VBCC April 2014 Vol 5, No 3

APRIL 2014 VOL 5 NO 3

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

Implications of the ACA for Cancer Care Where we are, what’s the future?

By Wayne Kuznar

economics of cancer care

Promise of Personalized Care Hinges on Reimbursement Reform Oncologists must lead the way

Jeffery C. Ward, MD

By Charles Bankhead

T

J Oncol Pract. 2014;10:83-86).

Oncologists must take the lead in moving past “medicine’s dark secret” of fee-for-service reimbursement into a system that more accurately captures the full spectrum of service provided to patients, such as bundled

he promise of big data–driven personalized healthcare mandates reform of the oncology reimbursement system, suggested Jeffery C. Ward, MD, Medical Oncologist, Swedish Cancer Institute, Edmonds, WA, in a recent commentary (Ward JC.

Continued on page 8

personalized medicine

Hollywood, FL—The Affordable Care Act (ACA) is in its infancy, but it is already changing oncology practice, said panelists at the 2014 National Comprehensive Cancer Network (NCCN) Conference roundtable discussion. The conse-

quences of the ACA include the changing composition of oncology patients, the risk pool of the exchanges, new payment and reimbursement models, acquisition fever, and oncology workforce demands, the panelists said.

Continued on page 10

Routine Cervical Cancer Screening Warranted Beyond Age 64

By Rosemary Frei, MSc

R

esults of a new study investigating the probability of a cervical cancer diagnosis among women aged 65 to 83 years using data from the UK Cervical Screening Call/Recall System indicate that the current practice may need to be changed. The new data show that the odds of such a diagnosis were 25% lower in women who had regular screening between the ages of 50 and 64 years compared

©2014 Engage Healthcare Communications, LLC

with women who did not have regular screening. Although the protective effect diminished gradually, it was still significant up to age 83 years, according to the investigators (Castañón A, et al. PLoS Med. 2014;11:e1001585).

Furthermore, the team calculated that there would be 149 fewer cervical cancers per 100,000 women if women continued to be screened for cervical cancer until age 75 instead of age 65.

Continued on page 30

14 New Genetic Markers Predict Risk for Prostate Cancer Of these mutations, 5 were newly discovered in this study

By Neil Canavan

A

mutation in any 1 of a suite of DNA repair pathway genes may predict not only the risk for familial prostate cancer, but also indicate the presence of a particular aggressive form of the disease, according to results of a new UK study from the Institute of Cancer Research in

London (Leongamornlert D, et al. Br J Cancer. 2014 February 20. Epub ahead of print).

If validated, the clinical utility of these newly identified genetic markers will play a key role in the precautionary monitoring of men with the mutations, as well as guide treatment choice Continued on page 26

inside IN THE LITERATURE . . . . . . . . . . . . . 4 Personalizing targeted therapy possible for advanced breast cancer

PERSONALIZED MEDICINE . . . . . . 27 New molecular test to monitor breast cancer recurrence risk

VALUE PROPOSITIONS . . . . . . . . . . 6 Novel value-based care coordination toolkit supported by ASH

COLORECTAL CANCER . . . . . . . . . 30 Bevacizumab improves survival in metastatic colorectal cancer

GASTRIC CANCER . . . . . . . . . . . . . . 11 Ramucirumab improves survival in patients with advanced gastric cancer

ONCOLOGY HIT . . . . . . . . . . . . . . . . 32 Transforming cancer care with EMRs using CMS’s meaningful use criteria

ABSTRACTS . . . . . . . . . 16 Abstracts to be presented at the 4th Annual AVBCC Conference

NCCN 2014 CONFERENCE . . . . . . . 33 BRAF and MEK inhibitors added as primary treatments for melanoma

速 速 (carfilzomib) for Injection Now Has a Permanent J Code: J9047 Kyprolis Kyprolis (carfilzomib) for Injection Now Has a Permanent J Code: J9047

treatment of patients with multiple myeloma who have received at least 2 prior ForFor thethe treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib immunomodulatory agent have demonstrated disease therapies including bortezomib andand an an immunomodulatory agent andand have demonstrated disease progression on within or within days of completion of last therapy.

Approval is based on response rate. progression on or 60 60 days of completion of last therapy.

Approval is based on response rate.

Clinical benefi t, such as improvement in survival or symptoms, been verifi Clinical benefi t, such as improvement in survival or symptoms, hashas notnot been verifi ed.ed.

THEPOWER POWEROF OF THE SECOND-GENERATION SECOND-GENERATION PROTEASOMEINHIBITION INHIBITION PROTEASOME TAKESFLIGHT FLIGHT TAKES

Important Safety Information Important Safety Information CONTRAINDICATIONS CONTRAINDICATIONS None.

None.

Evaluate cardiac imaging and/or other as indicated.

Evaluate withwith cardiac imaging and/or other teststests as indicated.

Withhold KYPROLIS for pulmonary hypertension Withhold KYPROLIS for pulmonary hypertension untiluntil resolved or returned to baseline consider whether resolved or returned to baseline and and consider whether to to restart KYPROLIS based a benefi t/risk assessment. restart KYPROLIS based on aon benefi t/risk assessment.

Pulmonary Complications: Dyspnea reported in 35% Pulmonary Complications: Dyspnea waswas reported in 35% of of patients enrolled in clinical trials.

Grade 3 dyspnea occurred patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, 1 death (Grade 5) was reported. in 5%; no Grade 4 events, and and 1 death (Grade 5) was reported. safety of KYPROLIS evaluated in clinical studies The The safety of KYPROLIS was was evaluated in clinical studies of of Monitor manage dyspnea immediately; interrupt and and manage dyspnea immediately; interrupt patients relapsed and/or refractory multiple myeloma. Monitor 526526 patients withwith relapsed and/or refractory multiple myeloma.

KYPROLIS until symptoms have resolved or returned KYPROLIS until symptoms have resolved or returned Cardiac Arrest, Congestive Heart Failure, Myocardial Cardiac Arrest, Congestive Heart Failure, Myocardial to baseline. to baseline.

Ischemia: Death due to cardiac arrest has occurred within Ischemia: Death due to cardiac arrest has occurred within Infusion Reactions: Infusion reactions characterized a day of KYPROLIS administration. onset or worsening Infusion Reactions: Infusion reactions werewere characterized a day of KYPROLIS administration.

NewNew onset or worsening a spectrum of systemic symptoms including fever, chills, of pre-existing congestive heart failure decreased spectrum of systemic symptoms including fever, chills, of pre-existing congestive heart failure withwith decreased left left by aby arthralgia, myalgia, facial flushing, facial edema, vomiting, ventricular function or myocardial ischemia occurred arthralgia, myalgia, facial flushing, facial edema, vomiting, ventricular function or myocardial ischemia havehave occurred weakness, shortness of breath, hypotension, syncope, chest following administration of KYPROLIS. Cardiac failure weakness, shortness of breath, hypotension, syncope, chest following administration of KYPROLIS. Cardiac failure tightness, or angina.

These reactions occur immediately events cardiac failure congestive, pulmonary edema, tightness, or angina.

These reactions can can occur immediately events (e.g.,(e.g., cardiac failure congestive, pulmonary edema, following infusion orto up24 tohours 24 hours administration ejection fraction decreased) reported in 7% of patients.following infusion or up afterafter administration of of ejection fraction decreased) werewere reported in 7% of patients.

KYPROLIS. Administer dexamethasone to KYPROLIS Monitor for cardiac complications manage promptly.

KYPROLIS. Administer dexamethasone priorprior to KYPROLIS Monitor for cardiac complications and and manage promptly. to reduce the incidence and severity of reactions.

Inform Withhold KYPROLIS for Grade 4 cardiac events to reduce the incidence and severity of reactions. Inform Withhold KYPROLIS for Grade 3 or34or cardiac events untiluntil patients of risk the risk symptoms, to contact physician recovery consider whether to restart KYPROLIS based patients of the andand symptoms, andand to contact physician recovery and and consider whether to restart KYPROLIS based if symptoms ofinfusion an infusion reaction occur. a benefi t/risk assessment.

Patients Heart if symptoms of an reaction occur. on aon benefi t/risk assessment.

Patients withwith NewNew YorkYork Heart Association Class III and IV heart failure, myocardial infarction Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) Association Class III and IV heart failure, myocardial infarction Lysis Syndrome: Tumor lysis syndrome (TLS) in preceding the preceding 6 months, conduction abnormalities Tumor in the 6 months, and and conduction abnormalities occurred following KYPROLIS administration in <of 1% of occurred following KYPROLIS administration in < 1% uncontrolled by medications at greater uncontrolled by medications maymay be atbegreater risk risk for for patients.

Patients with multiple myeloma and a high tumor patients. Patients with multiple myeloma and a high tumor cardiac complications. cardiac complications. burden should be considered at greater for TLS. burden should be considered to betoatbegreater risk risk for TLS. to receiving KYPROLIS, ensure patients are well Pulmonary Hypertension: Pulmonary arterial hypertension PriorPrior to receiving KYPROLIS, ensure thatthat patients are well Pulmonary Hypertension: Pulmonary arterial hypertension hydrated.

Monitor for evidence of TLS during treatment, (PAH) reported in 2% of patients treated KYPROLIShydrated. Monitor for evidence of TLS during treatment, and and (PAH) waswas reported in 2% of patients treated withwith KYPROLIS manage promptly.

Interrupt KYPROLIS is resolved.

Grade or greater in less 1%patients. of patients. manage promptly.

Interrupt KYPROLIS untiluntil TLSTLS is resolved. and and waswas Grade 3 or3greater in less thanthan 1% of

WARNINGS AND PRECAUTIONS WARNINGS AND PRECAUTIONS

1 1 KYPROLIS is engineered selective inhibition KYPROLIS is engineered forfor selective inhibition 2, 2, • Single-agent KYPROLIS phase 2 study results • Single-agent KYPROLIS phase 2 study results * * - Overall response (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Overall response raterate (ORR) of 22.9% in PX-171-003 study (95% CI: 18.0, 28.5) - Median duration of response of 7.8 months (95% CI: 5.6, - Median duration of response of 7.8 months (95% CI: 5.6, 9.2)9.2) • Most patients across all phase 2 studies (85%) need to discontinue therapy toadverse an adverse event • Most patients across all phase 2 studies (85%) did did not not need to discontinue therapy duedue to an event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, acute renal failure each) dyspnea, increased blood creatinine, andand acute renal failure (1%(1% each)

ADVERSE REACTIONS ADVERSE REACTIONS safety of KYPROLIS evaluated in clinical trials of 526 patients relapsed and/or refractory TheThe safety of KYPROLIS waswas evaluated in clinical trials of 526 patients withwith relapsed and/or refractory multiple myeloma. multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. most common were pneumonia (10%), • Serious adverse reactions were reported in 45% of patients.

TheThe most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), congestive heart failure (3%) acute renal failure (4%), pyrexia (3%), andand congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), pyrexia (30%) thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), andand pyrexia (30%) PX-171-003 a single-arm, multicenter clinical trial of KYPROLIS in 266 patients relapsed multiple myeloma and whose disease *Study PX-171-003 was awas single-arm, multicenter clinical trial of KYPROLIS in 266 patients with with relapsed multiple myeloma and whose disease had had *Study

response tomost the most recent therapy ordisease had disease progression during or within 60 days the most recent therapy.

Attime the time a ≤ 25% response to the recent therapy or had progression during or within 60 days of theofmost recent therapy.

At the of of a ≤ 25% patients had received a median of 5 prior of therapy.

The primary endpoint was ORR. Response was determined

by Independent studystudy entry,entry, patients had received a median of 5 prior lineslines of therapy.

The primary endpoint was ORR. Response was determined

by Independent Review Committee assessment International Myeloma Working Group criteria.

Review Committee assessment usingusing International Myeloma Working Group criteria.

References: 1. Demo SD,CJ, KirkAujay CJ, Aujay MA, al. Antitumor activity of PR-171, a novel irreversible inhibitor the proteasome.

Cancer Res. 2007;67(13):6383-6391.

References: 1. Demo SD, Kirk MA, et al. et Antitumor activity of PR-171, a novel irreversible inhibitor of theofproteasome.

Cancer Res. 2007;67(13):6383-6391.

2.

KYPROLIS [prescribing information].

South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

2. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012.

Thrombocytopenia: KYPROLIS causes thrombocytopenia ADVERSE REACTIONS Thrombocytopenia: KYPROLIS causes thrombocytopenia ADVERSE REACTIONS with platelet nadirs occurring around Day 8 of each 28-day cycle with platelet nadirs occurring around Day 8 of each 28-day cycle Serious adverse reactions were reported in 45% of recovery to baseline by start the start of next the next 28-day cycle. Serious adverse reactions were reported in 45% of and and recovery to baseline by the of the 28-day cycle. patients. The most common serious adverse reactions were In patients multiple myeloma, of patients experiencedpatients. The most common serious adverse reactions were In patients withwith multiple myeloma, 36%36% of patients experienced pneumonia (10%), acute renal failure (4%), pyrexia (3%), and thrombocytopenia, including Grade in 10%.

Thrombocytopeniapneumonia (10%), acute renal failure (4%), pyrexia (3%), and thrombocytopenia, including Grade 4 in 4 10%.

Thrombocytopenia congestive heart failure (3%). Adverse reactions leading to following KYPROLIS administration resulted in a dose reduction congestive heart failure (3%). Adverse reactions leading to following KYPROLIS administration resulted in a dose reduction discontinuation of KYPROLIS occurred in 15% of patients discontinuation of KYPROLIS occurred in 15% of patients and and inof 1%patients of patients discontinuation of treatment in 1% and and discontinuation of treatment withwith included congestive heart failure (2%), cardiac arrest, dyspnea, KYPROLIS in <of 1%patients. of patients.

Monitor platelet counts frequentlyincluded congestive heart failure (2%), cardiac arrest, dyspnea, KYPROLIS in < 1% Monitor platelet counts frequently increased blood creatinine, acute failure each). increased blood creatinine, and and acute renalrenal failure (1% (1% each). during treatment KYPROLIS. Reduce or interrupt during treatment withwith KYPROLIS. Reduce or interrupt dosedose as as clinically indicated. common adverse reactions (incidence ≥ 30%) clinically indicated.

TheThe mostmost common adverse reactions (incidence ≥ 30%) fatigue (56%), anemia (47%), nausea (45%), werewere fatigue (56%), anemia (47%), nausea (45%), Hepatic Toxicity and Hepatic Failure: Cases of hepatic thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), Hepatic Toxicity and Hepatic Failure: Cases of hepatic thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), failure, including cases, reported (< 1%). pyrexia (30%). failure, including fatalfatal cases, havehave beenbeen reported (< 1%). and and pyrexia (30%).

KYPROLIS can cause elevations of serum transaminases KYPROLIS can cause elevations of serum transaminases USE IN SPECIFIC POPULATIONS bilirubin.

Withhold KYPROLIS in patients experiencing USE IN SPECIFIC POPULATIONS and and bilirubin.

Withhold KYPROLIS in patients experiencing Grade or greater elevations of transaminases, bilirubin, Grade 3 or3greater elevations of transaminases, bilirubin, or or Since Since dialysis clearance of KYPROLIS concentrations dialysis clearance of KYPROLIS concentrations has has other enzyme abnormalities resolved or returned other liverliver enzyme abnormalities untiluntil resolved or returned to to not been not been studied, the drug should be administered studied, the drug should be administered afterafter the the KYPROLIS baseline.

After resolution, consider if restarting KYPROLIS is is dialysis baseline.

After resolution, consider if restarting dialysis procedure. procedure. appropriate.

Monitor enzymes frequently. appropriate.

Monitor liverliver enzymes frequently.

Please Brief Summary of the Embryo-fetal Toxicity: KYPROLIS cause harm Please seesee Brief Summary of the fullfull Embryo-fetal Toxicity: KYPROLIS can can cause fetalfetal harm Prescribing Information adjacent pages. when administered a pregnant woman based on its Prescribing Information on on adjacent pages. when administered to ato pregnant woman based on its mechanism of action findings in animals.

There are no mechanism of action and and findings in animals.

There are no adequate and well-controlled studies in pregnant women adequate and well-controlled studies in pregnant women using KYPROLIS. lzomib caused embryo-fetal toxicity using KYPROLIS. CarfiCarfi lzomib caused embryo-fetal toxicity in in pregnant rabbits at doses lower in patients pregnant rabbits at doses thatthat werewere lower thanthan in patients receiving the recommended dose.

Females of reproductive receiving the recommended dose.

Females of reproductive Pharmaceuticals, Pharmaceuticals logo, Kyprolis potential should be advised to avoid becoming pregnant while Onyx,Onyx, Onyx Onyx Pharmaceuticals, Onyx Onyx Pharmaceuticals logo, Kyprolis potential should be advised to avoid becoming pregnant while and Kyprolis logoallare all trademarks of Onyx Pharmaceuticals, and Kyprolis logo are trademarks of Onyx Pharmaceuticals, Inc. Inc. ©2013 Pharmaceuticals, Inc., South San Francisco, being treated KYPROLIS. ©2013 Onyx Onyx Pharmaceuticals, Inc., South San Francisco, CA CA being treated withwith KYPROLIS. 0512-CARF-243R1 December 2013 0512-CARF-243R1 December 2013

In the Literature Personalizing Targeted Treatment Possible for Advanced Breast Cancer

Metastatic breast cancer is a leading cause of death worldwide, with almost 40,000 women in the United States succumbing to the disease in 2013. Although advances in the treatment of breast cancer have been made, meta-

static disease is still largely considered incurable. In a prospective, multicenter, molecular-screening study, researchers investigated whether the identification of individual genomic alterations could lead to personalized targeted therapy in women with advanced breast cancer (André F, et al.

Lancet Oncol. 2014;15:267-274).

From June 16, 2001, to July 30, 2002, researchers recruited 423 patients with breast cancer with metastasis accessible for biopsy from 18 centers in France. The researchers utilized comparative genomic hybridization (CGH) array and Sanger sequencing on PIK3CA and AKT1 to assess metastatic biopsy samples from 5 of the

KYPROLIS™ (carfilzomib) for Injection Brief Summary of Prescribing Information. Please see the KYPROLIS package insert for full prescribing information.

INDICATIONS AND USAGE: KYPROLIS is indicated for the treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate [see Clinical Studies section of full PI]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In Cycle 1, KYPROLIS is administered at a dose of 20 mg/m2. If tolerated in Cycle 1, the dose should be escalated to 27 mg/m2 beginning in Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment may be continued until disease progression or until unacceptable toxicity occurs [see Dosage and Administration]. The dose is calculated using the patient’s actual body surface area at baseline. Patients with a body surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. Dose adjustments do not need to be made for weight changes of less than or equal to 20%.

Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma Cycle 1 Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS No 20 20 20 No 20 20 No No 20 (20 mg/m2): Dosing Dosing Dosing Dosing Cycles 2 and Beyonda Week 1 Week 2 Week 3 Week 4 Day Day Days Day Day Days Day Day Days Days 2 3–7 8 9 10–14 15 16 17–21 22–28 1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Dosing Dosing Dosing Dosing (27 mg/m2): a If

previous cycle dosage is tolerated.

Hydration and Fluid Monitoring. Hydrate patients to reduce the risk of renal toxicity and of tumor lysis syndrome (TLS) with KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluid volume status throughout treatment and monitor blood chemistries closely. Prior to each dose in Cycle 1, give 250 mL to 500 mL of intravenous normal saline or other appropriate intravenous fluid.

Give an additional 250 mL to 500 mL of intravenous fluids as needed following KYPROLIS administration. Continue intravenous hydration, as needed, in subsequent cycles. Also monitor patients during this period for fluid overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate with dexamethasone 4 mg orally or intravenously prior to all doses of KYPROLIS during Cycle 1 and prior to all KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity of infusion reactions [see Warnings and Precautions].

Reinstate dexamethasone premedication (4 mg orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose Modifications based on Toxicities. Recommended actions and dose modifications are presented in Table 2.

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment Hematologic Toxicity • Grade 3a or 4 Neutropenia • Grade 4 Thrombocytopenia [see Warnings and Precautions]

Recommended Action • Withhold dose.

• If fully recovered before next scheduled dose, continue at same dose level.

• If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

Non-Hematologic Toxicity Recommended Action • Withhold until resolved or returned to baseline.

Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (from 27 mg/m2 to • congestive heart failure; 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• decreased left ventricular • If tolerated, the reduced dose may be escalated to the function; previous dose at the discretion of the physician.

• or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension • Withhold until resolved or returned to baseline.

• Restart at the dose used prior to the event or reduced [see Warnings and Precautions] dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Pulmonary Complications • Consider restarting at the next scheduled treatment • Grade 3 or 4 with one dose level reduction (from 27 mg/m2 to [see Warnings and Precautions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Hepatic Toxicity • After resolution, consider if restarting KYPROLIS is • Grade 3 or 4 elevation of appropriate; may be reinitiated at a reduced dose (from transaminases, bilirubin or other 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) liver abnormalities with frequent monitoring of liver function. [see Warnings and Precautions)] • If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician. (continued)

4

Value-Based Cancer Care

I

APRIL 2014

centers. The primary end point was the proportion of patients to whom a targeted therapy could be offered.

Biopsy samples were obtained from 407 of the 423 enrolled patients. The study’s results showed that CGH array and Sanger sequencing was feasible in 67% and 70% of patients, respectively.

In 195 (46%) patients, a targetable ge-

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) • Withhold until renal function has recovered to Grade 1 Renal Toxicity or to baseline and monitor renal function.

• Serum creatinine equal to or • If attributable to KYPROLIS, restart at the next scheduled greater than 2 × baseline treatment at a reduced dose (from 27 mg/m2 to [see Adverse Reactions] 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If not attributable to KYPROLIS, restart at the dose used prior to the event.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Peripheral Neuropathy • Restart at the dose used prior to the event or reduced • Grade 3 or 4 dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 [see Adverse Reactions] to 15 mg/m2), at the discretion of the physician.

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

• Withhold until resolved or returned to baseline.

Other • Grade 3 or 4 non-hematological • Consider restarting at the next scheduled treatment with one dose level reduction (from 27 mg/m2 to toxicities 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2).

• If tolerated, the reduced dose may be escalated to the previous dose at the discretion of the physician.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

a

Administration Precautions. The quantity of KYPROLIS contained in one single‑use vial (60 mg carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to prevent overdosing. Do not mix KYPROLIS with or administer as an infusion with other medicinal products. The intravenous administration line should be flushed with normal saline or 5% Dextrose Injection, USP immediately before and after KYPROLIS administration. KYPROLIS should not be administered as a bolus. KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended only for single use. Unopened vials of KYPROLIS are stable until the date indicated on the package when stored in the original package at 2°C to 8°C (36°F to 46°F). The reconstituted solution contains carfilzomib at a concentration of 2 mg/mL. Read the complete preparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just prior to use. 2. Aseptically reconstitute each vial by slowly injecting 29 mL Sterile Water for Injection, USP, directing the solution onto the INSIDE WALL OF THE VIAL to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or until complete dissolution of any cake or powder occurs. DO NOT SHAKE to avoid foam generation. If foaming occurs, allow solution to rest in vial for about 2 to 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS is ready for intravenous administration. The reconstituted product should be a clear, colorless solution. If any discoloration or particulate matter is observed, do not use the reconstituted product. 5. When administering in an intravenous bag, withdraw the calculated dose [see Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.

6. Immediately discard the vial containing the unused portion. The stabilities of reconstituted KYPROLIS under various temperature and container conditions are shown in Table 3.

Table 3: Stability of Reconstituted KYPROLIS Storage Conditions of Reconstituted KYPROLIS

a

Stabilitya per Container Vial

Syringe

IV Bag (D5Wb)

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

4 hours

Total time from reconstitution to administration should not exceed 24 hours. b 5% Dextrose Injection, USP.

WARNINGS AND PRECAUTIONS: Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia. Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre‑existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials. These patients may be at greater risk for cardiac complications. Pulmonary Hypertension. Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment [see Dosage and Administration]. Pulmonary Complications. Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline [see Dosage and Administration and Adverse Reactions]. Infusion Reactions. Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions [see Dosage and Administration]. Inform patients of the risk and symptoms and to contact physician if symptoms of an infusion reaction occur [see Patient Counseling Information]. Tumor Lysis Syndrome. Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved [see Dosage and Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and Administration].

Hepatic Toxicity and Hepatic Failure. Cases of hepatic failure, including fatal cases, have been

Vol. 5

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No. 3

In the Literature nomic alteration was identified, most frequently in PIK3CA, CCND1, and FGFR1 (25%, 19%, and 13% of identified genomic alterations, respectively).

Of the 195 patients, 107 (55%) had multiple targetable genomic alterations. Rare genomic alterations (defined as occurring in <5% of the general population) were noted in 117 (39%)

patients, including AKT1 mutations, and EGFR, MDM2, FGFR2, AKT2, IGF1R, and MET high-level amplifications. Genomic analyses led to personalized therapy in 13% of the 423 patients (N = 55).

Of the 423 patients who received personalized therapy, 9% had an objective response, 21% had stable dis-

reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently [see Dosage and Administration and Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations].

ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections of the labeling: • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Hypertension [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Thrombocytopenia [see Warnings and Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. Clinical Trials Safety 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 with rates in the clinical trials of another drug, and may not reflect the rates observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS as monotherapy or with pre‑dose dexamethasone. Patients received a median of four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, cardiac disorder), end‑organ failure in 4 patients (multi‑organ failure, hepatic failure, renal failure), infection in 4 patients (sepsis, pneumonia, respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). Adverse reactions occurring at a rate of 10% or greater are presented in Table 4.

Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS

Event Fatigue Anemia Nausea Thrombocytopenia Dyspnea Diarrhea Pyrexia Upper respiratory tract infection Headache Cough Blood creatinine increased Lymphopenia Edema peripheral Vomiting Constipation Neutropenia Back pain Insomnia Chills Arthralgia Muscle spasms Hypertension Asthenia Hypokalemia Hypomagnesemia Leukopenia Pain in extremity Pneumonia Aspartate aminotransferase increased Dizziness Hypoesthesia Anorexia Pain Hyperglycemia Chest wall pain Hypercalcemia Hypophosphatemia Hyponatremia

All Gradesa 292 (55.5) 246 (46.8) 236 (44.9) 191 (36.3) 182 (34.6) 172 (32.7) 160 (30.4) 149 (28.3) 145 (27.6) 137 (26.0) 127 (24.1) 126 (24.0) 126 (24.0) 117 (22.2) 110 (20.9) 109 (20.7) 106 (20.2) 94 (17.9) 84 (16.0) 83 (15.8) 76 (14.4) 75 (14.3) 73 (13.9) 72 (13.7) 71 (13.5) 71 (13.5) 70 (13.3) 67 (12.7) 66 (12.5) 66 (12.5) 64 (12.2) 63 (12.0) 63 (12.0) 62 (11.8) 60 (11.4) 58 (11.0) 55 (10.5) 54 (10.3)

Patients (N = 526) [n (%)] Grade 3 Events 38 (7.2) 111 (21.1) 7 (1.3) 69 (13.1) 25 (4.8) 4 (0.8) 7 (1.3) 17 (3.2) 7 (1.3) 1 (0.2) 13 (2.5) 84 (16.0) 3 (0.6) 5 (1.0) 1 (0.2) 50 (9.5) 15 (2.9) 0 1 (0.2) 7 (1.3) 2 (0.4) 15 (2.9) 12 (2.3) 14 (2.7) 2 (0.4) 27 (5.1) 7 (1.3) 52 (9.9) 15 (2.9) 5 (1.0) 3 (0.6) 1 (0.2) 12 (2.3) 16 (3.0) 3 (0.6) 13 (2.5) 24 (4.6) 31 (5.9)

Grade 4 Events 2 (0.4) 7 (1.3) 0 54 (10.3) 1 (0.2)b 1 (0.2) 2 (0.4) 0 0 0 1 (0.2) 11 (2.1) 0 0 0 4 (0.8) 0 0 0 0 0 2 (0.4) 1 (0.2) 3 (0.6) 0 1 (0.2) 0 3 (0.6)b 1 (0.2) 1 (0.2) 0 0 0 3 (0.6) 0 8 (1.5) 3 (0.6) 3 (0.6)

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

One event was Grade 5 severity.

a

b

ease for more than 16 weeks, and 9% achieved clinical benefit, defined as an objective response, stable disease for at least 24 weeks, or both.

Biopsy-related serious (ie, grade 2 and grade 3) adverse events were reported in 9 patients, including grade 2/3 pneumothorax (N = 4), grade 2/3 pain (N = 2), grade 3 hematoma (N =

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1 or Grade 2 in severity. Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events occurred in 1%. Discontinuations due to increased blood creatinine and acute renal failure were 1% each. In one patient, death occurred with concurrent sepsis and worsening renal function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (including all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% of patients. Consider antiviral prophylaxis for patients who have a history of herpes zoster infection.

DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other drugs [see Clinical Pharmacology section of full PI].

USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS can cause fetal harm when administered to a pregnant woman. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and 2 mg/kg/day in rats and 0.2, 0.4, and 0.8 mg/kg/day in rabbits. Carfilzomib was not teratogenic at any dose tested. In rabbits, there was an increase in pre‑implantation loss at ≥ 0.4 mg/kg/day and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at the maternally toxic dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8 mg/kg/day in rabbits are approximately 20% and 40%, respectively, of the recommended dose in humans of 27 mg/m2 based on body surface area. Nursing Mothers. It is not known whether KYPROLIS is excreted in human milk. Since many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KYPROLIS, 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 KYPROLIS in pediatric patients have not been established.

Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal Impairment. The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS doses of 15 mg/m2 on Cycle 1, 20 mg/m2 on Cycle 2, and 27 mg/m2 on Cycles 3 and beyond.

The pharmacokinetics and safety of KYPROLIS were not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac Impairment. Patients with New York Heart Association Class III and IV heart failure were not eligible for the clinical trials. Safety in this population has not been evaluated.

OVERDOSAGE: There is no known specific antidote for KYPROLIS overdosage. In the event of an overdosage, monitor the patient and provide appropriate supportive care.

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility.

Carcinogenicity studies have not been conducted with carfilzomib. Carfilzomib was clastogenic in the in vitro chromosomal aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/ or Pharmacology. Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose in monkeys using dosing schedules similar to those used clinically resulted in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) systems. The dose of 2 mg/kg/dose in rats is approximately half the recommended dose in humans of 27 mg/m2 based on body surface area. The dose of 2 mg/kg/dose in monkeys is approximately equivalent to the recommended dose in humans based on body surface area.

PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients not to drive or operate machinery if they experience any of these symptoms. Advise patients that they may experience shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. Advise patients to contact their physicians if they experience shortness of breath.

Counsel patients to avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms of dizziness, lightheadedness, or fainting spells. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during treatment with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment while pregnant or breastfeeding. If a patient wishes to restart breastfeeding after treatment, advise her to discuss the appropriate timing with her physician. Advise patients to discuss with their physician any medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

1), grade 2 thrombosis (N = 1), and grade 3 hemorrhagic shock (N = 1).

Biopsy confirmed an alternative diagnosis in 4 patients, including evidence of lung cancer, skin cancer, and benign lung disease.

The investigators suggested that new strategies to guide individual treatment options are necessary for patients who have metastatic breast cancer that is refractory to standard treatments. Furthermore, multigene screening allowed for the identification of patients with genomic alterations that could be matched to drugs under evaluation in phase 1 and 2 trials.

Rituximab Active in Nodular Lymphocyte-Predominant Hodgkin Lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare type of Hodgkin lymphoma that represents approximately 5% of all cases. Unlike classic Hodgkin lymphoma, the malignant cells of NLPHL universally express CD20. Because rituximab (Rituxan) is an anti-CD20 monoclonal antibody, it has been evaluated as a treatment option for this patient population.

Previous preliminary results of a phase 2 clinical trial using single-agent rituximab in patients with NLPHL showed that the overall response rate was 100%, but the estimated median freedom from progression was less than 1 year. In a new study, researchers modified the study protocol of ri­ tuximab induction with and without maintenance rituximab in NLPHL to evaluate patient response rate at 2 years (Advani RH, et al. J Clin Oncol.

2014;32:912-918).

The study included 39 patients with previously treated or with newly diagnosed NLPHL. The initial protocol included 23 patients (ie, rituximab group) who received rituximab 375 mg/m2 administered once weekly for 4 weeks. The protocol was amended after this patient cohort had enrolled to include 16 patients (ie, rituximab plus maintenance group) who received maintenance dosing with rituximab 375 mg/m2 administered in 4 once-weekly doses at 6-month intervals for 2 years.

For patients with previously untreated disease, the median age at treatment was 38 years, and the median time from diagnosis to treatment induction was 4 months. The median time from original diagnosis of NLPHL to study entry in patients experiencing relapse was 12.7 years, and the median age at treatment was 44 years. The primary end point was progression-free survival (PFS), and the secondary end points were complete re-

Manufactured for: Onyx Pharmaceuticals, Inc., 249 East Grand Avenue, South San Francisco, CA 94080 U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 05-1088-00 ©2012 Onyx Pharmaceuticals, Inc. 1012-CARF-409 September 2012

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Advance Care Planning

VALUE PROPOSITIONS ASH Supports Novel Value-Based Care Coordination Toolkit

The focus on value-based care is growing not only in oncology but in all areas of medicine. The American Society of Hematology (ASH) has joined the American College of Physicians (ACP) in an effort to provide more effective patient care by increasing patient-centered communication between primary care physicians (PCPs) and hematologists. For this purpose, ASH has contributed several products to the ACP’s new resource tool, the High Value Care Coordination Toolkit (http://hvc.acponline.org/physres_care_ coordination.html).

This toolkit aims at increasing coordination between PCPs and specialty physicians. The High Value Care Coordination Toolkit includes 5 main components that can facilitate effective, value-based care coordination between PCPs and subspecialist physicians to enhance patient care. These 5 components are: • A checklist for referring a patient to a subspecialty practice • A checklist for a response from the subspecialist to a referral request • Pertinent data sets to include in the referral • Care coordination templates between a PCP and a specialist • Recommendations on how to prepare a patient for a referral.

Specific ASH contributions to the toolkit include modifications to the ACP’s General Specialty Out-Patient Referral Request Checklist for hematology, as well as pertinent data sets to facilitate effective referrals between PCPs and hematologists for blood disorders, including anemia (or iron deficiency), bleeding and bruising, hypercoagulability, and lymphadenopathy.

The toolkit is part of the ACP’s High Value Care initiative (http://hvc. acponline.org/), which is designed to help physicians and patients understand the benefits, harms, and costs associated with specific tests and treatment options for common clinical conditions in an effort to incorporate these aspects of care and to improve the patient’s health, prevent inappropriate treatment, and reduce wasteful practices. American Society of Hematology Press Release; April 11, 2014

Experienced Nurses Reduce Hospital Stay and Costs, Improve Outcomes

Paying more for experienced nurses pays off in the final analysis, according to the results of a new study. When more experienced nurses leave, hospitals often hire new nurses and contract temporary nurses, which leads to reduced productivity because of the lack of skills and the lack of experience of the new nurses, the researchers found. By contrast, care improves significantly when provided by nurses with extensive experience in their job.

This conclusion is based on a study of 900,000 medical records of admitted patients during 4 years at Veterans Affairs hospitals. A 1-year increase in the experience of a nurse resulted in a 1.3% reduction in hospital stays.

Furthermore, paying nurses overtime on a unit is more cost-effective than relying on temporary staffing.

“Reducing length of stay is the holy grail of hospital management because it means patients are getting higher quality, more cost-effective care,” commented senior author Patricia Stone, PhD, RN, Centennial Professor of Health Policy at Columbia Nursing. “When the same team of nurses works together over the years, the nurses develop a rhythm and routines that lead to more efficient care. Hospitals need to keep this in mind when making staffing decisions—disrupting the balance of a team can make quality go down and costs go up.” Bartel AP, et al. Am Economic J: Applied Economics. 2014;6:231-259

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Where Is the Value? SGR and ICD-10 Extensions Pose New Obstacles to Improving Patient Care

What was supposed to be a permanent fix to the sustainable growth rate (SGR) that will put a stop to the deep cuts to physicians’ payments by Medicare ended in a temporary fix that delays the decision by 1 year, and even more surprising, this was further linked to a delay (by at least 1 year) of the conversion from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic and procedural codes to the new ICD-10-CM codes. So what was supposed to bring value to the issue of physicians’ pay has instead managed to outrage providers and provider practices by a temporary fix that creates more uncertainty regarding physician reimbursement and disrupts the many months of preparations by physician practices that were getting ready to transition to the ICD-10 coding system by October 1, 2014.

Ardis Dee Hoven, MD, President of the American Medical Association, said, “This bill perpetuates an environment of uncertainty for physicians, making it harder for them to implement new innovative systems to better coordinate care and improve quality of care for patients.”

Lynne Thomas Gordon, CEO of the American Health Information Management Association (AHIMA), said, “On behalf of our more than 72,000 members who have prepared for ICD-10 in good faith, AHIMA will seek immediate clarification on a number of technical issues such as the exact length of the delay.”

Health plans and providers’ practices have spent large amounts of time and money preparing for the transition to the ICD-10—only to be put on hold for another year or so. This is not the best use of healthcare dollars, to be sure. Modern Healthcare, www.modernhealthcare.com/article/20140331/ NEWS/301019918; March 31, 2014

NIH Study Sheds Light on Genetic Link between Cancer and Aging—Can We Be on the Way to Prevention?

It is not new that aging is a risk factor for many types of cancer, but why this is the case was not understood. A recent study from the National Institutes of Health (NIH) has shed new light on that question, showing that the accumulation of age-associated biochemical changes in the process that helps to control genes may be at least in part responsible for the increased risk for cancer associated with old age.

Zongli Xu, PhD, and Jack Taylor, MD, PhD, from the National Institute of Environmental Health Sciences, which is part of the NIH, identified DNA methylation sites across the human genome that changed with age. They found that the sites that become increasingly methylated with advancing age are also disproportionately methylated in a variety of human cancers.

Their data come from the blood samples of >50,000 women who have had breast cancer.

“You can think of methylation as dust settling on an unused switch, which then prevents the cell from turning on certain genes,” Dr Taylor said.

“If a cell can no longer turn on critical developmental programs, it might be easier for it to become a cancer cell.” Dr Taylor said that DNA methylation appears to be part of the normal aging process and occurs in genes involved in cell development. Cancer cells often have altered DNA methylation; however, the team was surprised to find that 70% to 90% of the sites associated with age showed significantly increased methylation in 7 cancer types.

Dr Taylor suggests that age-related methylation may disable the expression of certain genes, making it easier for cells to transition to cancer.

“On your 50th birthday, you would have 50 of these sites that have acquired methyl groups in each cell,” Dr Xu suggests. “The longer you live, the more methylation you will have.” NIH Press Release; February 3, 2014

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In This Issue Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor

IN THE LITERATURE

PERSONALIZED MEDICINE

Personalizing targeted therapy possible for advanced breast cancer More…

New molecular test to monitor breast cancer risk More…

CERVICAL CANCER

VALUE PROPOSITIONS ASH supports value-based care coordination tool More…

ECONOMICS OF CANCER CARE Promise of personalized medicine hinges on reimbursement reform More…

Routine cervical cancer screening warranted after age 64

COLORECTAL CANCER Bevacizumab improves survival in metastatic colorectal cancer

ONCOLOGY HIT

Abstracts to be presented at the 4th Annual AVBCC Conference

High rate of overridden drug contraindication alerts for patients with cancer Transforming cancer care with EMRs using CMS’s meaningful use criteria

Human Resources Jennine Leale

PROSTATE CANCER

NCCN 2014 CONFERENCE

Associate Director, Content Strategy & Development John Welz

Phi index can choose patients with prostate cancer for active surveillance More…

The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly

Associate Editorial Director, Projects Division Terri Moore

ABSTRACTS

Director, Quality Control Barbara Marino

VBCC Editorial Board

Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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

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No. 3

BRAF and MEK inhibitors added as primary treatments for melanoma More…

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL 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 Linda D. Bosserman, MD, FACP President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

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

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

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

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

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

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

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

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

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

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

Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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.

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Economics of Cancer Care

Promise of Personalized Care Hinges on Reimbursement...

Continued from the cover

payments, he noted.

“The real threat to bringing big data and personalized cancer care to the communities where the vast majority of oncology patients are treated is an antiquated reimbursement system that only pays for care when it involves physician touches and infusion of drugs,” Dr Ward wrote.

“It is not just FFS [fee-for-service] medicine that is the problem but a particular ilk of FFS that only pays for some services, failing to reimburse at all for other essential services provided in oncology offices and clinics.”

Before big data can transform the healthcare sector of the economy, the industry has to make fundamental changes that ensure stakeholders capture the full value, “and that begins with how we pay for it,” wrote Dr Ward.

The emerging era of personalized medicine has its genesis in advances related to genetics, molecular biology, and other aspects of basic science and clinical medicine. However, the informatics revolution (big data) is the driving force, providing the capability to accumulate, assemble, and analyze the massive amount of information that makes personalized care possible.

Transforming Oncology Practice “Personalized medicine and big data hold the promise to transform oncology practice more, and more rapidly, than anything that has happened in the first 50 years of the history of our specialty,” Dr Ward noted in his article.

The amount of medical information doubles every 5 years, but the vast majority of digital medical data was developed in the past 2 years.

Moreover, 80% of the data remains raw and unstructured. Bringing order to all of that information and making it useful and usable requires advanced computing capability, as represented

by IBM’s Watson, which has demonstrated great potential for processing information in real time to facilitate clinical decision-making.

Big data has the potential to transform clinical practice and clinical research. Computer analysis will never replace a well-designed clinical trial, but will augment and improve the trial process.

“Common characteristics that bind a few responders to a particular therapeutic from a sea of otherwise indifferent information, and then effortlessly seek out patients with similar

8

characteristics will allow for rapid and efficient validation trials,” said Dr Ward. “Only when that happens can personalized medicine deliver on its promise.”

“The real threat to bringing big data and personalized cancer care to the communities where the vast majority of oncology patients are treated is an antiquated reimbursement system that only pays for care when it involves physician touches and infusion of drugs.”

—Jeffery C. Ward, MD

Payment Reform and Big Data in Oncology To quote from an article on P4 (predictive, personalized, preventive, participatory) cancer medicine, “each patient will be surrounded by a ‘virtual cloud’ of billions of data points that will uniquely define their past medical history and current health status,” (Hood L, et al. Nat Rev Clin Oncol.

2011;8:184-187). From the vast amount of data will come individualized algorithms that address a patient’s current clinical needs and provide for the patient’s future wellness.

To realize all that big data has to offer healthcare, reimbursement must be designed to complement personalized medicine, which will “incentivize processes designed to improve value and measure and reward efficacy, quality, and efficiency of care,” Dr Ward continued. As an example, he cited ongoing work by the American Society of Clinical Oncology’s Clinical Practice Committee.

Still evolving, the Clinical Practice

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Committee model bases core payments on monthly episodes of care.

The episodes are defined by multiple factors, including “the patient’s continuum of disease, new patient payments, treatment month payments, transition-of-care payments, and surveillance or nontreatment month payments,” Dr Ward noted.

“Any specific category of treatment may be expanded on the basis of acuity and/or complexity of the patient’s disease and the care given,” he said of the Clinical Practice Committee project. “Valuation of each core payment can be developed in a budget-neutral way to current reimbursement and increases and then tied to a medical inflation index.”

The payment system would provide for all the activities that go into various stages of the patient care process, from planning and initiation of treatment to follow-up and well care. Such bundled payments would account for a multitude of ancillary services, such as nurse educators, group sessions, and social work.

at a glance ➤ Oncologists must take the lead in developing the reimbursement system of the future Eventually, process measurements would be replaced by outcomes.

Inducements would be added over time, culminating in the development of a performance-based system.

Cancer Drug Pricing and Reimbursement Dr Ward acknowledged that incorporation of cancer drugs into the reimbursement system will be problematic, given that drugs often constitute the most costly item in the care of a patient with cancer. Fundamental changes to the current “buy-and-bill” system of administration will be required.

“When a margin proportionate to the cost of the drug is the provider’s reward for giving chemotherapy, it becomes quintessential FFS,” said Dr

“When a margin proportionate to the cost of the drug is the provider’s reward for giving chemotherapy, it becomes quintessential FFS. The incentives to not only give more chemotherapy but to preferentially use high-margin drugs, usually more expensive drugs and parenteral therapies, can only partially be overcome by strict value-based pathway adherence or enforcement.”

—Jeffery C. Ward, MD

As currently conceived, treatmentmonth payments would have a builtin scale that could be adjusted in accordance with the complexity of the disease and treatment regimen.

Transition payments would be incorporated to account for the extra time and service necessitated by a change in treatment plan.

“Fortunately, the electronic medical record and big data should make it much simpler to define the real work requirements and value of distinct bundles than the American Medical Association’s much-vilified Relative Value Scale Update Committee,” Dr Ward added.

The core bundled payments would increase or decrease as a result of the adoption of value-based pathways and quality-improvement activities.

Ward. “The incentives to not only give more chemotherapy but to preferentially use high-margin drugs, usually more expensive drugs and parenteral therapies, can only partially be overcome by strict value-based pathway adherence or enforcement.”

“The era of personalized medicine will require that ASP [average sales price]-based pricing be replaced and that a margin on drugs be taken out of the reimbursement equation,” Dr Ward added.

Oncologists must take the lead in developing the reimbursement system of the future. By failing to “answer the call,” oncologists risk allowing other parties—such as insurers and drug companies—to decide how oncology should be valued and reimbursed, Dr Ward concluded. n

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Economics of Cancer Care

Implications of the ACA for cancer...

Growing Burden on Patients Since the rollout of the ACA, the composition of patients with cancer has not changed from the perspective of risk, said W. Thomas Purcell, MD, MBA, Executive Medical Director, Oncology Services, University of Colorado Hospital, but many patients covered by commercial insurance are for the first time participating in a narrow network. In addition, many patients who qualify for Medicaid and those selecting Bronze plans have large copays and more out-of-pocket expenses than before; managing these expenses will be challenging.

The narrowing of networks has interrupted the continuity of care for some patients. “We’re getting situations in which patients are unable to come to us, because they are in a particular narrow network that we don’t cover,” Dr Purcell said.

“We’re getting situations in which patients are unable to come to us, because they are in a particular narrow network that we don’t cover.”

—W. Thomas Purcell, MD, MBA

Patients with rare or complex cancers best managed by an academic medical system that delivers multidisciplinary care may, therefore, not receive optimal management if the academic center is outside the patient’s narrow network, he said, “unless he pays out of pocket or we make an exception to treat him and cover the cost.”

Patients with immediate needs for care that could not be addressed previously are presenting at his clinic, said Mohammed S. Ogaily, MD, President, Michigan Society of Hematology and Oncology and Medical Director, Oakwood Center for Hematology and Oncology, Downriver. “Certainly, some [patients] are more complex because of the time that they have lacked coverage and did not seek medical care,” Dr Ogaily said.

When asked where the ACA falls short, Lee N. Newcomer, MD, MHA, Senior Vice President, Oncology, UnitedHealthcare, noted that the medical necessity clauses prohibit taking cost into consideration when balancing treatment options that deliver equal outcomes. “You have in any NCCN guideline multiple options for adjuvant

10

breast cancer therapy or the treatment of non–small-cell lung cancer. Some of them are far less expensive than others, but they have the same end results, and often may have the same toxicities. In those scenarios, we should be thinking about using lower-cost alternatives,” he said. “We’re not allowed to do that in Medicare or the ACA.” Risk Pool Uncertainty In this early stage of the ACA, the risk pool is uncertain, creating a quandary for insurers. Because enrollment in ACA by younger persons is lagging, insurers may have insufficient data to make premium bids for next year, said Elizabeth J. Fowler, PhD, JD, Vice President, Global Health Policy, Johnson & Johnson.

“If the risk pool stays risky, does the thing fall apart?” asked Clifford Goodman, PhD, Senior Vice President and Principal, The Lewin Group, who moderated the discussion.

Certain adjustments, such as a temporary reinsurance program, a temporary risk corridor program, and a permanent risk adjustment program, may be necessary, said Dr Fowler.

Other adjustments to the ACA, such as delaying the individual mandate, have been expensive to insurers as they continually reprogram their systems to comply with new regulations.

“It has been an extremely expensive product to roll out. It takes a lot of our time, energy, and resources to keep making all of the changes that occur. It takes money away from other innovative programs,” said Dr Newcomer.

“One of the things that you’re starting to see is provider networks looking at doing things like accountable care organizations [ACOs], oncology medical homes, and broad medical homes,” said Christian G. Downs, JD, MHA, Executive Director, Association of Community Cancer Centers. “I do worry a little bit though about providers going in risk, because that’s very difficult to manage and it’s not necessarily their area of expertise. There is some concern about providers going too quickly into models they don’t fully understand.”

In Michigan, although ACOs are sprouting, the enthusiasm for oncology medical homes has not been robust, said Dr Ogaily.

Integrated Networks The new payment and reimbursement models with a shared-savings environment will favor independent or group practitioners who have established relationships with payers, while

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See also NCCN Conference, page 33 Continued from the cover

putting at risk the practices that are not well integrated, said Mr Downs. Acquisitions of oncology group practices and hospital mergers may be the new norm, a trend that started with the Medicare Modernization Act, he said.

“The concept of an integrated network becomes very important,” Mr Downs said, noting the large number of disciplines involved in cancer care.

The ACA may facilitate integration with its mandates for quality care measures and reporting requirements.

Razor-thin margins, owing to lower government reimbursement for oncol-

Rating the ACA in 2020

Moderator Clifford Goodman, PhD, asked the panel members (1) how they would rate the ACA on a scale of 0 to 10 (with 10 being the most effective healthcare law in history) in looking back at it from the year 2020, and (2) what would be the most important way the ACA will impact cancer care.

Here are their answers: C.G. Downs—(1) 8.0 (2) Some type of payment reform, because quality is already there

E.J. Fowler—(1) 5.0-6.0, but if we ever get past the partisan bickering and fix it, then 8.0-9.0 (2) Increased focus on value as a result of pressure from quality metrics

M.A. Kolodziej—(1) 6.0 (2) Payment reform will lead to better integrated, coordinated care, with more transparency

L.N. Newcomer—(1) 5.0 (2) Team care; we’ll be figuring out how to do this as a team and winnowing out unnecessary things M.S. Ogaily—(1) 5.0 (2) Landscape of our practice will be transformed, with the jury still out on how this will impact us in the long-term W.T. Purcell—(1) 5.0 (2) Transparent quality metrics

J.C. Winkelmann—(1) 7.5 (2) Team care

“We’re seeing as much as a 10-fold increase in the price of a drug if a community practice is acquired by a hospital or facility. That’s 10-fold on drugs that are not cheap in the first place.”

—Lee N. Newcomer, MD, MHA

ogy treatments, are expediting hospital acquisition of physician practices, which are finding it difficult to survive on these low margins, according to Dr Newcomer. The consequence is an increase in prices as hospitals use their expanded leverage to negotiate fees.

“We’re seeing as much as a 10-fold increase in the price of a drug if a community practice is acquired by a hospital or facility,” Dr Newcomer said.

“That’s 10-fold on drugs that are not cheap in the first place. The patient pays for that with their copayments and deductibles…and we also have to raise premiums to cover it.”

Site of Care and Costs “One of the consequences of healthcare reform stimulated by the ACA is the requirement that, irrespective of site of service, you become sensitive to your price point and sensitive to quality metrics, because network

management is part of the strategy,” said Michael A. Kolodziej, MD, National Medical Director, Oncology Strategy, Aetna.

The rapid rate of consolidation has resulted in less opportunity to negotiate appropriate site-of-service payment rates (ie, site-of-service differential), he added. The cost differential between a community practice and large hospital system may not reflect differences in services but “winds up being a contracting issue,” Dr Kolodziej said.

Even though the site of care, the services, and the patients may not change when a hospital system acquires a community oncology practice, “the fee schedules convert to the hospital’s negotiated fee schedule, which would be typically higher than we can get in community physician-based clinics,” said Dr Newcomer.

The high rate of acquisition of community practices also runs the risk of leaving remote areas not adequately covered, because larger hospital systems tend to focus on large metropolitan areas, said Dr Ogaily. Traditionally, small community practices have been able to provide and extend coverage to remote areas.

Increasing Demand, Depleting Oncology Workforce The potential effect of a backlog of

Continued on page 11

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Gastric Cancer

Ramucirumab Improves Survival as Second-Line Therapy in Patients with Advanced Gastric Cancer San Francisco, CA—Phase 3 data from a global clinical trial have demonstrated an improvement in overall survival (OS) when the investigational angiogenesis inhibitor ramucirumab is added to chemotherapy as second-line therapy in patients with advanced gastric cancer.

The improvement in survival was more than 2 months with ramuciru­ mab when used after progression with first-line therapy in the Study of Paclitaxel with or without Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW), said lead investigator Hansjochen Wilke, MD, PhD, Director, Department of Oncology/Hematology and Center of Palliative Care, Kliniken Essen-Mitte, Germany, at the 2014 Gastrointestinal Cancers Symposium.

“This trial, and the recently published REGARD trial, demonstrate that ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer and gastroesophageal junction cancer,” said Dr Wilke.

Ramucirumab, a human IgG1 monoclonal antibody that blocks the vascular endothelial growth factor receptor 2, represents the only second-line agent to extend life by as much as 2 months for patients with advanced gastric cancer, commented

pears to be an active drug in the second-line setting that can be used instead of best supportive care or in addition to second-line chemotherapy for patients who can tolerate chemotherapy,” said Dr Krishnamurthi.

“Ramucirumab is an effective new drug for the treatment of patients with metastatic or locally advanced unresectable gastric cancer and gastroesophageal junction cancer.”

—Hansjochen Wilke, MD, PhD

Smitha S. Krishnamurthi, MD, Associate Professor of Medicine, Division of Hematology and Oncology, Case Western Reserve University School of Medicine, Cleveland, OH, who was not involved in the study.

“We’re excited to have what ap-

Implications of the ACA... patient demand created by the ACA on the hematology and oncology workforce needed to meet this demand was raised by Dr Goodman. When added to the demographic shift in the population, patient volumes may exceed the capability of the supply of hematologists and oncologists, necessitating increased use of physician extenders, said John C. Winkelmann, MD, Private Practice Physician, Oncology & Hematology Care, Cincinnati, OH. Other specialties are scrambling to add physician extenders as well, creating competition for their services.

“We’ve got to start over and figure out how we can meet the needs of this large group of cancer patients coming forward into the system. That means a whole different way of approaching,” said Dr Newcomer. Physicians may be the ones directing the care and devising treatment plans, with extenders administering treatments. The physician may then only be involved in the case of toxicity.

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Study Details RAINBOW involved 665 patients with metastatic gastroesophageal junction or gastric adenocarcinoma who exhibited disease progression within 4 months after standard first-line chemotherapy with platinum- and fluoropyrimidine-based combinations. The patients were randomized to a regimen of ramucirumab and paclitaxel or to paclitaxel alone.

Treatment was administered in 4-week cycles until disease progression, unacceptable toxicity, or death.

Adding ramucirumab to second-line paclitaxel significantly improved response rates, OS, and progression-free survival (PFS). The overall response rates were 28% in patients randomized to ramucirumab plus paclitaxel compared with 16% of patients randomized to paclitaxel alone (P = .001).

The median OS improved from 7.4 months with paclitaxel only to 9.6 months with the ramucirumab plus paclitaxel regimen, corresponding to a

Continued from page 10

“One of the consequences of healthcare reform...is the requirement that, irrespective of site of service, you become sensitive to your price point and sensitive to quality metrics, because network management is part of the strategy.”

—Michael A. Kolodziej, MD

“If we rethink it, we can solve the problem, but it needs changing the financing and needs changing how we work with all of our other ancillary providers that care for cancer pa-

tients,” Dr Newcomer said. “It can be done, but we’ll have to be innovative, and that’s the reason that all of us are toying with new ways of paying for cancer care. Whether it be episodes, bundles, or capitation, we’re trying to find a way to realign the incentives to help physicians and hospital communities restructure how they deliver that care. The quicker we can get to that, the better off we’ll all be.”

Provisions under the ACA were geared toward moving providers from a fee-for-service system that warrants volume to one that values outcomes and quality instead, said Dr Fowler.

“It’s a rough transition, particularly for providers that weren’t prepared or didn’t have the technology in place to do this,” she said.

“When you are thinking about what you need to do to meet the quality measures, you’ve got to start thinking about what matters to patients. That might be where survivorship and other issues come into play,” Dr Fowler said. n

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20% reduction in the hazard ratio with ramucirumab (P = .0169).

The 6-month survival rate was 72% versus 57%, and the 12-month survival rate was 40% versus 30% in the ramucirumab/paclitaxel arm versus the pac­litaxel only arm, respectively.

The median PFS was 4.4 months with the ramucirumab/paclitaxel regimen compared with 2.9 months for paclitaxel alone, corresponding to a 36% (P <.001) reduction in risk.

Patients who received ramucirumab plus paclitaxel also reported a reduction in pain and other improvements in their quality of life.

“We’re excited to have what appears to be an active drug in the second-line setting that can be used instead of best supportive care.”

—Smitha S. Krishnamurthi, MD

Adverse Events The most common side effects of treatment with ramucirumab and pac­ litaxel include neutropenia, leukopenia, hypertension, anemia, fatigue, abdominal pain, and asthenia. Although neutropenia was more often reported in the ramucirumab plus paclitaxel group, the incidence of febrile neutropenia was comparable to treatment with paclitaxel alone. All the side effects were manageable, and very few patients discontinued treatment because of them.

The most common grade ≥3 adverse events with ramucirumab were neutropenia (40.7% vs 18.8% in the placebo group), leukopenia (17.4% vs 6.7%, respectively), and fatigue (11.9% vs 5.5%, respectively); febrile neutropenia occurred with similar frequency in both groups (3.1% vs 2.4%, respectively).

Other grade ≥3 adverse events that occurred more often with ramuciru­ mab compared with placebo were hypertension (14.7% vs 2.7%, respectively), bleeding/hemorrhage (4.3% vs 2.4%, respectively), gastrointestinal bleeding (3.7% vs 1.5%, respectively), proteinuria (1.2% vs 0%, respectively), and gastrointestinal perforation (1.2% vs 0%, respectively).—WK n

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FOR YOUR ONCOLOGY PRACTICE NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer recommendations for abiraterone acetate (ZYTIGA®) plus prednisone1: Category 1* Asymptomatic pre-docetaxel mCRPC Symptomatic post-docetaxel mCRPC

FOR PATIENTS WITH mCRPC WHO HAVE PROGRESSED ON ADT† LOCAL‡

THERAPY

ADT

§

ZYTIGA PLUS PREDNISONE

®

For more information, please visit www.zytigahcp.com.

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.

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,

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

ZYTIGA Next ®

5.2 5 .

2 Months 5.2-month difference in median overall survival vs placebo plus prednisone (median OS: 35.3 months vs 30.1 months, respectively)

57% reduction in risk of radiographic progression or death vs placebo plus prednisone (median rPFS not reached vs 8.28 months, respectively)

Significantly increased median time to initiation of chemotherapy vs placebo plus prednisone (25.2 months vs 16.8 months, respectively)¶

Significantly increased median time to opiate use for prostate cancer pain vs placebo plus prednisone (not reached vs 23.7 months, respectively)¶

Hazard ratio (HR) = 0.792; 95% CI: 0.655, 0.956; P = 0.0151; prespecified value for statistical significance not reached.

HR = 0.425; 95% CI: 0.347, 0.522; P < 0.0001.

HR = 0.580; 95% CI: 0.487, 0.691; P < 0.0001.

HR = 0.686; 95% CI: 0.566, 0.833; P = 0.0001.

*Evidence and consensus level rating. †Study Design: ZYTIGA®, in combination with prednisone, was evaluated in a Phase 3, randomized, double-blind, placebo-controlled, multicenter trial in patients with mCRPC who had not received prior chemotherapy (N = 1,088). Patients were using a luteinizing hormone-releasing hormone (LHRH)

agonist or were previously treated with orchiectomy. In the ZYTIGA® arm, patients received ZYTIGA® 1,000 mg orally once daily + prednisone 5 mg orally twice daily. In the placebo arm, patients received placebo orally once daily + prednisone 5 mg orally twice daily. In this study, the coprimary efficacy endpoints were overall survival and radiographic progression-free survival. ‡Local therapy = radiation and/or surgery. § For many patients with mCRPC, gonadotropin-releasing hormone (GnRH)agonist therapy typically continues throughout the disease course, and is used concomitantly with other mCRPC treatments, including ZYTIGA®. This illustration is not intended to suggest that ZYTIGA® is the only treatment option following androgen-deprivation therapy (ADT).

Primary endpoint. ¶ Secondary endpoint.

Reference: 1. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.4.2013. © National Comprehensive Cancer Network, Inc 2013. All rights reserved. Accessed August 2, 2013. For the detailed recommendations, view the most recent and complete version of the Guideline on NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 003307-130924

hypercholesterolemia,hyperglycemia,elevatedAST,hypophosphatemia, elevated ALT and hypokalemia.

Drug Interactions—Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the coadministration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® 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.

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

Please see brief summary of full Prescribing Information on adjacent pages.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2013 10/13 003686-131001

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 terms Edema, Edema peripheral, Pitting edema, and Generalized edema all fractures with the exception of pathological fracture 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.

4 Includes 5 Includes 6 Includes

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 Placebo with Prednisone (N=542) Prednisone (N=540) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39.1 2.2 34.3 1.7 Edema2 25.1 0.4 20.7 1.1 Pyrexia 8.7 0.6 5.9 0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort3 30.3 2.0 25.2 2.0 Groin pain 6.6 0.4 4.1 0.7 Gastrointestinal disorders Constipation 23.1 0.4 19.1 0.6 Diarrhea 21.6 0.9 17.8 0.9 Dyspepsia 11.1 0.0 5.0 0.2 Vascular disorders Hot flush 22.3 0.2 18.1 0.0 Hypertension 21.6 3.9 13.1 3.0 Respiratory, thoracic and mediastinal disorders Cough 17.3 0.0 13.5 0.2 Dyspnea 11.8 2.4 9.6 0.9 Psychiatric disorders Insomnia 13.5 0.2 11.3 0.0 Injury, poisoning and procedural complications Contusion 13.3 0.0 9.1 0.0 Falls 5.9 0.0 3.3 0.0 Infections and infestations Upper respiratory tract infection 12.7 0.0 8.0 0.0 Nasopharyngitis 10.7 0.0 8.1 0.0 Renal and urinary disorders Hematuria 10.3 1.3 5.6 0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7 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

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.

OVERDOSAGE Human experience of overdose with ZYTIGA is limited.

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 20°C to 25°C (68°F to 77°F); excursions permitted in the range from 15°C to 30°C (59°F 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].

Table 4: Laboratory Abnormalities in >15% of Patients in the ZYTIGA Arm of Study 2 Abiraterone (N = 542) Placebo (N = 540) Laboratory Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Abnormality % % % % Hematology Lymphopenia 38.2 8.7 31.7 7.4 Chemistry Hyperglycemia1 56.6 6.5 50.9 5.2 High ALT 41.9 6.1 29.1 0.7 High AST 37.3 3.1 28.7 1.1 Hypernatremia 32.8 0.4 25.0 0.2 Hypokalemia 17.2 2.8 10.2 1.7 1Based 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 Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3) in full Prescribing Information].

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.

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 (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].

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: September 2013 003185-130920

4th Conference Abstracts Abstracts to Be Presented at the Fourth Annual Conference of the Association for Value-Based Cancer Care May 6-9, 2014 Lowes Hollywood Hotel, Los Angeles, CA

Category: Advocacy and Community Involvement

The Advocacy Connector: Bridging the Knowledge Gap

Joanne Vanak, RN, MSN1; Ellen Ivey, BS2; John Kerrane, MS, RPh3; Susan King, RN, MS, OCN4 1 Janssen Services, LLC, Horsham, PA; 2Johnson & Johnson Healthcare Systems, Inc.; 3Janssen Biotech, LLC; 4Pharmacyclics, Inc. Objective: There is a knowledge gap between the capabilities of advocacy groups and healthcare providers (HCPs) and patients. The need to create awareness about valuable resources, available through not-for-profit organizations, for HCPs, patients, and caregivers led to the creation of the “Advocacy Connector” (www.advocacyconnector.com). This web based resource links patients and HCPs to a variety of advocacy groups that serve to address a host of patient needs (e.g., emotional, educational and financial support). Initially, this resource will focus on the area of oncology and a rare disorder, Castleman’s disease.

Methods: Not-for-profit state and national level advocacy groups focusing on services directed towards oncology patients across the United States were given a survey to complete. Information regarding state-level advocacy groups was gleaned from all 50 states. Individuals within the groups were asked if they would participate in an on-line resource that would highlight the capabilities of their respective organizations. The advocacy groups identified their key services, the results of which were then reviewed and validated by an independent vendor.

Results: The Advocacy Connector is a compilation of information from both state and national level advocacy groups, specifically focused on the following cancer-related diseases: prostate, ovarian, breast, colorectal, and lung, as well as leukemia, lymphomas, and myelomas. Advocacy Connector is organized so that patients and HCPs can easily access information about each advocacy group according to the type of services they provide for each type of cancer. Available information includes: help-lines, alternative and complementary therapies, research, caregiver support, clinical trial information, counseling, end-of-life care, financial assistance, legal/insurance assistance, men’s health, pain management and palliative care, screening and early detection, spiritual support, survivorship, travel services, veteran services, wellness, nutrition and exercise, women’s health, and young adult cancer support. Materials may be printed for home-use by patients and caregivers. Telephone numbers for the resources are included in the printed information for those who have no access to computers. Information is also available in non-English languages (e.g., Spanish).

Conclusion: We believe the Advocacy Connector will help bridge the knowledge gap by increasing awareness of the extent of services offered by oncology advocacy groups and thereby increase patient knowledge, access to services, and overall satisfaction.

Category: Benefit Design and Coverage Trends

Benefit Design Trends and Value-Based Oncology Coverage Related Findings from the 2013 National Employer Survey FR Vogenberg, C Larson, M Rehayem, and L Boress

Background: Aside from healthcare reform, healthcare costs are a continued concern among employers and other purchasers that extend to biologics/oncolytics that are being increasingly scrutinized to demonstrate value over time. A significant cost challenge to employers, these drugs create logistical issues for patients, physicians, pharmacies, and manufacturers owing to their unique approval requirements, dosing, side effects, and distribution methods. Costs of biologics continue to be hard to track as they show up in both medical as well as pharmacy benefit claims.

Objective: To assess the change in level of benefit design, knowledge and communication gaps of employer plan sponsors in the area of specialty pharmacy (SP) and biologic products for conditions such as cancer, rare and immune disorders, and to identify opportunities for future benefit coverage innovation.

Methods: An online survey instrument was developed through an advisory council comprising self-funded employers in late fall 2013. The survey was disseminated through 25 business coalitions across the U.S. during 4Q2013 for completion

by February 2014. Results were then analyzed by the Midwest Business Group on

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Health (MBGH, Chicago, IL) and the Institute for Integrated Healthcare (IIH, Greenville, SC).

Results: The 85 self-funded employers of varying size and representative SIC types completed the survey. Multi-year results for the 2014 report derived from 2011-2013 survey trends indicated that there is a continuing knowledge gap about SP; and employer and senior leadership level understanding of SP. Similar to 2012, the 2013 results showed that many did not know whether their company’s claim costs for specialty drugs had increased along with a lack of priority for action.

Again in 2013, most employers are using primarily traditional benefit designs (e.g., tiered formularies, copay, and coinsurance) and not using first fill options instead of innovative benefit designs (i.e. value-based) that may be more appropriate for oncology/SP. Vendor performance continues to be highly valued yet the benefit designs continue to omit incentives to ensure aligned benefit designs for compliance to medication therapy or adherence to treatment. The growth of HDHPs is another example of the growing trend in cost sharing among employers.

Conclusion: There remain knowledge gaps and benefit design innovation opportunities lost among commercial plan sponsors that are important to those who manage oncology services or risk. 2013 survey findings demonstrate employers’ relatively low knowledge of SP drug design implications, appropriate support technologies and vendor contracting options available in their plan. Employers who improve their understanding of the many challenges in managing this area will be able to more effectively manage costs and drive better patient outcomes to meet their business objectives.

Category: Improving Patient Access, Initiation, and Adherence

Developing Clinically and Culturally Responsive Survivorship Care Plan for Breast Cancer Kimlin Ashing, PhD; Monica Rosales, PhD; Mayra Serrano, MPH; African American Cancer Coalition, Latina Breast Cancer Taskforce; Courtney Vito, MD, Benjamin Paz, MD; Jeffery Weitzel, MD; Lilly Lai, MD

Background: African and Latina-American breast cancer patients (BCA) experience the greatest morbidity and mortality, suggesting a critical need for improved surveillance and quality care. The Institute of Medicine (IOM) and the Commission on Cancer (CoC) recommend that survivors receive personalized Treatment Summaries and Survivorship Care Plans (TSSCP) in order to facilitate best practice in clinical surveillance and follow-up care. This TSSCP template development study joined advocacy, scientific and medical communities to comprise a diverse advisory council (AC, N=38) to inform the development of the TSSCP-AA (African American) and TSSCP-S (English and bilingual English-Spanish) templates targeting BCA. This study reports on the development, and preliminary stakeholder evaluation of TSSCP-AA and TSSCP-S. Methods: The overall study was guided by the Shared Care and Psychooncology Models, and Contextual Model of Health Related Quality of Life. The AC provided consensus input into the clinically and culturally relevant modifications of the American Society of Clinical Oncology (ASCO) TSSCP template to create the TSSCP-AA and TSSCP-S. Diverse stakeholders including patient advocates and health care professionals enlisted from cancer centers and community hospitals (n=51) evaluated the TSSCP-AA and TSSCP-S templates on the following domains: content, clarity, utility, and cultural and socioecological responsiveness.

Results: AC input revealed that the clinical (i.e., comorbidities) and cultural contexts (i.e., language, spirituality) must inform TSSCP to increase responsiveness and applicability to the target population. Preliminary evaluation analyses documented that stakeholders rated our TSSCP-AA and TSSCP-S templates as excellent to outstanding on content, clarity, utility, cultural responsiveness, and socioecological responsiveness (p<0.01).

Conclusion: The evaluation results imply that the TSSCP-AA and TSSCP-S templates achieved clinical and cultural responsiveness with high acceptability and utility among professionals and survivors. We created both paper and electronic versions of the TSSCP-AA and TSSCP-S for providers to create individualized TSSCPs.

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4th Conference Abstracts Category: Innovation in Practice Management

Improving Oncology Quality Through the Implementation of Evidencebased Clinical Pathways in a Payer’s Oncology Network Daniel McCrone, MD; Dudley Gill, MBA; Cecilia Tran, PharmD, BCOP; Michael Sturgill

Background: Physicians and health plans are collaboratively exploring clinical pathway strategies to improve patient outcomes, reduce treatment variation and reduce oncology cost. Studies have demonstrated that the use of pathways can lower the cost of care and that oncologist participation is a critical element for success.

Objectives: New Century Health (NCH), in partnership with a leading health plan and one of its Midwestern oncology networks, had two quality goals with the implementation of a chemotherapy prior authorization system: • Review all chemotherapy regimens for all patients • Measure treatment plan adherence to evidence-based clinical pathways Methods: As one component of a mandatory chemotherapy prior-authorization program, an online prior authorization system was used by oncology practices to submit chemotherapy treatment plans to NCH for approval. The system: • Captured detailed patient clinical information • Measured compendium and preferred pathway adherence rates. These data were shared with participating oncology practices on a quarterly basis.

For analysis, an average Baseline compendium adherence rate was determined reflecting participating practices for six cancer diagnoses (Breast, Colon, Lung, Lymphoma, Multiple Myeloma and Prostate). The Baseline rate was compared to the Review period rate.

Results: A comparison of the Review and Baseline period metrics indicated a statistically significant increase in the level of compendium-based chemotherapy treatment plans submitted by participating providers.

Statistic

Result

Baseline Target Metric (Q1 2011): On-Compendium Adherence % Review Period Target Metric Mean: On-Compendium Adherence % P-Value

(76/92) = 82.6% 91.8% .021

End Period Current Mean (Q4 2012): On-Compendium Adherence %

(115/118) = 97.5%

Conclusions: Implementation of an oncology prior authorization system that measures compendia-based adherence rates is associated with increased levels of evidence-based chemotherapy treatment plans by participating providers.

Category: Models of Care Delivery

Implementation Strategies for Integrated Health System Nursing Specialty Group Patricia E. Emerson, RN, MSN, OCN Riverside Health System

This session will focus on the concepts found to be most essential to the success of building, and sustaining a healthcare system wide oncology nursing network.

By highlighting our healthcare system’s quality commitment pillars, the framework uses people, integration, safety & quality, growth, and finance as guiding principles. This presenter will demonstrate how integration and collaboration has occurred as the result of monthly conference calls whereby subgroups report work being accomplished, and identify areas of opportunity representing all geographical locations within one health system. The Oncology Nursing Society’s values, mission, and commitment to the professional growth of oncology nurses has also served as a blueprint for the structured development of this team.

The Riverside Oncology Network is currently planning the third annual Oncology Nursing Conference, has reviewed and standardized all oncology nursing applicable policies and procedures, competencies, and orientation manuals, increased system wide Oncology Certified Nursing (OCN) percentile from 40% to 65% within two years, hosted educational dinner talks, developed a specialty group newsletter, and provided a collegial networking forum for the group to enhance standardization and core safety measures.

Category: Models of Care Delivery

Quality & Cost Implications of Patient Navigation

Cheryl Gelder-Kogan, MHSA, Frederick M. Schnell, MD, FACP, Avery Winslett Central Georgia Cancer Care, in partnership with the Cancer Clinics of Excel-

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lence (CCE), implemented a patient navigation program in order to improve the quality of life for its patients and to explore strategies that would simultaneously reduce the total cost of providing care to an oncology patient population. Early results demonstrate that a lay navigator is extremely effective in: • Helping patients maintain their proposed treatment regimens • Managing treatment associated symptoms • Avoiding trips to the emergency department • Minimizing inpatient hospitalizations • Educating the patient on the role of early palliative care, especially as a strategy to maintain a vigorous treatment schedule • Providing frequent care management interventions to identified high risk patients • Helping the patient understand available options when curative treatment is no longer feasible • Understanding and completing an advanced care directive, providing the patient and their loved ones with peace of mind • Helping to make the transition, when appropriate, to hospice care • Supporting and addressing the needs of caregivers • Providing needed emotional support for patients and caregivers • Finding financial, transportation and other resources to meet the needs of patients undergoing cancer treatment.

In response to the frustration on-call physicians have when patients experience symptoms after regular clinic hours, an “emergency” medication packet was developed. This emergency packet contains a very small supply of Ativan, Immodium, Dulcolax, Zofran and a prescription for Oxycontin. These drugs, which are frequently used by oncology patients but may not yet have been needed, enable the physicians to have the patient take something to address their symptoms—until they can be seen in the office the next day. Patients appreciate having something readily available, immediately at the time of need, and are grateful to avoid a trip to the emergency department.

Additionally, the navigation program has also explored strategies to ensure that all patient treatment regimens comply with nationally recognized and CCE approved treatment protocols and also monitors use of PET/CT scans, with an eye towards utilizing the lower cost test to answer the question being posed.

Early experience suggests that physicians benefit from having the navigator serve as “intermediary” and patient advocate. They appreciate that patients often feel more comfortable sharing details of their experiences with someone who is not directly “providing” their care.

The navigation program is tracking each intervention and estimating both the impact on quality for the patient and projecting total cost impact. The data generated from this program will be useful for other community based oncology programs looking to enhance the level of service provided to their patients and to payers that are addressing the total cost of care to high utilization and high cost oncology patients.

Category: Oncology Practice Management, Navigation, & Advocacy Day

How to Implement Oncology Disease Site Specific Multidisciplinary Centers (MDCs) Kelley D. Simpson and Tricia Strusowski, RN, MS

Patients, families and their caregivers are insisting on multidisciplinary care when they are diagnosed with cancer. Multidisciplinary care is a treatment planning approach that includes a surgeon, medical oncologist and radiation oncologist along with the cancer center support staff. The support staff could include a navigator, social worker, genetic counselor, dietitian and others as the specific disease site stipulates. The team meets with the patient and their family, reviews their test results, imaging, medical history and creates a plan of care based on national guidelines, diagnosis and stage of disease. The goals are to increase communication among the healthcare team, create an individualized treatment plan based on national guidelines, increase clinical trial enrollment, reduce time to treatment and avoid treatment breaks, and provide patient centered care by including the patient in the decision making process. The primary benefits to MDC care are: • To provide “one stop shopping” for the patient and their family; • To enhance the patient experience and informed decision making; • To elevate the accuracy of treatment plan by increasing discussion by physician and support staff; and, • To incorporate screening for barriers to care and psychosocial distress and coordinate with the appropriate support staff.

The treatment plan is highly coordinated and the patients value their participa-

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tion in the planning phase of their care. The patient leaves with a written summary and an assigned nurse navigator to ensure coordination of their appointments and coordinate support services.

There are many details when implementing multidisciplinary programs and clinics; this is where the process can become overwhelming for a cancer program.

The models and infrastructure of the multidisciplinary centers can vary based on the physical layout of the cancer center and availability of the physicians and support staff. Patient referrals and workflow before, during and after the MDC appointment must be meticulous and all staff must have a full understanding of their roles and responsibilities. The responsibilities must be completed in a specific order to ensure a successful patient visit—a couple of examples are gathering correct medical records, imaging and tests as well as insurance verification and authorization with a full review with the patient is required.

The day of the MDC visit may vary based on the cancer disease site, volume of patient appointments and physician interactions. Although the documentation and flow remain the same, the dynamics of the team may differ. High volume disease site MDCs will need to function very differently than low volume sites, with great options to enhance the logistics and patient flow while still ensuring an outstanding patient experience.

After the MDC appointment there is still a tremendous amount of work to be accomplished. The physician orders must be completed, dictation and billing in compliance with the financial department and follow-up treatment summary sent to the referring physician. The role of the navigator is vital to effectively review with the patient the treatment plan, coordinate appointments and answer any outstanding questions.

The overall multidisciplinary center experience for the patient, their family, physicians and the support staff is superb, providing high quality coordinated care.

This presentation will provide the details to ensure a successful implementation of multidisciplinary centers.

Category: Oncology Practice Management, Navigation, & Advocacy Day

Navigation: Patient Experience, Clinical and Financial Outcomes Kelley D. Simpson and Tricia Strusowski, RN, MS

Robust navigation programs across the country include outreach/screening, treatment and survivorship navigators. The Commission on Cancer (CoC) has outlined new standards to be phased in for 2015 on the navigation process, including a community needs assessment, psychosocial distress screening and the survivorship care plan. The role of the navigator is to assess the patient’s and family’s understanding of their diagnosis and treatment, assess and remove barriers, provide psychosocial screening, and coordinate support staff and appropriate resources.

The first step in the process is to complete a thorough community needs assessment to understand patients in the community and their specific needs and barriers to care.

This creates a strong foundation for the navigation program across the entire continuum of care. The navigation program must be created and modified to meet the needs of the patient through the community needs assessment. The navigation matrix created by the National Comprehensive Cancer Center Program (NCCCP) Navigation Networking Committee is another excellent tool to utilize to incorporate all the essential components into a program. The matrix categorizes 16 elements with levels 1 through 5. Every navigation program is unique and the role of the matrix is not to gauge one program against another but to provide guidance to create a stronger program. Some of the elements include key stakeholders, acuity systems, reporting/ quality measures, focus on disparities, clinical trials, etc. As the navigation program is built patient experience, clinical and financial outcomes should be a high priority, this will ensure the patient is always in the forefront and high clinical standards will help ensure financial strength.

The Institute of Medicine shared some staggering outcomes specific to the patient experience in oncology, the number one statement from cancer patients was “listen to me.” Other comments included…“tell me the full truth about my diagnosis,” “tell me about the risks.” Cost concerns were also a major worry as was not fully understanding all the options available for their cancer treatment. Patients want to participate in the care planning sessions with their health care team to make informed decisions. There are excellent measures to ensure a superb patient experience such as: • Measure outcomes/interventions related to barriers to care and distress screening • Report outreach/navigation of disparate populations • Patient experience survey

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• Quality of Life survey—Cancer Survivor version • Patient education packets for surgery • Caregiver toolkit • Patient appointment checklist • Survival toolkits for families • Tele-monitoring program for patients • Complementary and alternative therapies/outcomes • Cancer disease site specific rehabilitation programs.

Measuring clinical outcomes elevates the standard of oncology care. Every navigation program needs to incorporate research and quality measures into its foundation. Some examples are: • Clinical care in concordance with National Comprehensive Cancer Network (NCCN) or other national guidelines • Tumor conference audits, review of recommendations, NCCN guidelines and stage documentation • Time of diagnosis to first treatment modality • Survivorship surveillance plan compliance/monitoring • Monitoring of late/long term effects of cancer treatment • Creating standing order sets by cancer disease site for multidisciplinary teams • Clinical trial education and referrals to Cancer Research • Disease site specific clinical initiatives, example, measuring head and neck cancer patient referrals to dentist for dental clearance prior to initiating treatment • Oncology rehabilitation programs by cancer disease site.

Financial outcomes are very important for maintaining a navigation program.

Navigation programs can be very expensive and return on investment is critical.

Some financial outcomes to measure include: • Decrease emergency room visits and re-admissions • Medication reconciliation program • Self-pay patients assessed and referred to Medicare or Medicaid • Medical home for oncology patient • Length of stay reduction, partner with inpatient oncology unit • Downstream revenue for imaging, tests, procedures • Referrals to revenue generating support services • Patient retention rates/decrease outmigration • Care in concordance with NCCN or other national guidelines • Targeting primary care physician/specialist for referrals to specific disease site cancers, i.e. screening for lung cancer, referrals for navigation/support services.

In conclusion navigation, patient experience and outcomes are imperative for a state of the art cancer program. This presentation will provide ideas and examples to further enhance conference attendees’ navigation programs and or introduce new concepts for those preparing to institute a new program in alignment with CoC 2015 standards.

Category: Patient and Survivor Care

The Impact of Anthracycline on Progression-Free Survival and Time-toTreatment Failure in Patients with Metastatic Breast Cancer Receiving Eribulin Mesylate in a Community Oncology Setting Faria C1, Knoth R1, Jackson J2, Lunacsek O2, Hennenfent K2 Eisai, 2Xcenda LLC

1

Objectives: In a phase 3 study of metastatic breast cancer (MBC), eribulin demonstrated a significant overall survival improvement for heavily pretreated patients, including both prior anthracycline and taxane therapy. Eribulin is FDA-approved for these patients. This study’s purpose was to evaluate progression-free survival (PFS) and time-to-treatment failure (TTF) in anthracycline-experienced patients (AE) compared with anthracycline-naïve patients (AN) with MBC receiving eribulin therapy in a real-world practice setting.

Methods: Patients with MBC initiating eribulin (November 2010-January 2013) were identified in an electronic medical record database of 21 US community oncology practices. PFS and TTF were compared between the AE and AN cohorts using the Kaplan-Meier method and Cox proportional hazards models adjusted for age, region, presence of multiple metastatic sites, and number of metastatic therapy lines.

Results: Study criteria were met by 178 AE and 76 AN patients. Age was lower for the AE cohort (median AE=59 yrs vs AN=65 yrs, P=0.0006), while the proportions of patients with multiple metastatic sites (78% for both cohorts, P=ns), triple-negative MBC (AE=22% vs AN=21%, P=ns) and HER2-positive MBC (AE=17% vs AN=13%, P=ns) were similar. Number of metastatic lines of therapy prior to eribulin (median AE=5 vs AN=4, P=ns) were also similar. Of the AE patients, 57% received

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4th Conference Abstracts anthracycline in the adjuvant setting, 37% in the metastatic setting, and 6% in both settings. Median PFS (AE=3.3 mo vs AN=4 mo; P=0.5419) and median TTF (AE=2.8 mo vs AN=2.3 mo; P=0.6511) were not statistically different between cohorts, although PFS numerically favored AN, and TTF favored AE. Adjusted analyses did not show significant inter-cohort differences in the risk of progression (hazard ratio (HR)=1.073; 95% CI 0.753-1.53; P=0.6947; reference=AN) or risk of treatment failure (HR=0.953; 95% CI 0.717-1.267; P=0.7385; reference=AN).

Conclusion: In this retrospective study evaluating the impact of prior anthracyclines on treatment outcomes, MBC patients with and without prior exposure to anthracyclines achieved similar treatment benefit from eribulin.

Category: Patient and Survivor Care

Impact of Duration of Prior Taxanes on Progression-Free Survival and Time-to-Treatment Failure in Patients with Metastatic Breast Cancer Receiving Eribulin Mesylate in a Community Oncology Setting Faria C1, Knoth R1, Jackson J2, Lunacsek O2, Hennenfent K2 Eisai, 2Xcenda LLC

1

Objectives: Patients with metastatic breast cancer (MBC) commonly develop chemotherapy-resistant disease, leaving few effective treatment options. In a phase 3 trial, eribulin demonstrated a significant improvement in overall survival for heavily pretreated patients who received prior anthracyclines and taxanes. Moreover, in preclinical studies, eribulin retained activity against taxane-resistant cell lines. This study’s purpose was to evaluate the impact of the duration of prior taxane therapy on progression-free survival (PFS) and time-to-treatment failure (TTF) in patients with MBC treated with eribulin in a real-world practice setting.

Methods: Patients with MBC initiating eribulin (November 2010-January 2013) were identified in an electronic medical record database of 21 US community oncology practices. Two cohorts were created: patients who received ≥6 months of taxane therapy (TGE6) in the metastatic setting prior to eribulin, and patients who received <6 months of prior taxane therapy (TLT6). PFS and TTF during eribulin therapy were compared between the TGE6 and TLT6 cohorts. Treatment failure was defined as discontinuation of eribulin therapy for any reason, including progression, toxicity, or other/unknown reason. PFS and TTF were analyzed using the Kaplan-Meier method and Cox proportional hazards models adjusted for age, region, presence of multiple metastatic sites, and number of metastatic therapy lines.

Results: Study criteria were met by 54 TGE6 and 136 TLT6 patients. Age (median TGE6=62 yrs vs TLT6=61 yrs, P=ns), proportions of patients with multiple metastatic sites (TGE6=80% vs TLT6=77%, P=ns), triple-negative MBC (TGE6=15% vs TLT6=24%, P=ns) and HER2-positive MBC (TGE6=9% vs TLT6=15%, P=ns) were similar between cohorts. Number of metastatic lines of therapy prior to eribulin (median TGE6=6 vs TLT6=4, P=0.0067) was higher for the TGE6 cohort. Median PFS (TGE6=3.2 mo vs TLT6=3.4 mo; P=0.4909) and median TTF (TGE6=3.2 mo vs TLT6=2.7 mo; P=0.0518) were not statistically different between cohorts, although PFS numerically favored TLT6, and TTF favored TGE6. Adjusted analyses did not show significant inter-cohort differences in the risk of progression (hazard ratio (HR)= 0.824; 95% CI 0.56-1.214; P=0.3287; reference=TLT6) or risk of treatment failure (HR=0.732; 95% CI 0.525-1.02; P=0.0651; reference=TLT6).

Conclusion: In this retrospective study, patients receiving prior taxane therapy for less than 6 months achieved similar treatment benefit from eribulin compared with those patients who were treated with taxanes 6 months or longer in the metastatic setting.

Category: Policy, Advocacy, and Economy

Cost Considerations for New Oral Therapies for Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Previously Treated with Docetaxel Lorie A. Ellis1, R. Scott McKenzie1, Mekre Senbetta1 Janssen Scientific Affairs, LLC, Horsham, PA

1

Objective: Abiraterone acetate (AA) and enzalutamide (EN) are two novel oral agents approved for use in docetaxel-treated mCRPC patients. Phase 3 studies in docetaxel-treated mCRPC populations showed median treatment duration of 8 months for AA+prednisone (AA+P)1 and 8.3 months for EN.2 The budgetary impact of these products to payers depends upon real world treatment duration, adherence, and the proportion of patients utilizing each product. This research modeled expected pharmacy costs of AA+P or EN in docetaxel-treated mCRPC patients.

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Methods: Pharmacy costs for a 30-day supply of the recommended dosage of AA+P1 ($6,846.36) and EN2 ($7,889.55) were calculated using the following drug wholesale acquisition costs3: AA - $6,836.59 (10/15/13); P- 5mg tablet (West-Ward Inc, $16.28 per 100 units (9/25/13); or $9.77 for a 60 unit, 30-day supply); and EN - $7,889.55 (9/4/13). Costs of 8 or 12 treatment months per patient and for an estimated number of treated patients were modeled. Docetaxel-treated mCRPC population estimates were derived from a dynamic progression model.4 Results: In a 1,000,000 member plan, the model estimated 57 docetaxel-treated mCRPC patients. For a 240 day (approximately 8 month) treatment duration, estimated AA+P cost was $54,770.88 per patient and $63,116.40 per patient for EN, a difference of $8,345.52 per patient. The modeled cost for 360 days of therapy (approximately 12 months) was $82,156.32 per patient for AA+P and $94,674.60 per patient for EN, or a difference of $12,518.28 per patient. The expected budget impact of approximately 8 treatment months in a 1,000,000 member plan with 25% (14) of the estimated 57 docetaxel-treated mCRPC patients receiving AA+P and 25% (14) receiving EN was $766,792.32 (AA+P) or $883,629.60 (EN), a difference of $116,837.28. Based on similar assumptions, the expected budget impact of approximately 12 treatment months was $1,150,188.48 (AA+P) and $1,325,444.40 (EN), a difference of $175,255.92.

Conclusions: In this cost model, treatment of post-docetaxel mCRPC patients with AA+P was less costly than EN when treatment duration, adherence, and number of treated patients were held constant. EN therapy resulted in an additional $116,848.28 and $175,255.92 in plan spending for an 8 or 12 month course of therapy, respectively.

References:

1. Zytiga® Prescribing Information; Janssen Biotech Inc (2013).

2. Xtandi® Prescribing Information; Astellas Pharma US, Inc (2012).

3. Analysource/First Data Bank.

4. Solo K, et al. Presented at ASCO Annual Meeting, 2011.

Category: Policy, Advocacy, and Economy

Healthcare Resource Utilization (HRU) in Patients with Relapsed/ Refractory Chronic Lymphocytic Leukemia

Chris Kozma1, Terra Slaton1, Scott McKenzie2, Lorie Ellis2, Brad Schenkel2 CK Consulting, 2Janssen Scientific Affairs, LLC

1

Objective: There is a paucity of data regarding healthcare resource utilization (HRU) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

This observational study investigated patient demographics, CLL treatment patterns, and HRU during the six months following treatment initiation for relapsed/ refractory CLL. Methods: This observational analysis was conducted using commercially available U.S. administrative claims data. Inclusion criteria were age ≥18 years, relapsed (chemotherapy claims following a 90 day treatment gap after initial therapy) or refractory (claims for additional agents to initial therapy) CLL, and six months eligibility following the first relapsed/refractory chemotherapy date. Exclusion criteria included patients with claims for pregnancy or non-CLL chemotherapies. CLL chemotherapies of interest included alemtuzumab, bendamustine, chlorambucil, cyclophosphamide, cytarabine, doxorubicin, etoposide, fludarabine, lenalidomide, ofatumumab, oxaliplatin, pentostatin, rituximab, vincristine, or combinations. Demographics, CLL chemotherapy treatment patterns and HRU data were summarized using descriptive statistics. HRU patterns based on initial claims from 20052012 were analyzed for the six months following relapsed/refractory CLL therapy.

Results: This analysis identified 486 patients with a mean age of 70 (SD 11) years and 62% male. Initial therapy varied; however, 72% of relapsed/refractory CLL therapies consisted of one of the following regimens: rituximab monotherapy, chlorambucil monotherapy, cyclophosphamide-fludarabine-rituximab, and fludarabine-rituximab. Chemotherapy claims were observed during a mean of 2.3 (SD 1.5) months in the six months of follow-up. The HRU analysis identified 17% with claims for white blood cell colony stimulating factors, 12% with claims for red blood cell growth factors, 5% with claims for red blood cell transfusion, and 1% with claims for stem cell transplantation. The mean number of hospitalizations (including patients with no hospitalizations as zeros) was 0.2 (SD 0.5)/patient incurring a mean of 1.3 (SD 4.0) hospital days. In the 85 patients hospitalized, the mean hospital length of stay was 7.7 (SD 6.5) days.

Conclusions: This observational study of 486 CLL patients with relapsed/refractory CLL reported significant HRU in the six months following initiation of therapy for relapsed or refractory disease. These results provide an indicator of CLL disease Continued on page 20

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burden and allow stakeholders to estimate HRU in the six months following therapy initiation for relapsed/refractory disease.

Category: Policy, Advocacy, and Economy

Ibrutinib Therapy for Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia: A Budget Impact Analysis from a US Payer Perspective Senbetta M1, Dandappanavar A2, Schenkel B1, O’Day K2 1 Janssen Scientific Affairs, LLC, Horsham, PA 2 Xcenda, Palm Harbor, FL

Objective: In 2013, an estimated 15,680 new cases of chronic lymphocytic leukemia (CLL) were diagnosed, and 4,580 attributable deaths occurred in the US.1 Despite improvements in first-line therapy for CLL, a majority of patients eventually develop relapsed/refractory (R/R) disease and are faced with limited therapeutic options.2 Ibrutinib is FDA-approved for the treatment of CLL patients who have received at least one prior therapy. Due to increased health care costs, health plans are interested in the budget impact of new treatments. The purpose of this study was to estimate the budget impact of adding ibrutinib for R/R CLL to a US health plan formulary over a 1-year time horizon.

Methods: A model was developed to evaluate the budget impact of ibrutinib in a hypothetical 1-million member US health plan. Comparators included NCCN-recommended, commonly prescribed regimens for R/R CLL patients, including ofatumumab and lenalidomide monotherapies, and combinations of bendamustine + rituximab, lenalidomide + rituximab, and fludarabine + cyclophosphamide + rituximab. Dosing, administration, mean duration of therapy (DOT), and adverse event (AE) rates were based on package inserts for approved drugs and published literature for other regimens. Drug, administration, and AE costs were considered. The estimated treatment-eligible population was based on epidemiologic data and a database analysis. Market share was estimated for each treatment with and without ibrutinib. The incremental per-treated-member-per-month (PTMPM) and permember-per-month (PMPM) costs were calculated. One-way sensitivity analysis was performed.

Results: The model estimated a treatment-eligible population of 112 R/R CLL patients in a 1-million member health plan. Based on the comparators and assumptions listed above, the incremental budget impact of adopting ibrutinib for R/R CLL patients for a duration of 12 months is estimated to be $69.00 PTMPM and $0.01 PMPM. The model results were most sensitive to ibrutinib DOT, followed by number of previously treated CLL patients, and proportion of the health plan population ≥65 years of age.

Conclusions: The model results indicate that reimbursement of ibrutinib for eligible R/R CLL patients may have a minimal impact on a US health plan budget despite a longer DOT relative to the comparators in the model. This is relevant considering the efficacy and safety benefits of ibrutinib for this orphan disease with high unmet need.

References: 1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin.

2013;63(1):11-30.

2. Veliz M, Pinilla-Ibarz J. Treatment of relapsed or refractory chronic lymphocytic leukemia. Cancer Control. 2012;19(1):37-53.

Category: Policy, Advocacy, and Economy

Out-of-Pocket Costs Among Women with Metastatic Breast Cancer

Jacqueline Hall, MSPH1; Marco daCosta DiBonaventura, PhD2; Ronda Copher, PhD1; Claudio Faria, PharmD, MPH1; Rose Lorenzo, BA2 1 Eisai, Inc. Woodcliff Lake, NJ. 2 Kantar Health. New York, NY. Objectives: Metastatic breast cancer (mBC) accounts for about 4% of all incident breast cancer cases annually. Although a growing number of treatment options are available, many are expensive and can place an out-of-pocket (OOP) cost burden on the patient. The aim of this study was to provide current estimates of the OOP cost burden reported by women with mBC and how these costs vary by demographic factors.

Methods: Data were collected through a cross-sectional Internet survey of 181 women diagnosed with mBC who had prior experience with either a taxane, pacl-

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itaxel, or docetaxel. Patients provided demographic, health history, and monthly OOP cost information. Monthly OOP costs were stratified by various demographic factors; ANOVA tests were used to examine significant differences across these variables.

Results: Women had a mean age of 52.24 years (SD=9.11) and 93.92% were non-Hispanic white. Nearly half (47.51%) had annual household incomes greater or equal to $75K; 71.82% were college-educated and 89.50% had private insurance.

Mean overall OOP costs in the past month were $302 (SD=$785) for breast cancer treatments, $107 (SD=$200) for physician visits, $27 (SD=$51) for non-breast cancer treatments, and $12 (SD=$27) for non-breast cancer physician visits. There was a significant association between region and monthly OOP breast cancer treatment costs; specifically, women in the Midwest reported the highest costs ($587) compared with costs in other regions (South = $190 to Northeast = $198; p<.05). Although not significant, there was a trend toward higher breast cancer treatment costs among those with a college education ($322 vs. $254), higher incomes ($120 for those with an annual income of <$25K vs. $389 for those with $75K or more), and with private insurance ($317 vs. $244).

Discussion: Breast cancer-related treatment costs comprised the largest share of OOP costs for women with mBC, nearly triple that of breast cancer-related physician visits. Although the overall sample was generally affluent, OOP costs increased as socioeconomic indicator variables increased (e.g., education, income, insurance), potentially suggesting a greater ability and willingness to pay OOP costs among these subgroups.

Category: Quality Research and Patient Safety

Avoidance of Fulminant Liver Failure from Hepatitis B Reactivation with Chemoimmunotherapy: A Value-Based Approach Kevin B. Knopf, MD, MPH; and Samantha Siegel, MD California Pacific Medical Center, San Francisco, California

Fulminant liver failure is an almost invariably fatal complication of hepatitis B reactivation seen in patients who are infected with Hepatitis B and receive Rituximab and other anti-CD20 immunotherapies. In addition, fulminant liver failure can occur in cancer patients with Hepatitis B who are receiving cytotoxic chemotherapy. Often patients receiving these regimens are treated with curative intent (e.g. diffuse large cell non-Hodgkin’s lymphoma, adjuvant chemotherapy for breast cancer) and thus avoidance of this complication is desirable. The only known treatment for fulminant liver failure in this setting is orthotropic liver transplant.

We have developed a cost-effective approach to avoiding fulminant liver failure in a high risk population.

NCCN guidelines recommend screening for hepatitis B serologies in any patient who is to receive Rituximab therapy—which we extend to all therapies that are anti-CD20 including newer agents. Review of the literature regarding fulminant liver failure and cytotoxic chemotherapy revealed that the regimens most strongly associated with reactivation of HepB and fulminant liver failure were those that included doxorubicin and higher doses of cyclophosphamide. Therefore we have targeted Hepatitis B screening to patients receiving these two chemotherapy drugs.

To manage resources effectively we target patients felt to have a high probability of occult hepatitis B are screened—these include patients who have had a blood transfusion in a foreign country where screening of blood products for Hep B may not be 100%, those with a transfusion more than 20 years ago, and those patients where Hepatitis B can be passed vertically—including first and second generation Asian American immigrants.

Patients deemed at high risk are checked for Hepatitis B surface Antigen (HepBSag) and Hepatitis B Core (HepBCAb) antibodies only. No routine imaging is performed. Patients previously known to be HepBSag positive and patients who are discovered to be HepBSag positive who are to receive high-risk chemo/ immunotherapy are then started on entecavir (Beraclude) 0.5 mg a day two weeks before starting therapy and this is continued for 6 months after completion of therapy. Patients who are HepBAg– and HepBCab+ are monitored with HBV DNA levels monthly during therapy with initiation of entecavir if HBV DNA becomes detectable.

By selectively screening enriched populations for occult HepB infection, treating appropriate patients with entecavir, and minimizing laboratory testing and imaging we have created a value-driven cost-effective approach to minimizing fulminant hepatic failure in patients receiving chemo/immunotherapy. Cost estimates based on San Francisco pricing will be presented with the poster.

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1st oral kinase inhibitor for previously treated CLL

NOW APPROVED NEW

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

1 daily dose

FOR PREVIOUSLY TREATED CLL

INDICATION - IMBRUVICA™ is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established.

Learn more at www.IMBRUVICA.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage – Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA™ may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA™ for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections - Fatal and non-fatal infections have occurred with IMBRUVICA™ therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE).

Monitor patients for fever and infections and evaluate promptly.

Myelosuppression - Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity - Fatal and serious cases of renal failure have occurred with IMBRUVICA™ therapy. Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels.

Maintain hydration.

Please review the Brief Summary of full Prescribing Information on the following page. © Pharmacyclics, Inc. 2014 © Janssen Biotech, Inc. 2014 02/14

PRC-00287

Second Primary Malignancies - Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA™. Four percent of patients with MCL, had skin cancers, and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity - Based on findings in animals, IMBRUVICA™ can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA™. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

CLL: The most commonly occurring adverse reactions (≥ 20%) in the clinical trial were thrombocytopenia*, diarrhea (63%), bruising (54%), neutropenia*, anemia*, upper respiratory tract infection (48%), fatigue (31%), musculoskeletal pain (27%), rash (27%), pyrexia (25%), constipation (23%), peripheral edema (23%), arthralgia (23%), nausea (21%), stomatitis (21%), sinusitis (21%), and dizziness (21%). *Treatment-emergent decreases (all grades) of platelets (71%), neutrophils (54%) and hemoglobin (44%) were based on laboratory measurements per IWCLL criteria and adverse reactions.

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia (8%), hypertension (8%), ADVERSE REACTIONS – atrial fibrillation (6.3%), sinusitis (6%), skin infection (6%), MCL: The most commonly occurring adverse reactions dehydration (6.4%), and musculoskeletal pain (6%). (≥20%) in the clinical trial were thrombocytopenia*, diarrhea Treatment-emergent Grade 3 or 4 cytopenias were reported (51%), neutropenia*, anemia*, fatigue (41%), musculoskeletal in 35% of patients. pain (37%), peripheral edema (35%), upper respiratory tract infection (34%), nausea (31%), bruising (30%), dyspnea (27%), Five patients (10%) discontinued treatment due to adverse constipation (25%), rash (25%), abdominal pain (24%), vomiting reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas.

(23%), and decreased appetite (21%).

Adverse reactions leading to dose reduction occurred in 13% *Treatment-emergent decreases (all grades) of platelets (57%), of patients. neutrophils (47%) and hemoglobin (41%) were based on laboratory measurements and adverse reactions.

DRUG INTERACTIONS The most common Grade 3 or 4 non-hematological adverse CYP3A Inhibitors - Avoid concomitant administration with reactions (≥5%) were pneumonia (7%), abdominal pain (5%), strong or moderate inhibitors of CYP3A. If a moderate CYP3A atrial fibrillation (5.4%), diarrhea (5%), fatigue (5%), and skin inhibitor must be used, reduce the IMBRUVICA™ dose. infections (5%). Treatment-emergent Grade 3 or 4 cytopenias CYP3A Inducers - Avoid co-administration with strong CYP3A were reported in 41% of patients. Ten patients (9%) discontinued inducers. treatment due to adverse reactions in the trial (N=111).

SPECIAL POPULATIONS - Hepatic Impairment - Avoid use in The most frequent adverse reaction leading to treatment patients with baseline hepatic impairment. discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Brief Summary of Prescribing Information for IMBRUVICATM (ibrutinib) IMBRUVICATM (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICATM (ibrutinib) capsules

INDICATIONS AND USAGE IMBRUVICA is indicated for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. This indication is based on overall response rate. An improvement in survival or disease-related symptoms has not been established [see Clinical Studies (14.1) in full Prescribing Information].

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Five percent of patients with MCL and 6% of patients with CLL had Grade 3 or higher bleeding events (subdural hematoma, ecchymoses, gastrointestinal bleeding, and hematuria). Overall, bleeding events including bruising of any grade occurred in 48% of patients with MCL treated with 560 mg daily and 63% of patients with CLL treated at 420 mg daily.

The mechanism for the bleeding events is not well understood.

IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies.

Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in full Prescribing Information].

Infections: Fatal and non-fatal infections have occurred with IMBRUVICA therapy. At least 25% of patients with MCL and 35% of patients with CLL had infections Grade 3 or greater NCI Common Terminology Criteria for Adverse Events (CTCAE) [See Adverse Reactions]. Monitor patients for fever and infections and evaluate promptly.

Myelosuppression: Treatment-emergent Grade 3 or 4 cytopenias were reported in 41% of patients with MCL and 35% of patients with CLL. These included neutropenia (29%), thrombocytopenia (17%) and anemia (9%) in patients with MCL and neutropenia (27%) and thrombocytopenia (10%) in patients with CLL. Monitor complete blood counts monthly.

Renal Toxicity: Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy.

Treatment-emergent increases in creatinine levels up to 1.5 times the upper limit of normal occurred in 67% of patients with MCL and 23% of patients with CLL. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients with MCL and 4% of patients with CLL. Periodically monitor creatinine levels. Maintain hydration.

Second Primary Malignancies: Other malignancies have occurred in 5% of patients with MCL and 10% of patients with CLL who have been treated with IMBRUVICA. Four percent of patients with MCL, had skin cancers and 1% had other carcinomas. Eight percent of patients with CLL had skin cancers and 2% had other carcinomas.

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times those reported in patients with MCL and 20 times those reported in patients with CLL, receiving the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Renal Toxicity [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice.

Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (See Tables 1 and 2).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections.

Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Mantle Cell Lymphoma (N=111) System Organ Class

Preferred Term

Gastrointestinal disorders

Diarrhea Nausea Constipation Abdominal pain Vomiting Stomatitis Dyspepsia Upper respiratory tract infection Urinary tract infection Pneumonia Skin infections Sinusitis Fatigue Peripheral edema Pyrexia Asthenia Bruising Rash Petechiae Musculoskeletal pain Muscle spasms Arthralgia Dyspnea Cough Epistaxis Decreased appetite Dehydration Dizziness Headache

Infections and infestations

General disorders and administrative site conditions Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Respiratory, thoracic and mediastinal disorders Metabolism and nutrition disorders Nervous system disorders

All Grades (%) 51 31 25 24 23 17 11

Grade 3 or 4 (%) 5 0 0 5 0 1 0

34 14 14 14 13 41 35 18 14 30 25 11 37 14 11 27 19 11 21 12 14 13

0 3 7 5 1 5 3 1 3 0 3 0 1 0 0 4 0 0 2 4 0 0

Table 2: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with MCL (N=111) Percent of Patients (N=111) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

57

17

Neutrophils Decreased

47

29

Hemoglobin Decreased

41

9

* Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%).

Adverse reactions leading to dose reduction occurred in 14% of patients.

Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression.

Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients.

Chronic Lymphocytic Leukemia: The data described below reflect exposure to IMBRUVICA in a clinical trial that included 48 patients with previously treated CLL treated with 420 mg daily with a median treatment duration of 15.6 months.

The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, bruising, neutropenia, anemia, upper respiratory tract infection, fatigue, musculoskeletal pain, rash, pyrexia, constipation, peripheral edema, arthralgia, nausea, stomatitis, sinusitis, and dizziness (See Tables 3 and 4).

The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, hypertension, atrial fibrillation, sinusitis, skin infection, dehydration, and musculoskeletal pain.

Adverse reactions from the CLL trial (N=48) using single agent IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented in Table 3.

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with Chronic Lymphocytic Leukemia (N=48) All Grades Grade 3 or 4 System Organ Class Preferred Term (%) (%) 4 63 Gastrointestinal disorders Diarrhea 2 23 Constipation 2 21 Nausea 0 21 Stomatitis 2 19 Vomiting 0 15 Abdominal pain 0 13 Dyspepsia Infections and infestations Upper respiratory 2 48 tract infection 6 21 Sinusitis 6 17 Skin infection 8 10 Pneumonia 0 10 Urinary tract infection 4 31 General disorders and administrative Fatigue 2 25 site conditions Pyrexia 0 23 Peripheral edema 4 13 Asthenia 0 13 Chills 2 54 Skin and subcutaneous tissue disorders Bruising 0 27 Rash 0 17 Petechiae 0 19 Respiratory, thoracic and mediastinal Cough 0 15 disorders Oropharyngeal pain 0 10 Dyspnea 6 27 Musculoskeletal and connective tissue Musculoskeletal pain 0 23 disorders Arthralgia 2 19 Muscle spasms 0 21 Nervous system disorders Dizziness 2 19 Headache 0 10 Peripheral neuropathy Metabolism and nutrition disorders Decreased appetite 17 2 Neoplasms benign, malignant, Second 10* 0 unspecified malignancies* Injury, poisoning and procedural Laceration 10 2 complications Psychiatric disorders Anxiety 10 0 Insomnia 10 0 Vascular disorders Hypertension 17 8 *One patient death due to histiocytic sarcoma.

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) Percent of Patients (N=48) All Grades (%) Grade 3 or 4 (%) Platelets Decreased

71

10

Neutrophils Decreased

54

27

Hemoglobin Decreased

44

0

* Based on laboratory measurements per IWCLL criteria and adverse reactions Five patients (10%) discontinued treatment due to adverse reactions in the trial (N=48). These included 3 patients (6%) with infections and 2 patients (4%) with subdural hematomas. Adverse reactions leading to dose reduction occurred in 13% of patients.

Thirty-eight percent of patients had shifts from normal to elevated uric acid levels on study including 4% with values above 10 mg/dL. DRUG INTERACTIONS Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days with single dose AUC values of 1445 ± 869 ng • hr/mL which is approximately 50% greater than steady state exposures seen at the highest indicated dose (560 mg).

IMBRUVICATM (ibrutinib) capsules Avoid concomitant administration of IMBRUVICA with strong or moderate inhibitors of CYP3A. For strong CYP3A inhibitors used short-term (e.g., antifungals and antibiotics for 7 days or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider interrupting IMBRUVICA therapy during the duration of inhibitor use. Avoid strong CYP3A inhibitors that are needed chronically. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

Patients taking concomitant strong or moderate CYP3A4 inhibitors should be monitored more closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Information].

Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate inhibitors of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full Prescribing Information].

CYP3A Inducers: Administration of IMBRUVICA with strong inducers of CYP3A decrease ibrutinib plasma concentrations by approximately 10-fold.

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’s Wort). Consider alternative agents with less CYP3A induction [see Clinical Pharmacology (12.3) in full Prescribing Information].

Distributed and Marketed by: Pharmacyclics, Inc. Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA™ is a trademark owned by Pharmacyclics, Inc. ©Pharmacyclics, Inc. 2014 PRC-00339

Edward Li, PharmD, BCOP; Cecilia Tran, PharmD, BCOP; Barry Peterson, PharmD, BCOP, BCPS; Michael Sturgill; Stanley Forston Jr., MD, MPH Background: Evaluating the use of ESAs in the treatment of chemotherapy-induced anemia (CIA) is important due to concerns related to the impact on tumor progression, appropriate prescribing and the cost of therapy. New Century Health (NCH) evaluates requests for ESAs based on diagnosis, laboratory values, chemotherapy and intent of treatment. The purpose of this project is to serve as the baseline data for a quality improvement initiative with the goal of improving adherence to best practices, optimizing outcomes, reducing cost, and increasing efficiency of authorization processing.

Methods: We evaluated authorizations in 2013 for only CIA in patients with the following tumor types: breast, lung, colon, prostate, and diffuse large B-cell lymphoma (DLBCL). ESA authorizations were analyzed for approval status of the request, and if applicable, the reasons for request withdrawal. Clinicodemographic characteristics of the cohort, including concurrent chemotherapy, are examined using descriptive statistics.

Results: There were 266 patients and 404 ESA authorizations in 2013 for patients (average age 70 years, 59% female, 41% male) with lung cancer (54%), breast cancer (21%), DLBCL (9%), prostate cancer (8%), and colon cancer (8%). The majority of patients had one authorization (65%); few had 4+ (4%). ECOG performance status was 0 or 1 in 66% of patients.

Authorizations were approved in 67% of the cases and were withdrawn or discontinued in 25% of cases. For 78% of authorizations, chemotherapy was ordered within 90 days preceding the ESA request.

Conclusions: The use of ESAs in patients with lung cancer is an area for further examination, as is the concurrent use of chemotherapy with ESA authorizations.

Future implications are to further examine the effects of this management program on clinical outcomes, cost, and efficiency of processing authorizations.

Category: Quality Research and Patient Safety

Palonosetron for Chemotherapy-Induced Nausea and Vomiting: Description and Report of a Quality Management Program

Edward Li, PharmD, BCOP; Cecilia Tran, PharmD, BCOP; Barry Peterson, PharmD, BCOP, BCPS; Michael Sturgill; Stanley Forston Jr., MD, MPH Background: There is currently no consensus regarding the best intervention for low emetogenic chemotherapies. Palonosetron is preferred by guidelines in high/ moderate emetic chemotherapy but other treatment options may be more cost-effective in low-emetogenic regimens. This study describes a cohort of denied chemotherapy treatment authorization requests containing palonosetron for demographics, authorization request patterns, and cost.

Methods: This is a retrospective analysis of denied authorization requests containing palonosetron reviewed by New Century Health’s oncology quality management program from 1/2013 to 10/2013. Descriptive statistics identify: cohort demographics, reasons for withdrawal, and follow-up to authorization withdrawals. Lastly, cost impact was calculated based on the difference between the approved authorization request and the original, withdrawn request.

Results: We identified 378 cases; the cohort median age was 68 years with 42% men and 58% women. The most common tumor types were lung (24%), breast (21%), hematologic (11%), and colon/rectal/anal (10%). Reasons for denial include: no compendia support (81%), availability of therapeutic alternative (42%), clinical criteria not met (15%), and dosing/frequency errors (10%). The program prompted chemotherapy regimen changes in 156 cases and supportive care treatment changes in 222 cases; palonosetron was removed in 31% and 51% of the cases respectively. The total net cost savings based on all the changes within the cohort was $1,087,073. Evidence-based changes in therapy that resulted in enhanced care quality and increased cost totaled $757,473.

Conclusions: Palonosetron, while effective, may not be the most cost-effective option for low-emetic regimens considering other lower-cost 5HT3 antagonists are available. We were able to drive utilization toward the lower-cost antiemetic medications and influence changes in evidence-based chemotherapy prescribing choices.

Issued: February 2014

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T:14”

Active ingredient made in China.

Baseline Characteristics and Description of Authorizations for Erythropoiesis Stimulating Agents (ESAs): Step One of a Quality Improvement Program

B:14.25”

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions].

• Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills) suggestive of infection [see Warnings and Precautions].

• Renal toxicity: Inform patients of the possibility of renal toxicity. Advise patients to maintain adequate hydration [see Warnings and Precautions].

• Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions].

• Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant [see Warnings and Precautions].

• Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in full Prescribing Information].

• Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.5) in full Prescribing Information].

• Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions].

Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions].

• Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists.

Category: Quality Research and Patient Safety

S:13”

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category D [see Warnings and Precautions].

Risk Summary: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus.

Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at oral doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased post-implantation loss. The dose of 80 mg/kg/day in animals is approximately 14 times the exposure (AUC) in patients with MCL and 20 times the exposure in patients with CLL administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in animals is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily.

Nursing Mothers: It is not known whether ibrutinib 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 IMBRUVICA, 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 IMBRUVICA in pediatric patients has not been established.

Geriatric Use: Of the 111 patients treated for MCL, 63% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse events (atrial fibrillation and hypertension), infections (pneumonia and cellulitis) and gastrointestinal events (diarrhea and dehydration) occurred more frequently among elderly patients.

Of the 48 patients treated for CLL, 52% were 65 years of age or older. No overall differences in effectiveness were observed between these patients and younger patients. A greater number of adverse events were reported in those 65 years of age and older. Grade 3 or higher adverse events occurred more frequently among elderly patients (80% of patients 65 and older versus 61% of younger patients).

Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe renal impairment (CLcr < 25 mL/min) or patients on dialysis [see Clinical Pharmacology (12.3) in full Prescribing Information].

Hepatic Impairment: Ibrutinib is metabolized in the liver and significant increases in exposure of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) were excluded from IMBRUVICA clinical trials. There is insufficient data to recommend a dose of IMBRUVICA in patients with baseline hepatic impairment [see Clinical Pharmacology (12.3) in full Prescribing Information].

Females and Males of Reproductive Potential: Advise women to avoid becoming pregnant while taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations].

4th Conference Abstracts

Prostate Cancer

Phi Index Can Select Patients with Prostate Cancer for Active Surveillance

By Phoebe Starr

San Francisco, CA—A new tool called the Prostate Health Index (phi) can identify which patients with favorable-risk prostate cancer can safely be managed with active surveillance and which patients will probably require treatment. The phi index is relatively low tech and is calculated using 3 serum measurements: prostate-specific antigen (PSA), free/total PSA, and a measurement called [-2]proPSA. A preliminary study of the phi index in the active surveillance setting showed that it provided a more accurate estimate of the course of illness than PSA or free/total PSA. The study was reported at the 2014 Genitourinary Cancers Symposium.

“This is a new method for identifying which patients assigned to watchful waiting will need treatment. There are many patients who don’t need treatment even 10 years after diagnosis,” said lead investigator Andrew Eichholz, MD, of the Institute of Cancer Research, Royal Marsden NHS

Foundation Trust, Sutton, United Kingdom.

Dr Eichholz explained that phi is starting to be used in the prebiopsy setting in the United States. Although

“This is a new method for identifying which patients assigned to watchful waiting will need treatment. There are many patients who don’t need treatment even 10 years after diagnosis.”

—Andrew Eichholz, MD

he is quite enthusiastic about the applicability of phi in the active surveillance setting, he said, “It is not ready

for prime time. The phi index needs to be validated. We are the first group to study it [in this setting], and another group is also studying it. If it is validated, it could change the way we manage these patients.”

The investigators sought to determine the predictive value of phi in a retrospective study based on frozen blood samples from 370 patients collected at diagnosis a median of 11.4 years ago. The patients had stage T1/ T2 cancer, Gleason scores of ≤3 + 4, and a PSA of <15 ng/mL. Patients were monitored with PSA testing every 6 months and repeat biopsy every 2 years. Treatment was indicated for patients with a PSA velocity of >1 ng/mL annually or a Gleason score of ≥4 + 3 on repeat biopsy.

A total of 115 patients started treatment after a median of 11.4 years. Phi was significantly associated with the time to treatment (P <.001).

The test results were grouped into quartiles according to phi. The investi-

gators determined that the cutoff point for phi was <31.4 for the lowest-risk quartile and >58.5 for the highest-risk quartile. Among the lowest-risk patients, the test predicted that 95% would not need therapy within 5 years from diagnosis, whereas among the highest-risk patients, 54% would require treatment within 5 years.

After 10 years, 37% of the patients still did not require treatment, and approximately 20% needed treatment within 2 years of diagnosis.

“If phi is validated in this setting, it will be a useful tool for discussions with patients,” Dr Eichholz stated.

Phi received premarketing approval from the US Food and Drug Administration in June 2012 for use in men (not diagnosed with prostate cancer) with a PSA in the range of 4 ng/mL to 10 ng/mL. At that time, a multicenter study showed that phi reduced unnecessary biopsies by 31%.

The phi assay kit is marketed by Beckman Coulter. n

Imaging Choice May Influence Brachytherapy Outcomes

By Charles Bankhead

San Francisco, CA—Magnetic resonance imaging (MRI)-guided brachy­ therapy led to significantly less urinary dysfunction in men being treated for localized prostate cancer compared with ultrasound-guided techniques, according to a long-term prospective cohort study reported at the 2014 Genitourinary Cancers Symposium.

Patients who received brachytherapy guided with ultrasound had significantly higher rates of urinary obstruction and incontinence and worse incontinence-associated quality of life (QOL) at 3 months compared with brachytherapy guided with MRI (P = .01 to P = .002). Incontinence and QOL remained significantly different in favor of MRI guidance at 5 years (P = .05).

“MRI-guided brachytherapy is associated with reduced short- and longterm urinary dysfunction compared to standard ultrasound-guided brachy­ therapy,” concluded James A. Talcott, MD, Director, Center for Health Care Quality and Outcomes Research, Mount Sinai Beth Israel, New York, and colleagues.

“Current standard ultrasound-guid-

24

ed brachytherapy may produce less long-term incontinence than earlier thought, although it may grow over time.”

The findings add to those of a previous study by the same group, showing variations in short-term urinary outcomes at 2 hospitals that used different ultrasound-guided techniques.

Although widely used to treat clinically localized prostate cancer, brachytherapy can involve different techniques. The extent to which technique influences patient-reported outcomes has not been well studied.

Study Details Dr Talcott and colleagues prospectively followed 286 patients with clinically localized prostate cancer treated by brachytherapy at 3 Boston-area hospitals. One hospital used MRI-guided target volume, which avoids the transition zone. The other 2 hospitals used conventional ultrasound-guided techniques for brachytherapy.

Patients completed health surveys before treatment and at 1 and 3 months after treatment, then annually or every

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other year for 5 years of follow-up.

Questionnaires included the Prostate Cancer Symptoms Indexes, urinary QOL scale, SF-12 general health survey, and the Profile of Mood States.

“MRI-guided brachytherapy is associated with reduced short- and long-term urinary dysfunction compared to standard ultrasound-guided brachytherapy.”

—James A. Talcott, MD, and colleagues

Compared with the MRI group, patients treated with ultrasound guidance had scores on evaluations of acute urinary morbidity indicating more symptoms of obstruction or irritation (28.8 vs 20.0; P = .01), more incontinence (9.6 vs 2.2; P = .002), and worse incontinence-related QOL (10.2 vs 2.4; P = .0002). At the 5-year fol-

low-up, the ultrasound subgroup still had significantly more incontinence (7.5 vs 3.3; P = .05) and worse QOL (5.6 vs 1.2; P = .01).

Other patient-reported outcomes, including bowel and sexual function, did not differ significantly between the groups.

As a result of the study, the investigators discovered that within the subgroup of patients treated with ultrasound guidance, patients at 1 of the 2 hospitals reported significantly more urinary symptoms. A comparison of techniques showed that patients with more urinary symptoms were treated according to a protocol that includ­ ed the use of an indwelling urinary catheter.

Eliminating the catheter from the protocol led to similar urinary outcomes at the 2 hospitals during the remainder of follow-up.

“QOL outcomes vary by BT [brachytherapy] technique,” the investigators concluded. “Measuring QOL may provide useful information for patients choosing treatment and providers assessing their technique.” n

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In the Literature Rituximab Active in Nodular Lymphocyte-Predominant...

Continued from page 5

sponse and overall response rate.

After 4 weekly treatments, the overall response rate was 100%, with 67% of patients achieving complete response and 33% achieving partial response. No difference in the overall response rate was observed in previously treated patients versus the treatment-naïve patients.

At a median follow-up of 9.8 years in the rituximab group, the PFS was 3 years. At the median follow-up of 5 years in the rituximab plus maintenance group, the PFS was 5.6 years. The median overall survival (OS) was not reached in either group. The estimated 5-year PFS and OS rates for patients in the rituximab group compared with patients in the rituximab plus maintenance group were 39.1% and 95.7% versus 58.9% and 85.7%, respectively.

Treatment-related adverse events were minimal in both groups, and no grade 3 or 4 toxicities were observed.

A total of 23 patients experienced relapse, and 9 of these patients had evidence of transformation to aggressive B-cell lymphoma.

The researchers concluded that rituximab is well-tolerated and is an active single agent in patients with NLPHL who had received no previous treatment and in patients with relapsed disease. Although the responses are not durable in the majority of the patients, a substantial minority experience remission lasting more than 5 years.

Because single-agent rituximab is not curative for NLPHL, it should be primarily considered in patients in the relapsed setting. The potential for transformation of NLPHL to aggressive B-cell lymphoma underscores the importance of repeated biopsy and longer-term follow-up.

Dovitinib Active but Not Superior to Sorafenib in Patients with Metastatic Renal Cancer

Therapies targeting vascular endothelial growth factor (VEGF) and mTOR signaling pathways are standard first-line and second-line treatment options for patients with metastatic renal-cell carcinoma. However, an unmet medical need exists for patients who had previously received VEGF-targeted and mTOR inhibitor therapies.

Fibroblast growth factor pathway activation may be a mechanism of escape from VEGF-targeted therapies.

Dovitinib (TKI258) is an oral tyrosine kinase inhibitor that inhibits VEGF, fibroblast growth factor receptors, and platelet-derived growth factor

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receptors. Therefore, researchers from the Global Oncologic Learnings for Dovitinib (GOLD) trial sought to compare dovitinib versus sorafenib (Nexavar) as third-line targeted therapies in this patient population (Motzer RJ, et al. Lancet Oncol. 2014;15: 286-296).

GOLD was a multicenter, open-la-

bel, randomized, phase 3 trial that included 570 patients with metastatic renal-cell carcinoma with clear-cell or a component of clear-cell histology, and who had received 1 previous VEGF-targeted therapy (eg, sunitinib [Sutent] or bevacizumab [Avastin]) and 1 previous mTOR inhibitor (eg, everolimus [Afinitor] or temsirolimus

[Torisel]). In a 1:1 ratio, patients were randomly assigned to receive dovitinib 500 mg orally according to a 5-dayson and 2-days-off schedule (N = 284), or to sorafenib 400 mg twice daily (N = 286). Randomization was stratified by risk group and by region. Patient characteristics were well-balanced between both groups.

Continued on page 29

NEW FOR 2014

Principles in Value and Market Access

An educational session for product managers, reimbursement specialists, account managers, and marketers focusing on access, reimbursement, proving product value, and international markets.

CO-CHAIRS

MAY 6, 2014 Loews Hollywood Hotel Los Angeles, CA

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Gary M. Owens, MD

President Gary Owens Associates

AGENDA 10:45am – 11:00am

Introductions and Opening Remarks Grant Lawless, RPh, MD, FACP; Gary M. Owens, MD

11:00am – 11:40am

Changing Access and Payer Challenges in Oncology - Medicare and Commercial Speaker TBD

11:40am – 12:20pm

Proving the Value for Oncology Therapy Using Comparative Effectiveness Research Dan Malone, PhD, Professor, University of Arizona College of Pharmacy

12:20pm – 1:30pm

Lunch

1:30pm – 2:10pm

Methods and Tools for Optimal Reimbursement Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead

2:10pm – 2:50pm

Impact of Healthcare Reform, Affordable Care Act, and Accountable Care Organizations on the Coverage of Cancer Treatments Speaker TBD

2:50pm – 3:30pm

Impact of New Risk Models on Traditional Pharmaceutical Relationships Ken Schaecher, MD, FACP, CPC, Medical Director, SelectHealth

3:30pm – 4:00pm

Break

4:00pm – 4:40pm

Using Competitive Intelligence to Maintain Coverage and Access Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting

4:40pm – 5:20pm

Panel Discussion - Will improvements in clinical outcomes and efficacy come from new products or a more thoughtful use of existing products using new adaptations?

Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE) AVBCC2014May6agenda Asize_20714

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Personalized Medicine

14 New Genetic Markers Predict Risk... should disease onset occur.

“If we can more effectively screen these men,” wrote the investigators, “clinicians can potentially offer more tailored screening, staging and treatment pathways.”

Daniel Leongamornlert and colleagues from the Division of Genetics and Epidemiology at the Institute of Cancer Research in London, United Kingdom, found that the presence of even 1 of the so-called loss-of-function mutations increased the risk for prostate cancer by almost 2-fold compared with men without any of these mutations.

Furthermore, these mutations were more frequently associated with nodal involvement, tumor metastasis, and/ or advanced disease at the time of diagnosis.

Mechanism of Genetic Risk for Prostate Cancer Similar to Breast Cancer It has long been known that certain types of breast cancers run in families, in particular tumors associated with the BRCA1/BRCA2 mutations, which are observed in 10% of all breast cancer cases. However, mutations in these genes, and the resultant loss of function of the associated proteins, have been associated with other cancers, including ovarian and prostate cancer, which was only recently understood.

“This suggests that shared genetic and/or environmental factors may be causal for multiple cancer types,” wrote the investigators, a hypothesis thought to be particularly relevant for hormonal-related malignancies.

Because genomic instability is the hallmark of most cancers, the team expanded their focus to include a comprehensive set of genes related to DNA repair pathways.

New Mutations Identified A total of 191 men in the United Kingdom with a family history of prostate cancer were selected for this study; they were screened using the genetic assay known as the BROCA Cancer Risk Panel, in combination with second-generation DNA-sequencing technology to spot deleterious mutations.

The 14 loss-of-function mutations were identified in 8 genes, including ATM, BRCA1, BRCA2, BRIP1, CHEK2, MUTYH, PALB2, and PMS2.

Of the mutations found, 5 were discovered for the first time in this investigation, and no enrolled patient had more than 1 loss-of-function mutation.

Although the predictive value of these mutations in cases of familial prostate cancer was less than that seen in the example of BRCA1/BRCA2 and breast cancer—roughly 10% in breast

cancer versus 7.3% in prostate cancer—the implications for disease prognosis are striking.

“There was a significant association between LoF [loss-of-function] carrier status and the presence of nodal involvement…and metastasis,” the investigators stated. Regarding involvement

“If we can more effectively screen these men, clinicians can potentially offer more tailored screening, staging and treatment pathways… men with deleterious germline mutations in these genes should be considered for more intensive screening and treatment.”

—Daniel Leongamornlert, PhD Candidate, and colleagues

of the lymph nodes, there was an incidence rate of 42.9% for patients with prostate cancer and a loss-of-function mutation versus 1.3% for men without a mutation; for tumor metastasis, the rate was 30.0% versus 6.3%, respectively.

Loss-of-function mutation carriers

Continued from the cover also had a significantly greater risk for advanced disease (odds ratio, 15.09); even after the BRCA2 mutations known to be associated with poorer prognosis were excluded, the risk for advanced disease persisted.

Significant, Inherited Risk These newly revealed mutations also showed significant, inherited genetic penetration in families. Of the 191 enrolled men with ≥3 cases of prostate cancer in their family, 128 also had ≥1 case of breast, ovarian, or colon cancer in their family.

One participant with a mutation in the CHEK gene had 2 brothers with prostate cancer; the family of another enrolled man with a mutation in the ATM gene had a father with colon cancer, 4 of 8 brothers with prostate cancer, and his sister was reported to have had leukemia.

Overall, even after the most common loss-of-function mutations of BRCA1/BRCA2 were excluded from the analysis, the newly discovered mutations accounted for a 1.8 increased risk for prostate cancer.

“This finding could have important clinical implications as men with deleterious germline mutations in these genes should be considered for more intensive screening and treatment,” the investigators concluded. n

Oncotype DX May Not Be Necessary to Predict Recurrence in Low-Grade Breast Cancer Histologic analysis may be sufficient in a subset of patients

By Rosemary Frei, MSc San Diego, CA—Results of a new small study have shown that histology without the use of Oncotype DX Breast Cancer assay accurately predicts the risk for recurrence in low-grade breast carcinoma. Although Oncotype DX is useful in predicting recurrence in high-grade breast cancer, this study suggests that low-grade tumors may be adequately assessed for recurrence by histology only.

Two pathologists reviewed the clinical grade of breast tumors that also had been evaluated with an Oncotype DX assay, and found that in the 19 tumors that showed low-grade carcinoma on histology had an Oncotype DX recurrence score of ≤30, which indicates low- or intermediate-risk for recurrence. Of those tumors, 17 (89.5%) had a recurrence score of <18, which

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“The choice of sending a tumor for Oncotype DX analysis is still up to the patient and her treating clinician, and lowgrade tumors continue to be occasionally sent for Oncotype DX at our institution.”

—Scott M. Wendroth, MD

corresponds to low recurrence risk.

Scott M. Wendroth, MD, Pathology Resident, and Kristen A. Atkins, MD, Associate Professor of Pathology, Uni-

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versity of Virginia, Charlottesville, reported the results of their study at the 2014 United States and Canadian Academy of Pathology annual meeting. They hope to publish their results in the near future.

“The choice of sending a tumor for Oncotype DX analysis is still up to the patient and her treating clinician, and low-grade tumors continue to be occasionally sent for Oncotype DX at our institution,” said lead investigator Scott M. Wendroth, MD, University of Virginia, Charlottesville.

“Although our study was small, others have shown similar results, and we hope that these data are part of the discussion clinicians have with patients when deciding whether or not to use an expensive molecular test like Oncotype DX.”

A 2013 study that mirrors these results showed that routine histopathologic characteristics predict the Oncotype DX recurrence score in a subset of patients with breast cancer (Mattes MD, et al. Cancer Invest. 2013;31:604606).

Dr Wendroth said that their next step is to continue monitoring the correlations between the recurrence scores of any low-grade breast cancers from their institution that are analyzed

by Oncotype DX and the histology grade.

Dr Wendroth and Dr Atkins retrieved all low–Nottingham-grade tumors from their institutional archives that had also been evaluated with the Oncotype DX Breast Cancer assay.

They were blinded to the recurrence scores while confirming their histo­

Continued on page 28

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Personalized Medicine

New Molecular Test to Monitor Breast Cancer Recurrence by Sequencing Circulating Tumor Cells

By Wayne Kuznar

A

genomic test to sequence the circulating tumor cells (CTCs) from whole blood, ClearID Breast Cancer from Cynvenio Biosystems, is now available commercially to molecularly monitor for breast cancer recurrence. The test uses a standard blood draw from which DNA from tumor cells is isolated and interrogated using next-generation–sequencing tools to determine the presence of cancer-associated DNA mutations.

The Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory at Cynvenio has a validated protocol to recover CTCs and evaluate them for the presence of more than 4500 single-point genetic mutations.

“It is a great way to detect the metastatic process because that’s what these tumor cells in blood are responsible for. We’re going to give doctors an ability with the same blood draw to also monitor estrogen receptor status, progesterone receptor status, as well as human epidermal growth factor receptor 2.”

—André de Fusco

According to André de Fusco, Chief Executive Officer and Director of Cynvenio, the ClearID test is useful for patients with breast cancer who are at high risk for disease recurrence after treatment, because CTCs reflect the underlying biology of the disease process. “It is a great way to detect the metastatic process because that’s what these tumor cells in blood are responsible for,” Mr de Fusco said.

The ClearID test evaluates blood samples for elevated numbers of cells that are phenotypically characterized as CTCs. When elevated, the CTCs are examined for the presence of somatic mutations that are not found in the germline sequence. “These data can provide additional insight into the molecular character of disease, and do so with a very stringent analytical specificity due to the multiple biomarkers involved in the test and the evaluation of the CTC genome for somatic muta-

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tions,” according to the company.

Physicians who send in a blood sample using the patient sample kit receive a comprehensive report of ac-

tionable genomic alterations plus associated treatments for each alteration found. The fixed sample is stable for 96 hours without refrigeration. This plat-

form to enumerate and isolate CTCs has been patented.

The test, which can identify mutations present in as few as 1% of CTCs,

Continued on page 29

NeW foR 2014

Government and Employers An educational session for policymakers and employers focusing on healthcare reform, benefit design, insurance, and coverage trends.

Co-Chairs

May 7, 2014 Loews Hollywood Hotel Los angeles, Ca

Jayson Slotnik, JD, MPH

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

aGEnda

F. Randy Vogenberg, PhD, RPh

Principal Institute for Integrated Healthcare

8:30am – 8:40am

Introductions and Opening Remarks Jayson Slotnik, JD, MPH; F. Randy Vogenberg, PhD, RPh

8:40am – 9:25am

Session 1: Investor Community Views on Healthcare Market Winners and Losers Michael E. Meyers, MPH, Managing Director, Head of Investment Banking, T.R. Winston & Company

9:25am – 10:10am

Session 2: Insurance Innovation on Reinsurance and Benefit Design Trends Matthew Palmgren, PharmD, President, Healthcare Solutions in Int’Ovation Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC

10:10am – 10:15am

Break

10:15am – 11:00am

Session 3: Private Exchanges: Why Different from Public Exchange Trends for Oncology Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions

11:00am – 11:40am

Session 4: Diagnostics: Recent FDA and CMS Policies Impacting Access to Diagnostic and Oncology Drugs John Ridge, Senior Director, Managed Care and Reimbursement, Exact Sciences Timothy J. Thompson, Chief Executive Officer, Intervention Insights

11:40am – 12:00pm

Session 5: What’s Next with Healthcare Reform – Fixes or More Related to Oncology?

Denise Pierce, President and CEO, DK Pierce & Associates Jayson Slotnik, JD, MPH, Vice President of Reimbursement Strategy & Innovation, United BioSource Corporation F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare

12:00pm – 12:15pm

Break

12:15pm – 1:15pm

Lunch/Product Theater

1:15pm – 1:30pm

Break

1:30pm – 2:15pm

Session 6: Employer Onsite Clinic Trends from Wellness into Infusion and Emergent Care Larry Boress, President & CEO, Midwest Business Group on Health; Executive Director, National Association of Worksite Health Centers

2:15pm – 3:45pm

Meet the Experts Roundtables Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE)

3:45pm – 4:15pm

Poster Presentations

4:15pm – 5:00pm

Poster and Session Discussant

5:00pm – 7:00pm

Cocktail Reception in the Exhibit Hall

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Personalized Medicine

Personalized Cancer Care: Combination Therapies May Be Key to Hitting Tumor Heterogeneity

By Wayne Kuznar

Boston, MA—Combinations of targeted therapies will be key to overcoming resistance that occurs in tumor cells and leads to eventual failure of a single targeted agent, said Alex Adjei, MD, PhD, the Katherine Anne Gioia Chair in Cancer Medicine, Roswell Park Cancer Institute, Buffalo, NY, at the Second Global Biomarkers Consortium annual conference.

“Tumor heterogeneity is the predominant reason for therapeutic failure in cancer,” Dr Adjei said. The 2 types of resistance that occur in tumor cells are (1) initial resistance to treatment, and (2) an initial response to treatment followed by resistance (ie, secondary resistance). Secondary resistance may occur as the result of the formation of a resistance mechanism or a secondary mutation.

Personalized medicine includes 3 principles: • Treat those who will benefit • Avoid treatment of those who will not benefit • Avoid unnecessary toxicity.

Even targeted agents produce toxicities. Identifying the patients who have the highest likelihood of benefit and the lowest likelihood of toxicity will require the use of genomics-driven therapies made possible by detecting genetic alterations through techniques such as next-generation sequencing, said Dr Adjei.

Actionable Targets in NSCLC “The good news is that we are finding actionable targets, and there are drugs in the clinic to target them,” Dr Adjei said. He discussed some of the targets in non–small-cell lung cancer (NSCLC).

A translocation of echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor is a potent oncogenic driver, responsible for initiation and maintenance of certain cancers. It has been identified in a

Oncotype DX... logy-based grades.

Furthermore, they found that only 2 of the 19 low-grade tumors had a recurrence score of 18 to 30, a score that indicates low- to intermediate-risk, whereas the other 17 had a recurrence score of <18, which indicates low-risk.

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small subset of patients with NSCLC who respond to ALK inhibitors.

Inhibiting ALK signaling with agents such as crizotinib (Xalkori) has proved to be effective against cancers with ALK-driven pathways. In a phase 1 study of crizotinib in patients with ALK-positive refractory NSCLC, median progression-free survival was 10 months, with response rates as high as 60%.

“Tumor heterogeneity is the predominant reason for therapeutic failure in cancer.”

—Alex Adjei, MD, PhD

ROS1 rearrangements occur in approximately 1% of patients with NSCLC. The ROS1 and the ALK tyrosine kinase domains are similar; “they share about 77% of sequence homology,” said Dr Adjei. Crizotinib has also been shown to have antitumor activity in advanced ROS1-positive NSCLC, with overall response rates approaching 60%.

The rearranged during transfection (RET) kinase has also recently been identified as a potential new oncogenic driver in a subset of patients with NSCLC. Cabozantinib (Cometriq) has activity in NSCLC with rearrangements in RET, with clinical studies in patients with RET-translocated tumors

Continued from page 26 Dr Wendroth and Dr Atkins concluded that because adjuvant chemotherapy only benefits patients with high recurrence score breast tumors, those who have a low- or intermediate-grade tumor on histology may not need a molecular analysis. n

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starting soon, Dr Adjei said.

In NSCLC, activating BRAF V600E mutations occur in ≤2% of tumors, primarily adenocarcinoma, and is a therapeutic target. Dabrafenib (Tafinlar) is a reversible small molecule that has been studied in a single-arm open-label study of patients with NSCLC and BRAF V600E mutation whose disease had progressed with chemotherapy. In the first 20 patients treated, the overall response rate was 40% and the disease control rate was 60%. There was no difference in outcome by smoking status.

Targeting Resistance with Combinations The not-so-good news with the targeted drugs, Dr Adjei said, “is that we don’t cure anybody.” At least 40% of patients do not experience tumor regression with the targeted drugs. Most patients with NSCLC will develop resistance to crizotinib within 2 years.

These mechanisms of resistance are diverse, from the development of ALK resistance mutations to alternative signaling pathways.

“When it comes to ALK, we have second-generation compounds that appear to be very active,” Dr Adjei said. For example, alectinib has shown activity in patients in whom crizotinib has stopped working. LDK378 is an investigational selective inhibitor of ALK that appears to have activity in crizotinib-naïve patients and in those with molecularly defined crizotinib-resistant tumors.

With the current understanding of different molecular profiles within tumors, “combination therapy will be key.”

—Alex Adjei, MD, PhD In solid tumors, the critical question in personalizing therapy is whether primary resistance mechanisms (tumor heterogeneity) or acquired resistance are at play. The first convincing evidence of tumor heterogeneity came from Gerlinger and colleagues in 2012 (N Engl J Med. 2012;366:883-892), who took pre- and postsurgical biopsies of renal-cell tumors. They found that approximately 66% of mutations detected in single biopsies were not

at a glance ➤ Tumor heterogeneity is the predominant reason for therapeutic failure in cancer ➤ Because different molecular profiles are found within each tumor, combination therapy is key to overcoming drug resistance ➤ Identifying patients who are most likely to benefit and are least likely to experience drug toxicity requires genomics-driven therapies ➤ Inhibiting ALK signaling with drugs such as crizotinib is effective against tumors with ALK-driven pathways, but most patients develop resistance within 2 years ➤ Combination therapies have been difficult to execute because of overlapping toxicities uniformly present in multiple tumor biopsies. “Favorable prognosis” and “unfavorable prognosis” genetic profiles were present in different regions of the same tumor, and different inactivating PTEN mutations were present in various portions of the tumor.

With the current understanding of different molecular profiles within tumors, “combination therapy will be key,” said Dr Adjei. Combination therapies have been difficult to execute because of overlapping toxicities, such as erythematous rash and stomatitis, with mitogen-activated protein kinase (MEK) and protein kinase B (AKT) inhibitors.

Drug combinations should use agents that have nonoverlapping dose-limiting toxicities and have the ability to administer full doses of each agent. True cytotoxic synergy is important in the combination, as is dose schedule and sequence.

An example is the response obtained with the addition of an MEK inhibitor to continued treatment with the BRAF inhibitor vemurafenib (Zelboraf) in patients whose melanoma progresses with the single-agent vemurafenib.

Inhibiting MEK downstream from BRAF is an indirect attack on the RAS proteins that activate the MEK and other signaling pathways that lead to cell proliferation and survival, Dr Adjei explained. n

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In the Literature Dovitinib Active but Not Superior to Sorafenib...

Continued from page 25

The primary end point was progression-free survival (PFS) on masked central review. Efficacy was assessed in all patients who were randomly assigned, and safety was assessed in patients who received at least 1 dose of the study drug.

The findings showed no difference in PFS between the 2 treatment groups.

The median follow-up was 11.3 months. The median PFS times were 3.7 months in the dovitinib group and 3.6 months in the sorafenib group (hazard ratio [HR], 0.86; P = .063). No subgroup had a clinically significant PFS benefit with dovitinib versus sorafenib treatment in analysis by patient demographics and disease characteristics. Partial response was noted in 4% of the patients in each group. In the dovitinib and sorafenib groups, the median overall survival times were 11.1 months and 11 months, respectively (HR, 0.96).

Common grade 3 and 4 adverse events included hypertriglyceridemia

(14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), and anemia (5%) in the dovitinib group; and hypertension (17%), fatigue (8%), dyspnea (7%), palmar-plantar erythrodysesthesia (6%), and anemia (6%) in the sorafenib group. The most common serious adverse event in the dovitinib and

Personalized Medicine and Payers An educational session for payers focusing on cost efficiency, value, outcomes, and impacts on treatment of personalized medicine.

Co-ChAirs

May 8, 2014 Loews Hollywood Hotel Los angeles, Ca

AgendA 8:30am – 8:40am 8:40am – 9:20am

Continued from page 27

is designed to be a “blood to readout” solution, with reports available in 3 to 10 days, said Mr de Fusco. It offers the opportunity for longitudinal monitoring to track the disease course.

“We’re going to give doctors an ability with the same blood draw to also monitor estrogen receptor status, progesterone receptor status, as well as human epidermal growth factor receptor 2,” Mr de Fusco said. “In one single test, they’ll have pretty much everything they need to look at breast cancer. In the metastatic patient, they’re going to be interested in estrogen receptor and progesterone receptor status, but they may also want to know if there’s a PIK3CA mutation in an unresponsive patient in the third line of therapy.”

The advanced genomic reporting contains not only the cancer-associated mutations identified but also the targeted treatments—both those approved by the US Food and Drug Administration and those currently in clinical trials—to which the mutation is sensitive, as well as advice on off-label treatments. “The doctor doesn’t have to be a genetic oncologist to know what to do,” said Mr de Fusco. n

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efficacies when used as third-line targeted treatments for metastatic renalcell carcinoma. The findings provide efficacy data for future design of clinical trials of third-line therapies. The 11-month median overall survival highlights the need for study and identification of novel agents in this setting. n

NeW foR 2014

7:00am – 8:30am

New Molecular Test...

sorafenib groups was dyspnea (6% and 5%, respectively). Adverse events led to dose change or interruption in 51% of the patients receiving dovitinib and in 49% of the patients receiving sorafenib.

Although dovitinib showed activity, the researchers concluded that dovitinib and sorafenib had similar

9:20am – 10:00am

10:00am – 10:40am

10:40am – 11:20am

11:20am – 12:00pm

12:00pm – 12:15pm 12:15pm – 1:15pm 1:15pm – 2:45pm

2:45pm – 3:00pm 3:00pm – 4:00pm 4:00pm – 5:00pm 5:00pm – 7:00pm

Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Special Session: Value-Based Strategies for Patients with Multiple Myeloma Supported by funding from Millennium: The Takeda Oncology Company Introductions and Opening Remarks Michael A. Kolodziej, MD; Grant Lawless, RPh, MD, FACP Session 1: Personalized Medicine and Value Peter Bach, MD, MAPP, Memorial Sloan-Kettering Cancer Center Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna Session 2: Measuring the Value of Prognostic and Predictive Outcomes Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine Macey Johnson, Vice President of Managed Care and Reimbursement, BioTheranostics Session 3: Utilizing Big Data to ID Phenotypes and Predictive Outcomes Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint George W. Sledge, MD, FASCO, Chief of Oncology, Stanford University Department of Medicine Session 4: Value Paradigm in Drug Development Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Kevin Knopf, MD, MPH, California Pacific Medical Center Christiane Langer, MD, Lead Medical Director for CRC, GU, and GBM, Genentech Panel Discussion - How will personalized medicine impact future treatment and use existing therapy?

Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint Break Lunch/Product Theater Meet the Experts Roundtables Al Benson, MD, Professor of Medicine and Oncology, Northwestern University Medical School Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Break Poster Presentations Poster and Session Discussant Cocktail Reception in the Exhibit Hall AVBCC2014May8agenda Asize_20714

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Cervical Cancer

Routine Cervical Cancer Screening Warranted Beyond Age...

Continued from the cover

“Based on these results, we believe women should be screened beyond age 50, with at least 1 screen after turning 60, and possibly continuing screening until age 75,” said lead investigator Peter Sasieni, PhD, Professor of Bio­ statistics and Cancer Epidemiology, Wolfson Institute of Preventive Medicine, Queen Mary University, London.

The methods used by Dr Sasieni and colleagues included matching 1341 cases of invasive cervical cancer of women who were diagnosed at ages 65 to 83 years with 2646 controls matched for age and place of residence. A weighted logistic regression model was used to calculate the absolute risks for being diagnosed with cervical cancer.

The screening model involved the last 3 negative tests and having no high-grade cytology between the ages of 50 and 64 years.

The researchers could not collect data on potential confounding factors, such as sexual behavior and smoking, because this information is not gathered in the database they used. However, they made allowances for these factors by using sensitivity analyses.

Risk for Cervical Cancer Dr Sasieni and coinvestigators calculated an odds ratio (OR) of 0.25 for the risk for cervical cancer between the ages of 65 and 83 years among women who had been screened at least once every 5.5 years between ages 50 and 64 years compared with those who had

“Based on these results, we believe women should be screened beyond age 50, with at least 1 screen after turning 60, and possibly continuing screening until age 75.”

—Peter Sasieni, PhD not been screened during those ages.

Even women who had been screened only once every 9 to 15 years between the ages of 50 and 64 years were at a lower risk for cervical cancer in later years, with an OR of 0.54.

However, the researchers also found

that the protective effect of screening before age 64 years is reduced with advancing age. In women aged 50 to 64 years with a screening interval of 5.5 years or less compared with no screening, the OR for a cervical cancer diagnosis between the ages of 65 and 69 years was 0.12, compared with 0.27 for women aged 70 to 74 years, 0.46 for ages 75 to 79 years, and 0.49 for ages 80 to 83 years.

The team also estimated the possible effects of risk factors on which no data had been gathered, including on sexual behavior and smoking. They found that these factors could increase the risk by 18%. That translates into an OR of 0.14 instead of 0.12 of developing cervical cancer in women aged 65 to 69 years, 0.33 instead of 0.27 in women aged 70 to 74 years, and of 0.54 instead of 0.46 for women aged 75 to 79 years.

The team’s modeling of the effect of stopping screening at 75 years versus at 65 years per 100,000 women yielded 149 fewer cancers with the former scenario, based on cumulative incidence data from 1975.

In addition, the model suggests that there would be 182 additional

at a glance ➤ New evidence suggests that women be screened for cervical cancer after age 50, with at least 1 screen after age 60, and possible screening until age 75 ➤ The odds of a cervical cancer diagnosis were 25% lower in women who were screened regularly up to age 64 years ➤ Based on these data, 149 fewer cervical cancers per 100,000 women would occur if women were screened regularly to age 75 ➤ Furthermore, if women stopped screening at age 55, there would be 182 additional cancers per 100,000 women ➤ Although the protective effect of screening is reduced with age, the effect was still significant up to age 83 cancers per 100,000 women if screening stopped at age 55 years. n

Colorectal Cancer

In the Real World, Bevacizumab Improves Survival in Patients with Metastatic Colorectal Cancer

By Wayne Kuznar

San Francisco, CA—In routine patient care, adding bevacizumab (Avastin) to standard FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) improves progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC), according to data presented at the 2014 Gastrointestinal Cancers Symposium.

“There is consistent benefit in terms of PFS and a more substantial advantage in terms of 1-, 2-, and 3-year survival rates with the addition of bevacizumab to FOLFIRI,” said lead investigator Jean A. Maroun, MD, Professor of Medicine, University of Ottawa, and Medical Oncologist, Ottawa Hospital Cancer Centre, Ontario, Canada.

Bevacizumab plus FOLFIRI has become the standard of care for the

30

first-line treatment of mCRC, but few data exist about its utilization and effectiveness in the community.

“There is consistent benefit in terms of PFS and a more substantial advantage in terms of 1-, 2-, and 3-year survival rates with the addition of bevacizumab to FOLFIRI.” —Jean A. Maroun, MD

Dr Maroun and colleagues therefore looked at the outcomes of 470 patients with mCRC receiving standard first-

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at a glance ➤ Adding bevacizumab to the FOLFIRI regimen improves PFS and OS in patients with mCRC ➤ The median PFS was 17 months with FOLFIRI plus bevacizumab versus 13 months with FOLFIRI alone ➤ OS rates were 90% in the group receiving FOLFIRI plus bevacizumab and 77% in the group receiving FOLFIRI alone ➤ Patients receiving FOLFIRI plus bevacizumab had more cycles of chemotherapy but with more dose adjustments

line treatment with FOLFIRI alone or with FOLFIRI plus bevacizumab who were treated at the Ottawa Hospital Cancer Centre from January 2004 through August 2010.

A total of 176 (37%) patients received FOLFIRI plus bevacizumab, and 294 (63%) received FOLFIRI alone—127 before bevacizumab became available and 167 after. At the start of FOLFIRI therapy, the baseline characteristics were not significantly different between the 3 groups: the median age was 61 to 64 years, although a greater proportion of patients receiving bevacizumab were women compared with patients receiving FOLFIRI alone.

“Patients treated with FOLFIRI plus bevacizumab received more cycles of chemotherapy but with more dose adjustments,” said Dr Maroun.

Continued on page 31

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Colorectal Cancer

In the Real World, Bevacizumab Improves Survival...

Patients receiving FOLFIRI plus bevacizumab completed 3579 cycles of chemotherapy, compared with 2404 cycles that were completed by the 167 patients who received FOLFIRI alone after bevacizumab was available, and 1606 cycles that were completed by the 127 patients who received FOLFIRI before bevacizumab became available.

Patients receiving FOLFIRI alone had a median of 16 cycles before bevacizumab became available and 13 cycles after. Patients receiving FOLFIRI plus bevacizumab had a median of 14 cycles of FOLFIRI and a median of 15 cycles of bevacizumab.

Overall, ≥1 FOLFIRI dose adjustments were made in 78% of patients, with a median of 6 cycles to the first adjustment; 49% of patients had their first adjustment during the first 3 cycles. Bevacizumab was placed on hold in 95 (54%) patients: once in 35% of the patients, and twice in 25% of the patients. The median time off of bevacizumab was 37 days. The dose intensity across the 3 groups was approximately 76%.

Adverse events were responsible for at least 1 dose adjustment in 146 (83%) patients receiving FOLFIRI plus bevacizumab, and in 215 (73%) receiving FOLFIRI alone.

The median PFS was 17 months

By the numbers

with FOLFIRI plus bevacizumab. In patients receiving FOLFIRI before bevacizumab availability, the median PFS was 13 months, and in those receiving it after the availability of bevacizumab, it was 14 months.

Oncology Practice Management, Advocacy, and Navigation An educational session for practice managers and other care providers focusing on cancer care and innovative delivery techniques.

CO-CHAIRS

MAY 9, 2014 Loews Hollywood Hotel Los Angeles, CA

Session 1: Cancer Care in Crisis: An Imperative for Change Douglas Blayney, MD, Ann & John Doerr Medical Director, Cancer Center, Stanford University Medical Center; Professor of Medicine, Stanford University School of Medicine

9:15am – 10:30am

Session 2: Innovation in Practice Management and Care Delivery: A Progress Report on Value-Based Innovation Linda Bosserman, MD, FACP, President, Wilshire Oncology Medical Group John Fox, MD, Associate Vice President of Medical Affairs, Priority Health John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

10:30am – 10:45am

Break

10:45am – 11:45am

Session 3: Uniting the Patient, Provider, and Community Voice in Value-Based Cancer Care Terry Langbaum, Chief Administrative Officer, Kimmel Center, Johns Hopkins School of Medicine Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center Kim Thiboldeaux, President & CEO, Cancer Support Community

11:45am – 1:00pm

Lunch/Meet the Experts Roundtables John Fox, MD, Associate Vice President of Medical Affairs, Priority Health Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

1:00pm – 1:45pm

Keynote Address Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna

1:45pm – 2:00pm

Closing Remarks

cases in 2013 was 142,820

➤ The estimated deaths related in the United States is 20.8% for people aged 55 to 64 years, 24% for those aged 65 to 74 years, and 24.1% for those aged 75 to 84 years

➤ After age 84 years, the

risk for CRC decreases significantly

Sources: www.cdc.gov/cancer/colorectal/ statistics/index.htm; http://seer.cancer. gov/statfacts/html/colorect.html.

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Vice President, Program Development and Delivery Cancer Support Community

8:45am – 9:15am

➤ The estimated number of CRC

➤ The rate of new cases of CRC

Vicki Kennedy, LCSW

Introductions and Opening Remarks Linda Bosserman, MD, FACP; Vicki Kennedy, LCSW

died of CRC

to CRC in 2013 was 50,830

President Wilshire Oncology Medical Group

8:30am – 8:45am

mon cancer in both sexes

➤ In 2010, 52,045 Americans

Linda Bosserman, MD, FACP

AGENDA

➤ CRC is the third most com➤ In 2010, 131,607 Americans were diagnosed with CRC

year; 67%, 49%, and 56%, respectively, at 2 years; and 54%, 31%, and 44%, respectively, at 3 years. At the time of data cutoff, there was an insufficient number of events to estimate median OS, said Dr Maroun. n

NEW FOR 2014

➤ Of tumors that affect both sexes, CRC is the second leading cause of cancerrelated deaths in the United States

Over 3 years, OS rates in the 3 groups (FOLFIRI plus bevacizumab, FOLFIRI alone before bevacizumab availability, and FOLFIRI alone after the availability of bevacizumab) were 90%, 77%, and 78%, respectively, at 1

Continued from page 30

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Oncology HIT

High Rate of Overridden Drug Contraindication Alerts for Patients with Cancer

By Rosemary Frei, MSc

Washington, DC—Patients with cancer are often prescribed medications for the treatment of comorbid conditions, and some of those medications may have harmful drug interactions with the therapies used to treat their cancer. Computerized alert systems are now being used to inform providers or support personnel on such contraindications.

A new study reported at the 2013 American Medical Informatics Association meeting suggests that the vast majority of contraindication alerts for prescribed cancer medications on computerized provider order entry systems are overridden by various providers, including physicians and nurses, and many of these are done without an explanation.

Of the 214 contraindicated medication alerts for a population of 117 patients with cancer (adults and children) who were being treated at a large, multispecialty, ambulatory academic practice that provides care throughout the Houston community, 93% of alerts were overridden, according to data gathered by Elise G. Brune and Dean F. Sittig, PhD, Professor, University of Texas Health Science Center at Houston, under the supervision of Allison B. McCoy, PhD, Assistant Professor of Biostatistics and Bioinformatics, Tulane University, New Orleans, LA. Furthermore, 83.2% of the alerts were overridden without an explanation.

“The differences between specialty and provider types [of alerts] are likely due to those types with the highest override rates using the system more and seeing more alerts than others.

These high rates are not unique to cancer patients or our institution.”

—Allison B. McCoy, PhD

Study Details Physicians and nurses overrode all medication alerts they received, whereas medical assistants overrode 13% (8 of 62) of alerts. Members of several medical specialties overrode

all alerts, including oncologists, obstetrician/gynecologists, endocrinologists, and neurologists.

By contrast, otolaryngologists did not override most alerts, nor did pediatricians and plastic surgeons. The sample sizes were too small to determine whether any of the differences in alert override rates were significant.

“The differences between specialty and provider types [of alerts] are likely due to those types with the highest override rates using the system more and seeing more alerts than others,” said Dr McCoy. “These high rates are not unique to cancer patients or our institution.”

On average, there were 1.7 overridden alerts per patient. Of the 46 alerts for absolute drug contraindications, 95% were overridden, as were 15.8% (12 of 76) of alerts for potential contraindications, and all 75 of the alerts for contraindication cautions.

The Rationale Of the overrides with explanations, 5% were attributed to the benefit of the contraindicated medication outweighing the risk to the patient. Another 3% of the alerts were overridden because the clinician deemed the contraindication to present little risk to the patient, and the clinician gave appropriate warnings to the patient. A total of 2% of alerts were overridden because there were no reasonable alternatives for the patient. A

at a glance ➤ Drug interactions can interfere with the activity of cancer medications and can cause harm to patients ➤ A new study shows that the majority of drug alerts regarding medication contraindications in patients with cancer are overridden by the providers ➤ In this study, only 7% of alerts were not overridden ➤ These high rates are not unique to cancer providers but this trend may need to be reviewed more carefully by providers total of 83.2% of the alerts were overridden without an explanation. Only 7% of alerts were not overridden.

The researchers also found peaks and valleys in the alert and override patterns: the highest rates of alert overrides were in March, May, September, and December, with the lowest rates in January, April, June, and July. The rates of overriding also peaked at 9:00 am and at 1:30 pm, and dipped overnight and at noon.

Dr McCoy has received a grant to evaluate all medication alerts in detail, not just those for cancer medications. n

Harnessing CMS’s Meaningful Use Criteria to Transform Cancer Care with EMRs Washington, DC—A new framework for transforming cancer care by harnessing the meaningful use criteria of the Centers for Medicare & Medicaid Services (CMS) was proposed by a team of researchers at the 2013 American Medical Informatics Association meeting. The team proposed a system that uses electronic medical records (EMRs) to streamline every aspect of the care continuum, from clinical trial patient recruitment to maximizing quality and minimizing cost.

“We…realized that data from EMRs can be used in a much more systematic way for cancer care,” explained Arkalgud Ramaprasad, PhD, Visiting Professor of Computer Information

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Systems, University of Miami, Coral Gables, FL. “Our framework can be used to explore innovative strategies that further the mission of clinical medicine. For example, EMR vendors can align with pharmaceutical companies to develop an integrated portal for patient-assistance programs. The portal would provide useful information for providers and recipients to guide them on which treatment options are available and optimal,” Dr Ramaprasad said.

He and his colleagues believe that this approach will address the current complexity of treatment, the difficulty of patient recruitment, and the need for significant patient assistance, as

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“An integrated framework like this should help manage the cost, quality, safety, and affordability of cancer care.”

—Arkalgud Ramaprasad, PhD well as the need for patient education that will persist into the foreseeable future in cancer care.

The CMS Stages 1 and 2 meaningful use criteria focus on the implementation of tech­ nology and processes for the acquisition and distribution of information by or to providers and

recipients to manage healthcare efficiency, quality, safety, and disparities.

Dr Ramaprasad and Karan Srivastava, a medical student at the University of Miami, wove together the underpinnings of these criteria with all of the components of the cancer care system.

For example, the framework would include an EMR-based platform for decision support for cancer treatment prescriptions for physicians and patients, and for the education of patients about treatment adherence.

“An integrated framework like this should help manage the cost, quality, safety, and affordability of cancer care in the short and long terms,” said Dr Ramaprasad.—RF n

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NCCN 2014 Conference

Updated NCCN Guidelines for Non-Hodgkin Lymphoma Note Controversy Related to B-Cell Disease Management Cell of origin may soon influence treatment decisions

By Wayne Kuznar Hollywood, FL—The updated guidelines from the National Comprehensive Cancer Network (NCCN) for the management of non-Hodgkin lymphoma (NHL) includes new strategies in the management of diffuse large B-cell lymphoma (DLBCL) and new guidelines for T-cell lymphoproliferative disorders.

The updates were presented by Andrew D. Zelenetz, MD, PhD, Vice Chair, Medical Informatics, Department of Medicine, Memorial SloanKettering Cancer Center, New York, at the 2014 NCCN Conference.

The guidance for primary mediastinal B-cell lymphoma (PMBL) states that optimal first-line therapy is more controversial than for other subtypes of NHL, and includes the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen; dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, plus rituximab) regimen; and R-CHOP followed by the ICE (ifosfamide, carboplatin, and etoposide) regimen.

The new guidelines for induction therapy for stage I or stage II nonbulky DLBCL no longer distinguish between risk factors that are present and those that are not present.

The coexpression of the MYC protein and the BCL2 protein predict poor outcomes for a group of patients with DLBCL. This “double hit” by immunohistochemistry represents approximately 30% of patients. There is no evidence-based standard of care for patients with this MYC/BCL2 co­ expression lymphoma, who “really need to go on prospective clinical trials,” said Dr Zelenetz.

Dose-adjusted EPOCH-R, although effective at improving survival in patients with MYC-positive DLBCL, needs to be validated as a treatment for this subgroup of patients with DLBCL.

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The new guidelines for induction therapy for stage I or stage II nonbulky DLBCL no longer distinguish between risk factors that are present and those that are not present, because there is no evidence to support a differential management of patients with favorable or unfavorable risk factors, Dr Zelenetz said, even though patients with such risk factors have worse outcomes.

PMBL: 3 Treatment Options Produce Excellent Outcomes Currently, 3 treatment options are now included in the guidelines for the management of patients with PMBL: • R-CHOP followed by radiation therapy • Dose-adjusted EPOCH-R with optional radiation • And R-CHOP for 4 cycles, followed

by ICE, with optional radiation.

In a 2013 study by Dunleavy and colleagues, dose-adjusted EPOCH-R without radiation therapy was associated with an event-free survival of 100% over a median of 3 years of follow-up in 16 patients involved in a retrospective analysis. The 51 patients in the prospective cohort had an eventfree survival of 93% over 5 years. Of note, dose-adjusted EPOCH-R had no significant impact on cardiac function.

“I would argue that with a total of 67 patients, we need more data before we call this the standard of care,” said Dr Zelenetz.

“Given the demographics of this disease with high incidence in young women, avoidance of radiation is preferred,” he said. Hence, avoiding radiation is an option.

“R-mini-CHOP” an Option in Older Patients In patients aged >80 years with comorbidities, “R-mini-CHOP” has been added as a treatment option for patients with DLBCL. This regimen consists of dose-attenuated rituximab (375 mg/m2), a reduced dose of cyclophosphamide (400 mg/m2), halving of the usual doxorubicin dose (25 mg/m2), and a 1-mg flat dose of vincristine, as was established in a prospective study by Ballester and colleagues in their evaluation of 150 patients aged >80 years with DLBCL.

Therapy Based on Cell of Origin In the not-too-distant future, the cell of origin may influence the treatment choice. In this respect, the more promising results have been achieved with

“I would argue that with a total of 67 patients, we need more data before we call this the standard of care. Given the demographics of this disease with high incidence in young women, avoidance of radiation is preferred.”

What’s New in T-Cell Lymphoma?

Two new guidelines in T-cell lymphoma have been constructed for primary cutaneous CD30+ lymphoproliferative disorders and large granular lymphocytic leukemia.

For the lymphomatoid papulosis subtype of primary cutaneous CD30+ lymphoproliferative disorders, the primary treatment depends on the extent of the disease. Observation is preferred for patients with limited lesions who are asymptomatic, with the option to use topical steroids or phototherapy. For patients with extensive lesions or have symptoms, weekly methotrexate, phototherapy, systemic retinoids, topical steroids, or topical nitrogen mustard are options.

For patients with primary cutaneous anaplastic large-cell lymphoma (ALCL), surgical excision with or without radiation therapy is considered primary therapy for patients with solitary or grouped ALCL lesions. Weekly methotrexate, radiation therapy, systemic retinoids, observation (if asymptomatic), or interferon alpha-2B are options for primary therapy for patients with multifocal ALCL lesions.

—Andrew D. Zelenetz, MD, PhD

non–germinal center B-cell lymphoma (non-GCB), Dr Zelenetz noted, discussing several specific examples in this setting.

• Lenalidomide plus R-CHOP ameliorates the negative effect of the nonGCB phenotype and is well tolerated, including in elderly patients • Ibrutinib has shown clinically meaningful response rates in relapsed or refractory non-GCB, which is consistent with an essential role of B-cell receptor signaling in this subtype of disease • Bortezomib added to R-CHOP has also had success in early studies in the treatment of non-GCB DLBCL, and is now under investigation in 3 large-scale randomized trials for this purpose • The sequence of R-CHOP and ICE may be a more cost-effective way to achieve these same results in nonGCB tumors, Dr Zelenetz said.

APRIL 2014

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Surgical excision with or without radiation therapy is considered primary therapy for patients with solitary or grouped ALCL lesions.

For patients with T-cell large granular lymphocytic leukemia, the most common indications are cytopenias.

If patients with indolent disease are asymptomatic, the recommended management strategy is observation. The preference for symptomatic patients is enrollment into a clinical trial, “but many things work,” said Dr Zelenetz.

Immunosuppressive therapy with methotrexate or cyclophosphamide, or cyclosporine A without steroids, all have reasonable activity. Persistence is crucial when using cyclosporine A, Dr Zelenetz said, because responses may not be observed for several weeks. n

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NCCN 2014 Conference

Updated NCCN Melanoma Guideline Adds BRAF Inhibitor and MEK Inhibitor to First-Line Targeted Therapeutic Options Hollywood, FL—The updated National Comprehensive Cancer Network (NCCN) guidelines for the management of melanoma now include the BRAF inhibitor dabrafenib (Tafinlar) as a Category 1 recommendation for the primary treatment of patients with metastatic melanoma and BRAF mutation, as well as the use of the mitogen-activated protein kinase (MEK) inhibitor trametinib (Mekinist) for the treatment of patients with melanoma and BRAF mutation. These 2 drugs, which received US Food and Drug Administration (FDA) approval last year, are now added to the NCCN targeted therapies for the treatment of patients with advanced or metastatic melanoma.

John A. Thompson, MD, Medical Director, Phase 1 Clinical Trials Program, and Codirector, Melanoma Clinic, Seattle Cancer Care Alliance, WA, presented the updated guidelines at the 2014 NCCN Conference.

at a glance ➤ The NCCN guidelines now include dabrafenib as a Category 1 recommendation for the primary treatment of metastatic melanoma with the BRAF mutation ➤ The Category 1 preferred regimens for advanced or metastatic melanoma now include ipilimumab, vemurafenib, and dabrafenib ➤ However, dabrafenib can cause febrile toxicity, and the use of vemurafenib and dabrafenib can result in significant dermatologic complications ➤ Trametinib is recommended for the treatment of patients with melanoma and a BRAF mutation, as well as with dabrafenib in patients who are intolerant of a BRAF inhibitor ➤ For patients with wild-type BRAF mutation who have more aggressive and symptomatic disease, ipilimumab, or enrollment in a clinical trial, is recommended

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Updated Recommendations Dabrafenib is now recommended by the NCCN for patients with the BRAF V600 mutation; trametinib is indicated for use with dabrafenib in patients who are intolerant of a BRAF inhibitor.

Single-agent trametinib use is not recommended for patients with disease progression who had previous BRAF inhibitor therapy.

The Category 1 preferred regimens for advanced or metastatic melanoma now include ipilimumab, vemurafenib, and dabrafenib. The updated guideline notes that dabrafenib can be associated with significant febrile toxicity, and both vemurafenib and dabrafenib have the potential for significant dermatologic complications, including cutaneous squamous-cell carcinoma and extreme photosensitivity.

The Evidence Dr Thompson presented data from the literature to support these recommendations. A randomized study compared the use of dabrafenib with dacarbazine in 250 patients with metastatic BRAF-mutated metastatic melanoma; the median progression-free survival (PFS) was 5.1 months with dabrafenib and 2.7 months with dacarbazine, for a hazard ratio of 0.30 (Hauschild A, et al. Lancet. 2012;380:358-365).

Downstream from BRAF mutation, the other signaling molecule in melanoma is MEK. The first targeted MEK inhibitor to receive FDA approval was trametinib. In a study of 322 previously untreated patients with metastatic melanoma who were randomized to trametinib or to dacarbazine or paclitaxel chemotherapy, the median PFS was improved from 1.5 months in the chemotherapy arm to 4.8 months with trametinib, and the overall survival (OS) at 6 months improved from 67% to 81%, respectively (Flaherty KT, et al.

N Engl J Med. 2012;367:107-114).

In a follow-up study, Flaherty and colleagues examined the use of combined BRAF and MEK inhibitions at 2 doses in patients with metastatic melanoma, showing approximately 3 additional months of PFS with the 2 com­ bination regimens compared with dabrafenib monotherapy; the benefit extended to all the subgroups. How­ ever, dual blockade increased the incidence of fever and chills compared with dabrafenib monotherapy. “Often-

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Photo by Dr. P. Marazzi / Science Source

By Wayne Kuznar

times, the fever and chills require temporary cessation and resumption of therapy at lower doses, and supportive therapy such as acetaminophen, should be used,” Dr Thompson said.

Potential for Immune-Related Adverse Events Dr Thompson updated the field of immune checkpoint inhibitors in the treatment of melanoma. A 2013 multi-

When using the dual BRAF and MEK inhibition with dabrafenib and trametinib, “oftentimes, the fever and chills require temporary cessation and resumption of therapy at lower doses, and supportive therapy such as acetaminophen, should be used.”

—John A. Thompson, MD

center retrospective review by Luke and colleagues of 39 patients with metastatic uveal melanoma who received ipilimumab showed a median OS of 9.6 months; 18% of patients had grade III or IV toxicity.

“In treating patients with ipilimu­ mab, we have to be very careful in managing the potential for immunerelated adverse events,” said Dr Thompson. Toxicities include skin, gastrointestinal (GI), liver, endocrine system, and neurologic. The median time to skin toxicity is approximately 3 weeks, whereas GI toxicity manifests at approximately week 6, and endo-

crine events in the later stages of treatment, he said. GI toxicity, which occurs in up to 25% of patients treated with ipilimumab, can progress rapidly and requires active intervention.

The programmed death (PD)-1 medications in development for the treatment of patients with advanced melanoma are lambrolizumab and nivolumab. The responses observed with the PD-1 lambrolizumab in a 2013 study by Hamid and colleagues were “quite dramatic,” Dr Thompson said, with approximately 66% of patients demonstrating tumor shrinkage.

The median duration of response had not yet been reached at 11 months of follow-up.

In a 2013 study by Wolchok and colleagues in patients with advanced melanoma, the PD-1 agent nivolumab, used concurrently with ipilimumab, was associated with a 53% objective response rate, and a similar percentage of patients had immune-related grade III to IV toxicities. Of 53 patients in this arm, 16 had tumor reduction of more than 80% by 12 weeks.

First-Line Decisions At present, patients with the BRAF wild-type mutation who have low-volume metastatic melanoma and a 0 performance status are recommended to receive high-dose interleukin (IL)-2 or ipilimumab as first-line systemic therapy, or be enrolled in a clinical trial. For those with BRAF wild-type mutation who have more aggressive and symptomatic disease, ipilimumab or enrollment into a clinical trial (that combines cytotoxic agents with immune checkpoint inhibitors) are recommended, said Dr Thompson.

For patients with a documented BRAF mutation, patients with low-volume disease and a performance status of 0 are recommended to receive IL-2, ipilimumab, or a targeted agent as first-line therapy, or to be enrolled into a clinical trial. Molecular targeted therapy (or enrollment into a clinical trial) is suggested for patients with bulky disease who are symptomatic. n

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No. 3

COMING SOON A 4-PART SERIES

Value-BasedCare IN MULTIPLE MYELOMA

™

The therapeutic paradigm for multiple myeloma (MM) continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to discuss the most recent available data concerning improvements in cost of care, safety profiles, and patient preferences as they pertain to the use of emerging agents used in the treatment of patients with MM. IN MULTIPLE MYELOMA

Value-BasedCare

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November 2013 u 8th IN A SERIES

Cost-Effective Use of Imaging Modalities for Diagnosis and Monitoring in Multiple Myeloma

Topics include: • Effective Treatment of Newly

Diagnosed and Relapsed/ Refractory Patients with MM: Utilizing Optimal Dosing Regimens • Appropriate Duration of Therapy

for MM in a Value-Based Care Plan • Improving the Standard of Care

in MM: Interpreting Overall Survival Data and Assessing the Cost of a Complete Response • Establishing a Value-Based

Paradigm for the Management of Patients with MM: A Pharmacoeconomic Analysis of Treatment Options

Introduction Identification, characterization, and management of osteolytic bone lesions are key aspects of care in multiple myeloma (MM).1 A comprehensive, chart-based study from the Mayo Clinic, published in 2003, revealed that 84% of patients with myeloma developed skeletal lesions at some time during the course of their disease.2 Based on conventional radiography at the time of diagnosis, 79% of patients presented with at least one type of skeletal abnormality (Figure 1).2 In the decade since the publication of this influential study, these high estimates of skeletal-related events have held constant.1 What has changed, however, are the options available to clinicians for imaging the skeleton. Although radiographic skeletal survey remains the fundamental imaging study at both the initial workup and follow-up of the patient with MM, additional newer technologies can be utilized. These include magnetic resonance imaging (MRI), computed tomography (CT) scan, and positron emission tomography (PET) scan, which may be combined with CT scan (PET-CT). Bone densitometry is another imaging technology with application in the disease.3 These technologies may provide helpful diagnostic and follow-up information on the patient, but despite evidence-based guidelines on imaging in MM, there is currently no standard for their appropriate clinical use.3-7 Individual providers, institutions, and payers are tasked with the decision to deploy or to forego MRI, CT, and PET on a case-by-case basis. The choice to utilize these sophisticated imaging methods ultimately affects the value of myeloma care: overuse or inappropriate use of such technologies results in unnecessary utilization costs; failure to use the technologies when prudent may result in a lower quality of care.

This article will explore the current clinical evidence base for the use of various imaging methods in MM. It will also present expert consensus on the approach to imaging in selected patients.

These data and opinions are useful in making rational decisions to employ and to reimburse imaging in the patient with myeloma.

The most recent of the guidelines, from the National Comprehensive Cancer Network (NCCN), recommends radiographic skeletal survey for all patients at initial workup and for the follow-up of every patient annually or when symptoms are present.3 The NCCN makes provisional recommendations for MRI, CT, and PET scans, which are described as “useful under some circumstances” in initial workup and may be used “as clinically indicated” for follow-up surveillance.3 When is additional testing “useful” and “indicated”? Different organizations and experts have given various answers to this question. According to the NCCN, PET-CT scanning and MRI scans provide greater sensitivity than did conventional radiography.3 Therefore, during an initial workup in a patient who presents with bone pain, weakness, or other symptoms in

OVERVIEW The therapeutic paradigm for multiple myeloma continues to evolve at a rapid pace. The goal of this newsletter series, published by the Association for Value-Based Cancer Care™, is to provide readers with recent clinical advances in myeloma treatment, as well as stakeholder perspectives on how emerging data can be used to promote high-quality, cost-effective care.

Each supplement will discuss a specific topic to be considered when developing value-based strategies. In this final newsletter, we discuss strategies for ensuring value-based care as it is related to the use of imaging modalities in myeloma.

STAKEHOLDER’S PERSPECTIVE Assessing the Optimal Use of Imaging Modalities in Patients with Myeloma ...........................5

Imaging Options in MM: Evidence-Based Guidelines and Expert Consensus Since 2007, 5 different sets of clinical practice guidelines have been issued on the use of imaging technologies in MM (Table).3-7 These guidelines provide a good starting point for individual providers, institutions, and payers seeking to evaluate these modalities.

This newsletter has been supported by funding from Millennium: The Takeda Oncology Company

AVBCC100-8.indd 1

James R. Berenson, MD Institute for Myeloma & Bone Cancer Research West Hollywood, CA

An official publication of

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