQZ XJUI 7053*&/5 NBZ SFTVMU JO IFQBUPCJMJBSZ MBCPSBUPSZ BCOPSNBMJUJFT Monitor serum liver tests (ALT, AST, and bilirubin) prior to initiation of VOTRIENT and at least once every 4 weeks for the ďŹ rst 4 months of treatment or as clinically indicated. Inform patients that they should report signs and symptoms of liver dysfunction to their healthcare provider right away. t 1SPMPOHFE 25 JOUFSWBMT BOE UPSTBEFT EF QPJOUFT IBWF CFFO PCTFSWFE 1BUJFOUT should be advised that ECG monitoring may be performed. Patients should be advised to inform their physicians of concomitant medications. t $BSEJBD EZTGVODUJPO TVDI BT $)' BOE -7&' EFDSFBTF IBT CFFO PCTFSWFE JO patients at risk (e.g., prior anthracycline therapy) particularly in association with development or worsening of hypertension. Patients should be advised to report hypertension or signs and symptoms of congestive heart failure. t 4FSJPVT IFNPSSIBHJD FWFOUT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF BEWJTFE UP report unusual bleeding. t "SUFSJBM UISPNCPUJD FWFOUT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF BEWJTFE UP report signs or symptoms of an arterial thrombosis. t 3FQPSUT PG QOFVNPUIPSBY BOE WFOPVT UISPNCPFNCPMJD FWFOUT JODMVEJOH pulmonary embolus have been reported. Patients should be advised to report if new onset of dyspnea, chest pain, or localized limb edema occurs. t "EWJTF QBUJFOUT UP JOGPSN UIFJS EPDUPS JG UIFZ IBWF XPSTFOJOH PG OFVSPMPHJDBM function consistent with RPLS (headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances). t )ZQFSUFOTJPO BOE IZQFSUFOTJWF DSJTJT IBWF CFFO SFQPSUFE 1BUJFOUT TIPVME CF advised to monitor blood pressure early in the course of therapy and frequently thereafter and report increases of blood pressure or symptoms such as blurred vision, confusion, severe headache, or nausea and vomiting. t (* QFSGPSBUJPO PS mTUVMB IBT PDDVSSFE "EWJTF QBUJFOUT UP SFQPSU TJHOT BOE symptoms of a GI perforation or ďŹ stula. t 7&('3 JOIJCJUPST TVDI BT 7053*&/5 NBZ JNQBJS XPVOE IFBMJOH "EWJTF QBUJFOUT to stop VOTRIENT at least 7 days prior to a scheduled surgery. t )ZQPUIZSPJEJTN BOE QSPUFJOVSJB IBWF CFFO SFQPSUFE "EWJTF QBUJFOUT UIBU UIZSPJE function testing and urinalysis will be performed during treatment. t 4FSJPVT JOGFDUJPOT JODMVEJOH TPNF XJUI GBUBM PVUDPNFT IBWF CFFO SFQPSUFE Advise patients to promptly report any signs or symptoms of infection. t 8PNFO PG DIJMECFBSJOH QPUFOUJBM TIPVME CF BEWJTFE PG UIF QPUFOUJBM IB[BSE UP UIF fetus and to avoid becoming pregnant. t (BTUSPJOUFTUJOBM BEWFSTF SFBDUJPOT TVDI BT EJBSSIFB OBVTFB BOE WPNJUJOH IBWF been reported with VOTRIENT. Patients should be advised how to manage diarrhea and to notify their healthcare provider if moderate to severe diarrhea occurs t 1BUJFOUT TIPVME CF BEWJTFE UP JOGPSN UIFJS IFBMUIDBSF QSPWJEFST PG BMM concomitant medications, vitamins, or dietary and herbal supplements. t 1BUJFOUT TIPVME CF BEWJTFE UIBU EFQJHNFOUBUJPO PG UIF IBJS PS TLJO NBZ PDDVS during treatment with VOTRIENT. t 1BUJFOUT TIPVME CF BEWJTFE UP UBLF 7053*&/5 XJUIPVU GPPE BU MFBTU IPVS before or 2 hours after a meal).

VOTRIENT is a registered trademark of GlaxoSmithKline.

Š2012, GlaxoSmithKline. All rights reserved.

Revised 04/2012 VTR:7BRS Š2012 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. VOT319R0 August 2012

OCTOBER 2012

The data for the analysis came from the After Breast Cancer Pooling Project and included data for 9514 breast cancer survivors from 2 US cohorts and 1 Chinese cohort. All patients had a diagnosis of invasive breast cancer between 1991 and 2006. The findings were adjusted for clinical, sociodemographic, and lifestyle factors.

At a mean follow-up of 7.4 years, 1171 women died, 881 of whom died from breast cancer. In addition, a total of 1348 breast cancer recurrences occurred after that period. Despite large differences in daily intake of soy isoflavone between the Chinese and the American women, soy isoflavone consumption was inversely associated with cancer recurrence in both populations. This was true when the data were analyzed specifically by country, as well as when the data were combined for both populations.

Overall, consumption of â&#x2030;Ľ10 mg daily of soy isoflavones was associated with a nonsignificant increased reduction of all-cause mortality risk (HR, 0.87; 95% CI, 0.70-1.10), as well as nonsignificant risk reduction of breast cancerâ&#x20AC;&#x201C;specific mortality (HR, 0.83; 95% CI, 0.64-1.07). However, the risk reduction of disease recurrence was significantly greater with daily consumption of â&#x2030;Ľ10 mg of soy products (HR, 0.75; 95% CI, 0.61-0.92). These findings indicate that regular consumption of soy products can reduce the risk of recurrence in some women with breast cancer. Further studies are needed to confirm these data, and to elucidate specifically which types of breast cancer can benefit from these products.

The second prospective study was conducted in China and included Chinese women only (Zhang YF, et al. Asian Pac J Cancer Prev. 2012;13:479-482). The study was conducted between January 2004 and January 2006. Data were collected via face-to-face interviews, using questionnaires related to dietary habits and confounding factors.

After a median follow-up of 52.1 months (range, 9-60 months), 79 deaths related to breast cancer were reported. The data indicate that breast cancerâ&#x20AC;&#x201C;related mortality risk was inversely associated with a high intake of soy products. An average intake of >17.3 mg daily of soy isoflavones was found to be associated with a 36% to 38% mortality risk reduction.

Similarly, a high intake of soy protein was associated with a reduction in breast cancerâ&#x20AC;&#x201C;related death (HR, 0.71; 95% CI, 0.52-0.98).

Furthermore, a stratified analysis of estrogen receptor (ER) status suggested that ER-positive status is still associated with an improved prognosis with high intake of soy isoflavones

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8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D [see Warnings and Precautions (5.15)].

VOTRIENT can cause fetal harm when administered to a pregnant woman.

There are no adequate and well-controlled studies of VOTRIENT in pregnant women. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient. Administration of pazopanib to pregnant rats during organogenesis at a dose level of â&#x2030;Ľ3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC) resulted in teratogenic effects including cardiovascular malformations (retroesophageal subclavian artery, missing innominate artery, changes in the aortic arch) and incomplete or absent ossiďŹ cation. In addition, there was reduced fetal body weight, and preand post-implantation embryolethality in rats administered pazopanib at doses â&#x2030;Ľ3 mg/kg/day. In rabbits, maternal toxicity (reduced food consumption, increased post-implantation loss, and abortion) was observed at doses â&#x2030;Ľ30 mg/kg/day (approximately 0.007 times the human clinical exposure). In addition, severe maternal body weight loss and 100% litter loss were observed at doses â&#x2030;Ľ100 mg/kg/day (0.02 times the human clinical exposure), while fetal weight was reduced at doses â&#x2030;Ľ3 mg/kg/day (AUC not calculated). 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 the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking VOTRIENT. 8.3 Nursing Mothers: 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 serious adverse reactions in nursing infants from VOTRIENT, 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. 8.4 Pediatric Use: The safety and effectiveness of VOTRIENT in pediatric patients have not been established. In repeat-dose toxicology studies in rats including 4-week, 13-week, and 26-week administration, toxicities in bone, teeth, and nail beds were observed at doses â&#x2030;Ľ3 mg/kg/day (approximately 0.07 times the human clinical exposure based on AUC). Doses of 300 mg/kg/day (approximately 0.8 times the human clinical exposure based on AUC) were not tolerated in 13- and 26-week studies with rats. Body weight loss and morbidity were observed at these doses. Hypertrophy of epiphyseal growth plates, nail abnormalities (including broken, overgrown, or absent nails) and tooth abnormalities in growing incisor teeth (including excessively long, brittle, broken and missing teeth, and dentine and enamel degeneration and thinning) were observed in rats at â&#x2030;Ľ30 mg/kg/day (approximately 0.35 times the human clinical exposure based on AUC) at 26 weeks, with the onset of tooth and nail bed alterations noted clinically after 4 to 6 weeks. 8.5 Geriatric Use: In clinical trials with VOTRIENT for the treatment of RCC, 33% (196/582) of patients were aged â&#x2030;Ľ65 years. No overall differences in safety or effectiveness of VOTRIENT were observed between these patients and younger patients. However, patients >60 years of age may be at greater risk for an ALT >3 X ULN. Other reported clinical experience has not identiďŹ ed differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment: In clinical studies for VOTRIENT, patients with total bilirubin â&#x2030;¤1.5 X ULN and AST and ALT â&#x2030;¤2 X ULN were included [see Warnings and Precautions (5.1)]. An analysis of data from a pharmacokinetic study of pazopanib in patients with varying degrees of hepatic dysfunction suggested that no dose adjustment is required in patients with mild hepatic impairment [either total bilirubin within normal limit (WNL) with ALT > ULN or bilirubin >1 X to 1.5 X ULN regardless of the ALT value]. The maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin >1.5 X to 3 X ULN regardless of the ALT value) was 200 mg per day (N=11). The median steady-state Cmax and AUC (0-24) achieved at this dose was approximately 40% and 29%, respectively of that seen in patients with normal hepatic function at the recommended daily dose of 800 mg. The maximum dose explored in patients with severe hepatic impairment (total bilirubin >3 X ULN regardless of the ALT value) was 200 mg per day (N=14). This dose was not well tolerated. Median exposures achieved at this dose were approximately 18% and 15% of those seen in patients with normal liver function at the recommended daily dose of 800 mg. Therefore, VOTRIENT is not recommended in these patients [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Renal Impairment: Patients with renal cell cancer and mild/moderate renal impairment (creatinine clearance â&#x2030;Ľ30 mL/min) were included in clinical studies for VOTRIENT. There are no clinical or pharmacokinetic data in patients with severe renal impairment or in patients undergoing peritoneal dialysis or hemodialysis. However, renal impairment is unlikely to signiďŹ cantly affect the pharmacokinetics of pazopanib since <4% of a radiolabeled oral dose was recovered in the urine. In a population pharmacokinetic analysis using 408 subjects with various cancers, creatinine clearance (30-150 mL/min) did not inďŹ&#x201A;uence clearance of pazopanib. Therefore, renal impairment is not expected to inďŹ&#x201A;uence pazopanib exposure, and dose adjustment is not necessary.

In the first study, the investigators prospectively evaluated the potential association between consumption of soy-based foods after a diagnosis of breast cancer and cancer outcomes among American and Chinese women (Nechuta SJ, et al. Am J Clin Nutr.

2012;96:123-132).

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ESMO 2012 Conference

Updated Data Confirm Survival Benefits with T-DM1... ecitabine (Xeloda) in women with HER2-positive metastatic breast cancer. Women assigned to T-DM1 had a 32% lower mortality rate compared with those assigned to the lapatinib and capecitabine combination.

The median overall survival (OS) was 30.9 months with T-DM1 versus 25.1 months with lapatinib plus capecitabine, a significant (P <.001) 6-month difference. To date, a median OS of approximately 31 months is the best reported survival rate in a randomized trial in patients with HER2positive metastatic breast cancer. The full report of the EMILIA trial was simultaneously published online (Verma S, et al. N Engl J Med. Epub 2012 Oct 1) to coincide with the ESMO 2012 presentation.

Lead investigator Sunil Verma, MD, Assistant Professor, University of Toronto, Ontario, Canada, and a medical oncologist at Sunnybrook Odette Cancer Center, Toronto, noted that the survival benefit and safety of T-DM1 in EMILIA, “suggest that T-DM1 should be an important therapeutic option in the treatment of metastatic HER2-positive breast cancer.”

The global EMILIA trial randomized 991 patients with HER2-positive metastatic breast cancer to T-DM1 or to lapatinib and capecitabine in a 1:1 ratio. Participants were previously treated with trastuzumab and with a taxane. Patients were stratified according to their geographic region, the number of previous chemotherapy regimens for metastatic breast cancer or unresectable locally advanced disease, and the presence of visceral disease.

Grade 3 or higher adverse events

basis for the FDA approval, regorafenib achieved a sustained survival benefit in patients with heavily pretreated mCRC who had a good performance status score (ie, 0 or 1).

Regorafenib benefited all of the prespecified subgroups. The drug’s safety was as expected, with no new safety concerns emerging at the extended follow-up.

The study was stopped at the first interim analysis, because of a clear OS difference between the 2 arms, with a median of 6.4 months (95% confidence interval [CI], 5.8-7.0) for rego-

The survival benefit and safety of T-DM1“suggest that T-DM1 should be an important therapeutic option in the treatment of metastatic HER2-positive breast cancer.”

—Sunil Verma, MD

(AEs) were more frequent (57%) in the lapatinib plus capecitabine arm than in the T-DM1 arm (41%). Patients in the T-DM1 arm had a higher incidence of thrombocytopenia and increased serum aminotransferase levels, whereas the combination group had higher rates of diarrhea, nausea, vomiting, and hand-foot syndrome. Cardiac dysfunction rates were low and similar in both arms.

The CORRECT Trial According to updated results of the CORRECT trial, which was the

Continued from page 11

a median OS now of 22 months versus 9 months in the past,” Dr Soria said, “and this is accomplished with very mild toxicity.”

Even patients in the trial who initially received chemotherapy had a median OS of nearly 23 months, “because they received crizotinib,” he added.

Delayed Approval in Europe Dr Soria took advantage of the podium to voice his disapproval of the “reluctance” of the European Medicines Agency (EMA) to approve crizotinib. He noted that the US Food

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and Drug Administration (FDA) “welcomed the filing of single-arm data for accelerated approval,” whereas the EMA stated that any “conditional approval can only be granted on an established positive benefit-risk assessment.”

Although the FDA approved crizotinib less than 5 months after the submission of the single-arm data, the EMA has taken 14 months to review those data and is requiring additional randomized data, Dr Soria said. The EMA approval is expected by the end of October 2012. ■

at a glance ➤ The updated findings from the EMILIA trial show that T-DM1 prolonged survival in women with HER2-positive metastatic breast cancer ➤ The median OS was 30.9 months with T-DM1 versus 25.1 months with the lapatinibcapecitabine combination ➤ A median OS of 31 months is to date the best survival rate in patients with HER2-positive metastatic breast cancer ➤ The updated data from the CORRECT trial showed a sustained survival benefit and a 21% reduced risk of death in patients with heavily pretreated mCRC who received regorafenib versus placebo ➤ At 6 months, 52.2% of those receiving regorafenib were alive versus 43% of those receiving placebo ➤ 24% of patients in the regorafenib arm were alive at 1 year compared with 17% in the placebo arm

“Regorafenib is the first oral multitargeted TKI with proven activity in metastatic colorectal cancer….The drug represents a new potential standard of care for patients with chemorefractory metastatic disease.”

—Eric van Cutsem, MD, PhD

Crizotinib Superior to Chemotherapy...

Continued from cover

rafenib versus 5 months (95% CI, 4.45.9) for placebo.

A final updated OS analysis presented at ESMO 2012 confirmed the benefits of regorafenib by demonstrating a 21% reduced risk of death.

At 6 months, 52.2% of the patients in the regorafenib group were alive versus 43% of the patients receiving placebo; and 24% of those receiving regorafenib were alive at 1 year compared with 17% of those receiving placebo.

“Regorafenib is the first oral multitargeted TKI [tyrosine kinase inhibitors] with proven activity in metastatic colorectal cancer….The drug represents a new potential stan-

OCTOBER 2012

I

dard of care for patients with chemorefractory metastatic disease,” stated lead author Eric van Cutsem, MD, PhD, Professor, University of Leuven, and Head of the Division of Digestive Oncology at University Hospital Gasthuisberg in Leuven, Belgium.

The CORRECT clinical trial included 760 patients with mCRC who progressed despite previous treatment with several lines of standard therapies. Patients were randomized in a 2:1 ratio to oral regorafenib 160 mg daily or to placebo for 3 weeks on and 1 week off; both groups got best supportive care. Patients were treated until disease progression, unacceptable toxicity, or until the investigator’s decision to withdraw treatment.

Regorafenib-related AEs included hand-foot syndrome in 46% (all grades; grade 3, 16%); fatigue, 47.4% (all grades; grade 3, 9.2%); hypertension, 27.8% (all grades; grade 3, 7.2%); diarrhea, 38% (all grades; grade 3, 7%); and rash or skin desquamation in 26% (all grades; grade 3, 5.8%). A subgroup analysis showed no major differences in AEs between the 2 treatment arms. ■

www.ValueBasedCancerCare.com

17

Making

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

TAILORING a PRO tool for myelofibrosis

130T BSF BO JNQPSUBOU NFBOT UP EFNPOTUSBUF USFBUNFOU benefits in clinical trials. 6TF PG B 130 JOTUSVNFOU DBO evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement. *ODPSQPSBUJOH 130T JOUP B DMJOJDBM USJBM QSPHSBN QSPWJEFT B means for evaluating the impact of therapy from the patientâ&#x20AC;&#x2122;s perspective and helps patients and clinicians make betterinformed decisions.

.ZFMPĂĽ CSPTJT .'

JT B MJGF UISFBUFOJOH QSPHSFTTJWF EJTFBTF characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, EPVCMF CMJOE QMBDFCP DPOUSPMMFE TUVEZ $0.'035 * GPS +BLBĂĽ 4QMFFO SFEVDUJPO BT NFBTVSFE CZ JNBHJOH .3* PS $5

was the primary and biologic endpoint, and a reduction in total TZNQUPN TDPSF 544 UIF 130 NFBTVSF XBT B LFZ TFDPOEBSZ endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 5P JODMVEF 130T JO UIF USJBM B OPWFM JOTUSVNFOU IBE UP CF specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version NPEJĂĽ FE .'4"' W XBT ĂĽ OBMJ[FE BT QBSU PG UIF 4QFDJBM 1SPUPDPM "TTFTTNFOU QSJPS UP UIF JOJUJBUJPO PG $0.'035 * Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyteâ&#x20AC;&#x2122;s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDAâ&#x20AC;&#x2122;s draft guidance on 130T XBT ĂĽ OBMJ[FE JO

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, postâ&#x20AC;&#x201C;polycythemia vera myelofibrosis and postâ&#x20AC;&#x201C;essential thrombocythemia myelofibrosis.

Important Safety Information t 5SFBUNFOU XJUI +BLBĂĽ DBO DBVTF IFNBUPMPHJD BEWFSTF reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required t 5IF UISFF NPTU GSFRVFOU OPO IFNBUPMPHJD BEWFSTF reactions were bruising, dizziness and headache t 1BUJFOUT XJUI QMBUFMFU DPVOUT ¨ 9/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered t 1BUJFOUT EFWFMPQJOH BOFNJB NBZ SFRVJSF CMPPE USBOTGVTJPOT Dose modifications of Jakafi for patients developing anemia may also be considered t /FVUSPQFOJB "/$ ¨ 9/L) was generally reversible and was managed by temporarily withholding Jakafi t 1BUJFOUT TIPVME CF BTTFTTFE GPS UIF SJTL PG EFWFMPQJOH serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before TUBSUJOH +BLBĂĽ 1IZTJDJBOT TIPVME DBSFGVMMZ PCTFSWF QBUJFOUT receiving Jakafi for signs and symptoms of infection JODMVEJOH IFSQFT [PTUFS BOE JOJUJBUF BQQSPQSJBUF treatment promptly t " EPTF NPEJĂĽ DBUJPO JT SFDPNNFOEFE XIFO BENJOJTUFSJOH +BLBĂĽ XJUI TUSPOH $:1 " JOIJCJUPST PS JO QBUJFOUT XJUI

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

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

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

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

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

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

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MFâ&#x20AC;&#x201D;this is an important consideration when evaluating and treating patients.9 5IF '%" BQQSPWBM JODMVEFE QBUJFOUT XJUI JOUFSNFEJBUF SJTL BOE IJHI SJTL BT XFMM BT QBUJFOUT with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and BDBEFNJD FYQFSUT UP EFWFMPQ SFMFWBOU BOE WBMJEBUFE 130 JOTUSVNFOUT UIBU DBO CF JODPSQPSBUFE JOUP DMJOJDBM USJBMT 1,8 The approval PG +BLBĂĽ NBSLT B TJHOJĂĽ DBOU NJMFTUPOF JO XIJDI WBMJEBUFE 130 JOTUSVNFOUT DBO QSPWJEF TZNQUPN EBUB BOE EFNPOTUSBUF DMJOJDBM CFOFĂĽ U 5IF FYQFSJFODF XJUI +BLBĂĽ NBZ QSPWJEF B NPEFM GPS UIF GVUVSF VTF PG 130T JO NBSLFUJOH BQQMJDBUJPOT 8

renal or hepatic impairment [see Dosage and Administration].

1BUJFOUT TIPVME CF DMPTFMZ NPOJUPSFE BOE UIF EPTF UJUSBUFE based on safety and efficacy t 5IFSF BSF OP BEFRVBUF BOE XFMM DPOUSPMMFE TUVEJFT PG +BLBĂĽ in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus t 8PNFO UBLJOH +BLBĂĽ TIPVME OPU CSFBTU GFFE %JTDPOUJOVF nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.

6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011.

10. Data on File, Incyte Corporation.

a

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

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

Jakafi is a registered trademark of Incyte Corporation. Š 2012, Incyte Corporation. All rights reserved.

RUX-1130A 05/12

ESMO 2012 Congress

Continuation of Bevacizumab Beyond Progression Improves Outcome in Patients with Metastatic Colorectal Cancer

By Caroline Helwick

support

for Austria—More the continuation of treatment with bevacizumab beyond disease pro-

gression in patients with metastatic colorectal cancer was reported at the 2012 European Society for

Medical Oncology (ESMO) Congress, validating a small but growing body of previous data.

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All b Grade 3 Grade 4 Grades Grade 3 Grade 4 Parameter Grades BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved.

Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

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The phase 3 study, which was presented at the 2012 ESMO Congress by the Gruppo Oncologico Nord Ovest, randomized patients who had received bevacizumab plus first-line chemotherapy with a fluoropyrimidine (FOLFIRI [folinic acid, fluorouracil, irinotecan], FOLFOX [folinic acid, fluorouracil, oxaliplatin], or FOLFOXIRI [folinic acid, fluorouracil, irinotecan, oxaliplatin]) to receive a second line of chemotherapy using either FOLFOX or FOLFIRI alone (arm A) or together with bevacizumab (arm B).

Photo © European Society for Medical Oncology

Vienna,

“This is the second randomized trial investigating the impact of bevacizumab continuation beyond first progression. The continuation of bevacizumab in combination with second-line chemotherapy represents a new treatment option.”

—Gianluca Masi, MD

In the intent-to-treat analysis of 184 patients followed for a median of 18 months, the median progression-free survival (PFS) was 4.97 months without bevacizumab and 6.77 months in patients who continued to receive the drug, representing a 35% reduction in the risk of progression, reported Gianluca Masi, MD, Medical Director of Oncology at the University Hospital of Pisa, Italy.

A PFS analysis that adjusted for various stratification factors, age, and sex confirmed that bevacizumab added to chemotherapy improved PFS versus chemotherapy alone by 30%. Overall survival data are not yet mature, with the control arm having 52 deaths and the bevacizumab arm having 46 deaths so far.

“This is the second randomized trial investigating the impact of bevacizumab continuation beyond first progression,” Dr Masi said.

“The continuation of bevacizumab in combination with second-line chemotherapy represents a new treatment option.” ■

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Personalized Medicine See also 2012 ESMO Congress

But clinical utility is still in its infancy

He noted that even as the pool of biomarkers expands, treatment decisions for many tumor types are still based on clinical factors, such as age and performance status, sometimes even when biomarkers have been clinically validated.

Addressing the use of molecular markers in patients with colorectal cancer, Alberto Sobrero, MD, PhD, Head of the Medical Oncology Unit at Ospedale San Martino in Genoa, Italy, maintained that oncologists are a long way off from using molecular markers to routinely guide treatment.

He said that although the determination of KRAS status was “paradigm changing,” it applies to the metastatic setting only. The initial management of patients with colorectal cancer is not driven by molecular markers. “We choose anti-VEGF [vascular endothelial growth factor] therapy (ie, bevacizumab) based on ‘nothing,’ and other molecular markers are weak,” Dr Sobrero pointed out.

at a glance ➤ Personalized oncology is the future of cancer therapy, but for now, its clinical utility is rather limited ➤ Very few biomarkers are currently used in clinical practice for guiding treatment decisions, despite the plethora of tumor biology information ➤ Many types of cancer do not have biomarkers so far ➤ KRAS status was “paradigm changing,” but it applies to the metastatic setting only and does not apply in early management of patients with colorectal cancer ➤ Clinical trials should now only be conducted in selected patient populations, to advance the benefits of personalized medicine

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“We still have a long way to go before massive amounts of genetic alterations can be linked to cancer biology and translated into truly effective treatment strategies.”

—Martine J. Piccart-Gebhart, MD, PhD

alterations can be linked to cancer biology and translated into truly effective treatment strategies,” Dr PiccartGebhart noted.

But Do Molecular Markers Help in the Clinical Setting?

Several biomarkers are well established in the clinical setting, such as estrogen receptor status, HER2 status, epidermal growth factor receptor status, and KRAS gene expression. In the past year, BRAF and ALK abnormalities have joined the list.

But Matthias Preusser, MD, Neurooncologist, Department of Internal Medicine, of the Medical University of Vienna, acknowledged, “For most cancers, molecular profiling is still not clinically validated, although there are plenty of encouraging data emerging, including from presentations here at ESMO, to suggest that this could change in the near future.”

He asked, “Can we look forward to a day when tumors are fully profiled for all known biomarkers as standard practice? And if they are, will clinicians know the full extent and implications of the results they receive and the nuances that particular combinations of markers signify in terms of treatment? Or will we continue to stick rigidly to standard therapies, perhaps afraid of the risks and repercussions of following nonstandard treatments?”

“The use of biomarkers has provided a plethora of information in terms of tumor biology and sensitivity and resistance to treatment.

However,…very few biomarkers are currently being used to guide treatment decisions.”

—Evandro de Azambuja, MD, PhD

Photo © European Society for Medical Oncology

Vienna, Austria—“One of our themes at the 2012 ESMO Congress is personalized oncology,” European Society for Medical Oncology (ESMO) President Martine J. Piccart-Gebhart, MD, PhD, Professor of Oncology at the Université Libre de Bruxelles and Director of the Medicine Department at Jules Bordet Institute, Brussels, Belgium, said at a press briefing at the meeting. She noted that the numerous presentations on targeted therapy and diagnostics at ESMO are evidence that the field is rapidly moving forward.

Elucidating the complex molecular architecture of cancer offers the promise of “precision medicine,” Dr PiccartGebhart said, because targeted molecular therapies are becoming standard in the treatment of most tumor types.

But with this comes a massive amount of data derived from full genome sequencing, exome sequencing, DNA sequencing, RNA sequencing, and protein analysis.

The data from these analyses, as Dr Piccart-Gebhart pointed out, must be shared “efficiently” between academia, government, and industry. She predicted that it will take a “revolution” for this to occur sooner rather than later.

“We still have a long way to go before massive amounts of genetic

Photo © European Society for Medical Oncology

By Caroline Helwick

Photo © European Society for Medical Oncology

ESMO Theme: Personalized (“Precision”) Oncology Care Marches Forward

“For most cancers, molecular profiling is still not clinically validated, although there are plenty of encouraging data emerging, including from presentations here at ESMO, to suggest that this could change in the near future.”

—Matthias Preusser, MD

Laboratory Assays for Markers Need Validation “In my opinion, one major obstacle to bringing new biomarkers into use in everyday clinical work and for the benefit of patients is the lack of studies validating our laboratory assays,” Dr Preusser added. He called for more high-quality studies on the analytical

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performance of test methods—such as phase 1, 2, and 3 clinical trials for novel drugs—to determine which assays are best for a given biomarker.

“The use of biomarkers has provided a plethora of information in terms of tumor biology and sensitivity and resistance to treatment. However, not all types of cancer have biomarkers available for use. Actually, very few biomarkers are currently being used to guide treatment decisions,” agreed Evandro de Azambuja, MD, PhD, Medical Director of the Breast Data Centre and a member of the Ethical Committee at Jules Bordet Institute.

But the use of gene expression profiling has helped researchers, and now clinicians, understand tumor biology in several malignancies, with breast cancer at the forefront of this new approach. “So, without any doubt, we are progressing towards personalized medicine,” Dr de Azambuja said.

Dr de Azambuja also stressed the need to move from the current clinical trial model to one based on testing novel drugs in rationally selected patient populations, which was a theme echoed by many other investigators in presentations during the meeting.

“Clinical trials should no longer be conducted in unselected patient populations,” Dr de Azambuja suggested. ■

www.ValueBasedCancerCare.com

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Personalized Medicine

Is Personalized Cancer Care Affordable?

The business of medicine: all life has finite value

By Caroline Helwick Vienna, Austria—“Is personalized cancer care affordable?” asked Richard Sullivan, MD, PhD, Director of Kings Health Partners Institute of Cancer Policy and Global Health in the United Kingdom, in an invited presentation at the 2012 European Society for Medical Oncology Congress.

The short answer he gave was “no,” barring seismic shifts not only in the oncology landscape but also in the larger societal picture. He described 3 trends that will be disastrous for controlling the cost of care.

The first problem is the aging population. By the year 2014, 25% of the population in developed countries will be aged ≥70 years, and Dr Sullivan suggested that the “upper limit may well be over [age] 100.”

Second, there is the disturbing “dependency ratio,” which reflects the ratio of workers to pensioners; this has “plummeted,” because fewer children are being born, and it has “profound effects on the healthcare systems’ ability to deliver affordable care,” he pointed out.

Third, there is no sign of “morbidity compression,” a concept that has been proposed but does not seem to be holding up, that although longevity will increase, the chronic morbidity associated with aging will decrease,

at a glance ➤ The 3 trends that work against controlling the costs of medical care include the aging population, a dependency ratio, and a lack of morbidity compression ➤ The number of patients who are frail or who have bad health for a longer time is increasing, leading to a large cost burden ➤ The majority of increasing healthcare costs in oncology results from pricing ➤ Some suggest that personalized medicine will lead to affordable care, but this is not happening today ➤ The healthcare pipeline can be considered a “silo,” in which a large amount of agents and technologies are at the top, translational medicine is at the center, and the burden of disease is at the base

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“We have an embedded psychological drive for new things, and we love consuming medicines.

The result is increased spending on cancer drugs and technology. This is big business, and it is increasingly expensive.”

—Richard Sullivan, MD, PhD

and there will be “healthier aging.”

Without the realization of morbidity compression, he said, society cannot afford to support longer lifespans.

“New data suggest that in many countries, compression of morbidity is just not happening,” he reported.

“Instead, we are seeing increasing frailty and morbidity. Years spent in bad health are being expanded, and that has dramatic effects and is a huge cost burden.”

The Business Model of Medicine Raises Hard Questions Dr Sullivan then suggested that the “real problem” with the business model of medicine is that “all life has a price,” and therefore there is a “finite value.” This is determined by age, sex, geographic region, and employment, among other factors. This “value of statistical life” defines many things within society, including the amount of effort that is put into producing medicines and technologies, and how much society agrees to spend on healthcare, he said.

The debate over what is driving the cost of healthcare “rages back and forth,” Dr Sullivan added, with some arguing that costs are a result of greater utilization of healthcare resources, and others suggesting that

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high prices are to blame.

According to Dr Sullivan, 75% of increasing healthcare costs are a result of pricing. “Price is the predominant macro factor within cancer medicine,” he asserted.

There are also cultural issues at play.

“Humans are very pro-medicine. We have an embedded psychological drive for new things, and we love consuming medicines,” Dr Sullivan said.

“The result is increased spending on cancer drugs and technology. This is big business, and it is increasingly expensive.”

Data from 2007 to 2012 show that although sales are flattening in many therapeutic classes, oncology is undergoing extraordinary growth. The annual growth rate for spending is 10% for targeted agents and even 4% for traditional chemotherapy.

“The money involved in this is quite substantial, and this is just medicine, not biomarkers and other related things,” Dr Sullivan added.

dependency ratio, and so forth. Things keep getting stuck,” he said. “We have had to kill off 50% of the pipeline to get things running. The worry is that the outlet is far too narrow for what is going through.”

He added that the “global reality” of cancer is that outside of high-income countries, most patients with cancer present with late-stage disease. Costeffective surgery and radiotherapy are the mainstays of treatment in many populations, and cancer risk factors are a huge problem.

Public Health Concerns If one accepts that healthcare systems follow a “grain silo” model for capturing the overall economic impact, the system cannot hold, Dr Sullivan predicted.

“In public health terms, personalized medicine, as it currently exists, is almost irrelevant on the global scale,” Dr Sullivan pointed out.

“In public health terms, personalized medicine, as it currently exists, is almost irrelevant on the global scale.”

—Richard Sullivan, MD, PhD The hour-glass–shaped “grain silo” model features a wide opening at the top that represents translational medicine, a narrow center that forms the outlet through which the “grain” flows, and a wide base at the bottom that represents the burden of disease.

“If you put too much in at the top, or the grain is too big, it jams the outlet,” he said.

At the top, in the translational science bin, there are currently 624 new molecular entities in phase 1 to 3 trials, 412 prephase 1 agents awaiting trials, more than 1300 biomarkers, and an unknown number of technologies.

“Pushing up against this are all things that jam the outlet, including regulatory issues, economic issues, patient numbers, macroeconomics, the

“If we are not going to be more intelligent about personalized cancer care, it will end up...of no real value to society as a whole.”

—Richard Sullivan, MD, PhD

Are Personalized Medicine and Affordable Care Compatible?

“So, are we seeing the death of affordable cancer care with personalized medicine?” Dr Sullivan asked in closing. There are 2 schools of thought.

“One says that personalized medicine will deliver a future affordable care system. We will stratify patients and use less medicine, although it might be more expensive up front.

The fatalistic perspective says ‘no,’ that we will have Darwinian selection that is not based on rational choice,” he answered.

“My own concern is that personalized medicine has yet to deliver on its promises,” Dr Sullivan offered.

“Affordable cancer care is about fair cancer care,” and this is not happening, he said, when 62% of personal bankruptcy filings are a result of medical costs, for example. Furthermore, it is well known that putting money into the healthcare system does not, in itself, lead to better outcomes.

“If we are not going to be more intelligent about personalized cancer care,” he predicted, “it will end up looking like a supermodel with a Louis Vuitton handbag: lovely to look at, very expensive, affordable to only a few, and of no real value to society as a whole.” ■

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NOW AVAILABLE

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1111-CARF-147a July 2012 Printed in USA

KYPROLIS.com

Breast Cancer Symposium

Indirect Costs of Metastatic Breast Cancer... with early breast cancer and with the general population without cancer.

The study included data from the MarketScan Health and Productivity Management database (2005-2009), which includes information about absenteeism, short-term disability insurance, and workers’ compensation program services.

The indirect costs associated with sick leave and short-term disability were estimated by multiplying leave days with daily wages (2011 Bureau of Labor Statistics). Propensity score matching was performed for patients with early breast cancer in relation to patients with metastases.

The analysis included a cohort composed of 139 patients with metastases, 432 patients with early breast cancer, and 820 controls eligible for sick leave; a second cohort of those who were eligible for short-term disability included 432 patients with metastases, 1552 patients with early breast cancer, and 4682 controls. The mean age was approximately 50 years for all groups.

In the short-term disability cohort, the patients with metastases had a higher mean comorbidity index than

the patients with early breast cancer.

After matching by age, payer type, region, index year, and comorbidities, patients with metastases had significantly more short-term disability days

“Breast cancer is mostly prevalent in women of working age, and the breast cancer–related indirect costs, such as productivity loss, cannot be overlooked.”

—Yin Wan, MS and related costs than patients with early-stage breast cancer—41 days versus 25 days, and $6166 versus $3690, respectively.

Patients with metastases had more sick leave days and related costs than the controls—16 days versus 9 days, and $2383 versus $1282, respectively.

The patients with metastases also had significantly more short-term disability days and higher costs versus the controls—41 days versus 4 days, and

$6166 versus $558, respectively.

Patients with metastases had higher total mean leave days and related costs (40 days and $5975) than patients with early breast cancer (23 days and $3452) or the controls (5 days and $711).

The multivariate analysis was adjusted for age, region, health insurance, index diagnosis year, baseline chemotherapy, chemotherapy during follow-up, and Charlson comorbidity index. The analysis showed that patients with metastases incurred 48% greater short-term disability costs than patients with early breast cancer. The patients with metastases also incurred 56% greater sick leave costs and nearly 12 times higher short-term disability costs than the controls.

Older patients, non-HMO payers, and patients not receiving chemotherapy during follow-up were associated with lower short-term disability costs.

The differences in indirect costs between patients with metastatic breast cancer and early breast cancer may be partly explained by how resource intensive, more toxic, and longer lasting the treatment for metastatic breast cancer is compared with

Continued from cover

at a glance ➤ Breast cancer is prevalent among women of working age ➤ This new study is the first to compare the costs related to lost productivity of women with breast cancer ➤ The 432 patients with metastatic breast cancer had 41 days of short-term disability leave and $6166 of associated costs compared with 25 disability days and $3690 of associated costs for the 1552 patients with early-stage breast cancer treatment for early breast cancer, Ms Wan suggested.

The productivity losses of caregivers were not examined. The study relied on sick leave and short-term disability data as the only measures of productivity loss. Additional sources of productivity loss (ie, time spent seeking cancer treatment and care) were not assessed. ■

Fewer Women Undergo Mammography since Recent Task Force Recommendations “More than 90,000 fewer

By Charles Bankhead

San Francisco, CA—Within weeks of a government-backed recommendation against routine screening mammography in women aged <50 years, the screening rate had fallen below historic levels and subsequently has remained lower than the baseline rate, a group of researchers reported.

Two months after the US Preventive Services Task Force (USPSTF) recommendation, the screening rate among women aged 40 to 49 years was almost 8% lower compared with rates before the 2009 decision. Two years later, the screening rate among younger women was still 5% lower than during the period from January 2006 to October 2009.

“More than 90,000 fewer mammograms were performed in women aged 40 to 49 in the 2 years after the USPSTF update,” Amy T. Wang, MD, Assistant Professor of Medicine, College of Medicine, Mayo Clinic, Rochester, MN, and colleagues reported in a poster presentation at the 2012 Breast Cancer Symposium.

The screening rate did not change in

24

women aged 50 to 64 years, for whom the USPSTF recommended a 2-year screening interval instead of an annually.

“The results are consistent with the context of the update,” the researchers added. There was no difference in the 50-to-64 age-group, consistent with a more subtle change (biennial vs annual mammography). The modest decrease in the 40-to-49 age-group is consistent with a more radical change (ie, against routine mammography vs for it).

The results also are consistent with public resistance to the guideline change and the subsequent release of conflicting guidelines, Dr Wang and colleagues concluded.

The 2009 USPSTF recommendations ignited a controversy that continues to play out almost 3 years later. For the most part, the controversy has centered on the recommendation against routine screening mammography for younger women. By comparison, the change to a 2-year screening interval for women aged 50 to 64 years has evoked little comment.

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mammograms were performed in women aged 40 to 49 in the 2 years after the USPSTF update.”

—Amy T. Wang, MD

The American Cancer Society, the American College of Radiology, and several other professional and consumer advocacy groups assailed the recommendation for women aged <50 years. The American College of Obstetricians and Gynecologists issued updated and new screening guidelines that make no age-based distinctions in screening frequency.

Dr Wang and colleagues performed the first reported study to evaluate the impact of the USPSTF recommendations on screening rates in different age-groups. Analyzing administrative data from more than 100 health plans, the researchers included 11.4 million women in the study.

For the baseline period of January

2006 to October 2009, the rate of screening mammography was 39.3 per 1000 women aged 40 to 49 years and 47.0 per 1000 women aged 50 to 64 years. Two months after the USPSTF released the updated recommendations, the screening rate had decreased by 7.59% among women aged 40 to 49 years. A year after the update, the screening rate in the younger group remained 5.33% less than historic rates, and 2 years later, the screening rate in women aged 40 to 49 years remained 5.02% below baseline.

The mammography rate among women aged 50 to 64 years showed little variation from baseline after the release of the USPSTF update.

The results show that the USPSTF decision has affected care and clinical decision-making related to screening mammography, said invited discussant Thomas Buchholz, MD, Professor and Division Head, Department of Radiation Oncology, The University of Texas M.D. Anderson Cancer Center in Houston. The recommendations have influenced individual patients’ choices, doctors’ recommendations, and third-party decisions regarding coverage of mammography. ■

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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

© 2012 Novartis

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

9B?7 E8FC86G<I8?L

O 8ELG;EB@L6<A 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L

4A7

9B?7 E8FC86G<I8?L

O I8E4C4@<? 4 @B78E4G8 0) <A;<5<GBE 4A7 4 ):) <A;<5<GBE max 4A7 - <A6E84F87 5L 4A7

9B?7 E8FC86G<I8?L

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 Š Novartis ,

July 2012

Breast Cancer Symposium

An Underappreciated Cause of Cancer Death: Disparities in Treatment

By Caroline Helwick

The Challenge of Disparities Despite the gargantuan healthcare budget, many patients are not receiving even adequate care, Dr Brawley stressed.

“We waste a lot of money putting it

at a glance ➤ Disparities based on race, socioeconomic factors, and other nonclinical factors affect the outcomes of patients with cancer ➤ Of 39,000 projected deaths from breast cancer in the United States in 2012, an estimated 6000 may be preventable with appropriate therapy ➤ The breast cancer mortality rate is 22.4 per 100,000 white women and 31.6 per 100,000 black women, and the gap continues to widen annually ➤ Other disparities in breast cancer care include type of insurance, high poverty rate, and less education

VOL. 3

I

NO. 7

into areas where we don’t get much out of it, and we don’t put money into areas where we could save a large number of lives,” he maintained.

Photo © ASCO/Todd Buchanan 2012

San Francisco, CA—When cancer treatment is equal among patients, the outcomes are equal as well, “but there is not equal treatment” within the US population with cancer, according to Otis W. Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, and Professor of Hematology, Medical Oncology, Medicine, and Epidemiology at Emory University, Atlanta.

Dr Brawley discussed cancer care disparities at the 2012 Breast Cancer Symposium. He is the author of the 2012 exposé of the healthcare system, How We Do Harm: A Doctor Breaks Ranks About Being Sick in America (St. Martin’s Press).

“When we have conversations about expensive tyrosine kinase inhibitors and mTOR inhibitors, we must remember the $2.53 trillion in healthcare costs to the US in the year 2009. In comparison, the US spent $1.1 trillion on food. We all know that the US has the highest per-capita spending, but this does not translate into longer life expectancy. We are 50th, just behind Albania, which is 49th. We spend more on healthcare, and we don’t get what we pay for,” Dr Brawley said.

“My concern is that equal treatment yields equal outcomes among equal patients, but there is not equal treatment.”

—Otis W. Brawley, MD

Disparities in treatment are a pressing problem, Dr Brawley noted.

“Disparities” pertains to the concept that some populations (defined by race, socioeconomic class, and other descriptors) fare worse than others.

Although there are multiple reasons, disparities often occur because of a misuse of resources, he noted.

“My concern is that equal treatment yields equal outcomes among equal patients, but there is not equal treatment,” said Dr Brawley. “And there is not enough concern about, nor emphasis on, the fact that there is not equal treatment.”

More than 2 dozen patterns-of-care studies now demonstrate that there are racial disparities in appropriate care, Dr Brawley emphasized. Differences in patterns of care by race have been documented in patients with prostate, colon, breast, and lung cancers, but the full reasons for the differences have yet to be explained.

Black women with breast cancer are less likely to receive definitive therapy, including chemotherapy, hormonal therapy, and radiotherapy or surgery, for localized disease compared with white patients (Freedman RA, et al.

Cancer. 2011;117:180-189). Black women are also 40% less likely to be treated at high-quality hospitals, but not at

high-volume hospitals (Keating NL, et al. Med Care. 2009;47:765-773).

These disparities may account for the gap in breast cancer mortality: 22.4 per 100,000 white women versus 31.6 per 100,000 black women, according to data from the Surveillance, Epidemiology and End Results (SEER) database. The gap has widened every subsequent year since 1980. In addition, at every stage of the disease, uninsured patients have worse survival outcomes than insured patients.

However, disparities do not occur solely along racial lines. A 2012 study of 6734 patients with breast cancer in 7 states showed that 35% of the patients did not receive adjuvant chemotherapy that was consistent with clinical practice guidelines (Wu X-C, et al.

J Clin Oncol. 2012;30:142-150). Factors associated with nonstandard treatment include Medicaid status, a lack of private insurance, and living in highpoverty and low-education areas.

“We are not talking about mTOR inhibitors here. We are talking about standard adjuvant chemotherapy with the cheaper drugs,” Dr Brawley emphasized.

“There are disparities in care, no matter how you define the population and the care,” noted Dr Brawley.

“Sometimes, there is more emphasis on getting a new fourth-line chemotherapy agent to market than in providing adequate, decent care to people who simply need it.”

“There are disparities in care, no matter how you define the population and the care.

Sometimes, there is more emphasis on getting a new fourth-line chemotherapy agent to market than in providing adequate, decent care to people who simply need it.”

—Otis W. Brawley, MD

Equal Treatment Will Yield Equal Outcomes If patients can receive equal treatment, they can expect equal outcomes.

In breast cancer trials conducted by the

OCTOBER 2012

I

National Surgical Adjuvant Breast and Bowel Project, disease-free survival is similar for blacks and whites, although blacks have higher all-cause mortality, which is possibly a result of comorbidities. In addition, studies based on the SEER database show that after adjusting for treatment- and diseaserelated factors, comorbidities, and socioeconomic factors, the mortality rates are not significantly higher among black patients.

“Survival differences are no longer significant if you can overcome the socioeconomic problem of poverty,” Dr Brawley stated.

Paying the Cost of Treatment Disparities It is estimated that more than 230,000 American women will be diagnosed with breast cancer in 2012, and more than 39,000 will die from it. If all women with breast cancer received optimal therapy, up to 6000 of these deaths would be averted, Dr Brawley pointed out.

Dr Brawley reiterated that a substantial proportion of patients with cancer do not receive care that is in accordance with established guidelines. These patients are not getting the inexpensive treatments that are universally accepted, such as lumpectomies with radiotherapy and even adjuvant chemotherapy.

“At the same time we are spending more and more on expensive treatments,” said Dr Brawley. “We are talking about the latest $8000-a-month drug for third-line treatment of advanced disease that prolongs survival by 3 months, while we are missing the point: if we simply did the things we currently know, and applied the technology we currently have (such as mammography screening), we have the ability to save lives.” ■

www.ValueBasedCancerCare.com

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Breast Cancer Symposium

More Evidence Supports the Anticancer Effect of Metformin

By Charles Bankhead San Francisco, CA—Women with diabetes taking metformin had a significantly lower risk of breast cancer, an association that appeared to grow stronger with increasing duration of follow-up, results of a recent metaanalysis showed.

Overall, metformin users had a 17% lower risk of breast cancer compared with women who did not use the drug, including diabetic women who were taking other hypoglycemic agents. The reduction in risk increased

at a glance ➤ A new meta-analysis shows a consistent benefit of breast cancer prevention in women with diabetes ➤ Diabetic women using metformin had a 17% lower risk of breast cancer compared with nonusers; the risk reduction increased to 25% in those taking the drug for >3 years and to 32% when follow-up started before 1997 ➤ Obesity and diabetes are risk factors for breast cancer

to 25% among women who took metformin for >3 years and to 32% when follow-up started before 1997.

These findings add to some previously reported observational evidence that metformin has a protective effect against invasive breast cancer, according to a study reported at the 2012 Breast Cancer Symposium.

“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,” reported Nananda Col, MD, MPP, MPH, FACP, Professor of Medicine at the College of Osteopathic Medicine, University of New England in Biddeford, ME. “If this 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.”

Obesity and diabetes are risk factors for breast cancer, suggesting a possible association with insulin resistance.

Preclinical studies have provided evidence supporting an anticancer effect of metformin that is independent of insulin effects. Additional evidence that metformin has a protective effect against breast cancer has come from several observational studies.

Continuing the examination of the metformin–breast cancer relationship,

Dr Col and colleagues conducted a systematic literature review and metaanalysis of published studies. Their analysis included 7 independent studies—4 observational cohorts and 3 case-control studies.

The trials spanned the years 1989 to 2001, and the longest follow-up in any single trial was 21 years. The shortest follow-up was 9 years.

“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.”

—Nananda Col, MD, MPP, MPH, FACP

Collectively, the studies included >400,000 adults and 14,000 patients with diabetes. The smallest study had slightly more than 4000 participants, and the largest involved 207,000 adults.

All but 1 of the studies showed a reduced risk ratio for patients taking metformin. The magnitude of reduction across the studies ranged from 5%

to 40%. The 1 trial that did not yield a risk ratio <1 demonstrated a neutral effect of metformin (relative risk, 1.02).

Of the 7 studies included in the analysis, 4 had confidence intervals (CIs) that included 1.00.

After weighting the studies, the overall adjusted risk ratio was 0.83 (95% CI, 0.71-0.97). Subgroup analyses showed a consistent trend toward lower breast cancer risk in metformin users.

An analysis of the studies by year of inception showed that 3 studies beginning after 1996 were associated with an adjusted odds ratio (OR) of 0.95.

The 4 studies that began earlier yielded a combined OR of 0.68. Analysis by duration of treatment resulted in an OR of 0.75 for 4 studies whose participants continued taking metformin for >3 years versus 0.94 for 3 studies with a duration of treatment of ≤3 years.

These results are consistent with the results of a recently published analysis involving participants in the Women’s Health Initiative. This analysis yielded a hazard ratio (HR) of 0.75 for breast cancer among women with diabetes who were taking metformin. In contrast, women with diabetes who were taking other antidiabetic drugs had an increased risk of breast cancer, which is reflected in the 1.16 HR for breast cancer risk (Chlebowski RT, et al. J Clin Oncol. 2012;30:2844-2852). ■

Fewer Therapy Delays with Palonosetron than with Similar Antiemetics San Francisco, CA—An analysis of a large claims database showed that patients with breast cancer had fewer delays in chemotherapy and maintained better adherence to their regimens when treated with the 5-hydroxytryptamine 3 (5-HT3) receptor antagonist palonosetron (Aloxi) than with other agents in this antiemetic class.

“The 5-HT3 receptor antagonists have proven to effectively prevent and manage CINV [chemotherapyinduced nausea and vomiting], with palonosetron found to significantly lower CINV risk relative to other 5HT3 drugs,” reported Hope Rugo, MD, Professor of Medicine, University of California, San Francisco School of Medicine, and colleagues in a poster presentation. “However, little evidence exists regarding the impact of these drugs on chemotherapy adherence and preventing delayed therapy.”

Among patients treated with highly emetogenic chemotherapy (HEC), palo-

30

nosetron was associated with a >30% reduction in the frequency of treatment delays related to CINV. The difference increased to >60% for patients receiving moderately emetogenic chemotherapy (MEC).

The study also confirmed the previously reported higher efficacy of palonosetron versus other 5-HT3 receptor antagonists for preventing episodes of CINV, as reported at the 2012 Breast Cancer Symposium.

The team analyzed records in the HealthCore Integrated Research Database. Using National Comprehensive Cancer Network (NCCN) treatment guidelines, they searched the database for patients with early breast cancer who had claims for HEC or MEC regimens between January 2002 and October 2010.

Emetogenic drugs included in the search were cyclophosphamide, doxorubicin, epirubicin, and carboplatin.

HEC was defined as any regimen con-

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taining ≥1 HEC drug or containing ≥2 MEC drugs.

Claims related to the targeted chemotherapeutic regimens and agents were then cross-referenced with claims for 5-HT3 antagonists.

NCCN-recommended treatment cycles and rest periods were determined for each patient’s chemotherapy regimen, and the chemotherapy dose per cycle was calculated.

Dr Rugo and colleagues separated patients into 2 cohorts: palonosetron (all patients treated only with that agent) and “others” (those who received any other 5-HT3 antagonist).

Principal outcomes of interest were acute or delayed CINV, delayed therapy (lasting twice the “permissible gap” between cycles for the specific regimen), and adherence (receiving the requisite number of chemotherapy cycles within the recommended time frame).

The search revealed 4885 patients

treated with HEC regimens: 1782 who received palonosetron and 3103 who received other 5-HT3 antagonists. Another 1378 patients received MEC regimens (682 in the palonosetron cohort and 696 in the “others” category).

In the HEC subgroup, 27.33% of the palonosetron cohort had ≥1 CINV event compared with 35.68% in the other cohort (P <.001). The rates of CINV in the MEC subgroups were 33.72% with palonosetron and 49.71% with other 5-HT3 antagonists (P <.001).

In general, the multivariate analysis confirmed the superiority of palonosetron, based on these data: • CINV (HEC): odds ratio (OR), 0.61; P <.001 • CINV (MEC): OR, 0.51; P <.001 • HEC therapy delay: OR, 0.75; P = .08 • MEC therapy delay: OR, 0.37; P = .005 • HEC adherence: OR, 1.1; P = .18 • MEC adherence: OR, 1.29; P = .02.—CB ■

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2012 Conference

Health Plans Need Policies for Dealing with Off-Label Drug Use

By Caroline Helwick Houston, TX—To eliminate coverage inconsistencies and enhance relationships with providers, health plans should have specific policies for dealing with off-label use of oncologic drugs, said Kristen M. Reimers, RPh, Specialty Pharmacy Director and Clinical Operations Manager for Excellus Health Plans.

At the Second Annual Association for Value-Based Cancer Care Conference, Ms Reimers described the rationale for and the process of development and benefits of the off-label drug policy that she helped to develop at Excellus.

More than 60% of cancer therapies are the result of off-label prescribing, and drugs that are used off label often become part of the standard of care for some tumor types, she noted.

“Many off-label uses are effective, well documented in peer-reviewed literature, and widely used,” Ms Reimers said, but coverage determinations are inconsistent.

As noted by the National Comprehensive Cancer Network on its website, “The introduction and utilization of many innovative drugs and biologics in oncology practice, combined with their significant expense, has focused the attention of payers and other involved constituencies on processes and programs that facilitate the appropriate, effective, and efficient use of such agents,” she explained.

at a glance ➤ Excellus Health Plans has developed a policy for off-label use of oncology drugs that includes evidence-based decisions to facilitate appropriate and efficient use ➤ The policy eliminates inconsistencies in coverage and enhances relationships with providers ➤ It also helps to provide clear and concise determinations on efficacy, safety, and value regarding off-label use of drugs ➤ This new process includes a team of reviewers who receive off-label use requests and review, discuss, and monitor them, changing standards of care as necessary

32

Figure Off-Label Use Policy Issues with Off-Label Drug Use Ms Reimers cited a number of issues of concern with off-label drug use: • High risk for variation in treatment of relatively rare and complex cancers • Inconsistent application of policy (if there even is one) • Increased medical costs that result from inappropriate prescribing • Concerns about efficacy, safety, and ethics • Frustration among providers • Mandated coverage (by 39 states) when listed in compendia.

“These issues have led to prescriber frustrations and inconsistency in our determinations. In the absence of clear criteria, emotional responses often guide determinations,” Ms Reimers pointed out. “We needed to do something differently, which is why we developed our off-label drug use policy.”

“In making determinations we wanted to weigh the evidence and make clear and concise determinations on efficacy, safety, and value.”

—Kristen M. Reimers, RPh

Developing the Policy Ms Reimers and her colleagues developed a policy that emphasized evidence-based decisions. “In making determinations, we wanted to weigh the evidence and make clear and concise determinations on efficacy, safety, and value,” she said (Figure).

The policy acknowledges the New York state mandate that requires health plans to cover any US Food and Drug Administration–approved drug that is acceptable for the treatment of the malignancy in question by a recognized or authoritative compendium, or by a review article or editorial com-

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Evidence-based healthcare decisions Best practice

Uncertainty Abstract

Published journal article

Accept author’s conclusion

Review methods/ results

Accept/ modify author’s conclusion

ment published in a major peerreviewed professional journal.

In addition, the reviewers look at the strength of the recommendations.

Class I and IIa recommendations are always acceptable, whereas class IIb recommendations are acceptable in some, but not all, cases. These situations require a full literature search, with an emphasis on studies that are appropriately sized, that conclude that the drug used off label is generally safe in relation to the severity of the disease being treated and other existing treatment options, and that the study outcomes represent clinically meaningful outcomes experienced by patients, Ms Reimers stated.

“If the request is not supported by compendia or articles (abstracts and poster presentations are not acceptable), as listed above, then the request is not considered medically appropriate and will be denied as experimental or investigational,” she said.

Off-Label Use Policy Process “We also needed to change our process for reviewing these cases,” Ms Reimers noted. “Our current process was problematic. Our reviewers did not have time to devote to these unusual cases. We needed a dedicated team to review off-label requests.”

A collaborative team of reviewers was developed for policy implementation, including specially trained nurses, pharmacists, and medical directors.

Under the new process, nurses receive the off-label requests, then they contact the requesting physician’s office for more information in the form of progress notes, previous treatments and outcomes, laboratory and scan results, and so forth.

“The reviewers are looking for the doctor’s thought processes about this recommendation, and any literature to support it,” Ms Reimers commented.

Audit study data Weigh evidence Systematic review

Best information Efficacy, safety, value conclusions

In the next step, pharmacists initiate a systematic review process that weighs and documents the evidence; this report is then sent to the medical director. After the medical director’s review, the case is discussed at a joint meeting of all team members, who consider the merits of the case “coming from 3 different perspectives” and make a coverage determination.

These individual cases are discussed again during subsequent team conferences, where they are used as training experiences. “And we monitor our results, track appeals, and change policies, if we need to, as standards of care change,” she said.

“We developed an off-label drug use policy that uses a stepwise approach to tackling cases. Our goal was to improve consistency and we were able to achieve that.”

—Kristen M. Reimers, RPh

“We developed an off-label drug use policy that uses a stepwise approach to tackling cases. Our goal was to improve consistency and we were able to achieve that,” Ms Reimers reported.

Implementation of the new process has allowed Excellus to keep its individual drug policies up to date, she added. “Because we are combing through the literature more frequently, we are always proactive, tracking the pipeline, looking at what is happening at national meetings, and maintaining a dialogue with community experts….

We wanted to eliminate emotion in the decision-making process, and we were able to do so.” ■

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2012 Conference

Many Emerging Biomarkers, but Few Are... mutation, staining pattern, gene expression microarray) that can be associated with a clinically distinct prognosis, diagnosis, or response to a specific therapy.

“Biomarkers hold promise, and we are clearly making progress, but I say, ‘Not so fast!’ Paradoxically, they present challenges that we must deal with going forward, such as obtaining clinical trial data to prove they actually improve patient care,” said Dr Ellis, speaking at the Second Annual Conference of the Association for Value-Based Cancer Care.

Several biomarkers represent the enhanced understanding of cancer pathogenesis and have led to some remarkable therapeutic advances.

These include imatinib in chronic myeloid leukemia, all-trans retinoic acid in acute promyelocytic leukemia, ALK in lung cancer, epidermal growth factor receptor in lung cancer, and BRAF in melanoma, Dr Ellis said.

“But we need to be cautious about which biomarkers are reproducibly predictive of either prognosis or response before we consider them mainstream or primetime,” he suggested.

“They may do more harm than good.”

A Google search of “biomarker company” by Dr Ellis brought up almost 1.8 million results. These revealed mul-

“Biomarkers hold promise, and we are clearly making progress, but I say, ‘Not so fast!’ Paradoxically, they present challenges that we must deal with going forward, such as obtaining clinical trial data to prove they actually improve patient care.”

—Peter G. Ellis, MD

tiple “omics” (ie, genomics, proteomics) companies with products that

are deserving of further investigation, but the products lack sufficient data to be considered standard of care. Further research and expert consensus will be required for the products to be found useful, he said.

Examples of promising markers that require further testing are ERCC1 (which indicates resistance to platinum agents in lung cancer), thymidylate synthase (TS; high TS is associated with lack of response to 5-fluorouracil, capecitabine, and pemetrexed), and SPARC (secreted protein, acidic and rich in cysteine; high SPARC is associated with response to nab-paclitaxel), according to Dr Ellis.

The use of the ERCC1 marker, to spare patients with lung cancer the possibility of futile platinum treatment, is heavily promoted, but because these agents are the mainstay of treatment for lung cancer, Dr Ellis said he would not take a chance by eliminating them in his patients with an ERCC1 mutation before their use is proved.

In fact, a recent investigation points to a potential flaw in the whole biomarker landscape (Gerlinger M, et al.

N Engl J Med. 2012;366:883-892). Multiregion sequencing of metastatic renalcell carcinoma revealed high intratumor heterogeneity; some regions of a single tumor harbored genes sugges-

Continued from cover

at a glance ➤ Only a few biomarkers are currently reliable and can be routinely used to improve patient care ➤ Further research and expert consensus are required for many biomarkers to be used in clinical practice ➤ Before clinicians begin using the biomarkers that are now being heavily marketed, they should make sure they were proved valid in clinical trials

tive of a good prognosis, whereas other regions expressed genes that suggested the opposite.

“How do we know [that] what we biopsy and the markers we obtain are actually representative of the tumor?”

Dr Ellis asked.

Before clinicians begin using a host of biomarkers now being heavily marketed, they should be proved valid in clinical trials. Once that occurs, they should be incorporated into decision-support instruments, Dr Ellis concluded. ■

Evolving Strategies for Cost-Effective Cancer Management

By Caroline Helwick Houston, TX—A wealth of new agents and abundant clinical trial data supporting their use have led to multiple “acceptable” evidence-based options for treating tumors. This can make the “real-life” care of patients with cancer confusing with regard to disease outcomes and in the assessment of value propositions related to treatment, according to Atheer A. Kaddis, PharmD, Senior Vice President of Managed Markets, Diplomat Specialty Pharmacy, Flint, MI. At the Second Annual Association for Value-Based Cancer Care Conference, Dr Kaddis described the evolving strategies being applied to pay for cancer care in an ever-challenging landscape.

“We are having this conversation to try to determine the value of our available therapies and to learn how to manage them for the best outcomes at the lowest cost,” he said.

As payers grapple with finding value, Dr Kaddis says, they have some important unanswered questions, such as:

34

• How is the cost for new oncology agents justified?

• What is the most cost-effective option for a given tumor and treatment setting?

• Can significant restrictions be placed on oncology medications?

• What is the role of nondrug therapy?

• Should end-of-life discussions and interventions occur earlier in patients with serious illness?

• What can be done to prepare for the high-cost therapies currently in the pipeline?

Best Practice Strategies “The use of best practice strategies is growing, and offers opportunities for value,” Dr Kaddis said. These strategies, in order of importance to payers, include drug therapy management (high-touch patient care management), channel management (medical to pharmacy benefits), utilization management (prior authorization and step therapy), formulary management (use of preferred drugs), and drug cost

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“According to our data, 25% of patients discontinued therapy after the first partial fill (first month), and 50% of these patients died. This…has spurred discussions about limiting all oral oncolytics to partial fills when given as maintenance.”

—Atheer A. Kaddis, PharmD management (average wholesale price discount improvement).

The increase in the availability of oral anticancer agents elevates the

importance of formulary management and channel management in oncology, he said. For example, in renal-cell carcinoma, there are now 7 approved agents, lending this tumor type to formulary management, and as oral drugs replace their intravenous counterparts, there will be opportunities to shift drugs to specialty dispensing and away from the buy-and-bill model.

In addition, utilization management continues to be a powerful approach for payers, primarily employing prior authorization to ensure that prescribed agents are being appropriately used.

Adherence to these best practice strategies will yield savings opportunities. The impending entrance of biosimilars to the market raises the following questions and concerns in terms of drug utilization.

Questions and Concerns about Biosimilars ➤Will biosimilars cost less than brand-name reference products? If Continued on page 36

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2012 Conference

Companion Drug Testing Is Becoming Critical to Pharmacy Benefits Management Medco’s pharmacogenomic testing program

By Caroline Helwick Houston, TX—With the onslaught of drugs that will target genetic subsets of patients, companion diagnostic testing will become vitally important, said Jane F. Barlow, MD, MPH, MBA, Vice President of Clinical Innovation, Medco Health Solutions (now Express Scripts), New York, who spoke on personalized medicine during the 2012 Annual Conference of the Association for Value-Based Cancer Care.

“The whole area of pharmacogenomics testing is very important for safety, but also to ensure that the right drug, or at least not the wrong drug, is given to an individual patient,” she said (Figure).

More than 700 oncology drugs are currently in the pipeline, according to

the PharmaLive.com special report Drugs in Development: from Pipeline to Market (July 2011). This is 3 to 7 times higher than drugs for other conditions.

Drug development is increasingly partnering with diagnostics. A recent survey of pharmaceutical companies found that 12% to 50% of current clinical pipelines involve personalized medicine, 80% of companies have strategic partnerships related to personalized medicine, and 50% of drug trials collect DNA samples from trial participants (http://csdd.tufts.edu/ reports/description/impact_reports).

By 2024, it is expected that up to 20% of all new drugs (especially cancer drugs) will be labeled with a companion test (Kalorama Information’s World-

Figure Pharmacogenomic Testing of Cancer Tissue Helps Patients Get the Right Drug, or at Least Not Get the Wrong Drug

X

Colon cancer with KRAS mutation

Lung cancer ALK negative

use of wrong drug = !Prevent

Breast cancer HER2 negative

Genetic profile of cancer tissue

OK

Melanoma with BRAF mutation

“Today, all coverage programs are triggered by the drug. In the future, this may be based more on disease state.”

—Jane F. Barlow, MD, MPH, MBA wide Market for Cancer Diagnostics, 4th ed; July 2010).

“This has not come about at the speed initially anticipated, but once in development, we need to be prepared for how to think about using these tests,” Dr Barlow said.

How Companion Drug Testing will Change Coverage “Today, all coverage programs are triggered by the drug. In the future, this may be based more on disease state,” Dr Barlow predicted. “As we look at this field, we are realizing we need to take an approach that may be different in the future.”

Vital to this is more information matching tumor specifics to the patient’s characteristics, which will

Evolving Strategies for Cost-Effective... so, how much less? ➤Will biosimilars be accepted as alternatives to brand-name reference products by physicians, payers, and patients? ➤How will biosimilars be marketed by manufacturers and which manufacturers will develop these products? ➤How will biosimilars be identified? ➤What type of patent protection will biosimilars have? ➤Will there be manufacturing issues surrounding biosimilars? ➤Will biosimilars be substituted within a therapeutic class (ie, step therapy) or will they be considered alternatives only to the specific reference product? ➤Can we take information already

36

available on European biosimilars to speed entry into the US market? ➤What will happen to the brandname drug market in the United States? ➤Will the Centers for Medicare & Medicaid Services include biosimilars in their calculations to determine average sales price? ➤Will biosimilars be considered brand-name or generic drugs, or will we have to develop a new category?

Partial Fill Strategies The use of partial fills has been expanding for oral oncolytics, and the experience of Diplomat Specialty Pharmacy demonstrates the savings opportunities. The focus of the pro-

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guide treatment decisions and companion diagnostics. She predicted that a companion diagnostic test for a drug will foster “seamless coverage criteria for the whole course of treatment.”

Currently, Dr Barlow added, pharmacy benefits managers lack “visibility” of the whole swatch of the oncology drug landscape, because many are intravenous products and are reimbursed under medical benefits. “But we think about this as a whole, in terms of designing programs,” she said, and in terms of “the different levers that can be pulled to manage appropriate utilization.”

Medco’s “Levers” Medco’s main “levers,” she said, are pharmacogenomic testing, pharmacy drug utilization review programs, specialty therapy management protocols, and prior authorization criteria.

The pharmacogenomic testing program aims to ensure appropriate drug use, and it is paid for entirely by plan sponsors (typically, employers). The process is that opportunities for diagnostic testing are identified for the physician, the physician is told the test will be covered by the patient’s health plan, and if the physician wants to order the test, the patient is contacted and can agree to the test or decline it.

“On average, 50% of physicians say yes, and 50% of patients say yes,” Dr Barlow reported. “We just facilitate the test.”

The drug utilization program stores patients’ genetic test results, which Continued on page 37

Continued from page 34

gram has been on the oral agents erlotinib (Tarceva), sunitinib (Sutent), and sorafenib (Nexavar). The program is now expanding to include 10 drugs.

“Some of our payers are discussing putting partial fill limits (a 15-day supply) on all oral oncolytics used as maintenance,” Dr Kaddis said. “According to our data, 25% of patients discontinued therapy after the first partial fill (first month), and 50% of these patients died. This led us to believe that these therapies are being tried as a last-ditch effort. This was a shock to us, and has spurred discussions about limiting all oral oncolytics to partial fills when given as maintenance.”

Nearly 30% of Medicare expendi-

tures are made in the last year of life.

Instead of paying for cancer care when it is futile, Dr Kaddis suggests that payers support programs such as Cancer Coach, which focuses on palliative care for patients with a new cancer diagnosis, as well as the dying patient, and on quality of life versus quantity of service provided. The Cancer Coach program facilitates enrollment into hospices, with patient and family support, and coordinates interventions with the case management department.

Payers should partner with physicians to develop these programs, or at least encourage physicians to initiate productive end-of-life discussions with patients, Dr Kaddis suggests. ■

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Economic Issues in Oncology

Integrative Medicine Cuts Inpatient Costs in Oncology Care Unit

By Rosemary Frei, MSc Albuquerque, NM—Using yoga and other integrative medicine and complementary therapies can cut oncology-related inpatient costs by more than $150 per day as a result of the reduced need for pain medications, anxiolytics, and antiemetics, according to a recent study conducted at the Beth Israel Medical Center in New York

at a glance ➤ Incorporating integrative therapies in the inpatient oncology unit significantly reduces the number of medications patients use ➤ In this study, the cost of all medications was $888.91 in the control group compared with $419.89 in the Urban Zen integrative therapy group ➤ This difference translates into a daily $156 savings during a 3-day hospital stay ➤ Based on a 24-bed oncology unit and 261 weekdays, this daily saving translates to a $977,184 annual savings to the hospital

City; this daily reduction adds up to nearly $1 million annually when the savings are extrapolated to a 24-bed oncology unit in the hospital.

This study was presented at the 2012 Society for Integrative Oncology’s Ninth International Conference, and was conducted as part of the Urban Zen Initiative, which was cofounded

by Donna Karan, a private citizen who lost her husband to cancer.

Benjamin Kligler, MD, Vice Chair, Department of Integrative Medicine at Beth Israel Medical Center, and Jillian Friedman, supervisor of Urban Zen’s yoga therapy program, compared the costs of medications for 85 patients in the hospital’s standard oncology program with the costs for 72 patients who were admitted to were hospitalized in the medical oncology unit and were also involved in the Urban Zen’s program that included integrative yoga therapy, holistic nursing, and the use of patient navigators.

The 2 groups had similar baseline characteristics; approximately 50% of the patients in each group were female, white, and had a college education.

They also had roughly equivalent proportions of various types of cancer, the most common of which were head and neck cancers and the second-most common was lung cancer.

Inpatient Cost-Savings The investigators found that the average length of hospital stay was the same for the 2 groups—3 days.

However, the use of integrative therapies at the Urban Zen center was associated with a significant decrease in the use of antiemetics, anxiolytics, hypnotics, and other medications. The

“There is potentially an even greater impact on the length of stay on a surgical oncology floor, where the average stay is longer and more contingent on resolution of pain, return of bowel function, and other symptoms.”

—Jillian Friedman patients participating in the Urban Zen interventions received, on average, significantly fewer antianxiety and antinausea medications, as well as less opiate analgesics.

The investigators obtained cost data from the hospital’s pharmacy. Their analysis showed that the overall cost of all medications was $888.91 in the

Companion Drug Testing Is Becoming Critical... allows them to be reviewed when future treatments are prescribed. The drug utilization review would show, for example, that a patient may be a poor CYP2D6 metabolizer and thus needs drug dose adjustments. The specialty therapy management program applies primarily to high-priced drugs and focuses on patient support.

With the increase in oral drugs, the prior authorization criteria “lever” has become an important component of pharmacy benefits management.

Although some sponsors require testing before paying for a drug, in less rigid cases, a drug may be covered in the absence of test results; however, the pharmacist can take the opportunity to educate providers about pharmacogenomic testing, she said.

A look at a few common but expensive drugs that are linked to biomarkers illustrates how healthcare dollars can be used wisely or can be misspent (Table). “A fair proportion of the pop-

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Table

control group compared with $419.89 in the Urban Zen integrative therapy group, a significant difference. This difference of $469 for the 3-day hospital stay translates into a daily $156 savings during these 3-day stay.

These savings can be extrapolated to annual savings to the hospital of $977,184, based on 24 oncology inpatient beds and 261 weekdays annually (Urban Zen’s services are not available on weekends). Dr Kligler and Ms Friedman noted that even if only 50% of the patients with cancer chose to participate in the integrative therapy program, the annual cost-savings would amount to just under $500,000 (ie, $488,592).

This is offset somewhat by the cost of creating a dedicated unit to provide the complementary services and other support offered in the Center for Health and Healing, but the investigators calculated that the savings would still accrue to the hospital, at more than $250,000 annually in the third year, with annual savings continuing to grow thereafter.

“There is potentially an even greater impact on the length of stay on a surgical oncology floor, where the average stay is longer and more contingent on resolution of pain, return of bowel function, and other symptoms,” noted Ms Friedman, who said they may investigate this in the future. ■

Continued from page 36

Drug Coverage Review: Potential Savings on Select Oncology Drugs

Drug Erlotinib Vemurafenib Crizotinib Cetuximab injection

Cancer type

Target gene

Patients who lack genetic marker, %

Drug cost (average per full treatment cost), $g

Lung

EGFR

70a-c

68,260

Melanoma

BRAF

50d

136,000

Lung

ALK

95a-c

137,844

Colorectal

KRAS

60e

160,200

f

Trastuzumab injection

Breast

HER2

75

64,000

Lapatinib

Breast

HER2

75f

54,180

a

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: non-small cell lung cancer. Version 3.2011. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 30, 2012. b Keedy VL, et al. J Clin Oncol. 2011;29:2121-2127. c FDA news release. FDA approves Xalkori with companion diagnostic for a type of late-stage lung cancer. August 26, 2011. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm269856.htm. Accessed May 30, 2012. d Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. e Heinemann V, et al. Cancer Treat Rev. 2009;35:262-271. f Carney WP, et al. Breast Cancer Res. 2007;9:207. g Estimates based on internal analysis by Accredo.

ulation may not benefit from these drugs,” Dr Barlow emphasized, “and in these cases, you spend many dollars

on a course of treatment that basically has no value for the patient. That is why we are interested in diagnostic

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testing and, as pharmacy benefits managers, we feel that it is important to create these programs.” ■

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37

Economic Issues in Oncology

First Analysis of Medicare Costs Associated with Head and Neck Cancers Comorbidities and treatment choices the primary cost drivers for these malignancies

By Rosemary Frei, MSc Toronto, Canada—The first-ever analysis of Medicare payments for head and neck tumors shows that comorbidities and treatment choices are the primary drivers of the costs of each type of cancer; the study results

at a glance ➤ Comorbidities and treatment choice are the primary cost drivers of oral-cavity and oropharyngeal cancers ➤ Patients with oral-cavity cancer and 1 or 2 comorbidities had $13,342 higher cumulative costs than patients with no comorbidities; the cumulative costs for 3 comorbidities totaled $22,196 ➤ The 5-year cumulative costs are approximately $72,000 per case for oral-cavity cancer versus approximately $91,000 per case of pharyngeal cancer ➤ Patients who had chemotherapy, surgery, radiation, and the combination of surgery and radiation had higher cumulative costs than those who were not treated

were presented at the 2012 International Conference on Head and Neck Cancer. Consequently, the total 5-year cumulative costs per oral-cavity cancer case are approximately $72,000 and approximately $91,000 for oropharyngeal cancer.

In addition, there was no difference between the costs associated with distant metastases and with localized cancer was not significant for oral-cavity cancer, as well as in the cost for distant (or regional) and localized oropharyngeal tumors.

“We observed that mortality does increase significantly for regional and distant metastases—this is part of another analysis of ours that is currently under review,” said coprincipal investigator Christopher Hollenbeak, PhD, Chief, Division of Outcomes, Research and Quality, Pennsylvania State University College of Medicine, Hershey. “We feel that the best explanation for this is patients with regional and distant disease die sooner than patients with local disease. Cumulative costs stop upon death, but patients who survive continue to accumulate costs,” Dr Hollenbeak added.

This analysis was based on data from Surveillance Epidemiology and End Results (SEER)-Medicare database for patients aged ≥66 years who had a diagnosis of a first primary

tumor of the head or neck between 1995 and 2005. The costs were defined as payments made by Medicare for allcause medical treatments ranging from emergency department visits to durable medical equipment.

The cost of oral cancer is directly related to comborbities, with $13,342 increased cumulative costs for patients with oral-cavity cancer and 1 or 2 comorbidities and $22,196 for those with 3 comorbidities compared with those without comorbidities.

The increase is similar for pharyngeal cancer.

The costs of chemotherapy and most other drugs were not included in the analysis, because this information is not available from the SEER-Medicare database. The results were inflated to 2010 dollars using the Consumer Price Index.

Patients with oral-cavity cancer

tended to be older and were more likely to be female and white than those with oropharyngeal cancer.

The researchers also analyzed a control group without cancer; this group was age-, sex-, and race-matched in a 2:1 ratio to the cancer cases. The 2 groups had similar demographic characteristics.

The 5-year cumulative costs were $71,953 for each case of oral-cavity cancer and $91,393 for each case of pharyngeal cancer. When the patients with cancer were compared with the controls, the 5-year incremental costs were $26,850 higher for oral-cavity cancer and $47,467 higher for oropharyngeal cancer than for the controls.

Patients with oral-cavity cancer and 1 or 2 comorbidities had $13,342 higher cumulative costs than patients with no comorbidities; the cumulative costs for 3 comorbidities totaled $22,196.

The increased cumulative costs for oropharyngeal cancer were $14,139 for 1 or 2 comorbidities and $27,799 for 3.

For both types of cancer, significantly higher cumulative costs were seen for surgery, radiation, a combination of surgery and radiation, and chemotherapy compared with no treatment.

Dr Hollenbeak said he and his team will now study cost increases of patients with these 2 types of cancers at the end of life. ■

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Economic Issues in Oncology

Telemedicine Saves Time, Resources for Palliative Radiotherapy

By Rosemary Frei, MSc Montreal, Canada—Telemedicine reduces time spent on new-patient consultations for palliative radiotherapy, according to a study presented at the 2012 World Cancer Congress. Patients spent half as long attending a telemedicine consultation than an in-person consultation, and did not have to spend time on traveling to a radiotherapy center for this.

In addition, telemedicine consults allowed physicians to satisfactorily complete consultation tasks and have confidence in their resulting recommendations, said Rebecca Wong, MBChB, Professor of Radiation Oncology, University of Toronto, and Staff Radiation Oncologist at the Princess Margaret Hospital/University Health Network in Toronto, Canada.

Overall, among those who completed a questionnaire on the experience, 40 of 44 patients said they prefer telemedicine over an initial in-person consultation, and 32 of 39 physicians felt telemedicine was as good as, or better than, in-person consultation.

“While radiotherapy itself can’t be delivered at a distance, providing a consultation via telemedicine can facilitate informed consent and organization of radiotherapy planning and treatment,” said Dr Wong, who presented the study results.

The team prospectively studied 50 patients who live closer to a telemedicine center than a radiotherapy center and hence were given a first consultation with telemedicine, as well as another 50 individuals who live closer to a radiotherapy center and hence received an in-person consultation.

The 2 groups had similar baseline characteristics, but the patients using telemedicine were more likely to have a genitourinary cancer as the primary tumor, were more likely to be referred for brain metastases, and had a life expectancy of <6 months.

The primary outcome was time spent in the consultation. Telemedicine patients spent an average of 90 minutes in consultation compared with an average of 176 minutes for an in-person consultation. The average time to referral to radiotherapy was 11.7 days in the telemedicine group and 8.2 days for the in-person consultation group.

Patients and physicians expressed satisfaction with telemedicine, and a large majority of them said they prefer it over an in-person consultation. Furthermore, the physicians rated telemedicine and in-person consultation equally in terms of establishing a rapport with patients, adequate history-taking

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and evaluation of diagnostic tests, discussion of treatment options, and discussion of the radiotherapy plan.

The areas in which the 2 approaches were not comparable were the ability to perform the relevant physical exam

only with in-person consultations and a lower level (60%) of confidence in the radiotherapy recommendations when telemedicine was used compared with 100% for in-person consultation. In all cases, however, the treatment decision

was confirmed in a subsequent in-person assessment.

Investigations of this use of telemedicine should include ways to incorporate telemedicine into routine clinical practice. ■

ts and Providers with the Reimburse n e i t a P ment g Proc Helpin ess 1-888-587-3263 www.TevaCORE.com

Our C RE commitment CORE Hotline Offers Assistance Related to: Benefit verification and coverage determination Precertifications / prior authorization support Coverage guidelines and claim requirements of payers Personalized support through the claims and appeals process Templates for letters of medical necessity Cephalon Oncology Patient Assistance Program

To enroll in CORE Phone 1-888-587-3263 Monday through Friday, 9 AM to 8 PM (ET), fax 1-866-676-4073, or visit www.TevaCORE.com

Supporting Teva Oncology Products Reimbursement Assistance and Support through CORE - the Comprehensive Oncology Reimbursement Expertise Program

CephalonCares® Foundation offers a Patient Assistance Program to provide FDA-approved products free of charge for patients who qualify.

Teva Oncology also partners with patient advocacy organizations, such as the Leukemia & Lymphoma Society, and others that have programs designed to help patients access the treatment they need.

© Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved, ONC-2139, Printed in USA

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39

Drug Update

Pertuzumab a New Therapeutic Option for Patients with HER2-Positive Metastatic Breast Cancer

By Alice Goodman, Medical Writer

B

reast cancer is the most common cancer and the second leading cause of cancer death among women worldwide.1 In the United States, an estimated 230,480 new cases of invasive breast cancer, as well as an additional 57,650 cases of carcinoma in situ, were expected to be diagnosed in 2011. Approximately 39,500 deaths from breast cancer were expected to occur in 2011.2 During the years 2004 through 2008, the median age at the diagnosis of invasive breast cancer was 61 years.2 Most breast cancers are invasive or infiltrating at diagnosis. Of the cases diagnosed during 2000 through 2007, more than 60% were localized, approximately 38% were regional, approximately 7% were metastatic (stage IV), and approximately 2% were of unknown stage.2 The risk of death is increased with more advanced stages at diagnosis.3 In patients with invasive breast cancer (diagnosed 2001-2007), the estimated 5-year survival is 99% for localized disease, 84% for regional disease, and 23% for metastatic breast cancer.3 In addition to stage, molecular markers can provide important prognostic information that is helpful in selecting treatment. These markers include hormone receptor status (ie, estrogen and progesterone) and HER2 expression. Expression of the estrogen receptor (ER) and progesterone receptor (PR) confers a more favorable prognosis, whereas the risk of death is 1.5 to 2 times greater in the absence of ER and PR expression.2 Overexpression of HER2 (HER2positive) and triple-negative breast cancer (ER-negative, PR-negative, and HER2-negative status) are associated with a less favorable prognosis.

However, the availability of HER2targeted therapy, such as trastuzumab, has reversed much of the adverse prognostic impact of HER2 overexpression.2

HER2-Positive Breast Cancer Approximately 18% to 30% of all breast cancers are HER2-positive, and these tumors have a faster rate of proliferation than tumors that lack overexpression of HER2-neu.4,5 All invasive breast cancers should be tested by gene amplification or protein overexpression assays to identify HER2-positive breast cancers in women who can benefit from trastuzumab and other HER2-directed therapy.

In 2006, trastuzumab became the

40

first therapy targeted to the HER2-neu receptor to be approved by the US Food and Drug Administration (FDA).

At first, trastuzumab’s approval was restricted to the treatment of meta-static breast cancer, but the drug was subsequently found to be effective in early-stage HER2-positive breast cancer. In one of the pivotal studies that led to trastuzumab’s approval in the adjuvant setting, trastuzumab reduced the risk of recurrence by 52% and the risk of death by 33% in early-stage HER2-positive breast cancer versus chemotherapy alone.6

Pertuzumab’s approval was hailed as “an advancement in the treatment of breast cancer that has not been seen since Herceptin was launched over a decade ago.”

Lapatinib, a second HER2-targeted therapy, has been found effective in combination with capecitabine for the treatment of HER2-positive advanced breast cancer that has become resistant to trastuzumab.7 It was approved by the FDA for this indication in 2010.

The use of lapatinib is limited by its propensity to cause diarrhea, which occurs in approximately 40% of patients who take the drug.8 Pertuzumab, the third HER2-targeted agent with a unique mechanism of action, was approved in July 2012 by the FDA for the treatment of metastatic HER2-positive breast cancer in combination with trastuzumab plus docetaxel.

Pertuzumab’s approval was hailed as “an advancement in the treatment of breast cancer that has not been seen since Herceptin was launched over a decade ago.”9 As with trastuzumab, pertuzumab will be studied earlier in the course of breast cancer as adjuvant therapy in the Adjuvant Pertuzumab and Herceptin in Initial Therapy (APHINITY) trial.

Additional anti–HER2-targeted therapies are currently under development, including the novel immunoconjugate therapy T-DM1, which links trastuzumab to maytansine, a potent cytotoxic chemotherapy.5 The availability of increasing numbers of therapeutic options for the treatment of HER2-positive breast cancers provides hope to patients and challenges to cli-

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nicians as they determine the optimal use of these agents in combinations and in sequences.

Economic and Quality-of-Life Burden of Breast Cancer Cancer care is “big business” in the United States. The estimated cost of cancer care for survivors is in the billions of dollars. In 2010, 13.8 million cancer survivors had associated costs of $124.57 billion. In 2020, there will be an estimated 18.1 million cancer survivors, with an estimated price tag of $157.77 billion.10 These figures represent a projected 27% increase in the medical costs of cancer care in the United States from 2010 to 2020. The largest increases are expected in the continuing phase of care for prostate cancer (42%) and female breast cancer (32%).10 In addition to economics, the diagnosis and treatment of breast cancer, especially in the more advanced stages, are associated with quality-oflife and emotional burdens. Patients have to learn how to manage and organize their medical records, be concerned about paying for treatment, adhere to treatment, and they must be prepared to discuss their cancer with family and close friends. In addition, patients are advised to pay attention to good nutritional principles and incorporate exercise into their daily lives, even if they are experiencing fatigue.11 Breast cancer treatments may be associated with debilitating symptoms, including hot flashes, depression, cognitive problems (ie, “chemo brain”), weight gain, lymphedema, and painful sexual intercourse. Other treatment-related side effects can include nausea and vomiting, cardiac problems, hair loss, peripheral neuropathy, hematologic side effects, and mucositis.

Pertuzumab’s Mechanism of Action The mechanism of action of pertuzumab is distinct from that of trastuzumab. Trastuzumab binds to the subdomain IV of the HER2 extracellular domain and exerts its antitumor effects by blocking HER2 cleavage, stimulating antibody-dependent, cell-mediated cytotoxicity, and inhibiting ligand-independent HER2-mediated mitogenic signaling.12,13 Despite treatment with trastuzumab, most HER2-positive metastatic cancers will progress, which has led to efforts to develop new targeted

therapies, such as pertuzumab.

Pertuzumab is a humanized monoclonal antibody that binds to the HER2 receptor at a different site than trastuzumab. Pertuzumab prevents HER2 from dimerizing (or pairing) with other potential HER receptor partners, including EGFR/HER1, HER3, and HER4, resulting in decreased downstream signaling.14 Pertuzumab and trastuzumab have complementary mechanisms of action, so when these agents are used together, they achieve a more comprehensive blockade of HER2 signaling and greater antitumor activity than either agent alone in experimental models of breast cancer.15 Phase 2 clinical trials of this combination have borne out activity in HER2-positive metastatic breast cancer.16 Phase 3 Clinical Trial The phase 3 clinical trial Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) has led to the FDA’s recent approval of pertuzumab in combination with trastuzumab plus docetaxel in the treatment of metastatic breast cancer.16

Trial Design The study was a prospective, randomized, double-blind, placebo-controlled trial conducted from February 2008 through July 2010, at 204 centers in 25 countries. Patients with HER2positive metastatic breast cancer were randomized in a 1:1 ratio to receive either placebo plus trastuzumab plus docetaxel (control arm) or pertuzumab plus trastuzumab plus docetaxel (experimental arm). Patients were stratified according to geographic region (Asia, Europe, North America, or South America) and previous treatment status (previous adjuvant or neoadjuvant therapy, or no prior therapy).

Progression-free survival (PFS) was the primary end point; this was defined as the time from randomization to the first documented radiographic evidence of progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria or death from any cause within 18 weeks after the last assessment of tumors. Secondary end points were overall survival (OS), investigatorassessed PFS, the rate of objective response, and safety.

Patient Population The study enrolled 808 patients with Continued on page 41

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Drug Update

documented locally recurrent, unresectable, or metastatic HER2-positive breast cancer. HER2 status was determined centrally by means of immunohistochemistry or fluorescence in situ hybridization testing. Patients with measurable or nonmeasurable disease were eligible for the study.

Both treatment groups had comparable demographic and disease characteristics. The median age was 54 years, approximately 32% were Asian, approximately 59% were white, approximately 3% were black, and approximately 5% were other races.

Geographic distribution in both arms was similar; approximately 31% were from Asia, 38% from Europe, 17% from North America, and 14% were from South America.

Visceral metastases were present in approximately 78% of patients (Table 1). Approximately 48% were ER- or PR-positive, or both; approximately 50% were ER- and PR-negative; and the hormone receptor status of approximately 2% was unknown. Approximately 47% received previous adjuvant or neoadjuvant treatment, with approximately 40% receiving anthracycline; 25%, hormone therapy; 23%, a taxane; and 11%, trastuzumab.

Efficacy The PFS was significantly improved in the pertuzumab/trastuzumab/docetaxel arm (N = 402) versus the control arm using placebo plus trastuzumab and docetaxel (N = 406). The results of this trial are shown in Table 2. The median, independently assessed PFS was 12.4 months in the control arm versus 18.5 months in the pertuzumab-containing treatment arm, a difference of 6.1 months in favor of the addition of pertuzumab (P <.001). The improvement in PFS with pertuzumab was observed across all predefined subgroups.

In 88 patients who were previously treated with adjuvant or neoadjuvant trastuzumab therapy, the median PFS was 16.9 months in the pertuzumab arm (vs 10.4 months in the control arm); among 288 patients previously treated without trastuzumab, median PFS was 21.6 months in the pertuzumab arm versus 12.6 months in the controls.

An interim analysis of OS was performed after 165 events occurred; 96 deaths were reported in the control group versus 69 in the pertuzumab arm, a difference that did not meet the prespecified boundary for statistical significance. At a median follow-up of 19.3 months, a strong trend was observed toward a survival benefit

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with the pertuzumab combination.

Both groups were followed up for a median of 19.3 months.

The objective response rate was 69.3% in the control arm versus 80.2% in the pertuzumab arm.

Safety Profile Pertuzumab did not appear to add appreciable toxicity to trastuzumab plus docetaxel. The safety profile was generally similar in the 2 treatment arms. No increase in left ventricular systolic dysfunction was observed when pertuzumab was included in the treatment. Adverse events that were at least 5% higher in the pertuzumab arm than in the controls included diarrhea, rash, mucosal inflammation, febrile neutropenia (FN), and dry skin.

The rates of grade 3 or 4 FN were higher in the pertuzumab arm than in the control arm (13.0% vs 7.3%, respectively). The incidence of grade 3 or higher FN among Asian patients was 12% for controls and 26% for the pertuzumab arm; in patients from all other geographic regions, the rate of FN was ≤10% in both treatment arms.

Most of the deaths were a result of disease progression. The number and causes of other deaths were generally well balanced between the 2 arms.

Infections were the most common cause of death resulting from an adverse event. Table 3 lists adverse events in 13.5% or more of patients receiving pertuzumab.

Dosing The recommended initial dose of pertuzumab is 840 mg, given as a 60minute intravenous (IV) infusion, followed every 3 weeks by an IV infusion of 420 mg given over 30 to 90 minutes.

When trastuzumab is given along with pertuzumab, the recommended initial dose of trastuzumab is 8 mg/kg given as a 90-minute IV infusion, followed every 3 weeks by an IV infusion of 6 mg/kg over 30 to 90 minutes.

When docetaxel is given along with pertuzumab, the recommended initial dose is an IV infusion of 75 mg/m2. If the initial dose is well tolerated, the dose of docetaxel may be escalated to 100 mg/m2, given every 3 weeks.

Dose Modification If the dose of pertuzumab is delayed or missed, and the time between 2 sequential infusions is less than 6 weeks, the 420-mg infusion should be used. Waiting until the next planned dose is not recommended. If the time between 2 sequential infusions is 6

Table 1

Selected Baseline Characteristics of the ITT Population of CLEOPATRA

Characteristic

Placebo arm, %

Trastuzumab arm, %

77.8

78.1

49

47

ER-negative and PR-negative

48.3

52.7

HER2 status 3+ by IHC

91.4

87.1

HER2-positive by FISH

94.3

95.5

Visceral disease ER-positive, PR-positive, or both

CLEOPATRA indicates Clinical Evaluation of Pertuzumab and Trastuzumab; ER, estrogen receptor; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; ITT, intention-to-treat; PR, progesterone receptor.

Adapted from Baselga J, et al. N Engl J Med. 2012;366:109-119.

Table 2

Efficacy in the Randomized Pertuzumab Trial

Parameter

Pertuzumab + Placebo + trastuzumab + trastuzumab docetaxel + docetaxel N = 402 N = 406

HR (95% CI) P value

Progression-free survival (independent review) Patients with an event, N

191 (47.5%)

242 (59.6%)

Median months

18.5

12.4

69 (17.2%)

96 (23.6%)

343

336

Objective response (CR + PR)

275 (80.2%)

233 (69.3%)

Complete response

19 (5.5%)

14 (4.2%)

256 (74.6%)

219 (65.2%)

20.2

12.5

0.62 (0.51-0.75) <.0001

Overall survival (interim analysis) Patients with an event, N

0.64 (0.47-0.88) .0053a

Objective response rate Patients analyzed, N

Partial response Median duration of response, mo

a The HR and P value for the interim analysis of overall survival did not meet the predefined stopping boundary (HR ≤0.603; P ≤.0012).

CI indicates confidence interval; CR, complete response; HR, hazard ratio; PR, partial response.

Adapted from Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

weeks or longer, the initial 840-mg infusion should be readministered as a 60-minute infusion, followed every 3 weeks by an infusion of 420 mg over a 30- to 60-minute period. The rate of infusion may be slowed or interrupted if a patient experiences an infusionrelated reaction. Discontinue the infusion immediately for any serious hypersensitivity reactions.

If a patient experiences a decrease in left ventricular ejection fraction (LVEF) to <40% or an LVEF of 40% to 45%, with a ≥10% absolute decrease below baseline values, pertuzumab plus

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trastuzumab should be withheld for at least 3 weeks. If the LVEF recovers to >45%, or to 40% to 45% associated with an absolute decrease of <10% pretreatment values, pertuzumab may be resumed.

If the LVEF has not improved over 3 weeks, or declines further, strongly consider discontinuation of pertuzumab and trastuzumab.

Contraindications, Warnings, and Precautions There are no absolute contraindicaContinued on page 42

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Drug Update

Pertuzumab a New Therapeutic Option... tions to pertuzumab. Pertuzumab should not be taken during pregnancy, because the drug can cause birth defects and possible embryo-fetal death.

Before the initiation of pertuzumab, patients should be assessed for pregnancy and should be advised to use contraception during and after treatment with pertuzumab. Women who are inadvertently exposed to pertuzumab during pregnancy should consult the Genentech Adverse Event Line at 1-888-835-2555, and are encouraged

Table 3

to enroll in the MotHER Pregnancy Registry, by contacting 1-800-690-6720.

Although trastuzumab treatment has been reported to lead to decreased LVEF, pertuzumab does not appear to have additive harmful effects on LVEF. When pertuzumab was used in combination with trastuzumab and docetaxel in the CLEOPATRA trial, left ventricular dysfunction was seen in 4.4% versus 8.3% of patients in the placebo arm (ie, placebo plus trastuzumab plus docetaxel); and congestive heart fail-

Continued from page 41

ure was reported in 1% versus 1.8% of patients, respectively. Risk factors for decreased LVEF include previous exposure to anthracyclines or previous radiation to the chest wall.

Pertuzumab has not been studied in patients with suboptimal pretreatment LVEF values or other conditions associated with impaired LVEF, which include uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia, or a cumulative previous exposure to >360 mg/m2

Adverse Reactions in ≥13.5% (and any Grade 3/4 Reactions) in Patients Receiving Pertuzumab versus Placebo Pertuzumab + trastuzumab + docetaxel frequency rate, % (N = 407) All grades, % Grades 3/4, %

Body system/adverse reactions

Placebo + trastuzumab + docetaxel frequency rate, % (N = 397) All grades, % Grades 3/4, %

General disorders and administration-site conditions Fatigue

37.6

2.2

36.8

3.3

Asthenia

26.0

2.5

30.2

1.5

Peripheral edema

23.1

0.5

30.0

0.8

Mucosal inflammation

27.8

1.5

19.9

1.0

Pyrexia

18.7

1.2

17.9

0.5

Rash

33.7

0.7

24.2

0.8

Nail disorder

22.9

1.2

22.9

0.3

Diarrhea

66.8

7.9

46.3

5.0

Nausea

42.3

1.2

41.6

0.5

Vomiting

24.1

1.5

23.9

1.5

Stomatitis

18.9

0.5

15.4

0.3

Neutropenia

52.8

48.9

49.6

45.8

Anemia

23.1

2.5

18.9

3.5

18.2

12.3

20.4

14.6

13.8

13.0

7.6

7.3

Peripheral neuropathy

32.4

3.2

33.8

2.0

Headache

20.9

1.2

16.9

0.5

Myalgia

22.9

1.0

23.9

0.8

Arthralgia

15.5

0.2

16.1

0.8

16.7

0.7

13.4

0.0

14.0

1.0

15.6

2.0

29.2

1.7

26.4

1.5

Skin and subcutaneous tissue disorders

Gastrointestinal disorders

Blood and lymphatic system disorders

Leukopenia Febrile neutropenia

a

Nervous system disorders

Musculoskeletal and connective tissue disorders

Infections and infestations Upper respiratory tract infection Respiratory, thoracic, and mediastinal disorders Dyspnea Metabolism and nutrition disorders Decreased appetite

a Reported in association with a fatal outcome.

Adapted from Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

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doxorubicin or its equivalent. In patients who are taking pertuzumab, LVEF should be monitored at baseline and then every 3 months to ensure that the LVEF is within normal limits.

Infusion and hypersensitivity reactions can occur during treatment with pertuzumab. In the CLEOPATRA trial, hypersensitivity or anaphylaxis reactions occurred in 10.8% of patients in the pertuzumab arm versus in 9.1% of those in the placebo arm. Grades 3 and 4 hypersensitivity or anaphylactic reactions were reported in 2% versus 2.5% of patients, respectively.

Conclusion The FDA approval of pertuzumab for women with HER2 metastatic breast cancer provides a novel therapeutic option, with a new mechanism of action and improved duration of PFS, a welcome addition for this patient population. ■ References 1. International Agency for Research on Cancer.

GLOBOCAN 2008 [cancer fact sheet]. http://globocan. iarc.fr. Accessed September 4, 2012.

2. American Cancer Society. Breast cancer facts and figures 2011-2012. 2011. www.cancer.org/acs/groups/ content/@epidemiologysurveilance/documents/docu ment/acspc-030975.pdf. Accessed September 6, 2012.

3. Howlader N, Noone AM, Krapcho M, et al. SEER cancer statistics review, 1975-2008. Bethesda, MD: National Cancer Institute; 2011. http://seer.cancer.gov/ csr/1975_2008/#revision. Accessed September 4, 2012.

4. Wolff AC, Hammond ME, Schwartz JN, et al.

American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131:18-43.

5. Gradishar WJ. HER2 therapy—an abundance of riches. N Engl J Med. 2012;366:176-178.

6. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant therapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673-1684.

7. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER-2 positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743.

8. Becze E. Manage diarrhea and skin effects from lapatinib. www.onsconnect.org/2010/06/5min/managediarrhea-and-skin-effects-from-lapatinib. June 2010.

Accessed September 4, 2012.

9. BioTrends Research Group. Medical oncologists’ perceptions of newly launched Perjeta are very promising, despite initial concerns of increased cost associated with combining two premium-priced monoclonal antibodies to treat HER2-positive breast cancer [press release].

September 5, 2012. http://finance.yahoo.com/news/ medical-oncologists-perceptions-newly-launched133000945.html. Accessed September 6, 2012.

10. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 20102020. J Natl Cancer Inst. 2011;103:117-128.

11. Breastcancer.org. Day-to-day matters: exercise.

February 9, 2012. www.breastcancer.org/tips/exercise/.

Accessed September 5, 2012.

12. Junttila TT, Akita RW, Parsons K, et al. Ligand-independent HER2/HER3/P13K complex is disrupted by trastuzumab and is effectively inhibited by the P13K inhibitor GDC-0941. Cancer Cell. 2009;15:429-440.

13. Pertuzumab (Perjeta) [package insert]. South San Francisco, CA: Genentech, Inc; 2012.

14. Agus DB, Akita RW, Fox WD, et al. Targeting ligand-activated Erb2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2:127-137.

15. Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68:58785887.

16. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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“Managing patients with myeloma means staying current.”

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

7

Value-Based Care in Myeloma !"'&1"-. "3 '0.&1" &)/"-1&"2. )! +"-.+" /&1". -"' /"! /* *./ ,0 '&/4 )! ".. &..0". +" & ' ." /&*). #*."! '&)& & ). !1 ) "! +- /& " )0-.". )! +% -( &./. 2&'' '.* #* 0. *) /%" 0)&,0" % ''")$". &) /%" ( ) $"(")/ *# (0'/&+'" (4"'*(

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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

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.

President & CEO Brian F. Tyburski

Chief Operating Officer Pam Rattananont Ferris

Editorial Director Susan Berry susan@coexm.com

Copyeditor Dana Delibovi

Sincerely, Director, Production and Manufacturing Alaina Pede

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

Director, Creative and Design Robyn Jacobs

Quality Control Director Barbara Marino

Director, Digital and Media Anthony Romano

FACULTY

Web Coordinator Jose Valentin

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

Digital Content Specialist David Maldonado

Business Manager Blanche Marchitto

Bookkeeper Teresa Torgersen

Executive Administrator Jackie Luma

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

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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.

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

*Content will include non–FDA-approved uses.

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

Trial

Regimen

N

CR + VGPR Postinduction (%)

CR + VGPR Post-ASCT (%)

PFS

VTD vs TD

236

62a

82a

68% at 3 yr

238

28

64

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

15

55

Median 27 mo

VD vs vTD

99

36

58

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

N

1-Year Survival Probability

3-Year Survival Probability

All patients

141

.94

.78

RD patients

65

.89

.79

Rd patients

76

.97

.78

All patients

68

1.0

.94

RD patients

38

1.0

.95

Rd patients

30

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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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

31

MP

25

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

35

20 15 14

10

13

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

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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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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)

2

Obesity (BMI 30 kg/m ) Previous VTE

Doxorubicin

Central venous catheter or pacemaker Chronic renal disease (CrCl <40 mL/min)

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

2+

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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CONTINUING EDUCATION

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.

50

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

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IV indicates intravenous; SC, subcutaneous.

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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.

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