VBCC February 2013 VOL 4 NO 2

FEBRuary 2013 VOL 4 NO 2

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

Infection Poses Lethal Risk Early in Patients with Multiple Myeloma

By Charles Bankhead

Nab-Paclitaxel Added to Gemcitabine Extends Survival in Patients with Metastatic Pancreatic Cancer

By Mark Knight

© James Cavallini / Science Source

San Francisco, CA—A new “backbone” of therapy for metastatic pancreatic cancer could be the combination of nab-paclitaxel (Abraxane) and gemcitabine (Gemzar). When added to gemcitabine, weekly nab-paclitaxel improved survival in patients with advanced pancreatic cancer by nearly 2 months compared with gemcita­ bine alone, said Daniel D. Von Hoff, MD, FACP, Physician in Chief and Director of Translational Research,

Atlanta, GA—Many patients with multiple myeloma succumb to infection before they have a chance to benefit from cancer therapy, according to a new study from Sweden.

More than 20% of patients died of infection within a year of myeloma diagnosis. Patients had heightened susceptibility to bacterial and viral pathogens, reported Cecilie Blimark, MD, a consultant hematologist at Sahlgrenska University Hospital, Gothenburg, Sweden, at the 2012 American Society of Hematology meeting.

“We found the risk of specific infections, such as pneumonia and septicemia, to be more than 10 times higher in patients [with myeloma] Continued on page 30

Exploring Men’s Willingness to Pay for Prostate Cancer Screening to Avoid Unnecessary Biopsy and Treatment

By Rosemary Frei, MSc

D

utch researchers have peered into the minds and wallets of a group of men aged 55 to 75 years to determine what they are willing to trade for a reduced risk of prostate cancer–related death or to avoid unnecessary procedures and treatment.

Men with more education had a lower probability of opting for pros-

tate cancer screening. Furthermore, in aggregate, the men were willing to lose 2% of risk reduction in mortality related to prostate cancer or to pay on average €188 (in 2010 Euros; equivalent to $245 in 2010 US dollars) annually for a 10% reduced risk of unnecessary biopsy or treatment.

Continued on page 26

©2013 Engage Healthcare Communications, LLC

Translational Genomics Research Institute, Phoenix, regarding the results of a large international phase 3 clinical trial.

At present, “gemcitabine-containing combinations or 5-fluorouracil– containing combinations are treatments that clinicians may try first for stage IV disease,” Dr Von Hoff said.

Currently, nab-paclitaxel is approved by the US Food and Drug Continued on page 9

Cost-Effectiveness of MRI Screening in Women with Familial Breast Cancer Risk

By Caroline Helwick San Antonio, TX—Adding magnetic resonance imaging (MRI) to a breast cancer screening strategy for women with a familial risk of cancer costs approximately 2.6 times as much per life-years gained compared with screening with mammography

alone, Dutch researchers reported at the CTRC-AACR San Antonio Breast Cancer Symposium.

“Screening with MRI is most expensive in the youngest age categories, but these are also the age categoContinued on page 17

inside VALUE PROPOSITIONS . . . . . . . .

New Medicare rules save providers $676 million annually

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GI CANCERS SYMPOSIUM . . . . . . .7 Investigational ramucirumab extends survival in advanced gastric cancer HEALTH ECONOMICS . . . . . . . . . . 15 Cost comparison of mCRC treatments Women unwilling to pay for genetic breast cancer testing VBCC PERSPECTIVE . . . . . . . . . . 20 The importance of prioritizing palliative care in oncology

PERSONALIZED MEDICINE . . . . . 24 Molecular subtyping reclassifies early breast cancer New multigene score for breast cancer metastatic risk HEALTH POLICY . . . . . . . . .

HIPPA privacy and security regulations released

19, 28

LUNG CANCER . . . . . . . . . . . . . . . 33 Local ablation extends treatment time DRUG UPDATE . . . . . . . . . . . . . . . 34 Ponatinib a new option for adults with CML or Ph+ ALL

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

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

CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; 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 $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

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

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

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. *Melphalan+prednisone. † VISTA TRIAL: 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 prespecified 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 analysis was performed.

FDA Update Gleevec Approved for Children with Acute Lymphoblastic Leukemia

The US Food and Drug Admini­ s­ tration (FDA) approved a new indication for imatinib (Gleevec; Novartis) for the treatment of children with newly diagnosed Philadelphia chro-

mosome–positive (Ph+) acute lymphoblastic leukemia (ALL), the most common type of pediatric cancer.

Approximately 2900 children are diagnosed with Ph+ ALL annually in the United States. Imatinib, a tyrosine kinase inhibitor, should be used in combination with chemotherapy for the

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE for Injection 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 (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration.

WARNINGS AND PRECAUTIONS: 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 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% 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 require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%.

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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms.

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 bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 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) 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 (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

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 reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

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 reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) 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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, 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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Value-Based Cancer Care

treatment of children with Ph+ ALL. Imatinib’s safety and effectiveness in children were established in a clinical trial conducted by the Children’s Oncology Group and sponsored by the National Cancer Institute. The trial included 92 children with a very high risk of Ph+ ALL who were divided

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into 5 treatment groups; each successive group received a longer period of treatment with imatinib plus chemotherapy. The longest duration of treatment was 4 years.

The mortality rate was lower in parallel with increasing time of treatment with the combination therapy. The lowest mortality rate was seen in the group that received the combination therapy for 4 years: of the 50 patients who received imatinib for 4 years, 70% had event-free survival for that length of time.

The most common side effects reported in the children in this trial included decreased levels of infection-fighting neutrophils, decreased levels of platelets, liver toxicity, and infection. Imatinib is already approved by the FDA for several indications in patients with various types of Ph+ chronic myeloid leukemia.

(January 25, 2013)

FDA Expedites Approval of Generic Version of Doxil

Drug shortages have hit the oncology community hard. Determined to alleviate the much-publicized drug shortage associated with doxorubicin hydrochloride liposome injection (Doxil; Janssen), the FDA expedited the approval of the first generic version of this agent, which is produced

by Sun Pharma Global FZE (Sun).

The FDA’s Office of Generic Drugs is using a priority review process to expedite the review of generic applications for drugs on its shortage list.

The newly FDA-approved generic formulation of doxorubicin hydrochloride liposome injection will be available in 20-mg and 50-mg vials.

To address the shortage of doxorubicin hydrochloride liposome injection, in February 2012, the FDA announced that it would exercise enforcement discretion with regard to the temporary controlled importation of an alternative to Doxil, namely, Lipodox (doxorubicin hydrochloride liposome injection), which is produced by Sun and its authorized distributor, Caraco Pharmaceutical Laboratories, but is not approved by the FDA. Enforcement discretion was also used to release 1 lot of Janssen’s Doxil that is produced under an unapproved process.

The FDA announced that it would continue the importation of Lipodox, but when supplies of the approved generic formulation of doxorubicin hydrochloride liposome injection are sufficient to meet the projected US demand, the FDA would stop the use of any unapproved doxorubicin hydrochloride liposomal product in the United States. (February 4, 2013) n

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VALUE PROPOSITIONS New Medicare Rules Will Save Providers $676 Million Annually

Removing Medicare regulations that are deemed unnecessary or unjustifiably burdensome on providers and hospitals would save nearly $676 million annually, and $3.4 billion over 5 years, through a rule proposed by the Centers for Medicare & Medicaid Services (CMS) in support of President Obama’s call on federal agencies to modify and streamline regulations on business.

“We are committed to cutting the red tape for healthcare facilities, including rural providers,” said the US Department of Health and Human Services (HHS) Secretary Kathleen Sebelius. “By eliminating outdated or overly burdensome requirements, hospitals and healthcare professionals can focus on treating patients.”

Many of the rule’s provisions streamline the standards healthcare providers must meet to participate in Medicare and Medicaid, without jeopardizing patient safety. The proposed rule would: • Help small critical access hospitals and rural clinics by eliminating the requirement that a physician must be on site every 2 weeks, allowing physicians to provide care via telemedicine and other means that can reduce costs without sacrificing quality of care • Save hospital resources by permitting registered dietitians to order patient diets without the supervision of a physician, to free up physicians’ time • Eliminate unnecessary requirements that ambulatory surgical centers must meet to provide radiologic services • Permit trained nuclear medicine technicians in hospitals to prepare radiopharmaceuticals, without a supervising physician/pharmacist, particularly during off-hours • Eliminate a redundant data submission requirement for transplant centers, while maintaining strong federal oversight.

These rules are in addition to the rules CMS issued in May 2012 to reduce burdensome regulations for hospitals and providers, which are saving nearly $1.1 billion in the first year. HHS; February 4, 2013

Starr Cancer Consortium Awards $5 Million to 5 Research Teams to Advance Patient Care

The Starr Foundation’s sixth Starr Cancer Consortium (SCC) Grant Competition awarded $5 million to 5 cancer research teams focusing on discovering new cancer mechanisms related to genetic mutations or epigenetic involvement in a variety of cancers. The awards were given to the following 5 teams for these projects: • Rockefeller University: “Elucidating mechanism of histone H3.3 mutation-mediated oncogenesis in pediatric brain cancer” • Weill Cornell Medical College’s first team: “Comprehensive elucidation of the mechanisms of action of anticancer molecules” • Weill Cornell Medical College’s second team: “Discovery of AID-dependent epigenetic mechanisms in hematological malignancies” • Memorial Sloan-Kettering Cancer Center’s first team: “Define oncogenic mechanisms of protein methyltransferases SETDB1 and SUV39H1 in melanoma” • Memorial Sloan-Kettering Cancer Center’s second team: “Therapeutic targeting IDH1 and IDH2 mutations in acute myeloid leukemia and chondrosarcoma” “This Consortium has launched a number of innovative, collaborative cancer research projects that are already linking discoveries in the laboratory to the clinic. Better patient outcomes are our ultimate goal, and we see progress every year,” said Florence A. Davis, President of the Starr Foundation. Weill Cornell Medical College; February 1, 2013

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AACR Is Launching Cancer Immunology Research Journal

The American Association for Cancer Research (AACR) has announced the launch of its newest online journal, Cancer Immunology Research, in the spring at the AACR 2013 annual meeting. The announcement was made in conjunction with the establishment of a new annual AACR–Cancer Research Institute (CRI) award of $10,000—the AACR-CRI Lloyd J. Old Award in Cancer Immunology. The goal is “to take tumor immunology from animal research into clinical research and develop promising new cancer therapies.” AACR press release; January 22, 2013

HHS Allocates $1.9 Million to Establish Telehealth Programs for Underserved Populations

The HHS has allocated $1.9 million for new telehealth regional resource centers to serve rural and medically underserved populations. Qualified regional centers will each receive a $325,000 grant through the Telehealth Resource Center Grant Program. These funds are targeted for healthcare organizations and healthcare networks that are establishing medical services programs via telemedicine to reach patients at rural and medically underserved areas of the country.

Funding will be available through 2015, and those qualified for the funding will have to provide technical training and support for healthcare providers. The goal is to reach a large population of patients through telemedicine, as well as support research that will outline the best ways to promote telehealth services and resource centers to meet the needs of those living in remote and/or rural areas with limited access to medical services. mHIMSS.org; January 3, 2013

New Approach to Treatment Resistance in Head and Neck Cancers

The majority of head and neck tumors are associated with a deregulation of the PI3K/AKT/mTOR pathway, which has until now been seen as the culprit in treatment resistance in these cancers. However, new data recently published in Cancer Research show that this pathway is not necessarily the reason for tumor progression in this type of cancers. Because head and neck cancers are very heterogeneous, new research has focused on identifying the various drivers of tumor survival to understand why mTOR inhibitors only work in a few patients. “While a few tumors are dependent only on mTOR, others are dependent on both mTOR and AKT,” according to Pradip K. Majumder, PhD, Division of Cancer Biology, Mitra Biotech, Bangalore, India. “However, a majority of the mTOR pathway– activated tumors seemed to not be dependent on this axis for survival or maintenance.”

The use of targeted characterization of tumors resistant to dual AKT/ mTOR inhibitors showed that multiple pathways were involved in the tumor proliferation and likely explain tumor survival. Dr Majumder and colleagues are now using a systems biology approach called “tumor explants model” to differentiate the actual drivers of various mutations from those known as “passenger” mutations, which do not influence tumor survival. This distinction is critical for understanding why many drugs fail in early-phase clinical trials, as well as for stratifying patients for appropriate treatments and for developing new combination therapies.

“Using this approach, researchers may be able to develop a translational tool for further clinical development of novel anticancer drugs,” Dr Majumder said. AACR press release; January 29, 2013

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www.ValueBasedCancerCare.com

5

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

Gleevec approved for children with ALL Generic version of Doxil approved More….

The importance of prioritizing palliative care in oncology: how payers can assist providers

VALUE PROPOSITIONS

Molecular subtyping reclassifies breast cancer EndoPredict identifies women with ER+ breast cancer for late metastases More….

GI CANCERS SYMPOSIUM New antibody targeting VEGF receptor-2 extends survival in advanced gastric cancer Gene-expression profiling can help select drug therapy for pancreatic cancer More….

Associate Publisher Joe Chanley joe@greenhillhc.com

HEALTH ECONOMICS

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536

Comparing costs of metastatic CRC therapies Most women not willing to pay for genetic breast cancer testing More….

National Accounts Manager Zach Ceretelle Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

PERSONALIZED MEDICINE

HEALTH POLICY HIPAA privacy and security regulations released

ASH ANNUAL MEETING Ruxolitinib reduces myelofibrosis symptoms More….

DRUG UPDATE Ponatinib: new option for adults with CML or Ph+ ALL resistant/intolerant to TKI therapy

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL

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, FASCO 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 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1536 Fax: 732-992-1881

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

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FDA UPDATE

Naimish Pandya, MD University of Maryland Baltimore, MD

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

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

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

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

FEBRuary 2013

Ted Okon, BS, MBA Executive Director Community Oncology Alliance Washington, DC

Denise K. Pierce DK Pierce & Associates Zionsville, IN 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 Chief Executive Officer OncoMed Onco360 Great Neck, NY

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GI Cancers Symposium

In First-Line Metastatic CRC, Outcomes Comparable for Panitumumab and Bevacizumab

By Audrey Andrews

San Francisco, CA—A randomized phase 2 study that compared panitu­ mumab (Vectibix) and bevacizumab (Avastin) in the first-line treatment of metastatic colorectal cancer (CRC) showed these drugs to be similar in terms of progression-free survival (PFS) and overall survival (OS) benefits.

Although bevacizumab is approved by the US Food and Drug Admin­ istration for the first-line treatment of patients with metastatic CRC and wildtype KRAS status, panitumumab is not. The phase 2 PEAK study compared the drugs in 285 metastatic un­ resectable patients, in conjunction with modified FOLFOX6 given every 2 weeks.

“To our knowledge, this is the first study comparing an anti-EGFR [epidermal growth factor receptor] agent to bevacizumab in combination with an oxaliplatin-based regimen in KRAS wild-type patients with metastatic colorectal cancer,” said Lee Schwartzberg, MD, FACP, Medical Director, The West Clinic, Memphis and Chief of the Division of Hematology/Oncology, The Uni­ versity of Tennessee, Memphis.

The median PFS was 10.9 months with panitumumab and 10.1 months with bevacizumab (hazard ratio [HR], 0.87; P = .35). Median OS has not been

reached with panitumumab and was 25.4 months with bevacizumab (HR, 0.72; P = .14).

Dr Schwartzberg noted that while follow-up is short, the OS curves are separating, which suggests that a dif-

“To our knowledge, this is the first study comparing an anti-EGFR agent to bevacizumab in combination with an oxaliplatin-based regimen in KRAS wild-type patients with metastatic colorectal cancer.” Based on the results, panitumumab can be considered for use in this setting.

—Lee Schwartzberg, MD, FACP

ference could emerge with time, “although it’s still very early. We will be updating this in the near future.”

The overall response rates were 82% with panitumumab and 76% with beva­cizumab, and the resection rates were 13% and 11%, respectively. The

treatment exposure to the individual agents and the number of cycles received were the same between the arms.

In the subgroup analysis of treatment HRs, no clear differences were shown, although for PFS, panitumu­ mab was favored for patients with ≥3 metastatic sites (HR, 0.52). For OS, patients who were young, with a high tumor burden and with high levels of lactate dehydrogenase (factors often seen in the same patients, he pointed out), fared better with panitumumab as well, he noted.

These differences were “hypothesis-generating only,” Dr Schwartzberg emphasized.

The drugs were equally well tolerated, and no new safety signals were observed. “The safety profile in both treatment arms was similar to previous reported studies, and the treatment discontinuation rates due to adverse events [AEs] were similar between the arms,” Dr Schwartzberg said. He noted that although the side effect profiles were different for the 2 drugs, the percentage of AEs was not.

Grades 3 and 4 AEs were noted in 86% of the patients receiving panitumumab plus modified FOLFOX6 and in 76% of the patients receiving bevacizumab plus modified FOLFOX6;

at a glance ➤ This is the first randomized trial to compare panitumumab and bevacizumab in the first-line treatment of metastatic CRC ➤ Results show that these drugs have similar PFS and OS in this setting ➤ In addition, the 2 drugs were equally well tolerated, and no new safety signals were observed ➤ Based on these findings, one expert suggests that panitumumab can be considered as effective as bevacizumab in the first-line setting for KRAS wild-type metastatic CRC

AEs leading to permanent discontinuation of the drug occurred in 24% and 27% of the patients, respectively.

Dr Schwartzberg maintained that as a result of these findings he would consider panitumumab to be as effective as bevacizumab in the first-line setting for KRAS wild-type metastatic CRC, and he would feel “comfortable” using it. n

New Antibody Targeting VEGF Receptor-2 Extends Survival in Advanced Gastric Cancer San Francisco, CA—Ramucirumab as a second-line therapy extended overall and progression-free survival in a phase 3 clinical trial of patients with metastatic gastric cancer, said Charles S. Fuchs, MD, MPH, Director of the Center for Gastrointestinal Cancer at Dana-Farber Cancer Institute, Boston, and Professor of Medicine at Harvard Medical School, at the 2013 Gastrointestinal Cancers Symposium.

Patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma that progressed with first-line therapy who were randomized to ramuciru­ mab plus best supportive care had a median 1.4 months longer overall survival (OS) than patients assigned to placebo plus best supportive care.

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Photo by © ASCO/Todd Buchanan 2013

By Mark Knight

“The relative benefit of the antibody is very comparable to what has been achieved with chemotherapy, to the extent that it can achieve a similar benefit to second-line chemotherapy, and it has an excellent tolerability profile, which makes it an exciting option for patients.”

—Charles S. Fuchs, MD, MPH

Ramucirumab is a fully human monoclonal antibody that targets the vascular endothelial growth factor (VEGF) receptor-2. By binding the extracellular domain of the VEGF

receptor-2, it blocks the binding of VEGF ligands and inhibiting receptor activation.

The advantage in OS with ramucirumab mirrors the advantage

FEBRUARY 2013

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achieved with docetaxel or irinotecan as salvage chemotherapy compared with placebo in patients with pretreated gastric cancer (Kang JH, et al. J Clin Oncol. 2012;30:1513-1518).

“The relative benefit of the antibody is very comparable to what has been achieved with chemotherapy, to the extent that it can achieve a similar benefit to second-line chemotherapy, and it has an excellent tolerability profile, which makes it an exciting option for patients,” said Dr Fuchs.

Conducted in 30 countries, the study included 355 patients with meta­static gastric or GEJ adenocarcinoma whose disease progressed within 4 months after first-line platinum- and/or fluoropyrimidine-containing combination

Continued on page 8

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GI Cancers Symposium

Gene-Expression Profiling May Help Select Best Drugs for Pancreatic Cancer

By Caroline Helwick

San Francisco, CA—Gene-expression profiling (GEP) of circulating tumor cells (CTCs) may help to personalize chemotherapy for patients with pancreatic cancer by predicting how patients will respond to certain treatments, according to a study reported at the 2013 Gastrointestinal Cancers Symposium.

The approach described combines an assay for CTCs with a pharmaco­ genomic model that examines a patient’s genetic response to chemotherapy regimens.

CTCs are shed by tumors and can be obtained easily via a blood sample.

CTC sampling offers a much less invasive means of evaluating the molecular profile of a tumor than a standard biopsy. CTCs can also be used to monitor a patient’s response to treatment, as is already being done with breast cancer treatment.

“This research lays important groundwork for customizing treatments according to a patient’s genetic composition,” said Kenneth Yu, MD, of Memorial Sloan-Kettering Cancer Center, New York. “We’re seeing encouraging signs that this strategy can help us to determine which patients will benefit most from chemotherapy and to more quickly identify the development of treatment resistance, even before physical changes in the tumor appear.”

In the study, 50 patients with unresectable stage II to IV pancreatic cancer receiving 12 different drug regimens had CTCs collected before chemotherapy and upon disease progression;

total RNA was extracted and geneexpression analysis was performed. A pharmacogenomics model for the 12 chemotherapy regimens was applied to the patients’ genetic profiles to predict sensitivity to chemotherapy.

The genetic profiles of patients whose disease continued to respond to their treatment were compared with the genetic profiles of patients whose disease progressed.

“This research lays important groundwork for customizing treatments according to a patient’s genetic composition. We’re seeing encouraging signs that this strategy can help us to determine which patients will benefit most from chemotherapy and to more quickly identify the development of treatment resistance.”

—Kenneth Yu, MD The researchers investigated whether this pharmacogenomics model would predict treatment response and resistance, and whether the patients’ pharmacogenomics profiles would change when their cancer progressed. Indeed, differences were seen

“We are starting to use genetic makeup to make treatment decisions regarding which drugs work best against a patient’s tumor, and which may not work at all.”

—Neal J. Meropol, MD

in gene-expression profiles and in outcomes among the first 20 evaluable patients: 6 patients received treatment that the model predicted would be effective, 6 received a regimen predicted to elicit an “intermediate” response, and 8 received a regimen that was predicted to be ineffective.

“Patients who received a treatment that was predicted to be more effective actually did better,” Dr Yu reported. For the group predicted to

New Antibody Targeting VEGF Receptor-2... chemotherapy or within 6 months after adjuvant therapy.

The patients were randomized in a 2:1 ratio to infusions of ramucirumab every 2 weeks plus best supportive care or to placebo infusions plus best supportive care, and were treated until disease progression or intoler­ able toxicity was reached. The median duration of therapy was 8 months in the ramucirumab arm and 6 months in the placebo arm.

Median OS was 5.2 months with ramucirumab versus 3.8 months in placebo recipients, corresponding to a hazard ratio of 0.77 (P = .047).

The median time to disease pro-

8

gression favored ramucirumab over placebo (2.1 months vs 1.3 months, respectively).

At 6 months, OS was 42% in the ramucirumab arm versus 32% in the placebo arm, and at 12 months, OS was 18% in the ramucirumab arm versus 11% in the placebo arm.

The disease control rate, defined as complete remission, partial remission, or stable disease, was 48.7% in the ramucirumab recipients versus 23.1% in the placebo recipients (P <.001). The rates of stable disease were 45.4% in the ramucirumab arm versus 20.5% in the placebo arm.

The percentage of deaths attributed

Value-Based Cancer Care

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february 2013

to adverse events (AEs) was similar in each arm: 10.6% versus 13.0% in the

at a glance ➤ The rates of stable disease were 45.4% in the ramucirumab arm versus 20.5% in the placebo arm ➤ No unexpected safety concerns were found, and the death rate was similar in the 2 groups (10.6% with the ramucirumab group and 13.0% in the placebo group)

have an effective treatment, median time to progression was 7.3 months compared with 5.3 months for the intermediate group and 3.7 months for the resistant group.

Changes in chemotherapy sensitivity patterns were evident at disease progression, reflecting the development of treatment resistance. The disruption of particular genetic pathways predicted shorter or longer treatment responses, and some pathways were disrupted at the time of progression, but not before.

Dr Yu and his team concluded that pathway analysis can play a prognostic role in pancreatic cancer and in the identification of drug resistance. “Ultimately, we hope that this strategy could be used to determine which drug cocktail would be most suitable for the patient and to monitor patients during the course of therapy, so that treatments can be modified at the earliest molecular sign of disease worsening,” Dr Yu said.

Neal J. Meropol, MD, Chief of Hematology and Oncology, University Hospitals Case Medical Center at Case Western Reserve University, Cleveland, commented at a press briefing that this study “highlights the direction that the field of oncology is going, both for research and clinical practice,” toward the molecular characterization of tumors. “We are starting to use genetic makeup to make treatment decisions regarding which drugs work best against a patient’s tumor, and which may not work at all,” Dr Meropol added. n

Continued from page 7 ramucirumab and the placebo arms, respectively.

No unexpected safety findings were noted, said Dr Fuchs. Fatigue was the most frequently reported AE in each study arm (35.6%, ramucirumab; 40.0%, placebo). Hypertension rates were 16.1% versus 7.8% in the ramucirumab and placebo arms, respectively, and the rates of grade 3 hypertension were 7.6% with ramucirumab and 2.6% with placebo. No grade 4 hypertension was observed.

“The next logical question is what happens when you add ramuciru­ mab to chemotherapy,” concluded Dr Fuchs. n

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Administration for the treatment of breast cancer and non–small-cell lung cancer.

In a phase 1/2 study of 67 patients with advanced pancreatic cancer, the combination of nab-paclitaxel and gemcitabine demonstrated an overall response rate of 48%.

The median overall survival (OS) was 12.2 months for the combination at maximum tolerated doses (125 mg/ m2 of nab-paclitaxel followed by 1000 mg/m2 of gemcitabine on days 1, 8, and 15 every 4 weeks or to 1000 mg/ m2 of gemcitabine weekly for 7 weeks, and then on days 1, 8, and 15 every 4 weeks in the first-line setting).

Phase 3 Clinical Trial The results of a phase 3 randomized study powered for OS were presented by Dr Von Hoff at the 2013 Gastrointestinal Cancers Symposium.

The study, which was conducted at 151 sites in 11 countries, enrolled 861 patients with stage IV pancreatic can­ cer who had no prior treatment for metastatic disease. They were randomized to gemcitabine alone or to nabpac­ litaxel added to gemcitabine.

Patients were treated until they reached disease progression, and had computed tomography scans every 8 weeks.

The median OS was 8.5 months for patients assigned to nab-paclitaxel plus gemcitabine compared with 6.7 months for those assigned to gemcitabine alone, which represents a hazard ratio (HR) of 0.72 (P = .015).

The 1-year survival rate was 22% for patients who were given gemcitabine alone and 35% for patients who were also given nab-paclitaxel—a 59% improvement (P = .002); 2-year surviv-

Photo by © ASCO/Todd Buchanan 2013

Nab-Paclitaxel Added to Gemcitabine Extends...

“We were able to give the same dose intensity for long periods of time, so the 2 combine well. Because they combine well, it’s a scaffold you can add other things on to.”

—Daniel D. Von Hoff, MD, FACP

al more than doubled for patients who were given both gemcitabine and nab-paclitaxel, increasing from 4% to 9% (P = .021).

HRs were generally more favorable with nab-paclitaxel in patients with poorer prognostic factors, such as a lower Karnofsky Performance Score, the presence of liver metastases, 3 or more metastatic sites, and a CA19-9 ≥59 times the upper limit of normal, said Dr Von Hoff.

Among the patients who received subsequent therapy, the median survival was 9.4 months in patients ran-

domized to the combination versus 6.8 months in those assigned to gemcitabine alone (HR, 0.68; P = .072).

Progression-free survival was great­ er in patients who were given nabpaclitaxel and gemcitabine than in patients who were given gemcitabine alone (HR, 0.69; P = .024), as was the overall objective response rate (23% vs 7%, respectively) and the objective disease control rate (48% vs 33%, respectively).

No increase in life-threatening toxicity resulted from adding nab-pac­ litaxel to the patients’ treatment, despite a median duration of treatment that was 1.2 months longer than that given with gemcitabine alone.

The combination arm had higher rates of fatigue (17% vs 7%, respectively), peripheral neuropathy (PN; 17% vs <1%, respectively), and diarrhea (6% vs 1%, respectively). PN was rapidly reversible in the combination arm, and 44% of the patients in this arm who experienced grade ≥3 PN were able to resume treatment.

Grade ≥3 hematologic adverse events occurred at a higher rate with the addition of nab-paclitaxel. Of this group, 38% experienced grade ≥3 neutropenia and 31% experienced grade ≥3 leukopenia, compared with 27% and 16% of the patients, respectively, with gemcitabine alone. The rates of febrile neutropenia were low—1% with gemcitabine and 3% with nabpaclitaxel and gemcitabine.

Of those in the combination arm, 80% received the per-protocol dose compared with 75.2% of the patients in the gemcitabine arm. “We were able to give the same dose intensity for long periods of time, so the 2 combine

Continued from cover

well,” said Dr Von Hoff. “Because they combine well, it’s a scaffold you can add other things on to.”

“The immediate question would be the relative role of nab-paclitaxel plus gemcitabine versus FOLFIRINOX in our day-today practices….Obviously, a head-to-head comparison will answer these questions, but I’m not sure that a study like that will happen soon enough.”

—Philip Agop Philip, MD, PhD, FRCP

Remaining Questions “The immediate question would be the relative role of nab-paclitaxel plus gemcitabine versus FOLFIRINOX [oxaliplatin, irinotecan, fluorouracil, and leucovorin] in our day-to-day practices,” said Philip Agop Philip, MD, PhD, FRCP, Director of Gastrointestinal Oncology, Karmanos Cancer Institute at Wayne State University, Detroit.

“Related to this question is how to sequence these 2 regimens. Ob­ viously, a head-to-head comparison will answer these questions, but I’m not sure that a study like that will happen soon enough. Whenever it happens, we will have to wait several years before we get an answer,” Dr Philip said. n

In Patients with Colon Cancer, Genomic Classifiers Aid in Prognosis

By Caroline Helwick

San Francisco, CA—Genomic classifiers—in particular, ColoPrint and MSIPrint, best when combined—can identify high-risk subsets among patients with surgically resected stage II and stage III colon cancers, reported researchers from M.D. Anderson Cancer Center at the 2013 Gastrointestinal Cancers Symposium.

“The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help identify patients at higher risk who are more

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likely to benefit from additional treatment,” said lead investigator E. Scott Kopetz, MD, PhD, FACP, Assistant Professor, Department of Gastro­ intestinal Medi­ cal Oncology, Divi­ sion of Cancer Med­ i­ cine, at M.D. Anderson.

“Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment,” he added.

“The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help identify patients at higher risk who are more likely to benefit from additional treatment.”

—E. Scott Kopetz, MD, PhD, FACP

ColoPrint is a gene-expression classifier that distinguishes patients with low or high risk of disease recurrence.

It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts, and in technical studies. The 64-gene MSI-signature MSI-Print is a genomic signature for the detection of patients with colorectal cancer who have microsatellite instability phenotype and high mutation frequency, and is linked to deficient mismatch repair (dMMR). A dMMR system is present

Continued on page 14

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9

NEW INDICATION: ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

ADRENALS

PROSTATE TUMOR TISSUE

TESTES

ADT = androgen-deprivation therapy.

IMPORTANT SAFETY INFORMATION Contraindications—ZYTIGA® is not indicated for use in women.

ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in blood pressure, hypokalemia, or fluid retention. ZYTIGA® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in study 1) or NYHA Class II to IV heart failure (in study 2) because these patients were excluded from these randomized clinical trials. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated

with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity—Monitor liver function and modify, withhold, or discontinue ZYTIGA® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA®, every two weeks for the first three months of treatment, and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA® treatment and closely monitor liver function.

Increased ZYTIGA® Exposures With Food—ZYTIGA® must be taken on an empty stomach. No food should be eaten for at least two hours before the dose of ZYTIGA® is taken and for at least one hour after the dose of ZYTIGA® is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

I N T R O D U C I N G More than 20,000 patients with mCRPC have received ZYTIGA® (post-chemotherapy with docetaxel) to date.†1

MECHANISM OF ACTION ZYTIGA® is a CYP17 (17 -hydroxylase/C17, 20-lyase) inhibitor that inhibits androgen production at 3 sources: the testes, adrenal glands, and the prostate tumor tissue itself.

NEW EFFICACY DATA —In a recent Phase 3 clinical trial in patients with mCRPC who had progressed on ADT and had not received chemotherapy.* Efficacy was also demonstrated in a Phase 3 trial of patients who had received prior chemotherapy containing docetaxel.*

ZytigaOne™ is your single source for personalized access services for you and your patients: Visit www.zytigaone.com or call 1-855-998-4421. *Study Designs: ZYTIGA®, in combination with prednisone, was evaluated in 2 Phase 3, randomized, double-blind, placebo-controlled, multicenter trials in patients with mCRPC. Study 1 enrolled patients who received prior chemotherapy containing docetaxel (N = 1,195), whereas Study 2 enrolled patients who had not received prior chemotherapy (N = 1,088). In both studies, patients were using a luteinizing hormone-releasing hormone agonist or were previously treated with orchiectomy. In the active treatment arms, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the control arms, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In Study 1, the primary efficacy endpoint was overall survival. In Study 2, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. † Estimate based on sales and use data from May 2011 to November 2012.

Reference: 1. Data on file. Janssen Biotech, Inc.

www.zytigahcp.com Please see adjacent pages for brief summary of full Prescribing Information.

K08Z121176

Adverse Reactions—The most common adverse reactions (≥ 10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT, and hypokalemia.

Drug Interactions—ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index.

If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on its use with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution during treatment with ZYTIGA®.

Use in Specific Populations—Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 12/12 08Z12264B

ZYTIGA® (abiraterone acetate) Tablets Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

CONTRAINDICATIONS Pregnancy: ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations].

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1) in full Prescribing Information]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA [see Adverse Reactions].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction < 50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14) in full Prescribing Information]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Increased ZYTIGA Exposures with Food: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions].

• Adrenocortical Insufficiency [see Warnings and Precautions].

• Hepatotoxicity [see Warnings and Precautions].

• Increased ZYTIGA Exposures with Food [see Warnings and Precautions].

Clinical Trial 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 clinical practice.

Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.

The most common adverse drug reactions (≥10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy: Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5X ULN. Table 1 shows adverse reactions on the ZYTIGA arm in Study 1 that occurred with a ≥2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with ZYTIGA was 8 months.

ZYTIGA® (abiraterone acetate) Tablets Table 1: Adverse Reactions due to ZYTIGA in Study 1 System/Organ Class Adverse reaction Musculoskeletal and connective tissue disorders Joint swelling/discomfort2 Muscle discomfort3 General disorders Edema4 Vascular disorders Hot flush Hypertension Gastrointestinal disorders Diarrhea Dyspepsia Infections and infestations Urinary tract infection Upper respiratory tract infection Respiratory, thoracic and mediastinal disorders Cough Renal and urinary disorders Urinary frequency Nocturia Injury, poisoning and procedural complications Fractures5 Cardiac disorders Arrhythmia6 Chest pain or chest discomfort7 Cardiac failure8

ZYTIGA with Prednisone (N=791) All Grades1 Grade 3-4 % %

Placebo with Prednisone (N=394) All Grades Grade 3-4 % %

29.5 26.2

4.2 3.0

23.4 23.1

4.1 2.3

26.7

1.9

18.3

0.8

19.0 8.5

0.3 1.3

16.8 6.9

0.3 0.3

17.6 6.1

0.6 0

13.5 3.3

1.3 0

11.5 5.4

2.1 0

7.1 2.5

0.5 0

10.6

0

7.6

0

7.2 6.2

0.3 0

5.1 4.1

0.3 0

5.9

1.4

2.3

0

7.2 3.8 2.3

1.1 0.5 1.9

4.6 2.8 1.0

1.0 0 0.3

1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal

discomfort, and Musculoskeletal stiffness 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema 5 Includes all fractures with the exception of pathological fracture 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia 7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1 Abiraterone (N=791) All Grades Grade 3-4 Laboratory Abnormality (%) (%) Hypertriglyceridemia 62.5 0.4 High AST 30.6 2.1 Hypokalemia 28.3 5.3 Hypophosphatemia 23.8 7.2 High ALT 11.1 1.4 High Total Bilirubin 6.6 0.1

Placebo (N=394) All Grades Grade 3-4 (%) (%) 53.0 0 36.3 1.5 19.8 1.0 15.7 5.8 10.4 0.8 4.6 0

Study 2: Metastatic CRPC Prior to Chemotherapy Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5X ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the ZYTIGA arm in Study 2 that occurred with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

Table 3: Adverse Reactions in ≥5% of Patients on the ZYTIGA Arm in Study 2 ZYTIGA with Prednisone (N=542) System/Organ Class All Grades1 Grade 3-4 Adverse reaction % % General disorders Fatigue 39.1 2.2 Edema2 25.1 0.4 Pyrexia 8.7 0.6 Musculoskeletal and connective tissue disorders Joint swelling/ discomfort3 30.3 2.0 Groin pain 6.6 0.4 Gastrointestinal disorders Constipation 23.1 0.4 Diarrhea 21.6 0.9 Dyspepsia 11.1 0.0 Vascular disorders Hot flush 22.3 0.2 Hypertension 21.6 3.9 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 Dyspnea 11.8 2.4 Psychiatric disorders Insomnia 13.5 0.2 Injury, poisoning and procedural complications Contusion 13.3 0.0 Falls 5.9 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 Nasopharyngitis 10.7 0.0 Renal and urinary disorders Hematuria 10.3 1.3 Skin and subcutaneous tissue disorders Rash 8.1 0.0 1 Adverse events graded according to CTCAE version 3.0 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

Placebo with Prednisone (N=540) All Grades Grade 3-4 % % 34.3 20.7 5.9

1.7 1.1 0.2

25.2 4.1

2.0 0.7

19.1 17.8 5.0

0.6 0.9 0.2

18.1 13.1

0.0 3.0

13.5 9.6

0.2 0.9

11.3

0.0

9.1 3.3

0.0 0.0

8.0 8.1

0.0 0.0

5.6

0.6

3.7

0.0

ZYTIGA® (abiraterone acetate) Tablets

ZYTIGA® (abiraterone acetate) Tablets

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3-4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

(ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

Table 4: Laboratory Abnormalities in > 15% of Patients in the ZYTIGA Arm of Study 2 Laboratory Abnormality Hematology Lymphopenia Chemistry Hyperglycemia1 High ALT High AST Hypernatremia Hypokalemia 1Based

Abiraterone (N = 542) Grade 1-4 Grade 3-4 % %

Placebo (N = 540) Grade 1-4 Grade 3-4 % %

38.2

8.7

31.7

7.4

56.6 41.9 37.3 32.8 17.2

6.5 6.1 3.1 0.4 2.8

50.9 29.1 28.7 25.0 10.2

5.2 0.7 1.1 0.2 1.7

on non-fasting blood draws

Cardiovascular Adverse Reactions: In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with ZYTIGA compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo.

There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arms and no deaths in the placebo arms.

There were 7 (0.5%) deaths due to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the ZYTIGA arms.

DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications].: ZYTIGA can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with ZYTIGA. In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6-17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of ZYTIGA in pediatric patients have not been established.

Geriatric Use: Of the total number of patients receiving ZYTIGA in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease

OVERDOSAGE There have been no reports of overdose of ZYTIGA during clinical studies.

There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20oC to 25oC (68oF to 77oF); excursions permitted in the range from 15oC to 30oC (59oF to 86°F) [see USP controlled room temperature].

Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Patients should be informed that ZYTIGA and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.

• Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with ZYTIGA and prednisone.

• Patients should be informed that ZYTIGA must not be taken with food and that no food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking ZYTIGA with food causes increased exposure and this may result in adverse reactions.

• Patients should be informed that ZYTIGA is taken once daily and prednisone is taken twice daily according to their physician’s instructions.

• Patients should be informed that in the event of a missed daily dose of ZYTIGA or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.

• Patients should be apprised of the common side effects associated with ZYTIGA, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Patients should be advised that their liver function will be monitored using blood tests.

• Patients should be informed that ZYTIGA may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves.

Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with ZYTIGA.

Manufactured by: Patheon Inc. Mississauga, Canada Manufactured for: Janssen Biotech, Inc. Horsham, PA 19044 © Janssen Biotech, Inc. 2012 Revised: December 2012 2000005445 K08Z121174A

GI Cancers Symposium

Mayo Clinic Researchers Propose Screening Algorithm for HER2 in Patients with Esophageal Cancer

By Caroline Helwick

San Francisco, CA—The preferred screening test for human epidermal growth factor receptor (HER)2 stat­ us in surgical esophageal adenocarcinoma specimens is immunohistochemistry (IHC), with fluorescence in situ hybridization (FISH) restricted to cases with an indeterminate (2+) IHC score, according to investigators from the Mayo Clinic, Rochester, MN, who proposed a testing algorithm at the 2013 Gastrointestinal Cancers Symposium.

“Our findings support a testing algorithm for resected esophageal adenocarcinomas where IHC is used for initial screening, and FISH testing is restricted to cases with equivocal IHC results,” said Harry H. Yoon, MD, Assistant Professor of Oncology at the Mayo Clinic College of Medicine and the lead investigator of the study.

HER2 oncoprotein overexpression is a known driver of tumor aggressiveness in esophageal adenocarcinoma; the HER2 gene is amplified in 7% to 22% of cases. HER2-positive patients treated with trastuzumab (Herceptin) have improved survival; therefore, it is important to test for HER2 with IHC or FISH, he said.

A previous exploratory, single-center study suggested that IHC is more predictive of trastuzumab benefit than FISH, but this superiority has not been

Table

Predictive Value of Immunohistochemistry

IHC score

Positive, 3+

FISH nonamplified, N (%)

FISH amplified, N (%)

Total, N

146 (87)

21 (13)

167

10 (11)

Equivocal, 2+

Negative, 0 or 1+

401 (96)

70 (89) 16 (4)

89

417

FISH indicates fluorescence in situ hybridization; IHC, immunohistochemistry.

“Our findings support a testing algorithm for resected esophageal adenocarcinomas where IHC is used for initial screening, and FISH testing is restricted to cases with equivocal IHC results.”

—Harry H. Yoon, MD

established and each testing method has its advantages. IHC is faster, less labor intensive, and less expensive (as a result of the lower cost of reagents).

FISH, on the other hand, is less vulnerable to tissue artifacts and offers a more objective scoring system, Dr Yoon explained.

The current study evaluated the concordance of HER2 test results between IHC and FISH assays in 673 patients with unselected surgically resected esophageal adenocarcinoma.

Each tumor was evaluated by IHC in parallel with FISH in a blinded manner using US Food and Drug Administration–approved assays. A consensus IHC score was determined by 2 pathologists using tumor-specific criteria (negative, 0 or 1+; equivocal, 2+; positive, 3+). Gene amplification

by FISH was defined as a HER2/ CEP17 (chromosome 17) ratio of ≥2.

By FISH, 116 (17%) tumors tested positive. By IHC, 13% tested positive, 25% were indeterminate, 23% were nega­­­­tive by 1+, and 39% were negative by a 2+ score.

Among the 89 patients with an IHC 3+ score, 70 were FISH positive and 10 were FISH negative. Of the 107 inde-

terminate (2+) patients, 21 were FISH positive and 146 were FISH negative. Of the 417 IHC-negative patients, 16 were FISH positive and 401 were FISH negative.

This yielded a concordance rate of 95% between FISH and IHC 3+ patients and IHC-negative patients, and a 74% concordance rate when IHC 2+ patients were included.

HER2 amplification was detected in 89% of IHC 3+ cases, 13% of IHC 2+ cases, and in 4% of IHC 0 to 1+ cases (Table). Accordingly, using FISH as the reference standard, the positive predictive value of a positive IHC test (3+) was 89%, and the negative predictive value of a negative test was 96%. Importantly, the positive predictive value of an equivocal IHC score (2+) for detecting HER2 amplification was 13%, he said.

The sensitivity of IHC 2+ or 3+ was calculated to be 89%, and the specificity of IHC 3+ was 98%.

“In the largest study to date comparing HER2 testing methods in esophageal adenocarcinoma, a negative IHC result nearly excludes the presence of gene amplification by FISH,” Dr Yoon said, “whereas a positive result (3+) strongly predicts for the presence of amplification, and an equivocal IHC result (2+) is a weak predictor.” n

In Patients with Colon Cancer, Genomic Classifiers... in 10% to 20% of patients with sporadic colon cancer and is associated with a favorable prognosis in early-stage disease.

The population included 96 patients with stage II colon cancer and 94 patients with stage III colon cancer who were followed for a median of 64 months. In this cohort, ColoPrint was prognostic for recurrence. The test classified 56% of stage II and stage III patients as being at low risk for recurrence. The 3-year recurrence-free survival (RFS) rate was 90.6% for low-risk and 78.4% for high-risk patients, with a hazard ratio of 2.33 (P = .012). In univariate and multivariate analyses, ColoPrint and stage (stage III vs stage II) were the only significant factors to predict outcome.

The MSI-Print classified 24.6% of

14

patients as MSI high (which is prognostically favorable) and most of these (81%) were low risk by ColoPrint.

“Patients who were ColoPrint low risk and MSI high by signature had the best outcome, with a 3-year RFS of 95%, while patients with ColoPrint high risk had a worse outcome independently of the MSI status,” Dr Kopetz reported.

Of the patients, 25% were characterized as “MSI-Print high,” which was previously defined to incorporate both MSI-high tumors and additional tumors that share similar gene-expression features. In this population, MSIPrint did not provide independent prognostic ability, but it did provide additional information when combined with ColoPrint.

Low-risk ColoPrint patients had a good outcome independent of stage

Value-Based Cancer Care

I

february 2013

“Patients who were ColoPrint low risk and MSI high by signature had the best outcome, with a 3-year RFS of 95%, while patients with ColoPrint high risk had a worse outcome independently of the MSI status.”

—E. Scott Kopetz, MD, PhD, FACP or chemotherapy treatment. The RFS at 3 years was 90.1% for treated patients and 91.4% for untreated patients. ColoPrint high-risk patients treated with adjuvant chemotherapy

Continued from page 9

had a 3-year RFS of 84% compared with 70.1% for untreated patients (P = .037).

Dr Kopetz added that ColoPrint is independent of traditional American Society of Clinical Oncology (ASCO) high-risk features, with 50% of cases discordant based on the presence or absence of high-risk features and ColoPrint results. For example, among patients who were classified as high risk by ASCO clinical features, only 34% were high risk by ColoPrint and 41% were low risk.

Among those patients who were classified as low risk by ASCO clinical features, 16% were low risk by ColoPrint and 9% were high risk.

The genomic classifiers, therefore, add information above and beyond that obtained through conventional means, he noted. n

Vol. 4

I

No. 2

Health Economics

Costs of Second-Line Metastatic Colorectal Cancer Treatments Compared Table

By Caroline Helwick

San Francisco, CA—For the secondline treatment of patients with metastatic colorectal cancer (CRC), the total costs were 14% lower with bevacizu­ mab (Avastin) than with cetuximab (Erbitux), according to an analysis presented at the 2013 Gastrointestinal Cancers Symposium.

The study was presented by Elaine Yu, PharmD, of Genentech. The analysis was conducted using the UnitedHealthcare claims database and Medicare Advantage plan of patients who had 2 claims for CRC at least 30 days apart between 2007 and 2011, and evidence of 2 lines of therapy.

“This analysis gives a more accurate picture to the payers of what bevacizumab and cetuximab really cost in the real world,” Dr Yu said. She maintained that there is a frequent misperception that a course of beva­ cizumab costs $100,000, “and this is not so,” she said.

match rate increased. The initial positive predictive value of the algorithm for second-line therapy was 68.5%, which increased to 85.3% with refinement. “Corroboration with medical chart data led to algorithm refinements that improved the predictive performance of the claims-based algorithm in identifying metastatic colo­ rectal cancer patients with 2 lines of therapy and targeted agents in the second-line setting,” Dr Yu explained.

The final algorithm identified 2 mutually exclusive second-line cohorts receiving either bevacizumab (N = 450) or cetuximab (N = 119). The baseline characteristics were similar between the groups.

Algorithm Refined Administrative claims databases are useful for examining healthcare costs but are limited by algorithms that are used to identify lines of therapy.

Corroboration of algorithms with medical evidence can improve the accuracy of claims analyses, Dr Yu pointed out.

“We wanted to see how well the algorithm was performing, so we did a smaller chart review to determine if patients judged to have treatment in the second line were truly second-line patients. The first time around, the match rate was not very high,” she noted. “The algorithm, therefore, was not picking up patients accurately.

We found that there was room for improvement.”

After refining the algorithm, the

—Elaine Yu, PharmD

“Cetuximab is a more expensive drug, and the associated medical costs are also higher.”

The investigators found that patients using bevacizumab in the second-line setting often had received this drug in the first-line setting. (Bevacizumab recently became approved by the US Food and Drug Administration for both indications.) In the second-line setting, bevacizumab was more often used with oxaliplatin (Eloxatin), whereas cetuximab was used with irinotecan (Camptosar), which is indicated for this use, Dr Yu said.

Cost of Second-Line Treatment The adjusted total costs for treatment were significantly lower among the bevacizumab cohort (Table). The

Healthcare Costs for Duration of Second-Line Treatment

Chemotherapy

Targeted agent Medical Total

a

Cost of second-line bevacizumab, $ (N = 450)

Cost of second-line cetuximab, $ (N = 119)

Adjusted difference,b $ (P value)

30,639

43,459

11,950 (<.01)

61,360

70,867

12,318 (<.05)

15,371 58,313

9080

69,480

7738 (<.01)

13,809 (<.01)

Total costs are the sum of all paid amounts by a health plan and the patient for medical (inpatient, outpatient, office, emergency department, and other services) and pharmacy claims. b The adjusted difference between cohorts is based on a multivariate generalized linear model.

NOTE: All costs for chemotherapy and targeted agents include infusion costs. Total costs are the sum of all paid amounts by a health plan and the patient for medical and pharmacy claims. a

per-patient cost difference (adjusted, in the multivariate analysis) was $12,318 for the duration of second-line therapy and $2728 for a month of treatment compared with cetuximab, Dr Yu reported.

For the duration of second-line chemotherapy, the total costs per patient were $70,867 for cetuximab and $61,360 for bevacizumab. The costs for a month of treatment were $19,630 and $17,578, respectively. Medical costs were $69,480 and $58,313, respectively, for the duration of treatment and $19,167 and $16,791, respectively, for a month, Dr Yu reported.

The total medical cost for treatment was the sum of all health plan- and patient-paid amounts for all medical expenses (ie, inpatient, outpatient, office, and emergency department visits, and other services) and pharmacy claims.

“Cetuximab is a more expensive drug, and the associated medical costs are also higher,” she said. “The cost differences may be even higher for patients treated with bevacizumab in combination with oxaliplatin since the

2012 (poststudy) availability of generic oxaliplatin.”

The cost of the targeted agent for the course of treatment was $43,459 for cetuximab and $30,639 for bevacizumab, and the costs monthly were $12,012 and $8833, respectively.

The backbone chemotherapy, however, was more expensive for the patients receiving bevacizumab: $15,371 versus $9080 for cetuximab, which was an adjusted difference of $7738.

Although the adjusted targeted therapy cost was lower with bevaciz­ umab, there was no difference in the cost of the regimen because of significantly higher adjusted chemotherapy agent costs with bevacizumab versus cetuximab, Dr Yu noted.

Dr Yu acknowledged that although costs were adjusted to account for potential demographic and clinical differences between cohorts, there may have been other unobserved differences (eg, patient performance status, disease severity, and other factors unavailable in claims data) between the cohorts. n

Most Women Not Willing to Pay for Genetic Breast Cancer Testing San Antonio, TX—Direct-to-consumer (DTC) genetic testing using single nucleotide polymorphisms (SNPs) is of interest to women who are concerned about breast cancer; however, these women are unwilling to pay the current costs, researchers from the Department of Surgery and Institute for Health Policy Studies, University of California, San Francisco (UCSF), Medical Center, reported at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

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Table

Survey Results (N = 189)

Survey question

Yes, N (%)

No, N (%)

Are you interested in SNP testing?

165 (87)

24 (13)

Do you find DTC testing trustworthy?

70 (38)

Are you aware of what an SNP is?

18 (10)

Are you interested in DTC SNP testing?

128 (68)

167 (90) 60 (32)

112 (62)

DTC indicates direct-to-consumer; SNP, single nucleotide polymorphism.

SNP testing identifies genetic variations that may be correlated with a

risk for breast cancer and could be seen as a personalized tool in breast cancer

FEBRuary 2013

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prevention through more precise risk assessment. DTC SNP has been marketed aggressively. However, little is known about how women respond to this information, according to lead investigator Rebecca Howe, a UCSF researcher.

“DTC SNP testing may place a burden on physicians and other providers to discuss and help interpret DTC SNP results with their patients,” Ms Howe said.

Ms Howe and colleagues studied Continued on page 16

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Health Economics

Most Women Not Willing to Pay... patient interest in these kits, as well as their willingness to pay for SNP testing. The study included 189 women (mean age, 49 years) from the national Cancer Genetics Network.

The women had no personal history of breast cancer but did have a family history of breast cancer or ovarian cancer. Of those who tested positive, 31% had received BRCA testing, 8% of whom tested positive for BRCA1 and 3% tested positive for BRCA2 mutations. BRCA1 and BRCA2 mutations were found in family members of 13% and 7% of the women, respectively.

Trust of DTC SNP testing (P = .004), very high interest in testing (P <.001), and family history of BRCA1 mutation (P = .005) were associated with willingness to pay a higher amount. Age,

Continued from page 15

education level, Ashkenazi Jewish heritage, and the number of relatives with breast or ovarian cancers were not significant predictors of willingness to pay.

“The majority of women in our sample are interested in this type of genetic testing, but most are unwilling to pay the current cost of a DTC SNP testing kit,” Ms Howe acknowledged.—CH n

Announcing: J-code

J9042

CD30-directed therapy

effective 1/1/13

Important Safety Information

“The majority of women in our sample are interested in this type of genetic testing, but most are unwilling to pay the current cost of a DTC SNP testing kit.”

BOXED WARNING

Progressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS® (brentuximab vedotin).

Contraindication:

Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity.

—Rebecca Howe

Warnings and Precautions:

• Peripheral neuropathy: ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported.

ADCETRIS-induced peripheral neuropathy is cumulative. Treating physicians should monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness and institute dose modifications accordingly.

• Infusion reactions: Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion.

If an infusion reaction occurs, the infusion should be interrupted and appropriate medical management instituted. If anaphylaxis occurs, the infusion should be immediately and permanently discontinued and appropriate medical management instituted.

• Neutropenia: Monitor complete blood counts prior to each dose of ADCETRIS and consider more frequent monitoring for patients with Grade 3 or 4 neutropenia. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions or discontinuation. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. • Tumor lysis syndrome: Patients with rapidly proliferating tumor and high tumor burden are at risk of tumor lysis syndrome and these patients should be monitored closely and appropriate measures taken.

The women completed an online questionnaire that probed their knowledge and interest in DTC SNP testing and their willingness to pay for it (Table).

“Women wanted to discuss testing results with a provider (77% if above-average risk, and 59% if below-average), and they were interested in lifestyle interventions to reduce their risk (96% if above average and 69% if below). There was also a strong interest in regular mammograms even for women with below-average risk,” Ms Howe noted.

Approximately 70% of the women with below-average risk selected “none” when asked for their intervention choices. “The significant interest in lifestyle changes suggests that this intervention should be included in risk reduction conversations,” Ms Howe pointed out.

Women Not Willing to Pay But although the women were overall interested in SNP testing, they were generally not willing to pay for it, she said. Of those surveyed, 40% were willing to pay $100, approximately 10% were willing to pay $200, and 10% would pay $500.

Only approximately 5% would pay $1000 for SNP testing. The survey revealed that the average willingness to pay was $125.

CT SCANS confirmed responses in relapsed patients Mx8000 Ex: CT080100137 Se: 8002/4 Im: 130/208 Ax: 1623.9 120.0 kV 280.0 mA 1.3 mm/-0.5:1 Tilt: 0.0 0.0s Lin:DCM/ Lin:DCM/id:ID W:200 L25

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Health Economics

Cost-Effectiveness of MRI Screening in Women... ries in which MRI might potentially be most useful, since breast density is often high,” according to Sepideh Saadatmand, MD, of Erasmus Medical Center in Rotterdam, the Netherlands.

MRI has been shown to improve the sensitivity of breast cancer detection and to be cost-effective for BRCA mutation carriers; however, for women with a family history without a proven

genetic predisposition, the cost-effectiveness has been unclear, the investigators pointed out.

The study evaluated the cost-effectiveness of additional MRI for women

Continued from cover

with a familial risk in the large, prospective MRI Screening (MRISC) study. Investigators calculated the breast cancer incidence rate, the costs Continued on page 18

After multiple failures,

single-agent response Indicated for the treatment of:

Important Safety Information (continued)

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)1 • HL in patients who are not ASCT candidates after failure of at least 2 multiagent chemotherapy regimens1

HL: 73% objective response rate (ORR) (95% CI: 65%-83%)

1

32%

complete remission (95% CI: 23%-42%)1

40%

partial remission (95% CI: 32%-49%)1

N = 102, 15-77 years (median: 31 years)1

• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen1

sALCL: 86% ORR (95% CI: 77%-95%)

1

57%

complete remission (95% CI: 44%-70%)1

29%

partial remission (95% CI: 18%-41%)1

N = 58, 14-76 years (median: 52 years)1

The indications for ADCETRIS® (brentuximab vedotin) are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS.1

2011 August 19 Acq Tm: 14:05:52

• P rogressive multifocal leukoencephalopathy (PML): JC virus infection resulting in PML and death has been reported in ADCETRIS® (brentuximab vedotin)– treated patients. In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with newonset signs and symptoms of central nervous system abnormalities.

Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy.

Hold ADCETRIS if PML is suspected and discontinue ADCETRIS if PML is confirmed.

• Stevens-Johnson syndrome: Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

• U se in pregnancy: Fetal harm can occur. Pregnant women should be advised of the potential hazard to the fetus.

Adverse Reactions:

ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, nausea, anemia, upper respiratory tract infection, diarrhea, pyrexia, rash, thrombocytopenia, cough and vomiting.

Drug Interactions:

Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions.

512x512 B

A R

L Vp

Please see Brief Summary of full Prescribing Information, including Boxed WARNING, on the last page of this ad.

REFERENCE: 1. ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics, Inc; 2012.

US/BVP/2011/0104k

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855.4SEAGEN (855.473.2436) SeaGenSecure.com

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Health Economics

Cost-Effectiveness of MRI Screening in Women... per detected and treated breast cancer, and the costs per life-years gained using data from women who were deemed to have a cumulative risk of 15% to 50% in the MRISC study. The study was conducted from 1999 to 2007, screening 1597 women (aged

25-70 years) with annual mammography plus MRI and with clinical breast examinations every 6 months.

Various screening schemes were evaluated, and the costs per life-years gained were compared with the Dutch nationwide breast cancer screening

Brief Summary of Prescribing Information (see Package Insert for full Prescribing Information)

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) JC virus infection resulting in PML and death can occur in patients receiving ADCETRIS. Indications and usage These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with ADCETRIS. ADCETRIS® (brentuximab vedotin) is indicated for treatment of patients with Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates.

ADCETRIS is indicated for treatment of patients with systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multi-agent chemotherapy regimen.

Contraindications Pulmonary toxicity: Concomitant use of ADCETRIS and bleomycin is contraindicated due to pulmonary toxicity. In a clinical trial that studied ADCETRIS with bleomycin as part of a combination regimen, the rate of non-infectious pulmonary toxicity was higher than the historical incidence reported with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients typically reported cough and dyspnea. Interstitial infiltration and/or inflammation were observed on radiographs and computed tomographic imaging of the chest. Most patients responded to corticosteroids.

Warnings and precautions Peripheral neuropathy

ADCETRIS treatment causes a peripheral neuropathy that is predominantly sensory. Cases of peripheral motor neuropathy have also been reported. ADCETRIS-induced peripheral neuropathy is cumulative. In the HL and sALCL clinical trials, 54% of patients experienced any grade of neuropathy. Of these patients, 49% had complete resolution, 31% had partial improvement, and 20% had no improvement. Of the patients who reported neuropathy, 51% had residual neuropathy at the time of their last evaluation. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS.

Infusion reactions

Infusion-related reactions, including anaphylaxis, have occurred with ADCETRIS. Monitor patients during infusion. If anaphylaxis occurs, immediately and permanently discontinue administration of ADCETRIS and administer appropriate medical therapy. If an infusion-related reaction occurs, the infusion should be interrupted and appropriate medical management instituted. Patients who have experienced a prior infusion-related reaction should be premedicated for subsequent infusions.

Premedication may include acetaminophen, an antihistamine and a corticosteroid.

Neutropenia

Complete blood counts should be monitored prior to each dose of ADCETRIS and more frequent monitoring should be considered for patients with Grade 3 or 4 neutropenia. Prolonged (≥1 week) severe neutropenia can occur with ADCETRIS. If Grade 3 or 4 neutropenia develops, manage by dose delays, reductions, or discontinuations.

Tumor lysis syndrome

Tumor lysis syndrome may occur. Patients with rapidly proliferating tumor and high tumor burden may be at increased risk of tumor lysis syndrome. Monitor closely and take appropriate measures.

Progressive multifocal leukoencephalopathy

JC virus infection resulting in PML and death has been reported in ADCETRIS-treated patients.

In addition to ADCETRIS therapy, other possible contributory factors include prior therapies and underlying disease that may cause immunosuppression.

Consider the diagnosis of PML in any patient presenting with new-onset signs and symptoms of central nervous system abnormalities. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture or brain biopsy. Hold ADCETRIS dosing for any suspected case of PML and discontinue ADCETRIS dosing if a diagnosis of PML is confirmed.

Stevens-Johnson syndrome

MRI Screening Costs MRI screening detected 47 breast cancers among the 1597 women, leading to an incidence rate of 5.6

ADCETRIS® (brentuximab vedotin) was studied in 58 patients with sALCL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks.

Median duration of treatment was 24 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, anemia, peripheral sensory neuropathy, fatigue, nausea, pyrexia, rash, diarrhea, and pain. The most common serious adverse reactions experienced by patients with sALCL were septic shock (3%), supraventricular arrhythmia (3%), pain in extremity (3%), and urinary tract infection (3%).

Drug interactions In vitro data indicate that monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4/5.

Effect of other drugs on ADCETRIS

CYP3A4 Inhibitors/Inducers: MMAE is primarily metabolized by CYP3A. Co-administration of ADCETRIS with ketoconazole, a potent CYP3A4 inhibitor, increased exposure to MMAE by approximately 34%. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions. Co-administration of ADCETRIS with rifampin, a potent CYP3A4 inducer, reduced exposure to MMAE by approximately 46%.

Effect of ADCETRIS on other drugs

Co-administration of ADCETRIS did not affect exposure to midazolam, a CYP3A4 substrate. MMAE does not inhibit other CYP enzymes at relevant clinical concentrations. ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes.

Use in specific populations Pregnancy

Pregnancy Category D. There are no adequate and well-controlled studies with ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

In an embryo-fetal developmental study, pregnant rats received 2 intravenous doses of 0.3, 1, 3, or 10 mg/kg brentuximab vedotin during the period of organogenesis (once each on Pregnancy Days 6 and 13). Drug-induced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg/kg of the drug and included increased early resorption (≥99%), post-implantation loss (≥99%), decreased numbers of live fetuses, and external malformations (i.e., umbilical hernias and malrotated hindlimbs). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg/kg is approximately the same exposure in patients with HL or sALCL who received the recommended dose of 1.8 mg/kg every three weeks.

Nursing mothers

It is not known whether brentuximab vedotin 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 ADCETRIS 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 ADCETRIS have not been established in the pediatric population.

Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients.

Geriatric use

Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Safety and efficacy have not been established.

Renal impairment

The kidney is a route of excretion for MMAE. The influence of renal impairment on the pharmacokinetics of MMAE has not been determined.

Hepatic impairment

The liver is a route of clearance for MMAE. The influence of hepatic impairment on the pharmacokinetics of MMAE has not been determined.

Overdosage There is no known antidote for overdosage of ADCETRIS. In case of overdosage, the patient should be closely monitored for adverse reactions, particularly neutropenia, and supportive treatment should be administered.

Dosage and administration

Use in pregnancy

The recommended dose is 1.8 mg/kg administered only as an intravenous infusion over 30 minutes every 3 weeks. The dose for patients weighing greater than 100 kg should be calculated based on a weight of 100 kg. Do not administer as an intravenous push or bolus. Continue treatment until a maximum of 16 cycles, disease progression or unacceptable toxicity.

Adverse reactions ADCETRIS was studied as monotherapy in 160 patients in two phase 2 trials. Across both trials, the most common adverse reactions (≥10%), regardless of causality, were neutropenia, anemia, thrombocytopenia, lymphadenopathy, peripheral sensory neuropathy, peripheral motor neuropathy, headache, dizziness, fatigue, pyrexia, chills, pain, edema peripheral, upper respiratory tract infection, nausea, diarrhea, abdominal pain, vomiting, constipation, rash, pruritus, alopecia, night sweats, dry skin, cough, dyspnea, oropharyngeal pain, arthralgia, myalgia, back pain, pain in extremity, muscle spasms, insomnia, anxiety, decreased appetite and weight decreased.

ADCETRIS was studied in 102 patients with HL in a single arm clinical trial in which the recommended starting dose and schedule was 1.8 mg/kg intravenously every 3 weeks. Median duration of treatment was 27 weeks (range, 3 to 56 weeks). The most common adverse reactions (≥20%), regardless of causality, were neutropenia, peripheral sensory neuropathy, fatigue, upper respiratory tract infection, nausea, diarrhea, anemia, pyrexia, thrombocytopenia, rash, abdominal pain, cough, and vomiting.

The most common serious adverse reactions experienced by patients with HL include peripheral motor neuropathy (4%), abdominal pain (3%), pulmonary embolism (2%), pneumonitis (2%), pneumothorax (2%), pyelonephritis (2%), and pyrexia (2%).

General dosing information

Dose modification

Peripheral Neuropathy: Peripheral neuropathy should be managed using a combination of dose delay and reduction to 1.2 mg/kg. For new or worsening Grade 2 or 3 neuropathy, dosing should be held until neuropathy improves to Grade 1 or baseline and then restarted at 1.2 mg/kg. For Grade 4 peripheral neuropathy, ADCETRIS should be discontinued.

Neutropenia: Neutropenia should be managed by dose delays and reductions. The dose of ADCETRIS should be held for Grade 3 or 4 neutropenia until resolution to baseline or Grade 2 or lower. Growth factor support should be considered for subsequent cycles in patients who experience Grade 3 or 4 neutropenia. In patients with recurrent Grade 4 neutropenia despite the use of growth factors, discontinuation or dose reduction of ADCETRIS to 1.2 mg/kg may be considered.

ADCETRIS and its logo, SeaGen Secure and its logo, Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2013 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved. Printed in USA US/BVP/2011/0150c

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program (biennial mammography for women aged 50-75 years).

Stevens-Johnson syndrome has been reported with ADCETRIS. If Stevens-Johnson syndrome occurs, discontinue ADCETRIS and administer appropriate medical therapy.

There are no adequate and well-controlled studies of ADCETRIS in pregnant women. However, based on its mechanism of action and findings in animals, ADCETRIS can cause fetal harm when administered to a pregnant woman. Brentuximab vedotin caused embryo-fetal toxicities, including significantly decreased embryo viability and fetal malformations, in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with HL and sALCL. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving the drug, the patient should be apprised of the potential hazard to the fetus.

Value-Based Cancer Care

Continued from page 17 per 1000 women-years.

The cost per detected and treated cancer was €101,277 over all age categories. The costs strongly diminished as the age of the women increased, probably as a result of the higher breast cancer incidence, the researchers suggested.

The investigators calculated that screening with the MRISC study scheme (yearly mammography plus MRI and clinical breast examination every 6 months from ages 35 to 60 years) will reduce breast cancer mortality by 30%, at a cost per life-year gained of €122,208.

“Screening with MRI is most expensive in the youngest age categories, but these are also the age categories in which MRI might potentially be most useful, since breast density is often high.”

—Sepideh Saadatmand, MD

With yearly mammography and clinical breast examination alone (the standard Dutch approach), the estimated mortality reduction would be 21%, and the cost per life-year gained would be €47,940.

“Screening with MRI may improve survival for women with a familial risk for breast cancer, but it is expensive, especially in the younger age categories,” Dr Saadatmand concluded.

Breast density increases the incidence of breast cancer, whereas it decreases the sensitivity of mammography. Breast density, therefore, may be a key discriminator for selecting the optimal screening strategy for women with familial breast cancer risk, whether mammography or MRI, the investigators suggested.

A randomized controlled trial is needed to further elucidate the costeffectiveness of MRI, the investigators said. In the Familial MRI Screening Study, women aged 35 to 60 years with an estimated lifetime risk of breast cancer ≥20% as a result of family history will be randomized into 2 screening groups: yearly mammography plus clinical breast examination or yearly MRI plus clinical breast examination and mammography biennially, with mammographic density as a stratification factor. n

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

TARGET AUDIENCE

SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

SATURDAY, MAY 4, 2013

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 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

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

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 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT No. 2 I www.regonline.com/avbcc2013 Vol. 4

february 2013

*Agenda is subject to change.

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VBCC Perspective

The Importance of Prioritizing Palliative Care in Oncology: How Payers Can Assist Providers

By Ellen Licking, John Whang, MD, FACC, and Rhonda Greenapple, MSPH, Reimbursement Intelligence

T

oo often, palliative care, which was officially recognized as a medical specialty in 2006, is mistakenly thought to be synonymous with hospice care. Although palliative care includes the coordination of care for patients at the end of their lives, it more broadly aims to reduce patient suffering and is available to

all patients with serious disease. It is designed to be given alongside active care, and certain chemotherapies have important palliative properties, including reduction in pain and nausea and improved quality of life (QOL) by the use of more tolerable dosing mechanisms.

A provisional clinical opinion

1 Payers’ Approach to Pathways in Palliative Care Figure Q: How will palliative care be addressed by pathways?

50

47%

45

Respondents, %

40 35

32%

30 25 20 15

16%

10

5%

5 0

Concrete provider direction

Recommended as course of action

Referenced but with low mention only

Palliative will not be referenced in pathways

2 Anticipated Impact of ACOs on Cancer Care Figure Q: In what ways do you think an ACO can influence oncologic drug spending?

(Please rate on a scale of 1 to 5, where 1 is minimal influence and 5 is strong influence.)

4.2

Clinical pathways Coordination of care

4.4

Conservative use of supportive care therapies

3.9

Palliative care

4.0 3.6

Ancillary care

3.4

Early diagnosis Prevention 1.0

3.2

1.5

2.0

2.5 3.0 3.5 Mean rating

4.0

ACO indicates accountable care organization.

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FEBRuary 2013

4.5

5.0

published by the American Society of Clinical Oncology (ASCO) in February 2012 recommends integrating palliative care services into standard oncology practice at the time a person is diagnosed with metastatic cancer.1 Payers have taken notice. Based on recent survey data from Reimburse­ ment Intelligence (RI), payers see an opportunity to assist physicians in promoting palliative care via new tools, mainly evidence-based clinical pathways. Payers also see an opportunity to change compensation incentives so that providers are not financially penalized for offering patients palliative care options when appropriate.

Palliative Care: Reducing Cost and Extending Life The high cost associated with endof-life care is a major driver in healthcare spending in oncology, with an estimated 20% to 35% of cancer patients receiving chemotherapy in the last 14 days of life.2,3 Numerous randomized clinical trials show that when palliative care services are encouraged alongside standard oncology care, patient QOL (including overall mood and symptoms) improves, while treatment costs decline by as much as $4900 per patient.4 Indeed, a 2011 study by Temel and colleagues showed that palliative care, in addition to standard cancer care, allowed patients to live almost 3 months longer than patients who received usual care.5 In addition to advancing a provisional clinical opinion on palliative care, ASCO has taken an impor­ tant step in supporting the practice through its Quality Oncology Practice Initiative (QOPI) and by its participation in the Choosing Wisely campaign. An oncology practice–based quality improvement program, QOPI aims to improve cancer care by creating a culture of self-examination through chart review and benchmarking against peers. Such feedback is extremely effective in promoting the use of palliative care. When physicians at the University of Michigan were given feedback about their use of chemotherapy to treat patients with 2 weeks or less to live, the use of active therapy during this interval dropped from 50% to 20% in one quarter.6

How Payers Can Promote Palliative Care Payers, meantime, are eager to find politically acceptable ways to improve the management of end-of-life cancer care and reduce costs. When RI surveyed 49 payer executives representing 100 million US lives about their oncology management strategies in late summer 2012, 95% stated that they would use evidence-based clinical pathways to promote palliative care.

Actual implementation remains a crucial question, however, with payers split on how strongly these pathways would emphasize such practices. Nevertheless, 47% of executives surveyed noted that pathways language would include concrete direction for the appropriate transition to palliative care (Figure 1).

It is important to recognize that many of these programs are still in pilot mode and have yet to be broadly adopted by community oncologists. Moreover, there are significant adoption hurdles to overcome since oncologists are trained not to give up on patients and will default to recommending additional lines of therapy.

Indeed, at ASCO’s inaugural Quality Care Symposium in December 2012, Hui and colleagues reported that even at top-tier cancer centers like M.D. Anderson, palliative care is significantly underutilized, with a majority of patients (55%) not accessing palliative care services before death.7 Based on the recent RI survey, payers believe that new care delivery structures such as accountable care organizations (ACOs) and oncology medical homes can assist in changing provider treatment patterns. When payers were asked to rank on a scale of 1 (minimal impact) to 5 (strong impact) where ACOs would have the greatest influence on oncology care, greater utilization of palliative care was among the top-rated categories, alongside pathways, coordination of care, and a reduced need for supportive care therapies (Figure 2).

This suggests that the adoption of ACOs and pathways will mutually reinforce the emphasis on palliative care. As providers standardize practice patterns via clinical pathways that create direct prompts to transition patients to palliative care, the highly coordinated care teams working in Continued on page 21

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3 Health Plans’ Financial Incentives to Providers Figure

4 Comparing National and Regional Plans’ Financial Incentives to Providers Figure Q: Does your plan provide financial incentives to providers for any of the following? Please check all that apply.

Q: Does your plan provide financial incentives to providers for any of the following? Please check all that apply.

None

60%

Earlier palliative care counseling

None

60% 50%

10%

More conservative use of supportive care therapies (eg, colony-stimulating factors) Increased utilization of generics 10

20

30

40

50

60

70

Large

11%

More conservative use of supportive care therapies (eg, colony-stimulating factors)

40%

17% 22%

Increased utilization of generics 0%

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17%

Respondents, %

ACOs enable the transition from active treatment to palliation to occur.

Although pathway adoption and care coordination are good first steps, payers who want to lead in this arena must also create new reimbursement schemes to compensate physicians for the time spent on educating patients and family members about palliative care options. Such strategies move physicians away from the fee-forservice paradigm that rewards doctors for prescribing costly medicines and puts greater emphasis on compensating for cognition rather than script-writing.

In 2010, UnitedHealthcare, working with 5 community oncology offices, instituted an episode-of-care–based program in 19 discrete tumor types.8 (It has since expanded the program to include an additional oncology practice.) The resulting changes in practice patterns have yet to be published in a peer-reviewed journal.

However, participating practices clearly see a link between such changed incentives and increased use of palliative care. “Where it is most helpful is in enabling tough decisions regarding palliative care,” says John Hennessy, executive director of the Kansas City Cancer Center. “It allows us to be economically indifferent to the patient’s choice, whether that is to continue therapy, take a treatment holiday, or enter hospice. In a traditional fee-forservice environment, our economics

Plan size

20%

Medium

25%

0

0%

Earlier palliative care counseling

20%

67%

prioritize continuing therapy.”

Initiatives such as UnitedHealth­ care’s (and smaller pilots by the likes of Michigan’s Priority Health) are far from mainstream. Some 60% of payers surveyed by RI report that they do not currently provide financial in-

Payers can assist nonprofit organizations such as ASCO and the National Comprehensive Cancer Network in prioritizing palliative care, by encouraging providers to adopt evidence-based clinical pathways that support such services.

centives for providers that adhere to cost-management principles. Still, we are cautiously optimistic that payers are revamping their administrative and information technology systems to process claims via episode or bundled mechanisms.

Indeed, based on RI’s survey data, 25% of plans already link financial incentives to increased use of generics, and 10% incentivize earlier palliative care counseling (Figure 3). Of note,

50%

0

10

20

national plans, as opposed to smaller, regional payers, are more likely to adopt this approach (Figure 4).

Payers believe that drug manufacturers can also assist in driving palliative care use. Based on our survey, 73% of payers believe that manufacturers could support specific provider education efforts tied to the palliative properties of the drugs they manufacture. More than 60% believe manufacturers can play a role in broader palliative awareness-building initiatives (data not shown).

Conclusion The current political climate and the use of polarizing terminology such as “death panels” highlights the breadth of the misunderstanding of what palliative care is—and what it is not. Payers can assist nonprofit organizations such as ASCO and the National Comprehensive Cancer Network in prioritizing palliative care, by encouraging providers to adopt evidence-based clinical pathways that support such services.

New reimbursement schemes that do not penalize physicians for providing earlier palliative care are also essential. Our survey data suggest payers are eager to work with for-

FEBRuary 2013

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30 40 50 Respondents, %

60

70

ward-thinking providers to institute such programs, because they offer an important means of holding the line on rapidly rising oncology costs while offering highquality—if not superior—care to patients. n References

1. Smith TJ, Temin S, Alesi ER, et al. American Society of Clinical Oncology provisional clinical opinion: the integration of palliative care into standard oncology care. J Clin Oncol. 2012;30:880-887.

2. Wennberg JE, Fisher ES, Goodman DC, Skinner JS. Tracking the Care of Patients with Severe Chronic Illness: The Dartmouth Atlas of Health Care 2008. The Dartmouth Institute for Health Policy and Clinical Practice, Lebanon, NH. 3. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742.

4. Morrison RS, Penrod JD, Cassel JB, et al. Cost savings associated with US hospital palliative care consultation programs. Arch Intern Med. 2008;168:17831790.

5. Temel JS, Greer JA, Admane S, et al. Longitudinal perceptions of prognosis and goals of therapy in patients with metastatic non-small-cell lung cancer: results of a randomized study of early palliative care.

J Clin Oncol. 2011;29:2319-2326.

6. Blayney DW, McNiff K, Hanauer D, et al.

Implementation of the Quality Oncology Practice initiative at a university comprehensive care center.

J Clin Oncol. 2009;27:3802-3807.

7. Hui D, Kim SH, Kwon JH, et al. Access to palliative care among patients treated at a comprehensive cancer center. Oncologist. 2012;17:1574-1580.

8. Newcomer LN. Changing physician incentives for cancer care to reward better patient outcomes instead of use of more costly drugs. Health Aff. 2012;31:780785.

www.ValueBasedCancerCare.com

21

Making

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

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment benefits in clinical trials.2,3 Use of a PRO instrument can 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.

Incorporating PROs into a clinical trial program provides a means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make betterinformed decisions.4

Myelofibrosis (MF) is a life-threatening, progressive disease 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, double-blind placebo-controlled study, COMFORT-I, for Jakafi. Spleen reduction, as measured by imaging (MRI or CT), was the primary and biologic endpoint, and a reduction in total symptom score (TSS), the PRO measure, was a key secondary 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 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse 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 • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/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 • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

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 patient’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 patient’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 MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients 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 academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi 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 • Women taking Jakafi should not breast-feed. Discontinue 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 ≥35% 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 ≥50% 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 “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the 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. © 2012, Incyte Corporation. All rights reserved.

RUX-1130A 05/12

Personalized Medicine

Molecular Assays Reclassify Early Breast Cancer Type

By Phoebe Starr

San Antonio, TX—Molecular subtyping which has the potential to guide the of early breast cancers using Mamma­ selection of personalized therapy if the 1INC007Print JK0 BS 12P_Layout 1 11/16/11 AM the Page 1 tests are used prospectively. and BluePrint assays 9:16 allows precise and accurate prediction of the “The use of MammaPrint and molecular phenotype of the disease, BluePrint should be implemented in

the management of primary breast cancer for the selection of adjuvant therapy in the era of personalized care,” said lead investigator Massimo Cristofanilli, MD, FACP, Chair, De­

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 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). a Reactions Grades 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. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: November 2011 RUX-1040

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partment of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, at the 2012 San Antonio Breast Cancer Symposium.

A retrospective study of 208 tumor samples found that molecular subtyping with these 2 assays led to reclassification of 25% of the tumors, which would have been treated differently if the tests were applied prospectively.

“The use of MammaPrint and BluePrint should be implemented in the management of primary breast cancer for the selection of adjuvant therapy in the era of personalized care.”

—Massimo Cristofanilli, MD, FACP The study used frozen tumor samples from 208 patients. Of the patients, 59% were hormone receptor positive (estrogen receptor [ER]/progesterone receptor [PR]+), 20% were HER2 positive, and 24% were triple negative by locally assessed immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). All patients under­went lumpectomy or mastectomy with axillary staging.

The microarray-based assays included BluePrint and MammaPrint.

BluePrint is an 80-gene assay that discriminates between luminal-type, basal-type, and HER2-type breast cancer. MammaPrint is a 70-gene assay that substratifies luminal-type breast cancer into low-risk luminal A and high-risk luminal B breast cancers.

Breaking down the results of molecular subtyping showed that 13 of 188 (11%) tumors that were ER+, PR+, or HER2 negative are not classified as luminal type by BluePrint; 24 of 41 (61%) clinically HER2-positive patients are not classified as HER2 type

by BluePrint; and 10 of 49 (20%) triple-negative tumors are not classified as basal type by BluePrint.

Of the total patients, 51 were reclassified as a result of molecular subtyping. Of these, 28 patients were reassessed centrally for ER, PR, and HER2 status by IHC and FISH. The patients with luminal-type early breast cancer that was identified by BluePrint have excellent relapse-free survival rates of 97% for patients with luminal A cancer and 98% for patients with luminal B cancer. n

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Personalized Medicine

A New Multigene Score Identifies Women with ER-Positive Breast Cancer at Risk for Late Metastases Can help select therapeutic choices in a subgroup of patients

By Phoebe Starr San Antonio, TX—A multigene score called EndoPredict can help to identify women with estrogen receptor (ER)-positive/HER2-negative breast cancer who are likely to develop metastatic disease in the long-term.

EndoPredict is different from other multigene assays in its ability to predict late, rather than earlier, metastases, noted lead investigator Peter C. Dubsky, MD, Associate Professor, Department of Surgery, Medical University of Vienna, Austria, who presented results of a recent study at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

“Oncotype DX and other predictive tests that rely on genetic signatures are used to predict earlier recurrence within the first 5 years,” Dr Dubsky said. “It is important to be able to predict risk of late recurrence for ERpositive breast cancer, because after 5 to 10 years of follow-up, mortality rates are higher for ER-positive than for ER-negative breast cancer,” Dr Dubsky noted.

The test is not yet approved in the

United States. If these results are validated, then a low EndoPredict score could indicate the women who are able to forgo extended antihormonal therapy.

Unlike other multigene tests that are based solely on the molecular fingerprint of a tumor, the EndoPredict score factors in tumor biology data that are derived from tumor size and nodal status along with gene expression for 8 genes (3 proliferation genes and 5 ER-dependent genes) and 3 reference genes, similar to the techniques used in the Oncotype DX assay.

Study Results The study was conducted on paraffin-embedded tumor tissue from 1702 postmenopausal women with ER-positive/HER2-negative breast cancer who participated in 2 randomized trials, the Austrian Breast Cancer Study Group (ABCSG)-6 and ABCSG8. Of the total women, 33% had nodepositive disease. None of the women received adjuvant chemotherapy, but all of them were treated with some

form of hormonal therapy for 5 years, including tamoxifen (Nolvadex) alone or a sequence of tamoxifen and an aromatase inhibitor. The median age was 64 years.

“The entire cohort was low-tointermediate [clinical] risk,” Dr Dubsky stated.

“It is important to be able to predict risk of late recurrence for ER-positive breast cancer, because after 5 to 10 years of follow-up, mortality rates are higher for ER-positive than for ER-negative breast cancer.”

—Peter C. Dubsky, MD Using a predefined EndoPredict clinical score that combined the EndoPredict with nodal status and tumor size, 64% of the patients were determined to be at low risk for distant metastases according to a low EndoPredict score; 98.2% of these

Women with Triple-Negative Breast Cancer Very Likely to Carry BRCA1 Gene San Antonio, TX—Triple-negative breast cancer (TNBC) was strongly associated with BRCA1 status, but not with BRCA2 status, in a large study of medically insured women. The study showed that the number of patients with BRCA mutations with a TNBC profile is statistically significant.

Findings from a poster presented at the 2012 Annual CTRC-AACR San Antonio Breast Cancer Symposium suggest that patients with TNBC should be referred to a genetics counselor for further evaluation and possible genetic testing.

Women with TNBC are thought to be more likely to be BRCA carriers, but it is controversial whether newly diagnosed women with TNBC should be referred for genetic counseling. The recommendation for genetic counseling in this group of patients rests only on studies with small numbers of BRCA carriers. Thus, there is no clear guideline, explained lead author Reina

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Haque, PhD, MPH, a research scientist at the Department of Research and Development, Kaiser Permanente Southern California, Pasadena.

The study was conducted by investigators at Kaiser Permanente, a large health plan with >3.5 million diverse members at >200 medical centers throughout southern California.

The study was based on a retrospective cohort of 2105 women with breast cancer who were tested for BRCA mutations between 1997 and 2011.

The BRCA results were reported in the health plan’s clinical genetics registry.

Of the 2105 patients with breast cancer, 249 were carriers of a BRCA mutation; there were 143 BRCA1 carriers and 106 BRCA2 carriers.

Data linkages were performed for all patients with the National Cancer Institute-SEER (Surveillance, Epidemiology and End Results)–affiliated tumor registry; estrogen receptor (ER), progesterone receptor (PR),

and HER2 statuses were captured and were assessed by immunohistochemical or fluorescence in situ hybridization techniques. Patients were classified into the 2 main biologic subtypes of TNBC (ER-negative, PR-negative, HER2-negative) and non-TNBC (luminal A, luminal B, and HER2-enriched).

The association between TNBC and non-TNBC and BRCA1 or BRCA2 mutation status was examined.

The TNBC subtype was strongly correlated with BRCA status (P <.001).

Women with TNBC tumors were 5 times more likely to be BRCA carriers than women with non-TNBC tumors (odds ratio [OR], 5.6; 95% confidence interval [CI], 4.1-7.5).

The association between TNBC and BRCA1 was more robust (OR, 12.2; 95% CI, 8.3-17.9), and was unchanged after adjusting for age, stage at diagnosis, and race or ethnicity. TNBC was not associated with BRCA2 status (OR, 1.6; 95% CI, 0.9-2.7).

FEBRuary 2013

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women were free of distant metastases at 10 years and were 5 times less likely to remain free of distant metastases at 10 years than the 33% of women with a high EndoPredict score.

Further analysis showed that the proliferation genes added independent negative prognostic information for early recurrence, whereas the genes associated with ER signaling added independent prognostic information for late recurrence.

Clinical Implications Discussing the importance of the findings, Dr Dubsky noted, “We currently have around 20,000 women in ongoing extended/late endocrine therapy clinical trials….We see very low rates, and the efficacy data of these trials is unlikely to make individual decisions for women very simple.” He believes that “gene expression data may help establish patient subgroups with a very excellent prognosis and thus facilitate the therapeutic choice.”

EndoPredict is currently available for diagnostic use in Austria and Switzerland. Expanded studies are ongoing. n

at a glance ➤ Women with TNBC are thought to be more likely to be BRCA carriers ➤ Whether newly diagnosed women with TNBC should be referred for genetic counseling is controversial ➤ New findings suggest these patients should be referred for genetic counseling and possibly genetic testing ➤ The TNBC subtype was strongly correlated with BRCA status (P <.001) ➤ Women with TNBC tumors were 5 times more likely to be BRCA carriers than women with non-TNBC tumors These findings in a large sample of women suggest that patients with TNBC should be referred for further evaluation and for genetic testing, because results may inform treatment choice.—PS n

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Prostate Cancer

Exploring Men’s Willingness to Pay for Prostate Cancer Screening...

Continued from cover

“Physicians should be aware that men, particularly those with less education, may overestimate the benefit of prostate cancer screening, due to numeracy problems...and that therefore tailored prostate cancer screening programs may result in a betterinformed shared decision-making for screening,” wrote Esther W. de Bekker-Grob, PhD, a researcher and health economist at Erasmus Medical Center, Rotterdam, the Netherlands, and her colleagues (de Bekker-Grob EW, et al. Br J Cancer. 2013 Jan 29 [Epub ahead of print]).

“Increasing knowledge on overdiagnosis and overtreatment, especially for men with lower educational levels, is warranted to prevent unrealistic expectations from prostate cancer screening,” she continued.

The team formulated 2 versions of a questionnaire containing 16 choice sets on prostate cancer screening.

These were based on the prostate cancer screening literature and interviews

with 8 prostate cancer experts. A total of 459 men (average age, 63.3 years) from southwest Holland responded to the questionnaires.

The researchers divided the men into 3 groups: • Most men in the first group had a lower educational level, did not have anxiety or depression, and were willing to pay for prostate cancer screening • Most men in the second group also had a lower educational level and did not have anxiety or depression, but they were not willing to pay for screening • The third group largely comprised men who had a higher educational level, had anxiety or depression, and were not willing to pay for prostate cancer screening.

The men in all 3 groups indicated that a reduction in the risk of developing prostate cancer, a reduction in the risk of unnecessary treatment and biopsy, and costs are all important.

Those in the first group had a preference for annual or biennial screen-

“Physicians should be aware that men, particularly those with less education, may overestimate the benefit of prostate cancer screening.”

—Esther W. de Bekker-Grob, PhD ing, those in the second group did not have a preference for shorter or for longer screening intervals, and members of the third group preferred screening every 2 years versus screening every 4 years.

Willingness to Pay When all 3 groups were combined, the men were willing to pay an

average cost of: • €188 (or $245 US) for a 10% reduction in prostate cancer–related death • €33 ($43 US) annually for a 10% reduction in the risk of an unnecessary prostate biopsy • €38 ($50 US) annually for a 10% decrease in the risk of undergoing unnecessary treatment • €87 ($115 US) annually to access a prostate cancer screening program with a 2-year interval rather than a 4-year interval.

In addition, the men were willing to exchange 2% of the reduced risk of prostate cancer mortality for a 10% reduction in unnecessary treatment.

They were also willing to trade 1.8% of their reduced mortality risk for a 10% reduction in the probability of an unnecessary biopsy, and a 4.6% reduced risk of prostate cancer– related death for a 2-year screening interval rather than a 4-year screening interval. n

Preventive Therapy Preserves Sexual Function after Radiotherapy for Patients with Prostate Cancer

By Charles Bankhead

Boston, MA—Patients with prostate cancer reported significantly better sexual function for up to 2 years after radiation therapy when they took sildenafil (Viagra) on a daily basis during and after treatment, according to results of a placebo-controlled clinical trial.

Scores on the erectile function domain of the International Index of Erectile Function (IIEF) remained significantly better with sildenafil compared with placebo throughout the follow-up.

The findings are consistent with those reported for patients who underwent surgery for localized pros­­ tate cancer, Michael J. Zelefsky, MD, Vice Chair for Clinical Research in Radiation Oncology at Memorial Sloan-Kettering Cancer Center in New York, reported at the 2012 American Society for Radiation Oncology meeting.

“This is the first randomized, controlled trial demonstrating a benefit for pharmacologic intervention in a preventive mode—penile rehabilitation—in the treatment of patients who

26

receive radiation for prostate cancer,” said Dr Zelefsky.

Previous studies showed that sildenafil (and other members of the phos-

“This is the first randomized, controlled trial demonstrating a benefit for pharmacologic intervention in a preventive mode—penile rehabilitation— in the treatment of patients who receive radiation for prostate cancer.”

—Michael J. Zelefsky, MD

phodiesterase type-5 inhibitor class) leads to restoration of potency after definitive radiation therapy for prostate cancer in 60% to 70% of men. The success rate reflects the use of the drug as needed after treatment.

The concept of preventive therapy had not been evaluated in men treat-

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ed with radiation therapy. To test the concept, investigators enrolled 290 men with localized prostate cancer who were treated with external-beam radiation therapy, brachytherapy, or a combination of the 2 treatments.

Patients were randomized in a 2:1 ratio to sildenafil 50 mg daily or to placebo, beginning 3 days before treatment and continuing through 6 months after the treatment. Patients then switched to as-needed dosing.

Eligible patients had an IIEF score of ≥7, representing good sexual function at baseline.

The trial investigators randomized 295 patients, who were followed at 3-month intervals for a year and thereafter at 6 and 24 months. The patients completed the IIEF at each follow-up visit. The study population included 31 men who received short-course androgen deprivation therapy. None of the men benefited from preventive treatment with sildenafil, so they were excluded from analysis.

The final analysis comprised 142 men who completed the pretreatment IIEF survey and at least 1 posttreat-

ment survey. The primary end point was total IIEF score and scores on the individual domains of the scale.

The IIEF total score was significantly higher in the patients receiving sildenafil versus those receiving placebo at 6 months after definitive radiation therapy (58.6 vs 49.4, respectively; P = .006), as well as at 12 months and 24 months.

The group receiving sildenafil also had a significant improvement in total International Prostate Symptom Scale score versus the group receiving a placebo (P <.001).

These findings make preventive treatment with phosphodiesterase type 5 a new standard of care “for the time being,” said invited discussant Thomas M. Pisansky, MD, Professor of Radiation Oncology at the Mayo Clinic in Rochester, MN. Although more study is needed to confirm the results, the workup and follow-up of patients with prostate cancer who are treated with radiation therapy should include a validated assessment of sexual function, such as the IIEF, he added. n

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5/9/12 10:09 PM

Health Policy

Time to Review Practice Policies: HIPAA Privacy and Security Regulations Released

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

Mr Margulies is an Associate at Foley Hoag, LLP, Washington, DC; Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC

O

n January 17, 2013, nearly 3 years after its initial proposed rule, the US Department of Health and Human Services (HHS) issued the long-awaited and muchanticipated HIPAA “omnibus” rule, extending the scope of the privacy law beyond providers to their business associates and subcontractors and adding increased penalties.1 Regulated entities must be in compliance with the new rules by September 22, 2013, although covered entities and business associates will have up to 1 year after the 180-day compliance date to modify existing contracts to comply with these revised rules. Oncology practices should begin examining their policies now to ensure a seamless transition to these new rules.

Among the most dramatic changes to existing law is that HIPAA’s privacy and security requirements will now

Ross D. Margulies

Jayson Slotnik

Among the most dramatic changes to existing law is that HIPAA’s privacy and security requirements will now directly apply to business associates. directly apply to business associates.

Business associates will now include health information organizations, e-prescribing gateways, other entities

that provide data transmission services for covered entities and that require access on a routine basis, entities that offer a personal health record to individuals on behalf of a covered entity, and subcontractors. Penalties for noncompliance will range depending on the degree of culpability, including the number of individuals affected and whether there is a history of noncompliance.

Central to the new regulations (which total a whopping 563 pages) is the sharing of patient-protected health information (PHI). Patients are given new control over their PHI, including allowing patients to request a copy of their electronic medical record in an electronic format and permitting patients to instruct their provider not to share information about treatment with their health plan when the individual pays for that care out of pocket.

In addition, the final rule expands the definition of a “breach” under HIPAA, thus eliminating the “harm” standard, which previously allowed entities to avoid breach notification if they could demonstrate that the breach posed no significant risk of harm to the individual. Under the new rule, any impermissible use or disclosure of PHI is presumed a breach, unless a low probability that information has been compromised can be demonstrated.

Oncology practices are now tasked with the arduous effort of implementing what the HHS is calling “the most sweeping changes to the HIPAA privacy and security rules since they were first implemented.”1 n Reference

1.US Department of Health and Human Services. New Rule Protects Patient Privacy, Secures Health Infor­ma­ tion. Press Release. January 17, 2013. www.hhs.gov/ news/press/2013 pres/01/20130117b.html. Accessed February 2, 2013.

Prostate Cancer

Is Fatherhood a Risk Factor for Prostate Cancer?

By Rosemary Frei, MSc

S

ocioeconomic status and other nonphysiologic factors may be largely responsible for the apparent association between having fathered a child and an increased risk for prostate cancer, Swedish researchers have concluded.

They analyzed data from the National Prostate Cancer Register of Sweden and found that, although childless men had a significantly lower risk of prostate cancer than fathers, this association was attenuated when they took into account marital status and educational level.

The unadjusted odds ratio (OR) of developing cancer among childless men compared with fathers was 0.71 for cancers diagnosed by prostatespecific antigen (PSA) testing, and after adjustment it was 0.86. The ORs for cancers detected as a result of symptoms were 0.86 and 0.90, respectively.

“Our data indicate that the association between fatherhood status and prostate cancer is due to a large extent to socioeconomic factors influencing healthcare-seeking behavior, including testing of PSA levels, and that the re-

28

maining association may be due to confounding factors,” concluded lead investigator Pär Stattin, MD, PhD,

“Our data indicate that the association between fatherhood status and prostate cancer is due to a large extent to socioeconomic factors influencing healthcareseeking behavior, including testing of PSA levels, and that the remaining association may be due to confounding factors.”

—Pär Stattin, MD, PhD Department of Urology, Umeå Uni­ versity, Sweden, and colleagues in a new study (Wirén SM, et al. Int J Cancer.

2013 Jan 25 [Epub ahead of print]).

The investigators analyzed data

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from 117,328 men with prostate cancer and 562,644 without prostate cancer. They found an OR of 0.83 for prostate cancer among childless men compared with fathers in a univariate analysis. When the researchers then focused only on low-risk, localized tumors, they found the OR was even lower (0.74), whereas for metastatic cancer it was higher (0.93). After adjusting for marital status and educational level in a multivariate analysis, the team found that the overall OR for prostate cancer increased to 0.91 for childless men versus for fathers.

The respective adjusted ORs for lowrisk cancer and for metastatic disease were 0.87 and 0.92.

Married men had an unadjusted OR of 1.31 for prostate cancer, whereas divorced men had an unadjusted OR of 1.19.

Overall, men with more education had an unadjusted OR of 1.16 compared with men with less education.

There was a stronger association for low-risk tumors but a slightly weaker association for metastatic prostate cancer.

In addition, an unadjusted analysis

indicated men without children had an OR of 0.71 for cancer diagnosed

by PSA testing and of 0.86 for cancer detected from symptoms. These associations were attenuated in the adjusted analysis.

The team also found, overall, that the lowest OR for developing prostate cancer was in childless men with a low educational level. In a separate analysis, they found the association between fatherhood status and the risk of prostate cancer was stronger for low-risk tumors among men with a low educational level than among those with a high educational level.

“These associations are likely due to a higher uptake of PSA testing among married men and men with high educational levels,” the researchers concluded. That is, the results reflect propensity to obtain a diagnosis.

The extent to which the small remaining reduction in risk for cancer among childless men after adjustment for marital status and education is a result of residual confounding factors “cannot be elucidated by use of our data.” n

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SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

DESIGNATION OF CREDIT STATEMENTS SPONSORS

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. 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.

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Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 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 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

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ASH 2012 Highlights

Ruxolitinib Treatment Reduces Myelofibrosis Symptoms, Spleen Size

By Wayne Kuznar

Atlanta, GA—Ruxolitinib (Jakafi) alleviates symptoms such as fever, headache, weight loss, and fatigue, and reduces spleen size in patients with myelofibrosis. This finding, by the French Intergroup of Myeloproliferative Neoplasms (FIM), confirms those from the COMFORT-I and COMFORT-II trials, in which significant reductions in spleen volume were observed with ruxolitinib at weeks 24 and 48.

Ruxolitinib was approved by the US Food and Drug Administration in 2011 for the treatment of intermediate and high-risk myelofibrosis.

This analysis, led by Annalisa Andreoli, MD, Centre d’Investigations Cliniques, Hôpital Saint-Louis, Paris, France, included 241 patients with myelofibrosis, including primary myelofibrosis, postpolycythemia vera, and postessential thrombocythemia.

The patients received ruxolitinib via the Authorization for Temporary Utilization program, a French compassion-based patient initiative. Treat­ ment data were gathered at 3-month intervals over 1 year.

Almost all (99.2%) patients were receiving ≥1 therapies for myelofibrosis before taking ruxolitinib. Those therapies included hydroxycarbamide (Hydrea; 90.6%), pipobroman (Vercite 18.4%), immunomodulator drugs (17.1%), interferons (19.2%), erythropoietin (6.9%), splenic irradiation (6.9%), and corticosteroids (4.8%).

“Although the majority of patients were taking other treatments, 93.9% of patients still continued to experience constitutional symptoms, such as fever, malaise, or weight loss; in addition, 94.3% of patients had an evident enlarged spleen [median 15 cm <costal margin] at study start,” Dr Andreoli said.

Infection Poses Lethal... than in controls during the first year after diagnosis of multiple myeloma,” said Dr Blimark.

Infection risk doubled from the 1986-1993 period to the 2000-2004 period, raising questions about the possible contributions of modern myeloma therapy to the risk of infection.

“The increasing risk we observed in later years calls for more studies concerning new strategies regarding infectious complications and their prevention,” said Dr Blimark.

This first study of its kind was a large, population-based investigation of the magnitude of infection risk in patients with myeloma.

Infection has long been recognized as a major cause of morbidity and mortality in this patient population, but the extent of the risk had not been previously characterized.

The data came from the Swedish national cancer registry and included 9610 patients who had newly diagnosed multiple myeloma between 1988 and 2004. For each patient, investigators identified 4 individuals without myeloma who were matched for age, sex, and county of residence. The follow-up continued through 2007.

The results showed that 22% of the patients with myeloma died of infection during the first year after

30

Continued from cover

diagnosis. In addition, the patients had an infection hazard almost 12 times greater than that of the control group, including hazard ratios (HRs) of 11.0 for bacterial infections and 18.0 for viral infections.

Throughout the entire study, patients with myeloma had an infection

“We found the risk of specific infections to be more than 10 times higher in patients [with myeloma] than in controls.”

—Cecilie Blimark, MD HR of 7.1 versus the control group.

Overall HR was 7.0 for bacterial infections and 9.0 for viral infections.

The greatest differentials in HRs included those for meningitis (HR, 16.6), septicemia (HR, 15.6), and herpes zoster (HR, 14.8); other significant differences (P <.05) involved bacterial pneumonia (HR, 7.7), viral influenza (HR, 6.1), endocarditis (HR, 5.3), osteomyelitis (HR, 3.5), cellulitis (HR, 3.0), and pyelonephritis (HR, 2.9). n

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Treatment with ruxolitinib was started in 132 patients at 15 mg twice daily and in 103 patients at 20 mg

“Although the majority of patients were taking other treatments, 93.9% of patients still continued to experience constitutional symptoms, such as fever, malaise, or weight loss; in addition, 94.3% of patients had an evident enlarged spleen at study start.”

—Annalisa Andreoli, MD twice daily; 6 patients started the drug at other doses.

A mean reduced palpable spleen size was seen in 91.1% of patients at 3 months of treatment and in 83.3% at 6 months.

Constitutional-related symptoms were cleared in 65.3% of patients at 3 months and 70.2% at 6 months. The 21 patients who had 9 months of treatment had a reduction in spleen size and sustained reduced symptoms.

A total of 105 patients had ≥1 adverse event (AE), 33 of whom had severe AEs. The AEs associated with ruxolitinib therapy included hematologic conditions (56.8%), gastrointestinal (5.1%), and cardiac events (2.3%).

Hematologic AEs included thrombocytopenia in 60 patients, anemia in 37, and neutropenia in 3 patients.

Overall, 60 patients had dose changes, primarily as a result of thrombocytopenia (n = 36) and anemia (n = 13).

In addition, 18 patients stopped treatment (including 7 deaths). n

Second-Line Rituximab Maintenance for Follicular Lymphoma Cost-Effective

By Caroline Helwick

Atlanta, GA—Dutch investigators found that rituximab (Rituxan) maintenance in the second-line treatment of patients with follicular lymphoma (FL) was cost-effective, as reported at the 2012 American Society of Hematology meeting.

“Outcomes research was conducted to calculate the real-world costeffectiveness of second-line rituximab maintenance compared to observation in FL patients in the Netherlands,” said Hedwig M. Blommestein, MD, Institute for Medical Technology Assessment, Institute of Health Policy & Management, Erasmus University in Rotterdam, the Netherlands.

Two Dutch population-based registries were used to obtain data on patient characteristics, treatment, and resource utilization of patients diagnosed with FL in the past 20 years.

Patients responding to second-line chemotherapy were included in the observation or in the maintenance groups. A Markov model using only daily practice data was applied to calculate real-world cost-effectiveness.

Of 735 patients with FL, 57 pa-

tients met the criteria for the observation group and 49 were evaluated for maintenance. The researchers found that the maintenance group received significantly more rituximab in the second line, were evaluable a longer time from diagnosis, had significantly better 3-year overall survival (OS), and had significantly longer time until their next treatment. Three-year OS was 75% for the maintenance group versus 63% for the observation arm (P <.01), Dr Blommestein reported.

Daily practice data resulted in cost-effectiveness ratios of €5512 per quality-adjusted life-year (QALY) in the maintenance arm and €5669 per QALY with observation.

“Real-world FL patients are not identical to trial patients, which emphasizes the importance of studying real-world data,” Dr Blommestein noted. Although findings from nonrandomized groups should be analyzed with caution, he said, adding, “Nevertheless, real-world cost-effectiveness for second-line rituximab maintenance was favorable in our study.” n

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Breast Cancer

Drugs to Reduce Breast Cancer Risk Are Rarely Used Show Data from Geisinger Health System

By Caroline Helwick

San Antonio, TX—The uptake of US Food and Drug Administration (FDA)-approved drugs for risk reduction of breast cancer is still poor, as was confirmed by a study using the electronic health records (EHRs) from Geisinger Health System in Danville, PA. The researchers described the process of identifying women who are at increased risk for breast cancer and the use of risk-reducing drugs at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

Women who are at increased risk for breast cancer are eligible to take selective estrogen receptor modulators (SERMs) to reduce their risk.

The American Society of Clinical Oncology recommends that the 2 FDA-approved SERMs, tamoxifen (Nolvadex) and raloxifene (Evista), be considered for women aged >35 years who have a 5-year risk of 1.67% or greater, “but identifying those women can be both challenging and costly,”

said Joseph B. Leader, BA, Research Data Manager at Geisinger Health System.

“We used an electronic database from the Geisinger Health System Department of Radiology, with 77,000 women ages 35 to 90 years, to calculate the 5-year and lifetime risks of developing invasive breast cancer,” he said. They employed the National Cancer Institute Breast Cancer Risk Assessment macro, which calculates risk based on age, number of biopsies, presence of atypical hyperplasia, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and race. Demographic information was obtained from their EHR system.

A total of 5897 patients (mean age, 65.8 years) met the criteria for risk, including 1728 women with a 5-year risk of 2% to 2.5%, another 3188 with a risk of 2.5% to 3%, and 981 with a risk of ≥3%. The mean 5-year risk for the

at-risk population was 3.05% (maximum, 18.2%).

“These data from an integrated health system with an EHR closely reflect published national statistics that show the uptake of FDA-approved drugs for breast cancer risk reduction has been poor.”

—Joseph B. Leader, BA

Of all the patients, 4196 had a primary care physician (PCP), and 4113 had seen their PCP within the past year. Altogether, 5086 patients had seen any Geisinger physician within the past year.

Despite this access to a physician, only 239 at-risk patients had ever received a prescription for tamoxifen or raloxifene, and some received raloxifene for the prevention or treatment of osteoporosis and not for breast cancer risk reduction. “Only 40 women were currently taking tamoxifen or raloxifene,” Mr Leader reported.

“These data from an integrated health system with an EHR closely reflect published national statistics that show the uptake of FDA-approved drugs for breast cancer risk reduction has been poor, following the FDA approval of both tamoxifen and raloxifene for breast cancer risk reduction,” he said.

Strategies are being designed to increase the use of tamoxifen and raloxifene within the Geisinger health plan by using the risk score to identify the population and to attempt to intervene using a risk modification clinical program, Mr Leader noted. n

Real-World Evidence Shows Impact of Musculoskeletal Toxicity of Aromatase Inhibitors on Women with Breast Cancer

By Phoebe Starr

San Antonio, TX—Studies have suggested that musculoskeletal toxicity associated with aromatase inhibitor therapy can lead to noncompliance in up to 33% of women with breast cancer. A new, large cohort study at a single regional cancer center showed that the rate of musculoskeletal toxicity in women with early breast cancer who were treated with endocrine therapy was 64%.

The findings were presented at a poster session during the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Patients taking aromatase inhibitors had almost twice the frequency of musculo­ skeletal toxicity as those receiving tamoxifen (Nolvadex; 64% vs 36%, respectively).

These findings are similar to a 2011 report showing that 61% of women receiving aromastase inhibitors had musculoskeletal toxicity in clinical trials and 20% discontinued their therapy because of the toxicity (Gaillard S, et al. Breast Cancer Res. 2011;13:205).

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“Despite the high incidence of musculoskeletal toxicity observed in patients taking aromatase inhibitors, the majority continued treatment, with

“Despite the high incidence of musculoskeletal toxicity observed in patients taking aromatase inhibitors, the majority continued treatment, with only 22.9% of women discontinuing therapy for this reason.”

—Susan F. Dent, MD, BSc

only 22.9% of women discontinuing therapy for this reason,” stated lead investigator Susan F. Dent, MD, BSc, Medical Oncologist at the Ottawa Hospital Cancer Centre, Canada.

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The study was based on a retrospective chart review at the Ottawa Hospital Cancer Centre between January 1999 and December 2006. The population included 626 postmenopausal women (mean age, 59 years) with hormone receptor–positive early breast cancer who were treated with endocrine therapy, including at least 1 aromatase inhibitor.

The median follow-up was 98 months, and the median duration of treatment with an aromatase inhibitor was 59 months. The women had a total of 1117 prescriptions that included letrozole (Femara), anastrozole (Arimidex), exemestane (Aromasin), and tamoxifen.

Musculoskeletal toxicity developed in 68% of patients taking letrozole, 47.6% of those taking exemestane, 63.9% of those taking anastrozole, and 36% of those taking tamoxifen. The median times to developing musculoskeletal toxicity were 21 months, 9 months, 23 months, and 23 months, respectively.

The most frequent musculoskeletal toxicities were: • Arthralgias, 41% • Myalgias, 25% • Osteoporosis/osteopenia, 23% • Arthritis, 19%.

Treatment was discontinued for these toxicities significantly more often with any aromatase inhibitor than with tamoxifen (14.6% vs 4.8%, respectively; P <.001). Treatment strategies for musculoskeletal toxicity did not significantly impact adherence to therapy, except in the case of exemestane.

Among the group treated with exemestane, the adherence rate with no intervention was 33% and adherence increased to 80% with musculoskeletal toxicity intervention, including mediation and physiotherapy (P <.001).

Longer exposure to any endocrine therapy did not appear to increase the rate of musculoskeletal toxicity.

Among this group of women, 51% completed 5 years of endocrine therapy as prescribed. n

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Lung Cancer

Local Ablation Extends Therapy Duration for Patients with NSCLC, Improves Disease Control

By Charles Bankhead

Boston, MA—Patients with ALKpositive non–small-cell lung cancer (NSCLC) continued with crizotinib therapy more than twice as long when drug-resistant lesions were managed with local ablation, as shown by the results of a small clinical trial presented at the 2012 American Society for Radiation Oncology meeting.

“The traditional therapeutic paradigm has been to change therapies at progression, regardless of how limited the progression might be,” said Gregory Gan, MD, PhD, a radiation oncology resident at the University of Colorado in Aurora. “We asked whether a better alternative might exist to help patients remain on otherwise effective systemic targeted therapy.”

The time for receiving treatment averaged approximately 10 months in patients who did not receive ablative therapy compared with 21 months in patients who underwent ablative therapy for discrete lesions.

All of the patients who received ablative therapy had disease control at 6 months, and 10 of 12 patients had no progression after 12 months.

Local ablation has potential application in a substantial fraction of patients with NSCLC who have good overall disease control, except for isolated pockets of resistance, a phenomenon known as “oligoprogression,” according to this retrospective review of medical records for 38 patients with ALK-positive NSCLC who received crizotinib (Xalkori).

Subsequently, 12 patients had local ablation (radiation or surgery) of a total of 26 lesions. The remaining 26 patients were treated according to the conventional paradigm.

The 12 patients who had ablative therapy used crizotinib continuously, taking a break only on the day of the ablation.

Progression-free survival (PFS) in crizotinib-treated patients ranged from 8 to 10 months. The 12 patients who had ablative treatment had a mean PFS of 10 months. After ablation of isolated lesions, the patients continued to receive crizotinib for an additional 11 months.

Dr Gan and colleagues examined the relationship between biological equivalent dose (BED) of radiation and disease control. The median BED was 58.6 Gy. The best disease control occurred in patients treated to a BED of >100 Gy. Other measures of effective dose delivered also suggested

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better control with higher doses.

The investigators published expanded results in December (Weickhardt AJ, et al. J Thorac Oncol. 2012;7:18071814). The study population had expanded to 65 patients, including some treated with the epidermal growth fac-

tor receptor (EGFR) inhibitor erlotinib.

The median time to progression was 9.0 months with crizotinib and 13.8 months among patients with EGFR mutations who were treated with erlotinib (Tarceva).

Of the 51 patients who progressed

february 2013

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on therapy, 25 met the criteria for local ablative therapy. All but 1 of the patients had irradiation as ablative therapy.

After local ablative therapy, 19 of the 25 patients progressed again after a median follow-up of 6.2 months. n

www.ValueBasedCancerCare.com

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Drug Update

Ponatinib: New Option for the Treatment of Adults with CML or Ph+ ALL that Is Resistant or Intolerant to Previous Therapy with Tyrosine Kinase Inhibitors

By Lynne Lederman, PhD, Medical Writer

L

eukemias are cancers involving the bone marrow and blood, and they account for approximately 4% of cancer deaths.1 The majority of leukemias occur in adults aged >20 years, and the incidence is higher in men than in women. Leukemias are classified by the type of cell involved (ie, lymphocytic or myeloid) and the rate of progression (ie, acute or chronic). Chronic myeloid leukemia (CML) and acute lymphocytic leukemia (ALL) account for approximately 2.5% and 6%, respectively, of deaths resulting from leukemia.1 CML arises from the unregulated production of white blood cells in the bone marrow that results from a constitutively active tyrosine kinase that is the fusion product of the Abelson murine leukemia (ABL) gene on chromosome 9 and the breakpoint cluster region (BCR) gene on chromosome 22 after a reciprocal translocation be­ tween these chromosomes forms the Philadelphia chromosome (Ph). A related fusion protein occurs in a subset of cases of ALL (ie, Ph -positive [Ph+] ALL).2-4

The Burden and Impact of CML and ALL The American Cancer Society esti-

mates that there will be almost 6000 new cases each of CML and ALL in 2013 in the United States, and that 610 deaths will result from CML and 1430 deaths from ALL.1 Leukemia is often associated with fatigue, pallor, bleeding, bruising, weight loss, and infections. In acute leukemia, these signs and symptoms may appear suddenly, whereas in chronic leukemia, there may be few symptoms that progress slowly.1 The 5-year survival rate for CML increased from 31% for patients diagnosed during 1990-1992 to 56% for those diagnosed during 2002-2008.1 The increase in survival for patients with CML is mainly the result of the development of targeted therapies,1 known as the BCR-ABL–specific tyrosine kinase inhibitors (TKIs).5 The 5-year relative survival rate for ALL overall has increased from 41% during the 1975-1977 period to 68% in the 2002-2008 period.1 The prognosis for Ph+ ALL is worse than that for other subtypes of ALL.4 The current treatment options for CML include the TKIs imatinib (Gleevec) and nilotinib (Tasigna), which are specific BCR-ABL TKIs; and dasatinib (Sprycel) and bosutinib

Baseline Demographics and Disease Characteristics in the Phase 2 Pivotal Trial Efficacy population Characteristic N = 444

Table 1

Median age, yrs (range)

59 (18-94)

Men, N (%) Women, N (%)

236 (53) 108 (47)

Race, N (%) White Black Asian Other

349 (79) 25 (6) 57 (12) 13 (3)

ECOG performance status 0 or 1, N (%)

Median time from diagnosis to first dose, yrs (range) Resistant to previous TKI therapy, N (%) Presence of ≥1 BCR-ABL kinase-domain mutations, N (%) Previously approved TKIs, N (%) 1 2 ≥3

409 (92)

6.1 (0.3-28.5) 374 (88) 244 (55) 29 (7) 166 (37) 249 (56)

ECOG indicates Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor.

Adapted from Reference 9.

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(Bosulif), which inhibit both ABL and Src kinases.3 These agents may be used as a part of combination therapy for patients with Ph+ ALL.4 Although many patients with CML who receive imatinib have a complete cytogenetic response, 25% of patients have disease that either does not respond initially to imatinib (primary resistance) or that progresses after initial response (secondary resistance).

Ponatinib offers a new treatment option for patients with CML, especially those with the T315I mutation, whose disease is not responding to other agents.

Secondary resistance may be caused by a mutation in the ABL kinase domain known as the T325I (or gatekeeper) mutation, because it prevents imatinib, dasatinib, and bosutinib from entering the ATP-binding pocket and inhibiting the kinase. Resistance to imatinib and other TKIs is associated with many other mutations and other as-yet unidentified causes.

However, the presence of a kinasedomain mutation is associated with a high risk for disease progression.3,6 Patients may also develop intolerance

to approved TKIs.3 Therefore, there remains a need for new agents that are effective in patients with resistant disease.

Ponatinib Fills an Unmet Need On December 14, 2012, the US Food and Drug Administration (FDA) granted accelerated approval to ponatinib (Iclusig; ARIAD Pharmaceuticals) based on the results from a phase 2 clinical trial. Ponatinib is indicated for the treatment of adult patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML that is resistant to or is intolerant of previous TKI therapy or for patients with Ph+ ALL that is resistant to or intolerant of previous TKI therapy.7 Ponatinib offers a new treatment option for patients with CML, especially those with the T315I mutation, whose disease is not responding to other agents. According to the FDA, these patients have had few therapeutic options. This approval provides patients with earlier access to ponatinib, while the manufacturer conducts additional studies to confirm the clinical benefit and the safe use of this new agent.8 The prescribing information for ponatinib states that the indication was based on the response rate to the drug, and that no trials have confirmed an improvement in disease-related symptoms or increased survival with this drug.9 Continued on page 36

Table 2 Efficacy of Ponatinib in Patients with Resistant or Intolerant ChronicPhase CML Cohort Patients with Patients with Total resistant/ T315I Cytogenetic patients intolerant disease mutation response N = 267 N = 203 N = 64 MCyR,a % (95% CI)

54 (48-60)

Median time to MCyR, days (range)

84 (49-334)

CCyR, % (95% CI)

Median duration of MCyR

44 (38-50)

49 (42-56) 37 (31-44)

70 (58-81) 66 (53-77)

Not reached

The primary end point for chronic-phase CML cohorts was MCyR, which combines both complete (no detectable Ph+ cells) and partial (1%-35% Ph+ cells in at least 20 metaphases) cytogenetic responses.

CCyR indicates complete cytogenetic response; CI, confidence interval; CML, chronic myeloid leukemia; MCyR, major cytogenetic response; Ph+, Philadelphia chromosome–positive.

Adapted from Reference 9. a

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2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

TM

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 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 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 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.

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

Drug Update

Ponatinib: New Option for the Treatment of Adults...

Table 3 Efficacy of Ponatinib in Patients with Resistant or Intolerant Advanced Disease (Including Resistant/Intolerant and T315I Mutation Cohorts) BP-CML AP-CML Ph+ ALL Hematologic response N = 62 N = 83 N = 32 Major response,a % (95% CI)

Complete response,b % (95% CI)

Median time to major response, days (range)

Median duration of major response, months (range)

52 (41-63)

31 (20-44)

41 (24-59)

47 (33-55)

21 (12-33)

34 (19-53)

21 (12-176)

29 (12-113)

20 (11-168)

9.5 (1.1-17.7)

4.7 (1.8-14.1+)

3.2 (1.8-8.8+)

Primary end point for patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, which combines complete hematologic responses and no evidence of leukemia. b Complete hematologic response: white blood cell ≤institutional upper limit of normal, absolute neutrophil count ≥1000/mm3, platelets ≥100,000/ mm3, no blasts or promyelocytes in peripheral blood, bone marrow blasts ≤5%, <5% myelocytes plus metamyelocytes in peripheral blood, basophils <5% in peripheral blood, no extramedullary involvement (including no hepatomegaly or splenomegaly).

ALL indicates acute lymphocytic leukemia; AP, accelerated phase; BP, blast phase; CI, confidence interval; CML, chronic myeloid leukemia; Ph+, Philadelphia chromosome–positive.

Adapted from Reference 9.

Table 4 Summary of Ponatinib Warnings and Precautions Warnings and precautions Thrombosis/ thromboembolism

Other CV events

a

Hepatotoxicity Pancreatitis Hemorrhage Myelosuppression

Tumor lysis syndrome Dosing and Administration Ponatinib is administered orally once daily at a recommended dose of 45 mg.9

Dose Modification

Dose modifications are suggested if patients experience neutropenia or thrombocytopenia that is unrelated to their leukemia.

The dose of ponatinib should be modified or the treatment should be interrupted if serious nonhematologic reactions occur. Treatment may be resumed once the event has resolved, or if the benefit of resuming therapy outweighs the risk; in patients with serious ischemic reactions, in addition to considering the risk-benefit ratio, ponatinib should be resumed only if the patient has no other treatment options.9

Use with CYP3A Inhibitors

The recommended dose should be reduced to 30 mg once daily when administering ponatinib with strong cytochrome (CY) P3A inhibitors.9 Clinical Pharmacology

Mechanism of Action

Ponatinib is a TKI that was designed to inhibit the BCR-ABL genetic mutations, including drug-resistant mutations that arise during treatment.9 Ponatinib is the only TKI that is active against the T315I mutation of BCR-ABL,7 which is the most frequent mutation, occurring in up to 20% of

36

patients with TKI resistance.2 In vitro, ponatinib inhibited the tyrosine kinase activity of ABL and T315I-mutant ABL, as well as that of additional kinases, including members of the vascular endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast growth factor receptors, and ephrin receptors; the Src families of kinases; and KIT, RET, TIE2, and FLT3.9,10 Phase 2 Clinical Trial Ponatinib was approved on the basis of the pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial in patients with CML or Ph+ ALL whose disease was resistant to or intolerant of previous TKI therapy, or whose leukemia had the T315I mutation of BCR-ABL.7,9,11,12

Trial Design

The phase 2 PACE trial was a single-arm, open-label, international, multicenter trial. The starting dose for all patients was 45 mg of ponatinib once daily. A total of 449 patients were enrolled, of whom 444 were evaluable for efficacy. Patients were assigned to 1 of 6 cohorts based on disease phase, resistance or intolerance to previous TKI therapy (ie, dasatinib or nilotinib), and the presence of the T315I mutation. Disease phases included CP-CML, AP-CML, and BPCML/Ph+ ALL.9,11,12 The primary efficacy end point in CP-CML was major cytogenetic response, which includ­

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Continued from page 34

Compromised wound healing

Gastrointestinal perforation Embryo-fetal toxicity

Description

CV, cerebrovascular, and peripheral vascular thrombosis; serious arterial thrombosis, 8%a; MI, 5%; VTE, 3%; serious cerebral vascular or peripheral arterial events, 2% each

Congestive heart failure: any grade, 7%; serious, 4% Cardiac arrhythmias: includes bradyarrhythmias (1% required pacemaker implantation; tachyarrhythmias) Hypertension: overall, 67%; serious requiring urgent intervention, 2% Fluid retention: overall, 23%; serious, 3%; 1 fatal brain edema Fatal in 3 patients; AST or ALT elevation, 56% (8% grades 3 or 4) Clinical, 6%; grade 3, 5%; lipase elevation, 41%

Overall, 24%; serious events including fatal events, 5%; most common with grade 4 thrombocytopenia Severe, 48%

Serious in 2 patients (<1%); serious hyperuricemia, 7% No formal studies, but could occur 1 patient with fistula 38 days postcholecystectomy

Can cause fetal harm based on method of operation and animal studies

Refers to proportion of patients in the pivotal trial (N = 444).

ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; MI, myocardial infarction; VTE, venous thromboembolism.

Source: Reference 9. a

­­ complete and partial cytogenetic ed responses.

The primary efficacy end point in patients with AP-CML, BP-CML, and Ph+ ALL was major hematologic response, defined as a complete hematologic response or no evidence of leukemia.9

Patient Population

The study included 267 patients with CP-CML (resistant or intolerant cohort, N = 203; T315I mutation cohort, N = 64), 83 patients with APCML, 62 patients with BP-CML, and 32 patients with Ph+ ALL.9 Key baseline demographic and disease characteristics of the evaluable patients are listed in Table 1 (page 34).

Safety Profile

At the time of the safety analysis, the median duration of treatment with ponatinib was 337 days in patients with CP-CML, 362 days in patients

with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL. The median dose intensity was 37 mg, or 83% of the expected 45-mg dose. Overall, the most frequent nonhematologic adverse reactions (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.9 The rates of treatment-emergent adverse events (AEs) resulting in discontinuation were 13% in the patients with CP-CML, 11% in AP-CML, 15% in BP-CML, and 9% in the patients with Ph+ ALL. The most frequent AEs that led to treatment discontinuation were thrombocytopenia (4%) and infections (1%).

Dose modifications (delays or reduction) resulting from adverse reacContinued on page 38

Vol. 4

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Continuing Education

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Registered participants will receive e-mail announcements as new educational activities become available.

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Drug Update

Ponatinib: New Option for the Treatment of Adults... tions occurred in 74% of the patients.

The most common adverse reactions (≥5%) that led to dose modifications include thrombocytopenia (30%), neutropenia (13%), increases in lipase (12%), rash (11%), abdominal pain (11%), pancreatitis (6%), and alanine aminotransferase, aspartate aminotransferase, or an increase in gammaglutamyl transferase (6%). Myelo­ suppression occurred in all patient populations.

The frequencies of grade 3 or 4 thrombocytopenia, neutropenia, and anemia were higher in patients with AP-CML, BP-CML, and Ph+ ALL (47%, 57%, and 47%, respectively) than in patients with CP-CML (36%).

Patients with Ph+ ALL had the highest rates of grades 3 and 4 neutropenia and leukopenia (63%); patients with BP-CML had the highest rates of grades 3 and 4 anemia (55%) and lymphopenia (37%).9

Response

At the time of the analysis for response, the median follow-up was 10 months (with a minimum of 6 months of follow-up for all ongoing patients).

The median duration of ponatinib treatment was 281 days in patients with CP-CML, 286 days in patients with AP-CML, 89 days in patients with BP-CML, and 81 days in patients with Ph+ ALL.9 The efficacy results for patients with CP-CML are summarized in Table 2 (page 34).

The efficacy results for patients with AP-CML, BP-CML, and Ph+ ALL are summarized in Table 3 (page 36).

Warnings and Precautions The ponatinib prescribing information contains a Boxed Warning about arterial thrombosis and hepatotoxicity, advising clinicians about the potential for these serious events with this medication.

The Boxed Warning includes the following9: • Arterial thrombosis. Cardiovas­ cular, cerebrovascular, and peripheral vascular thrombosis, including fatal myocardial infarction and stroke, have occurred in patients receiving ponatinib.

In clinical trials, serious arterial thrombosis occurred in 8% of patients receiving ponatinib. In patients receiving ponatinib who develop arterial thrombotic events, ponatinib should be interrupted and discontinuation should be considered.

• Hepatotoxicity. Hepatotoxicity, liver failure, and death have occurred in patients receiving ponatinib. Hepatic function should be monitored before and during treatment. For hepatotoxicity, ponatinib should be interrupted and then reduced or discontinued.

Call for Papers

Cancer Care Theme Issue American Health & Drug Benefits will be publishing a theme issue on cancer care in mid-2013 The growing focus on targeted therapies and diagnostics, and the ever-increasing cost of cancer care, require a thorough examination of current and emerging trends in oncology, focusing on benefit design, utilization, and health outcomes.

Readers are invited to submit manuscripts for this issue, including original research, costeffective analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends.

All articles will undergo the journal’s rigorous peer-review process.

Manuscripts must follow the format described in the Information for Authors at www.AHDBonline.com.

Areas of particular interest include: ➤ Benefit ➤ Best

care and health disparities

considerations in cancer care

➤ Emerging

trends in hematology/oncology

➤ End-of-life ➤ Health

➤ Managing ➤ Palliative

practices in oncology

➤ Cancer ➤ Cost

design for cancer therapies

plan initiatives in oncology

care

➤ Pathways

and practice guidelines

➤ Personalized ➤ Survivorship ➤ Targeted

issues

toxicities of cancer therapies

medicine in oncology programs

cancer therapies

➤ Value-based

cancer care

Submit articles to editorial@engagehc.com.

For more information, call 732-992-1889.

38

Value-Based Cancer Care

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Continued from page 36

Other warnings and precautions are summarized in Table 4 (page 36).

Conclusion Ponatinib is now being further investigated in a phase 3 randomized clinical trial that is comparing ponatinib with imatinib in patients with newly diagnosed CP-CML.13 As the second-generation BCR-ABL inhibitors are replacing imatinib in the treatment of newly diagnosed CML, the aim of this trial is to determine if ponatinib is effective in this patient population, and if it has the ability to prevent the emergence of resistant mutations that occur with other TKIs.10,13 A recent commentary by J.M. Goldman regarding the multikinase activity of ponatinib, as well as the preliminary results in patients with CML that is resistant to imatinib and second-generation TKIs, suggest that ponatinib may be “another step forward in the march toward real success with molecularly targeted therapy for cancer.”6 n References

1. American Cancer Society. Cancer Facts & Figures 2013. Atlanta, GA: American Cancer Society; 2013.

2. Cortez JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075-2088.

3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Chronic myelogenous leukemia. Version 3.2013. NCCN.org.

Accessed December 19, 2012.

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia. Version 2.2012. NCCN.org.

Accessed January 9, 2013.

5. Carella AM, Goldman JM, Martinelli G, et al.

Chronic myeloid leukemia: the basis of treatment for tomorrow. Haematologica. 2011;96:1737-1739.

6. Goldman JM. Ponatinib for chronic myeloid leukemia. N Engl J Med. 2012;367:2148-2149.

7. ARIAD Pharmaceuticals. ARIAD announces accelerated approval by FDA of Iclusig (ponatinib) for patients with CML and Ph+ ALL resistant or intolerant to prior tyrosine kinase inhibitor therapy. December 14, 2012. http://phx.corporate-ir.net/phoenix.zhtml?c= 118422&p=irol-newsArticle_print&ID=1767523&high light =. Accessed January 17, 2013.

8. FDA News Release. FDA approves Iclusig to treat two rare types of leukemia. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ ucm332252.htm. Accessed January 17, 2013.

9. Iclusig (ponatinib) tablets for oral use. Prescribing information. Cambridge, MA; ARIAD Pharma­ ceu­ ticals, Inc; December 2012.

10. O’Hare T, Shakespeare WC, Zhu X, et al. AP24535, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell.

2009;16:401-412.

11. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: a pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol.

2012;30(suppl):Abstract 6503.

12. Cortes J, Kim DW, Pinilla J, et al. PACE: a pivotal phase 2 trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Haematologica.

2012;97(suppl 1):453.

13. ARIAD EPIC PR. ARIAD announced initiation of randomized phase 3 trial of ponatinib in newly diagnosed patients with chronic myeloid leukemia. http://phx.corporate-ir.net/phoenix.zhtml?c= 118422&p=irol-newsArticle&ID=1719432&high light=. Accessed January 17, 2013.

Vol. 4

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No. 2

THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

TARGET AUDIENCE

SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

SATURDAY, MAY 4, 2013

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 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

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

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 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

*Agenda is subject to change.

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Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you.

That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: • Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

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