VBCC March 2013 VOL 4 NO 3

MARCH 2013 VOL 4 NO 3

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

Introducing the Third Annual Conference of the Association for Value-Based Cancer Care

By Burt Zweigenhaft, BS, Chief Executive Officer and Chairman, OncoMed Onco360; Co-chair of the AVBCC Conference

Healthcare of Tomorrow: Digital, Genomic, and Patient-Focused Through the looking glass with Dr Eric J. Topol

By Caroline Helwick New Orleans, LA—As a leader in the movement to modernize healthcare through the latest technology, Eric J. Topol, MD, the Gary and Mary West Endowed Chair of Innovative Med­ icine, Professor of Genomics, Depart­ ment of Molecular and Experimental Medicine, Scripps Research Institute,

La Jolla; Director of the Scripps Translational Science Institute, La Jolla; and Chief Academic Officer, Scripps Health, San Diego, CA, proposes creative and effective ways to treat patients that will also dramatically reduce the cost of care.

Continued on page 34

For Stage II Colon Cancer, Oncotype DX Proves Cost-Saving

By Audrey Andrews As we know, the American healthcare system is going through exorbitant changes, changes that will affect all providers and all stakeholders in the cancer care ecosystem. The goal of the Association for Value-Based Cancer Care (AVBCC) is to bring together all the cancer care stakeholders in one unified meeting to discuss the many issues facing us today. One of the main objectives of the AVBCC Annual Conference is to be able to map out and help guide our members and attendees through the various changes in the US healthcare system.

Continued on page 7

Personalized Immunotherapy plus Sunitinib Doubles Survival in Advanced Kidney Cancer AGS-003 proceeds to phase 3 trial

©2013 Engage Healthcare Communications, LLC

with chemotherapy,” said Steven R. Alberts, MD, MPH, Medical Director of the Clinical Research Office, Chair of Medical Oncology, Professor of Oncology, College of Medicine, and a consultant for the Division of Medical Oncology, Mayo Clinic Cancer Center, Rochester, MN. The treatment decision-making process should take into account recurrence risk factors. The 12-gene assay has been clinically validated in patients with stage II colon cancer to predict the risk of recurrence after surgery, and has been shown to influContinued on page 12

inside

By Wayne Kuznar Orlando, FL—A personalized immunotherapy (AGS-003) in conjunction with sunitinib (Sutent) nearly doubled the expected progression-free survival (PFS) and overall survival (OS) in patients with unfavorable-risk metastatic renal-cell carcinoma (RCC), according to results from a single-arm phase 2 trial.

The results support an ongoing phase 3 study of the approach in which patients with metastatic clearcell RCC are being randomized to

San Francisco, CA—For assessing prognosis in patients with stage II colon cancer, the 12-gene Oncotype DX Colon Cancer Assay increases quality-adjusted survival and is costsaving, according to a new study reported at the 2013 Gastrointestinal Cancers Symposium.

“Patients with stage II, T3 colon cancer have an 88% cancer-specific survival rate at 5 years. The challenge remains to identify the individuals with a higher risk of recurrence for whom adjuvant chemotherapy would be considered and spare the remaining patients the toxicity and cost associated

AGS-003 plus sunitinib or to sunitinib alone, with OS as the primary end point, said Asim Amin, MD, PhD, codirector of Immunotherapy at Levine Cancer Institute, Charlotte, NC. Durable remissions with vascular endothelial growth factor–targeted therapies (ie, sunitinib) are rare in patients with advanced RCC, especially in unfavorable-risk patients.

Immunotherapy with interleukin-2 has demonstrated success in the

Continued on page 38

FROM THE EDITOR . . . . . . . . . . . 4 Transforming cancer care by controlling costs and improving outcomes VALUE PROPOSITIONS . . . . . . . . .

New biomarkers for early diagnosis of renal cancer

5

FDA UPDATE . . . . . . . . . . . . 10, 11 Trastuzumab emtansine for late-stage breast cancer HEALTH ECONOMICS . . . . . . . . . . 12 Postorchiectomy surveillance less cost-effective than other options

AVBCC ABSTRACTS . . . . . . . . . . . 19 Abstracts will be presented at the Third Annual Conference of the Association for Value-Based Cancer Care, May 2-5, 2013 HEALTH POLICY . . . . . . . . . 34, What does the deficit reduction mean for oncology?

36

DRUG UPDATE . . . . . . . . . . . . . . . 40 Pomalidomide: a new thirdgeneration immunomodulatory drug for multiple myeloma

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM * SUSTAIN IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

PROF35855_Provenge_VBCC_DR.indd 2

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer.

The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

3/12/13 4:00 PM

From the Editor

Transforming Cancer Care by Controlling Costs and Improving Outcomes

By Craig Deligdish, MD, Chief Medical Officer, Oncology Resource Networks, and Editor-In-Chief, Value-Based Cancer Care

V

alue Based Cancer Care (VBCC) was first published in May 2010, and the first annual meeting of the Association of Value-Based Cancer

Care took place in May 2011. During the past 3.5 years, this publication and its annual meeting have provided a forum for stakeholders to address

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011.

2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

©2013 Dendreon Corporation.

All rights reserved. January 2013.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-01.13-002.00

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Value-Based Cancer Care PROF35855_Provenge_VBCC_DR.indd 3

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My goal... will be to ensure that VBCC provides readers the resources that may help them to understand the value proposition around managing the cost of treatment while improving patient results and patient satisfaction.

important issues that impact the value proposition facing patients with cancer, providers, and payers in an open and challenging fashion. Both the annual meeting and VBCC have focused on a dialogue around strategies for optimizing value in cancer care delivery.

As I contemplate my role as Editorin-Chief of VBCC, I plan to enlist the expertise of the journal’s editorial board and others to continue to address innovative trends that enhance value-based care and examine the impact of diagnostic modalities, new therapies, and other initiatives that alter the value proposition, while improving outcomes and influencing how we think about cancer care.

In the past 30 years, patients and providers have witnessed and experienced a transformation in cancer care. Today, cancer costs account for approximately 5% of US healthcare spending. As patients with cancer live longer, it is expected that they will consume an even larger proportion of US healthcare dollars. Today, annual direct costs for the treatment of cancer exceed $100 billion in the United States, with an annual burden of more than $200 billion. As technology and drug costs increase, the cost of cancer care is expected to continue its upward trend. This, coupled with efforts by public and private payers to reduce reimbursements for cancer care, makes it imperative that providers of care in this vulnerable population integrate cost-saving strategies while maintaining optimal quality of care. Almost everyone who understands these challenges agrees that the current trends are not sustainable.

It has only been relatively recently that the provider community and

the public have begun to appreciate the impact of cost on cancer care.

The concepts of evidence-based cancer care, value, quality, cost, and the value equation have been brought to the forefront as providers and payers experiment and re-explore payment methodologies that potentially reward those who are willing to bear risk or improve value. The effort and the cost of the infrastructure necessary to achieve these goals should not be underestimated. Although one of the driving factors in how payers and providers think about cancer care has been the increasing cost of care, more recently the debate that has resulted from the Affordable Care Act (ACA) has furthered the discussion about rationing and has taken the end-of-life care discussion to a new level. The increasing role of government-sponsored healthcare will no doubt alter the way patients and providers think about care. With the ACA in place, the impact of government-sponsored healthcare and the ACA on private health insurance will begin to influence how care is delivered.

The past several years have provided us with a preview of how the consolidation of providers into hospital-based networks can increase the cost of healthcare. Hospital mergers and physician-practice acquisitions have occurred at rates that have not been seen in years. The ultimate impact of these factors on quality, access, and cost for patients with cancer and on providers has yet to be realized.

VBCC will be examining these changes on our country’s delivery system.

The effect of commoditizing cancer care through the use of guidelines and pathways that standardize approaches to diagnosis and treatment will also be examined. We will continue to examine changes in delivery systems that provide a more patient-centered approach to enhance quality and accountability while altering physician and patient behavior. We will simultaneously attempt to measure the value of personalizing care by examining innovative approaches to diagnoses and treatments, with a focus on value for evidence-based and non– evidence-based modalities.

My goal as Editor-in-Chief will be to ensure that VBCC provides readers the resources that may help them to understand the value proposition around managing the cost of treatment while improving patient results and patient satisfaction in a rapidly evolving care continuum. n

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No. 3

VALUE PROPOSITIONS Participation in ASCO’s Quality Practice Program Improves Performance Scores

Oncology practices that participate in the American Society of Clinical Oncology (ASCO)’s Quality Oncology Practice Initiative (QOPI)—a program of self-reported metrics on performance measures—demonstrate improved performance scores on several measures, including: • Providing adjuvant chemotherapy (which has shown to improve survival) for breast, colorectal, and non–small-cell lung cancers: ≥90% of participating practices perform as recommended • Improved uptake of new clinical practice (following new guidelines or clinical evidence): from 5% to 69% in the past 4 years.

“This study further shows that participation in quality assessment programs like QOPI should provide reassurance to people living with cancer that they are receiving high-quality care,” said Sandra M. Swain, MD, FACP, ASCO President. “Nearly 600 practices in the United States are already participating in QOPI, in part because it provides a systematic process, library of diverse quality measures, collection tool, and reliable information to assess the care they provide. QOPI is also the gateway to QOPI-Certification, which recognizes practices that demonstrate performance on designated QOPI measures and meet certification standards for quality and safe care.” ASCO in Action; March 12, 2013

imaging, which is of high cost, is seldom performed without any specific reasons, developing a blood-tumor biomarker is a great chance to detect the silent killer.” The new test was developed by Dr Cho and colleagues from Genomine, Inc. American Association for Cancer Research; March 11, 2013

With Cost of Gene Sequencing Declining, a New Algorithm Brings Predictive Modeling Closer to Practice

Two researchers at the University of Southern California (USC) developed a new algorithm that may soon bring gene sequencing closer to clinical practice by predicting the value of DNA sequencing and making it less costly. “It seems likely that some clinical applications of DNA sequencing will become routine in the next five to ten years,” said Andrew Smith, a computational biologist at USC. “For example, diagnostic sequencing to understand the properties of a tumor will be much more effective if the right mathematical methods are in place.”

The new algorithm helps to decide how much DNA to sequence, which can significantly reduce the cost and time associated with the procedure and bring it one step closer to wide use in clinical practice. University of Southern California Press Release; February 24, 2013

ASCO Shines Light on Palliative Care: New Online Program Will Translate Latest Research into Practice

ASCO and the American Academy of Hospice and Palliative Medicine (AAHPM) have announced the launch of a new collaboration to promote the delivery of high-quality palliative care for patients with advanced cancer. The 3-year project will focus on the complex needs of patients with advanced cancer that involve relieving cancer-related symptoms for this patient population. The initiative will create a web-based platform to disseminate evidence-based palliative care approaches in oncology. The platform will include customized learning modules, social networking capabilities, and a toolbox with evidence-based resources to help providers translate the latest research findings into clinical practice.

“We recognize that palliative care is an essential component of care for patients with cancer. This partnership will help get the latest palliative care evidence directly into the hands of oncologists so that palliative care can be provided as early as possible,” said Sandra M. Swain, MD, FACP, ASCO President. “Never before has technology been leveraged to quickly spread practice-changing research and to connect oncologists, allowing them to share best practices in palliative care.” ASCO in Action; March 6, 2013

New Biomarkers May Soon Help the Early Diagnosis of Renal-Cell Cancer, Reduce Mortality

A new immunoassay to detect the presence of 3 biomarkers is under review by the US Food and Drug Administration (FDA) and may soon become available to help the early diagnosis of renal-cell carcinoma. This test is based on the identification of 3 biomarkers for renal-cell cancers: nicotinamide N-methyltransferase (NNMT), L-plastin (LCP1), and nonmetastatic cells 1 protein (NM23A). New data published in March (Kim SD, et al. Cancer Epidemiol Biomarkers Prev. 2013;22:390-398) show that the new immunoassay had a 94.4% accuracy rate in identifying patients with renal-cell carcinoma and a 90% accuracy rate in identifying blood samples from healthy controls.

“Renal-cell cancer…is one of the most difficult forms of cancer to detect and treat properly because it remains silent until disseminating to other organs,” said coinvestigator Nam Hoon Cho, MD. “Furthermore, because

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No. 3

New Breast Cancer Drug a Projected Blockbuster, with Annual Cost of Approximately $94,000

The recently FDA-approved antibody-drug conjugate trastuzumab emtansine (Kadcyla; Roche/Genentech), also known as T-DM1, for patients with advanced HER2-positive breast cancer is expected to become the new blockbuster therapy for patients with breast cancer. This drug will cost $9800 monthly and approximately $94,000 for a course of therapy lasting 9.5 months. Projected peak sales for this drug have ranged from $2 billion to $5 billion annually. “Kadcyla is an antibody-drug conjugate representing a completely new way to treat HER2-positive metastatic breast cancer, and it helped people in the EMILIA study live nearly six months longer,” said Hal Barron, Chief Medical Officer at Roche and Head of Global Product Development. FierceBiotech; February 22, 2013

Copper Depletion Therapy May Prevent Tumor Metastasis in High-Risk Triple-Negative Breast Cancer

Results of a small, phase 2 study conducted by researchers from Weill Cornell Medical Center show promising benefits of an anti-copper medication (tetrathiomolybdate) in preventing the migration of tumor cells in patients with high-risk triple-negative breast cancer. The median survival for patients with metastatic triple-negative breast cancer is 9 months.

The results of this study show that depleting copper in patients with triple-negative breast cancer who are at high risk of relapse extends eventfree survival considerably. In this study, 4 patients remained disease free for between 3 and 5.5 years, and only 2 of 11 patients with a history of advanced triple-negative breast cancer relapsed within 10 months after using this medication. “The anti-copper compound appears to be keeping tumors that want to spread in a dormant state,” said Linda Vahdat, MD, Director of the Breast Cancer Research Program at Weill Cornell Medical Center. Dr Vahdat expects to start a phase 3 trial in the near future. Weill Cornell Medical Center Press Release; February 13, 2013

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www.ValueBasedCancerCare.com

5

In This Issue

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

FROM THE EDITOR

GU CANCERS SYMPOSIUM

Transforming cancer care by controlling costs and improving outcomes

Similar outcomes with 18 versus 32 months of androgen ablation added to radiation in highrisk prostate cancer More….

VALUE PROPOSITIONS New biomarkers for early diagnosis of renal-cell cancer can reduce mortality New breast cancer drug a projected blockbuster More….

Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1882

FDA UPDATE

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

Trastuzumab emtansine for breast cancer More….

Vice President, Director of Sales & Marketing Joe Chanley joe@greenhillhc.com

HEALTH ECONOMICS

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

Oncotype cost-saving in stage II colon cancer Postorchiectomy surveillance less cost-effective than other options More….

Vice President of Finance Andrea Kelly Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino

AVBCC ABSTRACTS Abstracts will be presented at the Third Annual Conference of the Association for Value-Based Cancer Care, May 2-5, 2013

HEALTH POLICY Healthcare of tomorrow: digital, genomic, and patient-focused More….

DRUG UPDATE Pomalidomide: a new third-generation immunomodulatory drug for relapsed/refractory myeloma

Business Manager Blanche Marchitto

VBCC Editorial Board

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

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

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

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

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

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

Ira Klein, MD, MBA Aetna Hartford, CT Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care, San Francisco, CA

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy Aetna, Hartford, CT Denise K. Pierce DK Pierce & Associates Zionsville, IN

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 © 2013 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.

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

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

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

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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

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

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY David Hom, MBA Solucia Farmington, CT Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

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Naimish Pandya, MD University of Maryland Baltimore, MD

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

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

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

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Marcus Neubauer, MD Medical Director, Oncology Services McKesson Specialty Health The Woodlands, TX

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC, Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

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

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Onco360, Great Neck, NY

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2013 Conference

Introducing the Third Annual Conference of the Association for Value-Based Cancer Care...

Continued from cover

Changes in Reimbursement and Purchasing We are at an inflection point in cancer drug distribution and management. We are seeing the typical wholesaler-to-physician channel control change rapidly. Managed market payers are stepping up and exerting more control over what happens in oncologist offices. The landscape is changing in terms of reimbursement and their contracting capabilities as managed market payers are responding as we experiment and move into an accountable care organization (ACO) world.

It is very important that the AVBCC Annual Conference convenes an agenda and forum to guide and mentor people through the changes, and to be able to inflect strong opinions and to encourage people to participate in helping flush out important changes in the chain to ensure that we can impact change in a very positive way.

It is no longer the traditional wholesaler-to-physician group purchasing organization (GPO) model in this business today. This is rapidly changing as managed market payers’ control and oversight of cancer care are taking hold and are influencing the outcomes of decisions, pathways, formulas, reimbursement, and prior authorization.

It is very important that your staff gets to meet and see all of the stakeholders and decision makers in this chain of rapidly changing events that impact cancer care today. Without that, you and your organization are not going to be prepared for the market changes, and the impact on your brand could be tremendous.

Then again, if you attend the meeting and you observe and understand the changes, enter into the discussion and debate, and lastly, you have the foresight to plan for the changes, hence you will be more successful in the long-run.

An All-Inclusive Agenda We have an all-inclusive agenda. It allows us in the mornings, over the couple of days that we meet, to have all the “big-ticket” topics discussed by some of the greatest thought leaders— the people who are driving change in the oncology space today—whether it is regulatory, reimbursement, coverage, policy, benefits, healthcare systems, hospital systems, or the large community practices that are changing the way we operate in cancer care.

This allows all of the stakeholders, main issues, and agendas to be discussed in an open forum. We have

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panels, channel experts, and key opinion leaders. This is important; you never see such a mix in this business.

Our afternoon tracks allow you to have breakouts, depending on whether it is reimbursement, genetics, product launch, pathways, or care management that is important to you. These are all separate tracks that allow you and your staff to move around with flexibility in the afternoon, and to make sure that you cover the wide array of topics that we have available to enjoy and learn from.

We all know how important networking is. I know that we are in an e-mail and health information exchange market. But meeting key opinion leaders and exchanging in open dialogue, and being able to sit with them at lunch, at breakfast, or between sessions and hear what their thoughts are, is very important.

This is the only conference where the key people in the channel are at the meeting, and they are available for you to meet and to have personal time with them. There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC Annual Conference in its third year, in Hollywood, FL. This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today.

Meeting Key Opinion Leaders Who are these key opinion leaders specifically? For the most part, they are the medical directors of the big insurance plans, the ones who are leading the charge in cancer care, whether in Medicare, Medicaid, or in commercial plans. We have certain leaders that you may recognize, because you have read about them frequently in many publications, including the association’s publication—Value-Based Cancer Care.

We have coding experts. We have advocacy experts. We have policy experts.

This is why the AVBCC annual Conference is a very inclusive meeting, because we bring all the stakeholders together.

When we put together the agenda, our goal was to make sure that we had the right people, the right health plans, the right health systems, and the right leaders. We did not want to see ourselves with another small, myopic view of this industry. We knew that the only way to effect change in a positive way is to get everyone and every voice in the room together to share

There is no better way to get ahead and to stay ahead in cancer care than to be at the AVBCC Annual Conference.

This is your chance to see some of the greatest key opinion leaders, the people who are truly driving change in cancer care today.

information. That is the overall goal of the AVBCC Annual Conference— inclusiveness.

I have always believed that it is very important to meet face to face with the key people who are driving change in the business. One of the goals of our association is to make sure that we have a cast that includes everyone who is leading that change. We have people from Aetna, and people from the University of Pittsburgh Medical Center. We have people from hospital systems, such as the “Roswells” and the “Dana-Farbers” of the world. We have employer groups and coalitions, such as Caterpillar, Delta, the National Business Group on Health, United­ Healthcare, and many others.

The goal of the AVBCC Annual Conference is to bring them all together to make sure that we all have access to each other, and that we could share ideas in an open forum and help chart the future of cancer care in America.

This is why you want to be with us at this meeting, and this is why you need to have your staff attend the conference.

This is the only meeting I am aware of that affords this type of inclusive

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venue, where everyone in the space can get to meet those important leaders who are driving change in cancer care.

One of the most important things that we know is changing is the distribution model as we are moving from the typical manufacturer to the wholesaler through GPO to communitybased or system-based oncologists. As the system is changing, manufacturers are now finding that they are no longer totally dependent on the wholesale channel or on GPOs to make and control the influential buying decisions to drive their products to market. Today it is being heavily influenced by the managed care channels and by payers’ coverage and reimbursement decisions.

In this meeting, in addition to having all the managed market payers represented, we also have the new stakeholders in the distribution channel. We have specialty pharmacies, we have oncology pharmacies, and we have hospital systems and others that are now taking hold of a new distribution model in cancer care.

As this business is changing, what

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For the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of last therapy. Approval is based on response rate.

Clinical benefit, such as improvement in survival or symptoms, has not been verified.

THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION TAKES FLIGHT

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma.

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. 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 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.

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.

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 infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions.

Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur.

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. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved.

Kyprolis™ (carfilzomib) for Injection is engineered for selective inhibition1 • Single-agent KYPROLIS phase 2 study results2,* - Overall response rate (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, 9.2) • Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each) ADVERSE REACTIONS The safety of KYPROLIS was evaluated in clinical trials of 526 patients with relapsed and/or refractory multiple myeloma.

• Serious adverse reactions were reported in 45% of patients. The most common were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%) • The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%) *Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma and whose disease had a ≤ 25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

References: 1. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383-6391.

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

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.

Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been 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 enzyme abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently.

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.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of 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).

The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of the full Prescribing Information on adjacent pages.

©2012 Onyx Pharmaceuticals, Inc., South San Francisco, CA 0512-CARF-243 September 2012

FDA Update Pomalidomide Receives Accelerated Approval for Myeloma

The US Food and Drug Admini­ stration (FDA) accelerated the approval of pomalidomide (Pomalyst capsules; Celgene) for the treatment of patients with multiple myeloma who have received at least 2 previous myeloma therapies, including lenalidomide (Revlimid) and bortezomib (Velcade), and whose disease progressed while

receiving these therapies or within 60 days of stopping the last therapy.

“Pomalyst is the third drug in a class of immunomodulatory agents that includes lenalidomide and thalidomide, and is the second drug approved in the past year to treat multiple myeloma,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval provides

an additional treatment option for patients who have not responded to other drugs.”

The recommended dose for pomalidomide is 4 mg, to be taken orally on days 1 to 21 within a 28-day cycle and repeated until disease progression.

The approval is based on the results of a multicenter, randomized, openlabel clinical trial that included 221 patients with relapsed and/or refractory myeloma despite treatment with

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 2 Dosing Dosing Dosing Dosing (27 mg/m ): 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]

• • •

• Non-Hematologic Toxicity Cardiac Toxicity Grade 3 or 4, new onset or worsening of: • congestive heart failure; • decreased left ventricular function; • or myocardial ischemia [see Warnings and Precautions] Pulmonary Hypertension [see Warnings and Precautions]

Pulmonary Complications • Grade 3 or 4 [see Warnings and Precautions]

Hepatic Toxicity • Grade 3 or 4 elevation of transaminases, bilirubin or other liver abnormalities [see Warnings and Precautions)]

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• • •

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.

Recommended Action Withhold until resolved or returned to baseline.

After resolution, consider if restarting KYPROLIS at a reduced dose is appropriate (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.

• Withhold until resolved or returned to baseline.

• Restart at the dose used prior to the event or reduced 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.

• Consider restarting at the next scheduled treatment with one dose level reduction (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.

• Withhold until resolved or returned to baseline.

• After resolution, consider if restarting KYPROLIS is appropriate; may be reinitiated at a reduced dose (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2) with frequent monitoring of liver function.

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

lenalidomide and bortezomib. Patients were randomized to pomalidomide alone or to pomalidomide plus lowdose dexamethasone. The overall response rate was 7% with pomalidomide alone compared with 29% with the combination of pomalidomide plus low-dose dexamethasone; the median response duration was 7.4 months with the combination.

The most common side effects reported in this trial were fatigue and

reported (< KYPROLIS i reported (< liver abnor KYPROLIS in KYPROLIS liver abnorm Adverse Rei KYPROLIS pregnantRea w Adverse well‑control pregnant wo pregnant ra well‑controll reproductive pregnant rab If this drug reproductive shou Ifpatient this drug ADVERSE patient shou of the labelin ADVERSE R • Cardia of the labelin • Pulmon • Cardiac • Pulmon • Pulmon • Infusio • Pulmon • Tumor • Infusion • Thromb • Tumor L • Hepatic • Thromb The most c • Hepatic trials of pat The most co diarrhea, a trials of pati under wide diarrhea, an be directly under widely observed be directlyinc received observed KY in four treatm received KYP causes with four treatme attributed to causes with cardiac dis attributed to infectiondiso in cardiac intracranial infection in adverse rea intracranial pneumonia adverse rea reactions le pneumonia heart failur reactions lea each).failure Adve heart TableAdver 4: In each).

Patients T Table 4: In Patients Tr

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. a

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

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

Fatigue Anemia Fatigue Nausea Anemia Thromboc Nausea Dyspnea Thrombocy Diarrhea Dyspnea Pyrexia Diarrhea Upper resp Pyrexia Headache Upper resp Cough Headache Blood crea Cough Lymphope Blood crea Edema pe Lymphopen Vomiting Edema per Constipati Vomiting Neutropen Constipatio Back pain Neutropeni Insomnia Back pain Chills Insomnia Arthralgia Chills Muscle sp Arthralgia Hypertens Muscle spa Asthenia Hypertensio Hypokalem Asthenia Hypomagn Hypokalem Leukopeni Hypomagn Pain in ext Leukopenia Pneumoni Pain in extr Aspartate Pneumonia Dizzinessa Aspartate Hypoesthe Dizziness Anorexia Hypoesthes Pain Anorexia Hyperglyce Pain Chest wall Hyperglyce Hypercalce Chest wall Hypophosp Hypercalce Hyponatre Hypophosp a National Can Hyponatrem

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

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yocardial ation. New unction or ents (e.g., in 7% of Grade 3 or enefit/risk ass III and normalities at greater sion (PAH) han 1% of ROLIS for to restart ulmonary 3 dyspnea d manage seline [see tions were lgia, facial tightness, stration of severity of to contact mor Lysis < 1% of d to be at ee Dosage y. Interrupt KYPROLIS cycle and ma, 36% of following nuation of treatment nistration]. have been

FDA Update asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper respiratory tract infections, back pain, and pyrexia. Pomalidomide is approved with a Boxed Warning regarding the risk for embryo-fetal toxicity and venous thromboembolism; therefore, this third immunomodulatory drug is available only through the Pomalyst Risk Evaluation and Mitigation Strategy program.

(February 8, 2013)

Trastuzumab Emtansine the Newest Therapy for Late-Stage HER2-Positive Breast Cancer

The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (Kadcyla; Genentech), better known as T-DM1, is the fourth drug approved by the FDA for the treatment of patients with late-stage HER2-positive breast cancer, but this drug offers a new mechanism of action by combining the previ-

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 reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other KYPROLIS is appropriate.

Monitororliver enzymes frequentlyAfter [seeresolution, Dosage and Administration and liver abnormalities until resolved returned to baseline. consider if restarting Adverse Reactions].

Embryo-fetal Toxicity.

KYPROLIS can cause harmand when administeredand to a KYPROLIS is appropriate.

Monitor liver enzymes frequently [see fetal Dosage Administration pregnant woman based on its mechanism of action and findings in animals.

There are no adequate Adverse Reactions]. Embryo-fetal Toxicity. KYPROLIS can cause fetal harm when administered toand a well‑controlled womenofusing Carfilzomib caused toxicity pregnant womanstudies based inonpregnant its mechanism actionKYPROLIS. and findings in animals.

Thereembryo‑fetal are no adequate andin pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of well‑controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS. pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of If this drug is used during if thebecoming patient becomes while taking thisKYPROLIS. drug, the reproductive potential shouldpregnancy, be advised or to avoid pregnantpregnant while being treated with should be apprised of the potential to thebecomes fetus [seepregnant Use in Specific Populations].

Ifpatient this drug is used during pregnancy, or ifhazard the patient while taking this drug, the ADVERSE REACTIONS: following adverse are discussed greater detail in other sections patient should be apprised The of the potential hazardreactions to the fetus [see Use ininSpecific Populations]. of the labeling: ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] of the labeling: • Pulmonary Hypertension [see Warnings and Precautions] • Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia [see Warnings and Precautions] • Pulmonary Complications [see Warningsand andPrecautions] Precautions] • Pulmonary Hypertension [see Warnings • Infusion Reactions [see Warnings and Precautions] • Pulmonary Complications [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] • Infusion Reactions [see Warnings and Precautions] • Thrombocytopenia [see Warnings andand Precautions] • Tumor Lysis Syndrome [see Warnings Precautions] • Hepatic Toxicity and Hepatic Failure [see Warnings • Thrombocytopenia [see Warnings and Precautions] and Precautions] The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical • Hepatic Toxicity and Hepatic Failure [see Warnings and Precautions] trials of patients with multiple myeloma were fatigue, anemia, nausea, thrombocytopenia, dyspnea, The most common adverse reactions (incidence of 30% or greater) to KYPROLIS observed in clinical diarrhea, and pyrexia.

Clinical Trials Safety Experience. clinical trials are conducted trials of patients with multiple myeloma were fatigue, anemia, Because nausea, thrombocytopenia, dyspnea, under widely adverseSafety reaction rates observed in the clinical clinical trials a drug cannot diarrhea, and varying pyrexia.conditions, Clinical Trials Experience.

Because trials ofare conducted be directly with ratesadverse in the clinical another in drug, and may notofreflect rates under widelycompared varying conditions, reactiontrials ratesofobserved the clinical trials a drugthe cannot observed medical practice.

A total 526 patients relapsed and/or myeloma be directlyincompared with rates in theof clinical trials with of another drug, andrefractory may not multiple reflect the rates received KYPROLIS as monotherapy or with pre‑dose dexamethasone.

Patients received a median observed in medical practice. A total of 526 patients with relapsed and/or refractory multiple myelomaof four treatment cycles with a median cumulative KYPROLIS dose of Patients 993.4 mg.

Deaths due to of all received KYPROLIS as monotherapy or with pre‑dose dexamethasone. received a median causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not four treatment cycles with a median cumulative KYPROLIS dose of 993.4 mg. Deaths due to all attributed to disease progression were cardiac in 5 patients (acute coronary syndrome, cardiac arrest, causes within 30 days of the last dose of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not cardiac disorder), failure 4 patients (multi‑organ hepatic failure,cardiac renal failure), attributed to diseaseend‑organ progression wereincardiac in 5 patients (acutefailure, coronary syndrome, arrest, infectiondisorder), in 4 patients (sepsis, tractfailure, bacterial infection), dyspnea and cardiac end‑organ failurepneumonia, in 4 patientsrespiratory (multi‑organ hepatic failure, renal failure), intracranial in 1 patient each, andrespiratory 1 patient tract found bacterial dead of unknown Serious infection in hemorrhage 4 patients (sepsis, pneumonia, infection),causes. dyspnea and adverse reactions were reported in 45% patients. mostfound common adversecauses. reactions were intracranial hemorrhage in 1 patient each, and 1 The patient deadserious of unknown Serious pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse adverse reactions were reported in 45% patients. The most common serious adverse reactions were reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, andand acute renal congestive failure (1% reactions leading to discontinuation of KYPROLIS occurred in 15% of patients included each).failure Adverse reactions at a rateincreased of 10% orblood greater are presented in Table 4. failure (1% heart (2%), cardiacoccurring arrest, dyspnea, creatinine, and acute renal TableAdverse 4: Incidence of occurring Adverse Reactions in ≥ 10% of Multiple Myeloma each). reactions at a rate of Occurring 10% or greater are presented in Table 4.

Patients Treated with KYPROLIS Table 4: Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma Patients Treated with KYPROLIS Patients (N = 526) [n (%)] Patients (N = 526) Grade 3 Grade 4 All [n (%)] a Events Events Event Grades Grade 3 Grade 4 All a Fatigue 292 (55.5) 38 (7.2) 2 (0.4) Events Events Event Grades Anemia 246(55.5) (46.8) 111 (21.1) Fatigue 292 38 (7.2) 27 (1.3) (0.4) Nausea 236 (44.9) 7 (1.3) 0 Anemia 246 (46.8) 111 (21.1) 7 (1.3) Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Nausea 236 (44.9) 7 (1.3) 0 Dyspnea 182 (34.6) 25 (4.8) 1 (0.2)b Thrombocytopenia 191 (36.3) 69 (13.1) 54 (10.3) Diarrhea 172 (32.7) (0.8) (0.2)b Dyspnea 182 (34.6) 254(4.8) 11(0.2) Pyrexia 160 (30.4) (0.4) Diarrhea 172 (32.7) 47 (1.3) (0.8) 12(0.2) Upper respiratory tract infection 149 (28.3) 17 (3.2) 0 Pyrexia 160 (30.4) 7 (1.3) 2 (0.4) Headache 145 (27.6) 7 (1.3) Upper respiratory tract infection 149 (28.3) 17 (3.2) 00 Cough 137 (26.0) 1 (0.2) Headache 145 (27.6) 7 (1.3) 00 Blood creatinine increased 127 (24.1) 13 (2.5) 1 0(0.2) Cough 137 (26.0) 1 (0.2) Lymphopenia 126(24.1) (24.0) 84 (16.0) 11 (2.1) Blood creatinine increased 127 13 (2.5) 1 (0.2) Edema peripheral 126(24.0) (24.0) 3 (0.6) 0 Lymphopenia 126 84 (16.0) 11 (2.1) Vomiting 117(24.0) (22.2) 5 (1.0) Edema peripheral 126 3 (0.6) 00 Constipation 110(22.2) (20.9) (0.2) Vomiting 117 51(1.0) 00 Neutropenia 109(20.9) (20.7) 50 (9.5) 4 0(0.8) Constipation 110 1 (0.2) Back pain 106(20.7) (20.2) 15(9.5) (2.9) 0 Neutropenia 109 50 4 (0.8) Insomnia 94(20.2) (17.9) 0 Back pain 106 15 (2.9) 00 Chills 84(17.9) (16.0) 1 0(0.2) Insomnia 94 00 Arthralgia 83 (15.8) Chills 84 (16.0) 17 (1.3) (0.2) 00 Muscle spasms 76 (14.4) 2 (0.4) Arthralgia 83 (15.8) 7 (1.3) 00 Hypertension 75 (14.3) 15 (2.9) 2 0(0.4) Muscle spasms 76 (14.4) 2 (0.4) Asthenia 73 (13.9) 12 (2.3) (0.2) Hypertension 75 (14.3) 15 (2.9) 21(0.4) Hypokalemia 72 (13.7) 14 (2.7) Asthenia 73 (13.9) 12 (2.3) 13 (0.6) (0.2) Hypomagnesemia 71 (13.5) (0.4) 0 Hypokalemia 72 (13.7) 142(2.7) 3 (0.6) Leukopenia 71 (13.5) 27 (5.1) 1 0(0.2) Hypomagnesemia 71 (13.5) 2 (0.4) Pain in extremity 70 (13.3) 0 Leukopenia 71 (13.5) 277 (1.3) (5.1) 1 (0.2) Pneumonia 67 (12.7) 52 (9.9) 3 (0.6) Pain in extremity 70 (13.3) 7 (1.3) 0 b Aspartate aminotransferase increased 66(12.7) (12.5) 15(9.9) (2.9) 1 (0.2)b Pneumonia 67 52 3 (0.6) Dizzinessaminotransferase increased 66(12.5) (12.5) (1.0) (0.2) Aspartate 66 155(2.9) 11(0.2) Hypoesthesia 64(12.5) (12.2) 0 Dizziness 66 53 (0.6) (1.0) 1 (0.2) Anorexia 63 (12.0) 1 (0.2) Hypoesthesia 64 (12.2) 3 (0.6) 00 Pain 63 (12.0) 12 (2.3) Anorexia 63 (12.0) 1 (0.2) 00 Hyperglycemia 62 (11.8) 16 (3.0) 3 (0.6) Pain 63 (12.0) 12 (2.3) 0 Chest wall pain 60(11.8) (11.4) 3 (0.6) 0 Hyperglycemia 62 16 (3.0) 3 (0.6) Hypercalcemia 58(11.4) (11.0) 13 (2.5) 8 0(1.5) Chest wall pain 60 3 (0.6) Hypophosphatemia 55(11.0) (10.5) 24 (4.6) Hypercalcemia 58 13 (2.5) 83 (0.6) (1.5) Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0.

Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) One event was Grade 5 severity.

National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. b One event was Grade 5 severity. a

b

Vol. 4

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ously approved drug trastuzumab (Herceptin) for the treatment of HER2positive disease with ADC technology that targets cancer cell growth more directly and has shown improved survival in clinical trials. T-DM1 is indicated for the treatment of patients who have previously received trastuzumab and 1 of the taxanes for breast cancer.

The approval was expedited under the FDA’s priority review program.

“Kadcyla is trastuzumab connected

Description of Selected Adverse Drug Reactions. Renal Events: The most common renal adverse reactions were increase in blood creatinine (24%)Renal and renal failure (9%), which were mostly Description of Selected Adverse Drug Reactions.

Events: The most common renal Grade or Grade 2 in increase severity. inGrade renal adverse in 6% of were patients and adverse1 reactions were blood 3 creatinine (24%) reactions and renal occurred failure (9%), which mostly Grade 4 events occurred in 1%. Grade Discontinuations due to reactions increasedoccurred blood creatinine andpatients acute renal Grade 1 or Grade 2 in severity.

3 renal adverse in 6% of and failure were 1%occurred each. Ininone death occurred concurrent and and worsening renal Grade 4 events 1%.patient, Discontinuations due towith increased bloodsepsis creatinine acute renal function [see1% Dosage Administration].

Peripheral Peripheral neuropathy (including failure were each.and In one patient, death occurred Neuropathy: with concurrent sepsis and worsening renal all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% function [see Dosage and Administration]. Peripheral Neuropathy: Peripheral neuropathy (includingof patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious all events of peripheral sensory neuropathy and peripheral motor neuropathy) occurred in 14% of peripheral neuropathy events occurred in < 1% of patients, which resulted in dose reduction in < 1% patients enrolled in clinical trials. Grade 3 peripheral neuropathy occurred in 1% of patients. Serious and treatment discontinuation in < 1%. Withhold or discontinue treatment as peripheral neuropathy events occurred in < 1% of patients, which resulted in doserecommended [see reduction in < 1% Dosage and Administration]. Herpes Virus Infection: Herpes zoster reactivation was reported in 2% and treatment discontinuation in < 1%. Withhold or discontinue treatment as recommended [see of patients. antiviralHerpes prophylaxis patients Herpes who have a history of herpes infection.

Dosage and Consider Administration].

Virusfor Infection: zoster reactivation waszoster reported in 2% INTERACTIONS: Carfilzomib is primarily metabolized peptidase and epoxide hydrolase ofDRUG patients.

Consider antiviral prophylaxis for patients who have via a history of herpes zoster infection. activities, and as a result, the pharmacokinetic profile of carfilzomib is unlikely to be affected by DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase concomitant of cytochrome P450 profile inhibitors and inducers. is not expected activities, andadministration as a result, the pharmacokinetic of carfilzomib is Carfilzomib unlikely to be affected by to influence exposure of other drugs [see Clinical Pharmacology section of full PI]. concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected IN SPECIFIC Pregnancysection Category toUSE influence exposure ofPOPULATIONS: other drugs [seePregnancy.

Clinical Pharmacology of fullDPI].[see Warnings and Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while USE IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy Category D [see Warnings and being treated with KYPROLIS. Based on its mechanism of action and findings in animals, KYPROLIS Precautions]. Females of reproductive potential should be advised to avoid becoming pregnant while can cause when administered to a pregnant woman. being treatedfetal withharm KYPROLIS. Based on its mechanism of action andCarfilzomib findings incaused animals,embryo‑fetal KYPROLIS toxicity in pregnant doses that to were lower than in patients receiving the recommended can cause fetal harmrabbits when at administered a pregnant woman.

Carfilzomib caused embryo‑fetal dose. IfinKYPROLIS used at during if thethan patient becomes pregnant taking this toxicity pregnant israbbits dosespregnancy, that wereorlower in patients receiving thewhile recommended drug, IftheKYPROLIS patient should be during apprised of the potential hazard to the fetus. Carfilzomib was administered dose. is used pregnancy, or if the patient becomes pregnant while taking this intravenously to pregnant rats and rabbits during the period of organogenesis at doses of 0.5, 1, and drug, the patient should be apprised of the potential hazard to the fetus. Carfilzomib was administered 2 mg/kg/daytoinpregnant rats andrats 0.2,and 0.4,rabbits and 0.8 mg/kg/day in of rabbits.

Carfilzomib was not teratogenic intravenously during the period organogenesis at doses of 0.5, 1, and any dose tested. there increase inin pre‑implantation losswas at ≥not 0.4teratogenic mg/kg/day 2atmg/kg/day in rats In andrabbits, 0.2, 0.4, andwas 0.8anmg/kg/day rabbits. Carfilzomib in Inearly resorptions andan post‑implantation loss and a decrease fetalmg/kg/day weight at atand anyan increase dose tested. rabbits, there was increase in pre‑implantation loss at ≥in0.4 the maternally toxic dose of 0.8 mg/kg/day.

The doses of 0.4 and 0.8 mg/kg/day in rabbits are and an increase in early resorptions and post‑implantation loss and a decrease in fetal weight at 2 approximately respectively, of the in humans of 27inmg/m the maternally 20% toxic and dose40%, of 0.8 mg/kg/day.

Therecommended doses of 0.4 dose and 0.8 mg/kg/day rabbitsbased are on body surface Mothers.ofIt the is not known whether approximately 20%area. and Nursing 40%, respectively, recommended doseKYPROLIS in humansisofexcreted 27 mg/min2 human based milk.

Since manyarea. drugsNursing are excreted in human milkknown and because the potential for serious on body surface Mothers.

It is not whetherofKYPROLIS is excreted in adverse human reactions nursing infants KYPROLIS, a decision be made discontinue nursing milk.

Sinceinmany drugs are from excreted in human milk andshould because of thewhether potentialto for serious adverse or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue nursing The safety the anddrug, effectiveness KYPROLIS pediatric ofpatients have not mother. been established. orUse. to discontinue taking intoofaccount the in importance the drug to the Pediatric Geriatric Use. Inand studies of KYPROLIS were no observed in safety Use. The safety effectiveness of there KYPROLIS in clinically pediatricsignificant patients differences have not been established. and efficacy between patients less than 65 years of age and patients 65 years of age and older.

Renal Geriatric Use. In studies of KYPROLIS there were no clinically significant differences observed in safety Impairment.

The pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in and efficacy between patients less than 65 years of age and patients 65 years of age and older. Renal patients with The normal renal function and and safety those with mild, moderate, and severe Impairment. pharmacokinetics of KYPROLIS were evaluated in a renal Phaseimpairment 2 trial in and patients chronic dialysis.

Onand average, patients were treated for usingimpairment KYPROLIS patients with on normal renal function those with mild, moderate, and25.5 cycles severe renal 2 2 doses of 15 mg/m on Cycle 1, 20 mg/m on Cycle 2, and 27 mg/m

on Cycles 3 and beyond. and patients on chronic dialysis. On average, patients were treated for 5.5 cycles using KYPROLIS 2 The pharmacokinetics safety of KYPROLIS by the renal doses of 15 mg/m2 onand Cycle 1, 20 mg/m2 on were Cyclenot 2, influenced and 27 mg/m on degree Cycles of3 baseline and beyond. impairment, including and the patients dialysis. were Since not dialysis clearance of KYPROLIS concentrations The pharmacokinetics safety ofon KYPROLIS influenced by the degree of baseline renal has not been studied,thethepatients drug should be administered the dialysis procedure [see Clinical impairment, including on dialysis.

Since dialysisafter clearance of KYPROLIS concentrations Pharmacology section of PI].should Hepatic efficacyprocedure and pharmacokinetics has not been studied, thefull drug be Impairment. administered The aftersafety, the dialysis [see Clinical of KYPROLIS have not been evaluated in patients with baseline hepatic impairment.

Patients with the Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy and pharmacokinetics offollowing laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper KYPROLIS have not been evaluated in patients with baseline hepatic impairment. Patients with the limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Cardiac following laboratory values were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 × upper New York Class III and IV heart failure were eligible Impairment. limit of normal Patients (ULN) andwith bilirubin ≥ 2 Heart × ULNAssociation [see Clinical Pharmacology section of full PI].not Cardiac for the clinicalPatients trials. Safety in this population has not been Impairment. with New York Heart Association Classevaluated.

III and IV heart failure were not eligible OVERDOSAGE: There is no known specific has antidote for KYPROLIS for the clinical trials.

Safety in this population not been evaluated. overdosage. In the event of an overdosage, monitor and specific provide antidote appropriate OVERDOSAGE: Theretheis patient no known for supportive KYPROLIS care. overdosage. In the event of an NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. overdosage, monitor the patient and provide appropriate supportive care.

Carcinogenicity studies have not been conducted with carfilzomib.

Carfilzomib was clastogenic in the NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, and Impairment of Fertility. in vitro chromosomal test inconducted peripheralwith bloodcarfilzomib. lymphocytes.

Carfilzomib not mutagenic Carcinogenicity studiesaberration have not been Carfilzomib waswas clastogenic in the the chromosomal in vitro bacterial reverse test mutation (Ames) blood test and was not clastogenic thenot in vivo mouse ininvitro aberration in peripheral lymphocytes.

Carfilzomibinwas mutagenic micronucleus assay.

Fertility studies have not inbeen No inbone the marrow in vitro bacterial reverse mutation (Ames) testwith and carfilzomib was not clastogenic the conducted. in vivo mouse rat and monkey toxicity effects on reproductive tissues were noted during 28‑day repeat‑dose bone marrow micronucleus assay. Fertility studies with carfilzomib have not been conducted. No studies or in 6‑month rat and 9‑month monkey chronic toxicity studies.

Animal Toxicology and/ effects on reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity or Pharmacology. studies or in 6‑monthMonkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg rat and 9‑month monkey chronic toxicity studies.

Animal Toxicology and/ (approximately 1.3 times recommended dose in humans of 27 mg/m2 based on body surface area) or Pharmacology.

Monkeys administered a single bolus intravenous dose of carfilzomib at 3 mg/kg 2 experienced hypotension, increased heart rate, and increased serum levels of troponin‑T. The repeated (approximately 1.3 times recommended dose in humans of 27 mg/m based on body surface area) bolus intravenous administration carfilzomib ≥ 2 mg/kg/dose in rats and 2 mg/kg/dose experienced hypotension, increasedofheart rate, andatincreased serum levels of troponin‑T. The repeatedin monkeys using dosing schedulesof similar to those clinically resulted that were bolus intravenous administration carfilzomib at ≥used 2 mg/kg/dose in rats inandmortalities 2 mg/kg/dose in due to toxicities occurring in the similar cardiovascular failure, resulted cardiac in fibrosis, pericardial fluid monkeys using dosing schedules to those (cardiac used clinically mortalities that were accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal due to toxicities occurring in the cardiovascular (cardiac failure, cardiac fibrosis, pericardial fluid (glomerulonephropathy, tubular necrosis, dysfunction), and pulmonary (hemorrhage/inflammation) accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/hemorrhage), renal systems. The dose of 2 mg/kg/dose in rats dysfunction), is approximately the recommended dose in humans (glomerulonephropathy, tubular necrosis, andhalf pulmonary (hemorrhage/inflammation) 2 of 27 mg/m based body surface area.isThe dose of 2 mg/kg/dose in monkeys dose is approximately systems.

The dose of 2onmg/kg/dose in rats approximately half the recommended in humans the recommended dosearea. in humans based body surfaceinarea. ofequivalent 27 mg/mto2 based on body surface The dose of on 2 mg/kg/dose monkeys is approximately PATIENT COUNSELING INFORMATION: Discuss the following with patients equivalent to the recommended dose in humans based on body surface area. prior to treatment with KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: PATIENT COUNSELING INFORMATION: Discuss the following with patients prior to treatment with fever, chills, rigors, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS KYPROLIS: Instruct patients to contact their physician if they develop any of the following symptoms: may cause dizziness, dropofinthe blood Advisepatients patientsthat not KYPROLIS to drive or fever, chills, fatigue, rigors, chest pain, fainting, cough, orand/or swelling feet pressure. or legs. Advise operate machinery they experience of these Advise patients they may experience may cause fatigue, ifdizziness, fainting,any and/or dropsymptoms. in blood pressure.

Advisethat patients not to drive or shortness of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within operate machinery if they experience any of these symptoms. Advise patients that they may experience a day of dosing.

Advise patients to contact theirwith physicians if they shortness of breath. shortness of breath (dyspnea) during treatment KYPROLIS. Thisexperience most commonly occurs within patientsAdvise to avoid dehydration, since patients receiving KYPROLIS therapy may experience aCounsel day of dosing. patients to contact their physicians if they experience shortness of breath. vomitingpatients and/or to diarrhea.

Instruct patients seek medical if they experience symptoms Counsel avoid dehydration, since topatients receivingadvice KYPROLIS therapy may experience of dizziness, lightheadedness, or fainting spells.

Counsel females of reproductive potential to use vomiting and/or diarrhea. Instruct patients to seek medical advice if they experience symptoms contraceptive measures to prevent pregnancy treatment with KYPROLIS. Advise the ofeffective dizziness, lightheadedness, or fainting spells.

Counselduring females of reproductive potential to use patient that if she becomes pregnant duringpregnancy treatment,during to contact her physician immediately.

Advise effective contraceptive measures to prevent treatment with KYPROLIS. Advise the patients not to take KYPROLIS treatment while pregnant or breastfeeding.

If a patient wishes to restart patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise breastfeeding afterKYPROLIS treatment,treatment advise herwhile to discuss theorappropriate timing her wishes physician.

Advise patients not to take pregnant breastfeeding.

If awith patient to restart patients to discuss with theiradvise physician medication they are timing currently prior to starting breastfeeding after treatment, her toany discuss the appropriate withtaking her physician.

Advise treatment KYPROLIS, or prior to starting new medication(s) during treatment with toKYPROLIS. patients to with discuss with their physician any any medication they are currently taking prior starting treatment with KYPROLIS, or prior to starting any new medication(s) during treatment with KYPROLIS.

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

MARCH 2013

I

to a drug called DM1 that interferes with cancer cell growth,” said Dr Pazdur. “Kadcyla delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival.”

The safety and effectiveness of T-DM1 were evaluated in a clinical trial of 991 patients who were randomized to T-DM1 or to lapatinib plus capecitabine. Results showed that patients who received T-DM1 had a median progression-free survival (PFS) of 9.6 months compared with 6.4 months PFS with lapatinib plus capecitabine— an impressive 50% increase in PFS. In addition, the median overall survival (OS) was 30.9 months with T-DM1 compared with an OS of 25.1 months with the combination of lapatinib plus capecitabine (for more information, see page 24).

T-DM1 was approved with a Boxed Warning regarding the risk for liver toxicity, heart toxicity, and death associated with this drug. Furthermore, because this treatment can cause severe life-threatening birth defects, pregnancy status should be verified before initiating therapy with T-DM1 and should be avoided in women who are pregnant.

The most frequent side effects reported with T-DM1 were nausea, fatigue, muscle or joint pain, thrombocytopenia, elevated liver enzymes, headache, and constipation. (February 22, 2013)

Radium-223 Granted Priority Review by FDA

The FDA has granted priority review to radium-223 (radium-223) dichloride (Bayer), formerly known as Alpharadin, for the treatment of patients with prostate cancer. The New Drug Application for radium-223 is being reviewed for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This designation supports the manufacturer’s “ongoing effort to make this compound available as early as possible for patients in need of new treatment options,” said Kemal Malik, MD, Member of the Bayer HealthCare Executive Committee and Head of Global Development.

Radium-223 is a therapeutic alpha particle–emitting pharmaceutical with targeted antitumor effect on bone metastases that has been developed for patients with CRPC and bone metastases. The application is based on results from the pivotal phase 3 ALSYMPCA trial, in which radium-223 plus best standard of care significantly increased OS by 44% compared with placebo plus best standard of care (P = .007), resulting in a 30.5% mortality risk reduction. (February 13, 2013) n

www.ValueBasedCancerCare.com

11

Health Economics

For Stage II Colon Cancer, Oncotype DX Proves... ence physicians’ recommendations in the adjuvant chemotherapy setting, Dr Alberts said.

The study assessed whether the use of the assay would improve outcomes while lowering medical costs for patients with stage II, T3, DNA mismatch repair–proficient (MMR-P) tumors. Patients with MMR-P tumors typically have worse outcomes than patients with mismatch repair–deficient tumors.

The data set came from a prospective trial of 141 patients that investigated clinicians’ actual adjuvant chemotherapy recommendations before and after the assay. The use of the assay frequently changed treatment recommendations. Although 48% of physicians recommended only observation before the assay (no chemotherapy), 70% recommended it after receiving the results.

Reduced Utilization Although 24% of physicians recommended 5-fluorouracil (FU) monotherapy before the assay, 13% recommended it after. Furthermore, although 28% of physicians recommended 5-FU plus

oxaliplatin (Eloxatin) before the assay, only 17% would prescribe oxaliplatin after the assay.

Based on this study, adjuvant chemotherapy use would decrease from 52% to 30% with this assay; 11% of patients

“Savings are expected to persist even if the cost of oxaliplatin decreases by greater than 75% due to generic substitution. If the future cost of oxaliplatin is one fourth of the current cost, the use of the 12-gene assay saves on average $1108 per patient.”

—Steven R. Alberts, MD, MPH would receive a more intense chemotherapy option, and 33% of patients would receive a less intense option.

After evaluating how chemotherapy may reduce recurrences while in-

Table

Continued from cover

Cost Impact of Oncotype DX Colon Cancer Cost without Cost Cost assay, $ with assay, $ difference, $

Cost component 12-gene assay Acute adjuvant chemotherapyrelated costs Drugs Administration Adverse events Long-term costs

14,188 1635 8157

53,514

Total

77,493

creasing adverse events (AEs), the investigators concluded that there was a net increase of 0.083 years in quality-adjusted survival.

Costs Reduced Overall medical costs decreased by $4203 per patient on average with the assay, and the cost of managing AEs decreased by $3268 (Table).

The lifetime cost of treating with 5-FU plus oxaliplatin was significantly higher than with monotherapy, both in terms of the drug costs and the administration costs (+$28,242) and the

3640

3640

8449 966 4889

–5738 –668 –3268

73,290

–4203

55,345

1831

cost of managing AEs ($17,689), Dr Alberts further noted.

The costs were most sensitive to change in the overall adjuvant chemotherapy use, the benefit of 5-FU monotherapy, and the cost of drugs for 5-FU plus oxaliplatin chemotherapy.

“Savings are expected to persist even if the cost of oxaliplatin decreases by greater than 75% due to generic substitution,” Dr Alberts predicted.

“If the future cost of oxaliplatin is one fourth of the current cost, the use of the 12-gene assay saves on average $1108 per patient.” n

Postorchiectomy Surveillance Less Cost-Effective than Other Management Options

By Phoebe Starr

Orlando, FL—Para-aortic radiotherapy, dog leg radiotherapy, and 1 cycle of carboplatin (Paraplatin) are cost-effective options for the treatment of patients with stage I testicular seminoma, but surveillance is not a cost-effective option, according to a cost analysis that factored in reimbursement costs for salvage bleomycin (Blenoxane), etoposide phosphate (Etopophos), and platinum (BEP) chemotherapy after a potential relapse. This analysis was presented at the 2013 Genitourinary Cancers Symposium.

When salvage BEP therapy was factored into the costs, surveillance alone was more costly and less effective compared with the other 3 strategies.

Approximately 50% of the estimated 8000 new cases of testicular seminoma annually are stage I, explained presenting investigator John Cox, MD, chief resident, Department of Radiation Oncology, University of Texas Medical Branch at Galveston.

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Value-Based Cancer Care

Approximately 80% to 85% of patients with stage I testicular seminoma who are managed with surveillance do not relapse, and therefore they do not require adjuvant therapy. For patients who relapse, para-aortic radiotherapy, dog leg radiotherapy, or cisplatin-based chemotherapy are effective treatments.

The goal of the cost analysis was to assess the costs that are associated with each management strategy in 2011 and in 2012, after the National Comprehensive Cancer Network (NCCN) changed its guidelines to reduce the use of imaging and laboratory tests during postorchiectomy surveillance follow-up. The NCCN 2012 guidelines remained unchanged for adjuvant radiation. The analysis also sought to assess the costs associated with the required 10-year follow-up for each strategy.

“Total reimbursement costs changed greatly for treatment and follow-up with imaging and markers from 2011 to 2012 for recommendations for 10

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years of follow-up for both surveillance and single-agent carboplatin,” Dr Cox said.

“Total reimbursement costs changed greatly for treatment and follow-up with imaging and markers from 2011 to 2012 for recommendations for 10 years of follow-up for both surveillance and single-agent carboplatin.”

—John Cox, MD

The analysis used the expected 5-year failure rate of 18% for surveillance, 4% for para-aortic radiotherapy and for dog leg radiotherapy, and 5% for carboplatin. Medicare reimburse-

ment rates were used to determine the actual reimbursement for each treatment course over a 10-year period.

Based on the current NCCN guidelines, the total Medicare reimbursement in 2012, when factoring in the cost of salvage therapy, was: • $10,643 for surveillance • $11,648 for para-aortic radiotherapy • $9662 for dog leg radiotherapy • $7870 for carboplatin.

In 2011, reimbursements for the 4 strategies, respectively, were $20,986; $11,517; $9394; and $20,365.

The incremental cost ratio for the default strategy of salvage chemotherapy with 3 cycles of BEP was calculated at $12,139.

No data on quality of life in these men with decades-long life expectancy and no quality-adjusted data were included in this study.

Dr Cox and colleagues plan to do further analyses of the costs and patient variables that are associated with adjuvant treatment modalities in this patient population. n

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Health Economics

Robotic Gastrectomy No Better, but More Costly, than Laparoscopic Surgery minutes, respectively; P <.001). Blood loss did not differ significantly with robotic procedures nor did the length of hospital stays. Patients regained bowel function slightly faster with robotic surgery (2.8 days vs 3.0 days, respectively). The disease recurrence rates were 5.4% after robotic surgery and 3.6% after standard laparoscopic gastrectomy.

This study did not involve an analysis of functional outcomes or costs associated with the 2 surgical techniques. Those factors cannot be ig-

Similar Outcomes Both techniques led to 5-year 94% overall survival and 92% disease-free survival rates. Disease stage did not significantly alter survival results.

“Robotic assistance in gastrectomy for gastric cancer is associated with acceptable long-term and oncologic outcomes and is an effective alternative [to conventional laparoscopic surgery] with satisfactory shortterm outcomes,” said Woo Jin Hyung, MD, PhD, Department of Surgery, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea. “Robotic surgery might help expand the indication for minimally invasive surgery in gastric cancer.”

Dr Hyung reported findings from a review of 313 patients who underwent robotic gastrectomies and 524 patients who underwent conventional laparoscopic gastrectomies for nonmetastatic gastric cancer between 2004 and 2009. Patients with stage ≥II disease received adjuvant chemotherapy.

The patients who opted for robotic surgery were younger (54.5 years vs 59.3 years, respectively; P <.001) and more often had total gastrectomies (27% vs 20%, respectively; P = .016).

On average, robotic procedures required significantly more overall recovery time (219 minutes vs 149

Photo © ASCO/Todd Buchanan 2013

San Francisco, CA—Patient survival after minimally invasive gastrectomy was identical with robotic-assisted and conventional laparoscopic surgery, according to data from a large patient series that was presented at the 2013 Gastrointestinal Cancers Symposium.

“Robotic surgery might help expand the indication for minimally invasive surgery in gastric cancer.”

—Woo Jin Hyung, MD, PhD

nored in contemporary comparisons of robotic and conventional laparoscopic surgery, said Donald E. Low,

MD, FACS, Director, Esophageal Center of Excellence, Head of Thoracic Surgery and Thoracic Oncology, Fellowship Director, Ryan Hill Re­ search Foundation, and Codirector, Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA. Cost is an especially contentious issue regarding robotics, and would likely become even more so if the United States were to adopt reimbursement policies such as those in South Korea; patients who opt for robotic surgical procedures versus conventional laparoscopy have to pay the difference in cost, which can be substantial, said Dr Low. Cost Implications In the absence of cost-related data specific to gastrectomy, Dr Low referenced a recent study of 300 rectal surgery procedures (Baek SJ, et al. World J Surg. 2012;36:2722-2729). Roboticassisted procedures cost approximately $5000 more than laparoscopic surgeries, and patients’ out-of-pocket costs for robotic procedures averaged $11,500. Hospitals netted $689 per robotic procedure and $1671 per standard laparoscopic surgery.

The Korean clinical experience is consistent with other recent comparisons of robotic and conventional laparoscopic surgery, according to Dr Low. In general, comparative studies have shown similar patient outcomes with the 2 surgical approaches and substantially higher costs associated with robotic-assisted procedures, including system acquisition, instrumentation, and maintenance costs.

“Robotic surgery is equivalent to—

Photo © ASCO/Todd Buchanan 2013

By Charles Bankhead

“Robotic surgery is equivalent to—but not better than—laparoscopic surgery for major cancer procedures.

Robotic gastrectomy currently provides no measurable outcome benefits and is likely significantly more expensive.”

—Donald E. Low, MD, FACS but not better than—laparoscopic surgery for major cancer procedures,” said Dr Low. “Robotic gastrectomy currently provides no measurable outcome benefits and is likely significantly more expensive.”

Future randomized studies of robotic surgery must focus on identifying advantages of robotic techniques rather than on demonstrating equivalence to conventional laparoscopic surgery, he added. n

Oxaliplatin Overused in Patients with Colon Cancer

By Caroline Helwick

San Francisco, CA—Oxaliplatin (Elox­­ atin) may be overused in the adjuvant treatment of colon cancer, based on results of a survey of community-based oncologists and clinical investigators that was presented at the 2013 Gastrointestinal Cancers Symposium.

“Our results suggest that expectations for oxaliplatin benefit often exceed reality, and that oncologists may need to revisit the decision process,” said Kathryn Ziel, PhD, of Research To Practice in Miami, FL. “In a nutshell,

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oncologists may be using too much oxaliplatin. Given the toxicity profile, especially neurotoxicity that can persist for years, the decision to use adjuvant oxaliplatin should be made in the context of the actual benefit accrued to patients.”

Recent long-term clinical trial follow-up suggests that adding oxaliplatin to a fluoropyrimidine in the adjuvant treatment of colon cancer may provide less benefit than was originally believed. A recent report showed a lack of overall survival and

disease-free survival benefits when oxaliplatin was added to the treatment regimen of 2246 patients with stage II colon cancer and elderly patients with colon cancer (Tournigand C, et al.

J Clin Oncol. 2012;30:3353-3360).

“We wanted to document current usage of adjuvant chemotherapy and physician perceptions and practices in this regard,” Dr Ziel said.

Survey Details Dr Ziel and colleagues recruited 25 clinical investigators specializing in

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gastrointestinal oncology and 77 practicing oncologists to complete a survey and provide data for 408 recent cases from their practices. Approximately 50% of the participants had ordered the 12-gene Oncotype DX Colon Cancer Assay to assist in decision-making.

The participants were asked, “What is the absolute benefit in recurrence risk reduction you believe is needed to justify using a fluoropyrimidine and oxaliplatin?” Their answer was a 5-year 5% reduction to use a fluoropyContinued on page 14

www.ValueBasedCancerCare.com

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Health Economics

Oxaliplatin Overused in Patients... rimidine, and another 5% reduction to add oxaliplatin.

The investigators posed a number of hypothetical scenarios involving patients of various ages with different tumor burdens and disease characteristics, and participants had to estimate risk and say how they would treat these patients. Finally, they were queried about the last 3 patients they treated with stage II and stage III colon cancer.

The results showed that: • Significant heterogeneity was evident in the treatment of a 60-yearold versus a 75-year-old patient.

Not surprisingly, the use of oxaliplatin was less frequent for older patients, but 1 of 6 oncologists would choose this approach for a 75-year-old patient with a low-risk (T3N0M0) tumor • For a higher-risk stage II tumor (T4N0M0), the oncologists estimated the risk of recurrence to be modestly different with and without

treatment, and their predictions were in line with those derived from Adjuvant!Online

“Oncologists may be using too much oxaliplatin.

Given the toxicity profile, especially neurotoxicity that can persist for years, the decision to use adjuvant oxaliplatin should be made in the context of the actual benefit accrued to patients.”

—Kathryn Ziel, PhD

• For a stage III tumor with 2 positive nodes, the respondents correctly predicted a relatively substantial

Continued from page 13

benefit that is similar to what is derived from Adjuvant!Online, but their estimates may not reflect recent long-term follow-up showing less benefit with oxaliplatin than previously believed • When T stage increased, treatment preferences shifted dramatically toward a fluoropyrimidine plus oxaliplatin regimen, even for older patients; observation without treatment was infrequently used • For grade 2 T4N0M0 patients, treatment was similar regardless of recurrence score, indicating that physicians have not embraced or are unaware of recent data showing that Oncotype DX can assist in deciding whether to include oxaliplatin for stage II and III diseases • Consistent with predicted benefits, almost all participants recommended a fluoropyrimidine plus oxaliplatin regimen for both younger and older patients with 2 positive nodes.

Patients aged ≥70 years with stage II disease received considerably less intensive therapy. The majority of patients with stage III tumors received a fluorouracil/capecitabine regimen.

“The physicians wanted to see a 5% benefit in order to use oxaliplatin; in actuality, in stage II patients the benefit is only about 2%, according to Adjuvant!Online,” Dr Zeil noted.

“Roughly one third of the oncologists [36% of investigators and 29% of practicing oncologists] would treat a 60-year-old T3N0M0 patient with oxaliplatin,” Dr Zeil reported.

For T3N0M0 stage II tumors and for T4N0M0, patients aged >60 years were less likely to be prescribed oxaliplatin, “but we still saw that 17% would add oxaliplatin in the treatment of a T3N0M0 patient older than 60,” Dr Ziel added.

She suggested that the greater use of predictive assays will help physicians avoid using oxaliplatin in cases where its use is not justified. n

2013 Conference

Introducing the Third Annual Conference of the Association for Value-Based Cancer Care...

Continued from page 7

we have done at the AVBCC is to make sure that we have at this Third Annual Conference all of the people who are effecting change, so that they can discuss that change and what it means to the healthcare markets. One of the major challenges that most manufacturers have to address today in the cancer marketplace will be dealing in a comparative world of clinical- and cost-effectiveness, where evidence is increasingly being weighed to come up with the value-based purchasing proposition.

The “New World” of Healthcare Part of the mission of the AVBCC is to come up with a formula for value-based purchasing that will include not only clinical elements but economic elements of overall cost as well. Part of our agenda is to make sure that the association can put forth a framework for “value-based purchasing” and the corresponding proper process and formula for evaluating effectiveness so appropriate contracting for cancer drug therapies is in the marketplace.

The timing of the Third AVBCC Annual Conference could not be bet-

14

ter. We are coming right off of an national election. We did not know whether ObamaCare was going to last. Now we know that health information exchanges, state exchanges, and the novel products of the “new world” of healthcare are going to take effect and are here to stay, and change is permanent.

Obviously, we are moving from a utilization-focused model to a quality model of healthcare. These changes are going to be dramatic. These issues are part of the agenda of change that we are going to be discussing this year at the AVBCC Annual Conference in the various segments and forums.

Community- versus Hospital-Based Care

Also at this year’s AVBCC conference, we are going to explore one of the biggest changes in cancer care— the move from community oncology to hospital-based cancer care. We have representatives from the Community Oncology Alliance, the Association of Community Cancer Centers, the National Comprehensive Cancer Network, the American Society of

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Clinical Oncology, and others, who are going to be discussing these changes.

We have seen a tremendous consolidation in the purchase of hematology and oncology practices by hospital

is going on, and must be able to predict the new models of distribution and service, given the consolidation and the changes in cancer care as we go forward.

Personalized Medicine

We are moving from a utilization-focused model to a quality model of healthcare. These changes are going to be dramatic.

These issues are part of the agenda of change that we are going to be discussing this year at the AVBCC Annual Conference. systems as they are getting ready for ACO opportunities. This is going to have a dramatic impact on our marketplace. We are going to explore this critical change in depth in some of the sessions. Anyone who is involved in this oncology space must know what

Personalized medicine is probably going to be launched through cancer care. Why? Because cancer is so expensive, and all of the molecular tests that can really make a difference in clinical utility and driving change are going to be the companion diagnostics to cancer care. Thus, given the effect on comparative effectiveness research and the value-based approach of cancer care purchasing, the economics around personalized medicine makes economic sense to embrace beyond the quality drivers.

This is a hugely important topic, and it is part of our agenda at the Third Annual Conference of the AVBCC, where we have experts who will be speaking on the impact of personalized medicine, companion diagnostics, and molecular pathways as we move forward in improving patient care in America. n

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Genitourinary Cancers Symposium

Similar Outcomes with 18 Months versus 36 Months of Androgen Ablation Added to Radiation in High-Risk Prostate Cancer Orlando, FL—Similar overall survival (OS) and disease-specific survival were achieved after 18 months of androgen ablation therapy compared with 36 months when combined with radiation therapy as primary therapy for patients with high-risk prostate cancer. A shorter course of androgen ablation has the potential to reduce unwanted side effects and to improve quality of life, and it may reduce the cost of prostate cancer therapy, according to the results of a phase 3 clinical trial reported at the 2013 Genitourinary Cancers Symposium.

“The side effects of hormonal therapy make the lives of most of our patients quite miserable,” said lead investigator Abdenour Nabid, MD, Associate Professor, Department of Radiation Oncology, Centre Hos­ pita­lier Universitaire de Sherbrooke, Quebec, Canada. These side effects include “castration syndrome” (ie, hot flashes, decreased sexual drive, impotence, and fatigue), musculoskeletal complaints, cardiovascular effects, and other problems.

The optimal duration of androgen ablation therapy for patients with high-risk prostate cancer is debatable.

“A shorter course could reduce the quantity and intensity of its unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years,” Dr Nabid stated.

This study enrolled 630 patients with node-negative, high-risk prostate cancer (stage T3 or T4) who received

Photo © ASCO/Todd Buchanan 2013

By Phoebe Starr

“A shorter course could reduce the quantity and intensity of [androgen ablation’s] unpleasant side effects as well as treatment costs. We hope these results will convince doctors that they can stop hormone therapy after 1.5 years instead of 2 to 3 years.”

—Abdenour Nabid, MD radiotherapy to the pelvic area and to the prostate bed. Patients were randomized to 18 months of androgen ab­­­la­tion therapy (bicalutamide [Caso­ dex] for 1 month plus goserelin [Zola­ dex] every 3 months) versus 36 months of androgen ablation therapy. Andro­ gen ablation was started 4 months before radiation and was continued during and after radiation.

The patients (median age, 71 years)

in the 2 arms had comparable demographic and disease characteristics, including the numbers of patients with a prostate-specific antigen >20 ng/mL and a Gleason score of >7. In both groups, 20% of the patients had Gleason scores of 9 and 10.

At a median follow-up of 77 months, the 2 groups had no significant difference in biochemical failure, metastasis, bone-only metastasis, and cause of death. Mortality rates were 22.9% (N = 71) in the 18-month hormone therapy arm and 23.8% (N = 76) in the 32month arm. Of these 147 deaths, 116 were deemed unrelated to prostate cancer.

“Prolonging androgen ablation therapy will not prevent bone metastasis,” Dr Nabid stated.

The 5-year OS rates were 92.1% in the shorter-duration cohort versus 86.8% in the longer-duration cohort, and 10-year OS rates were 63.6% versus 63.2%, respectively. The 5-year disease-specific survival rate was 97.6% for the shorter-duration arm versus 96.4% for the longer-duration arm; the 10-year disease-specific survival rates were 87.2% in both arms.

The most frequent cause of death was a second cancer (7.3% of patients); 4.9% died of prostate cancer in both groups, and 4.4% died of cardiovascular disease in both groups.

“This study shows that 18 months of androgen ablation does the job.

Treatment with 18 months of androgen blockade is safe in localized prostate cancer and could represent a threshold for no further gain,” Dr Nabid said.

at a glance ➤ Survival was similar with 18 months of androgen ablation alone versus 36 months when added to radiation therapy for patients with high-risk prostate cancer ➤ At a median follow-up of 77 months, the 2 groups had no significant difference in biochemical failure, metastasis, bone-only metastasis, and cause of death ➤ Prolonging androgen ablation therapy will not prevent bone metastasis ➤ The 5-year OS rates were 92.1% in the shorter-duration cohort versus 86.8% in the longer-duration cohort, and 10-year OS rates were 63.6% versus 63.2%, respectively ➤ Although currently not the standard of care, shortening therapy to at least 24 months will likely be acceptable, the researchers suggest

Although the full peer-reviewed publication of the results, as well as longer follow-up, are needed to change the standard of care to 18 months, the investigators agreed that shortening the course of therapy to at least 24 months will prove to be acceptable. n

Orlando, FL—Surveillance for small renal masses achieves similar outcomes in the elderly compared with the standard approach of surgery, according to a large retrospective analysis reported at the 2013 Genitourinary Cancers Symposium. These findings suggest that both the costs and the complications associated with surgery can be avoided in elderly patients, especially patients with a shorter life expectancy and/or comorbid conditions.

The analysis of more than 8300 elderly patients with small renal masses showed that surveillance and surgery each led to a 3% rate of kidney cancer–

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Photo © ASCO/Todd Buchanan 2013

Surveillance an Option for Small Renal Masses in the Elderly “Our analysis shows that physicians can be comfortable telling an elderly patient that the likelihood of dying from kidney cancer is low with both surveillance and surgery, and that kidney surgery is unlikely to extend their lives.”

—William C. Huang, MD specific mortality during 59 months of follow-up. However, patients managed with surgery had more deaths from all causes and cardiovascular (CV) complications compared with

those managed with surveillance.

“Our analysis shows that physicians can be comfortable telling an elderly patient that the likelihood of dying from kidney cancer is low with both

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surveillance and surgery, and that kidney surgery is unlikely to extend their lives. This is especially important for an older patient who is not healthy enough to tolerate anesthesia and surgery. However, surgery is still a standard option for healthier older patients with a longer life expectancy,” said lead investigator William C. Huang, MD, Assistant Professor, Uro­logic Oncology, New York University Langone Medical Center, New York City.

The study used the Surveillance, Epidemiology and End Results registry database linked to Medicare claims Continued on page 16

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Genitourinary Cancers Symposium

Targeted Therapies Added to Docetaxel Don’t Extend Survival in Metastatic Prostate Cancer Results from 2 different trials with different drugs may suggest a need for a novel study design

By Phoebe Starr Orlando, FL—The latest in a string of failed trials of targeted therapies added to docetaxel (Taxotere) in patients with metastatic castration-resistant prostate cancer (mCRPC) were presented at the 2013 Genitourinary Cancers Symposium. No survival benefit was observed with the addition of aflibercept (Zaltrap) to do­ce­ taxel plus prednisone in the VENICE trial or with the addition of dasatinib (Sprycel) to docetaxel plus prednisone in the READY trial.

These trials are expensive to mount and manage, and the medical community, including patients, invests a great deal of time and energy in these trials in hopes of identifying a treatment that improves outcomes. The formal discussant of these trials, William K. Oh, MD, Chief and Professor of Medicine, Hematology and Medical Oncology, Ichan School of Medicine at Mount Sinai in New York City, stated that much stronger phase 2 evidence is needed before mounting yet another trial of a new agent added to docetaxel in this setting. He suggested that novel trial designs based on molecular-guided enrollment would be a step forward.

The VENICE Trial The large multinational, multicenter, double-blind VENICE trial randomized 1224 men with mCRPC who had progressive disease while receiving hormonal therapy or surgical castration to first-line therapy with aflibercept plus docetaxel versus to docetaxel alone. Aflibercept is a potent antiangiogenic fusion protein that binds vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor, and there are preclini-

cal data to support its use.

At a median follow-up of 35 months, no difference in overall survival (OS), the primary end point, was observed. The OS rate was 22.1% in the aflibercept arm versus 21.1% in the placebo arm. Progression-free survival (PFS) in the 2 arms was a median of 6.9 months versus 6.2 months, respectively. The time to the first skeletal-related event (SRE) was almost identical in both groups, with a median of 15.3 months versus 15 months, respectively.

“This study provides a lesson that when we design large phase 3 trials, we need strong evidence of improved activity with the agent we want to study. As of yet, no added agent has improved upon docetaxel plus prednisone in men with mCRPC.” —Ian F. Tannock, MD, FRCPC, PhD Patients in the aflibercept arm had a higher rate of toxicities, including serious adverse events (AEs), compared with patients in the placebo arm. Grade 3 or 4 AEs were reported in 77% of patients in the aflibercept arm versus 48.5% of patients in the placebo arm.

“This study provides a lesson that when we design large phase 3 trials, we need strong evidence of improved activity with the agent we want to study. As of yet, no added agent has improved upon docetaxel plus pred-

nisone in men with mCRPC,” stated Ian F. Tannock, MD, FRCPC, PhD, Professor of Medical Oncology and Medical Biophysics, Princess Margaret Cancer Center, Toronto, Canada.

READY Trial Although preclinical evidence and early phase 1 and 2 trials suggested that dasatinib, an Src kinase inhibitor, plus docetaxel was a reasonable combination to study, the phase 3 clinical trial READY failed to show a benefit.

“Clearly we were getting the wrong sig­ nals,” stated Dr Oh. He said that better evidence is needed before mounting these very expensive and time-consuming trials. Dr Oh suggested that one approach may be a novel trial design with molecular-guided enrollment.

Based on the early-phase clinical trials, the READY trial investigated the benefits of dasatinib in patients with progressive mCRPC. “The disappointing part of this trial is that dasatinib did not improve median overall survival versus docetaxel alone.

The survival curves for both arms were virtually identical,” said lead investigator John C. Araujo, MD, PhD, Assistant Professor, Department of Genitourinary Medical Oncology, M.D. Anderson Cancer Center, Houston, TX. The survival curves were 21.5 months for dasatinib and 21.2 months for docetaxel.

READY was a multinational, randomized, double-blind, placebo-controlled phase 3 clinical trial that randomized 1522 patients with mCRPC 1:1 to receive either docetaxel 75 mg/ m2 every 3 weeks plus prednisone with double-blinded dasatinib 100 mg every day (N = 762) or docetaxel plus placebo (N = 760).

Surveillance an Option for Small Renal Masses... for patients aged ≥66 years to identify patients who were diagnosed with small renal masses (ie, <4 cm in diameter). A total of 7148 patients had a pathologic diagnosis; 78% underwent surgery, and 22% were managed by surveillance.

At a median follow-up of 59 months, 2078 deaths were reported. The rate of kidney cancer–specific mortality was 3% in each group.

Overall, 21% of the patients died,

16

and 24% experienced a CV event during follow-up. Over time, surveillance was associated with a significantly lower risk of experiencing a CV event compared with surgery (P >.001) and a 49% lower risk of death from any cause.

Patients in the surgical group underwent a variety of surgical procedures, including total and partial nephrectomies. When asked about the link between surgery and CV events,

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Dr Huang said that even partial removal of kidney tissue could impair kidney function and could cause CV problems, but he noted that this is theoretical.

“Watchful waiting is a reasonable option for elderly patients with small kidney masses. Most of these small tumors are found incidentally on imaging for other reasons. We don’t know which of these lesions will become malignant. We would like to avoid

Median OS for the dasatinib-containing arm was 21.5 months versus 21.2 months for docetaxel/placebo.

No OS benefit was observed for dasa­ tinib in any of the subgroups.

“The disappointing part of this trial is that dasatinib did not improve median overall survival versus docetaxel alone. The survival curves for both arms were virtually identical.”

—John C. Araujo, MD, PhD

Dasatinib failed to achieve significant improvement over docetaxel alone in any of the secondary end points, including response rate, urinary N-telopeptide (a marker of bone turnover), PFS, or pain reduction.

However, dasatinib did extend time to first SRE, which has not yet been reached in the dasatinib arm versus 3.1 months in the placebo arm. Dr Araujo said that this was to be expected, because dasatinib positively affects bone.

No meaningful changes were seen between the 2 arms in response rates, bone turnover markers, PFS, or pain reduction. Treatment-emergent AEs were seen in 18% of patients in the dasatinib arm versus 9% in the placebo arm. Serious AEs were reported in 30% of patients in each arm. The death rate 30 days after the last dose was 10% in the dasatinib arm versus 6% in the placebo arm. n

Continued from page 15 unnecessary surgery in this group of patients. It is important that this study showed no negative impact on increasing kidney cancer mortality with watchful waiting. However, the study showed that surgical intervention increased the risk of cardiovascular events and death,” noted Bruce Roth, MD, Professor of Medicine, Division of Oncology, Washington University, St Louis, MO, an expert who was not involved in the study.—PS n

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Genitourinary Cancers Symposium

Tivozanib Offers Potential for Better Survival in Patients with Advanced Kidney Cancer

By Mark Knight

Orlando, FL—The investigational agent tivozanib did not improve overall survival (OS) compared with sorafenib (Nexavar) in a phase 3 trial of patients with advanced renal-cell carcinoma, but the study’s design probably prevented a meaningful comparison of survival.

In the TIVO-1 study, no difference in OS between the 2 treatments emerged, despite superior progression-free survival (PFS)—which was the primary end point—with tivozan-

at a glance ➤ Although tivozanib did not improve OS compared with sorafenib in this phase 3 trial, the reason was likely the study’s design ➤ At final analysis, 27% of patients did not discontinue tivozanib versus 12% of those receiving sorafenib ➤ Median PFS was 8.4 months after crossover from sorafenib to tivozanib ➤ The selectivity of tivozanib translated into a better safety profile ➤ The investigators suggest this agent should be an option for patients with advanced renal-cell carcinoma

ib, said Robert J. Motzer, MD, an oncologist, Genitourinary Oncology Ser­ vice, Department of Medicine, Me­ morial Sloan-Kettering Cancer Center, New York, at the 2013 Genitourinary Cancers Symposium.

Tivozanib is a highly selective and potent tyrosine kinase inhibitor (TKI).

“It’s felt that inhibition of the VEGF [vascular endothelial growth factor] receptor is the most important part of response to treatment, and so a drug that inhibits the receptor more strongly is believed to be potentially more effective,” said Dr Motzer. “Sorafenib attacks many different kinases, including the VEGF receptor, but many of the other kinases it attacks are believed to contribute to some of the side effects of the drug.”

In TIVO-1, 517 patients with advanced renal-cell carcinoma were randomized to receive either 1.5 mg of tivozanib once daily for 3 weeks, followed by 1 week off of the drug, or 400 mg of the first-generation TKI sorafenib twice daily continuously in a 4-week cycle.

The study achieved its primary end point, with tivozanib showing superior results compared with sorafenib in terms of PFS (11.9 months vs 9.1 months, respectively; P = .042).

In a prespecified subgroup analysis of patients who were treatment-naïve for metastatic disease, the PFS benefit of tivozanib was 12.7 months versus 9.1 months with sorafenib (hazard

ratio, 0.75; P = .037).

As part of the design of the extension phase of TIVO-1, patients who had disease progression while receiving sorafenib based on investigator assessment were eligible to receive tivozanib, and patients who progressed while taking tivozanib received subsequent treatment accord-

“The antitumor activity of tivozanib may be contributing to the overall survival of patients randomized to sorafenib in TIVO-1. [Tivozanib] warrants regulatory approval and should be an option for patients.”

—Robert J. Motzer, MD ing to regional standards of care. Of the 257 patients receiving sorafenib, 70% advanced to next-line VEGF therapy, including 155 patients who started next-line tivozanib at the time of the final analysis. Only 10% of the patients in the tivozanib arm received next-line VEGF therapy.

The median OS was 28.8 months for tivozanib and 29.3 months for sorafenib. Because survival has been

improving in patients with advanced renal-cell carcinoma with the advent of targeted therapies, PFS is used as the primary end point in clinical trials, “because it gives you an answer faster,” said Dr Motzer.

At final analysis, 27% of patients were alive and had not discontinued tivozanib versus 12% of patients who were alive and had not discontinued sorafenib.

“The antitumor activity of tivozanib may be contributing to the overall survival of patients randomized to sorafenib in TIVO-1,” he said. Median PFS was 8.4 months after crossover from sorafenib to tivozanib, and tumor shrinkage occurred in 74% of patients after patients taking sorafenib switched to tivozanib.

The selectivity of tivozanib translated into a better safety profile, said Dr Motzer. Patients receiving sorafenib had higher overall rates of diarrhea (32% vs 22%, respectively), hand-foot syndrome (54% vs 13%, respectively), and alopecia (21% vs 2%, respectively) compared with the tivozanib arm.

“The one side effect that occurs most commonly with tivozanib is hypertension. It’s believed that hypertension relates to the ability to inhibit the VEGF receptor. It’s actually an on-target effect,” he noted.

Dr Motzer stated that he believes that tivozanib “warrants regulatory approval and should be an option for patients.” n

Call for Papers

Cancer Care Theme Issue American Health & Drug Benefits will be publishing a theme issue on cancer care in 2013 Readers are invited to submit manuscripts for this issue, including original research, cost-effective analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends. All articles will undergo the journal’s rigorous peer-review process.

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

Areas of particular interest include: ➤ Benefit ➤ Best

practices in oncology

➤ Cancer ➤ Cost

design for cancer therapies care and health disparities

considerations in cancer care

➤ Emerging

trends in hematology/oncology

➤ End-of-life ➤ Health

issues

plan initiatives in oncology

➤ Managing ➤ Palliative

toxicities of cancer therapies

care

➤ Pathways

➤ Personalized

medicine in oncology

➤ Survivorship

programs

➤ Targeted

cancer therapies

➤ Value-based

cancer care

and practice guidelines

Submit articles to editorial@engagehc.com. For more information, call 732-992-1889.

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THIRD ANNUAL

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

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

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

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

Registration

FRIDAY, MAY 3, 2013

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

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

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

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

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

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

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

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

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

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

2:45 pm - 3:30 pm

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

Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

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

4:30 pm - 5:15 pm

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

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

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

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

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

9:15 am - 10:00 am

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

PROGRAM OVERVIEW

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

LEARNING OBJECTIVES

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

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

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

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

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

TARGET AUDIENCE

SPONSORS

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

COMMERCIAL SUPPORT ACKNOWLEDGMENT

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

SATURDAY, MAY 4, 2013

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

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

11:00 am - 11:45 am

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

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

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

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

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

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

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

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

9:15 am - 10:00 am

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

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

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

11:00 am - 11:45 am

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

11:45 am - 12:00 pm

Summary and Conclusion of Conference

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

18 Value-Based Cancer Care I march 2013 www.regonline.com/avbcc2013

*Agenda is subject to change.

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AVBCC Third Annual Conference Abstracts Abstracts to Be Presented at the Third Annual Conference of the Association for Value-Based Cancer Care May 2-5, 2013 Westin Diplomat, Hollywood, FL

Category: Cost-Effectiveness Analysis

Budgetary Impact of Adding Ziv-Aflibercept to a Health Plan Formulary as a Post-Oxaliplatin Biologic Option for Treating Patients with Metastatic Colorectal Cancer

Xin Gao, PhD;1 Mei Xue, MBA;1 Dan Hennessy, PhD;2 Susan Pacconi;2 Edward Drea, PharmD;2 Stephen F. Thompson, MS2 1 Pharmerit North America LLC, Bethesda, MD; 2Sanofi, Bridgewater, NJ

Background: Advanced colorectal cancer treatment options are evolving with a multitude of chemotherapeutic agents, biologics (both epidermal growth factor receptor inhibitors and anti-angiogenic agents), and a newly approved tyrosine kinase inhibitor available to treat metastatic colorectal cancer (mCRC) patients.

Objectives: To develop a transparent model for examining the budgetary impact, from the perspective of health care payers in the United States, of adding ziv-aflibercept as a biologic option for patients with mCRC following treatment with an oxaliplatin-containing regimen.

Methods: A Markov model was developed to simulate the transition of patients receiving treatment for mCRC through health states (progression-free survival, progressive disease, and death) that are typically observed in a clinical setting. The comparators to ziv-aflibercept were chosen based on 2012 National Comprehensive Cancer Network® Clinical Practice Guidelines in Oncology and comprised bevacizumab, cetuximab, and panitumumab, in addition to a category titled “New Emerging Drug,” to allow for the tracking of the budgetary impact of a new market entrant. The model time frame was 1 year, with a 90-day cycle length. Previous market data, cost of biologics (in 2012 US dollars), biomarker testing (assumed for all patients), drug administration and monitoring, adverse events, and death/terminal care, as well as the efficacy and adverse event data based on pivotal trials, were incorporated into the budget impact analysis.

Results: The estimated proportion of health plan members treated with biologics for mCRC after an oxaliplatin-based regimen was 169 patients/1 million population.

For a hypothetical health plan of 1 million members, prior to introduction of zivaflibercept into the health plan, the estimated total annual cost was $19,202,835 for patients with mCRC after treatment with an oxaliplatin-containing regimen, with the per-member-per-month cost of $1.60. After the introduction of ziv-aflibercept, with an estimated first year market share of 32.2%, the annual cost would increase by 0.6% ($123,995) to $19,326,830. The per-member-per-month cost increment increase would be $0.01. Adding ziv-aflibercept to the formulary will increase total costs in drug acquisition, but will decrease drug administration costs and death-related costs. Sensitivity analysis using the most recent market share data as the baseline reveals varying budgetary impact.

Conclusions: Under the model assumptions that are largely based on approved product labeling, the predicted budgetary impact of the introduction of ziv-aflibercept will lead to a <1% increase in the total budget with an incremental per-memberper-month cost of $0.01, reflecting minimal budgetary impact from a payer perspective. The budget impact model was created to allow for health plans to modify a large majority of the variables in order to perform their own budget impact analysis using different assumptions.

Category: Cost-Effectiveness Analysis

Cesium-131 (Cs-131) Brain Brachytherapy (BT) Post Resection: A Preliminary Cost Comparison Analysis with Other Radiation Therapy Emad Youssef, MD; Theresa Thomas, MSc; Heyoung Mcbride, MD; David Brachman, MD

Background: Radiation therapy is considered the main line of treatment after resection of brain metastases, atypical meningioma or primary brain tumors.

Different techniques are used for radiation therapy, including intensity-modulated radiation therapy (IMRT) and stereotactic radiosurgery (SRS). The use of SRS in patients with brain metastases increased significantly especially with conflicting data about the survival benefit of whole brain radiation (WBRT). In addition to the initial capital outlays, the cost of using SRS or IMRT is considered of major negative financial impact on the health system. We have recently begun the use of real-time implanted radioactive Cs-131 sources to the tumor bed after resection of brain tumors.

Objective: We report the direct cost of treating these cases, comparing it with the literature data using SRS (one-five fractions) and IMRT (average of 30 fractions). Of note, all patients would otherwise have undergone either IMRT or SRS

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if they elected not to have brachytherapy.

Methods: Retrospective review of 10 consecutive intraoperative Cs-131 brain implants which were placed immediately after tumor resection. We report global charges related to the brachytherapy implant direct cost, including all applicable Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision (ICD-9) procedure cost, seed cost and charges for carrier material were captured. Added operating room time was calculated and postoperative complications were documented.

Results: The mean direct cost in our patients was $17,540 (range $11,006-$36,203).

This compared favorably to the literature mean cost for IMRT and SRS of ($35,431) and ($22,152) respectively. Most of the cost was for the radioactive seeds purchase.

Added operating room time ranged from 12-20 minutes. No postoperative radiation related complications or tumor recurrence had been observed (follow up ranges from 2-14 months).

Conclusions: Compared to IMRT and SRS, direct cost of brachytherapy is reasonable. Additional economic studies are needed to calculate the indirect cost savings including the additional time lost from work and lack of transportation-related costs. We were encouraged by our initial data to pursue a prospective in house trial for a more detailed cost effectiveness analysis of this modality.

Category: Cost-Effectiveness Analysis

Cost-Effectiveness of Denosumab versus Zoledronic Acid in an Ambulatory Oncology Clinic Dhimant Patel, MD; Jessie Lawton, PharmD, BCOP; Jordan Kennedy, PharmD Candidate; Stephanie Shuey, PharmD; Amy Kamien, PharmD; Jeff Waise, PharmD

Background: Denosumab and zoledronic acid (ZDA) are used in the management of bone metastases and osteopenia secondary to hormonal therapy in patients with cancer. Study results range from suggesting similar efficacy between the two agents to possible superiority of denosumab in certain populations. Advantages to deno­ sumab may include superiority of denosumab at preventing skeletal related events (SRE’s) as documented by Cochrane systematic review, denosumab’s subcutaneous administration being more convenient than the 15 minute ZDA infusion and denosumab not requiring renal dose adjustments. A drawback to denosumab is the drug cost can be significant. With varying data, we found benefit in doing a snapshot evaluation of our current practice at this particular time.

Objective: A comparison of the cost-effectiveness of denosumab and ZDA in oncology patients treated in the ambulatory setting was performed. Indicators reviewed were cost of the drug, laboratory monitoring, administration, Medicare reimbursement rates and potential differences in safety/clinical benefit as seen through published studies.

Method: We identified doses dispensed of ZDA and denosumab. A patient timing study was performed by RN interviews and observation. We obtained the current cost of ZDA and denosumab, SCr, heparin flush, IV tubing, 0.9% NaCl 100 mL bag, IV infusion and a SQ injection. We calculated the reimbursement per dose and then utilized the information to calculate total cost and reimbursement per dose.

Results: Drug use was looked at via ordering from 10/1/11 to 3/31/12 at selected Aurora Outpatient Oncology Clinics. Total doses reviewed included 1384 doses of ZDA and 438 doses of denosumab. The ZDA doses in CPOE system were further evaluated (654 total) and revealed a 21.25% dose adjustment rate. The results of the timing study showed an average of 1 hour treatment for ZDA, with a breakdown of 30-45 min for lab-work/calculations to be completed and 15-30 min for RN interaction and infusion. The denosumab SQ injection duration for rooming the patient and administration of the drug was an average of 15 minutes total. The overall cost for a ZDA administration was $1083 and Medicare reimbursement was $934. The overall cost of a denosumab injection was $1708 with a Medicare reimbursement rate of $1723. The safety and efficacy studies were reviewed to look for potential differences.

Conclusion: For our outpatient-based oncology clinic perspective, denosumab was found to be cost-effective to administer at that point in time. It also provided a more convenient administration, decreased patient time while not requiring dosing adjustments for renal impairment. We concluded that denosumab was a viable option for our oncology patients with bone metastases secondary to breast or prostate cancer at that time. With ZDA potentially going generic in April 2013, we will continue to re-evaluate the new pricing/reimbursement structure as it becomes available.

Continued on page 20

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AVBCC Third Annual Conference Abstracts Payer Current and Future Utilization of Pathways: A Research Study Rhonda Greenapple, MSPH, Reimbursement Intelligence

Background: Clinical pathways are a growing payer management technique for controlling costs and standardizing care. Their use in other therapeutic areas has helped payers control costs and standardize care; however, use of pathways in oncology has not been assessed.

Objective: To determine trends in payer use of pathways in management of oncology therapies and to identify specific tumor types that are current and future focuses in pathway design.

Methods: Using our Reimbursement Intelligence Network (RIN), we reached out to Medical and Pharmacy Directors at a variety of plan types to ascertain their perspectives on the use of guidelines and pathways in oncology. There were a total of 49 respondents, including 19 Medical Directors and 30 Pharmacy Directors, covering 100 million lives in the United States across all channels (Medicare, Commercial, and Medicaid). Approximately 39% of respondents were from small plans (covering less than 750,000 lives), 28% were from medium-sized plans (covering 750,000-2.5 million lives), and 33% of respondents represented large plans (covering more than 2.5 million lives). About 33% of respondents were from national plans, while 67% were from regional plans.

Results: Only 39% of payers have actually implemented pathway programs in oncology. Of the payers surveyed that did not already have a clinical pathway, 59% said they are not currently implementing pathways. However, among those who are using pathways, a disproportionate share is commercial plans (42%) and Medicaid (40%), not Medicare (25%). Only 25% of Medicare-focused plans anticipate implementing clinical pathways in the future, while more than 40% of commercially focused plans intend to do so. About half of plans (53%) anticipate that pathways also will be integrated into provider ratings, and a minority (42%) sees a role for pathways in product formulary placement or tier status. When payers have implemented pathways, the tumor types with the highest costs have been initial targets, with breast (84%), lung (63%), colorectal (63%), and prostate (37%) with the highest penetration of pathway implementation.

Conclusions: Payers view clinical pathways as an important tool for reducing drug costs, especially with respect to tumor types that carry high treatment costs. Nearterm strategies such as step edits and coverage via the pharmacy versus medical benefit will continue to play a significant role in oncology reimbursement decisions, but product companies need to understand how existing clinical pathway programs will impact provider access to products to more accurately forecast their future impact as the concept gains national traction.

Category: Guideline/Pathway Impact

Evaluating Payer and Physician Adherence and Understanding of Clinical Pathways and Guidelines in Oncology Treatment Lee Goldberg; Shaili Shah; Cassandra Habura

Background: Clinical pathways have been in existence since the 1980s1 to guide treatment of oncology patients based on established treatment evidence. Despite their tenure in the healthcare space, there is still much debate over the implementation and use of clinical pathways in medical practices. Faced with rising healthcare costs, payers have begun to show a greater interest in clinical pathways as a utilization management tool and as a way to control costs.

Objective: To assess how payers and the physicians they reimburse are currently utilizing and addressing clinical pathways in their management of oncology patients.

Methods: The Zitter Group performs a three-arm study consisting of concurrent web-based quantitative surveys with managed care executives, oncologists, and practice managers biannually. It is designed to provide a portrait of the managed care and oncology practice environments. The managed care arm most recently included 102 managed care decision-makers from large national and important regional and independent plans. The oncologist arm included 100 oncologists from a variety of practice groups across the country. The practice manager arm included 100 practice managers from a variety of practice groups across the country. The payer and oncologist arms were specifically surveyed to obtain the results for this portion of the study.

Results: Significantly more payers have pathways in place (62%) in summer 2012 than did so in the summer of 2011 (46%). These increases were primarily seen in breast cancer and were equally spread among early, middle, and late stages of the disease. A majority of payers note that at least 61% of oncologists in their network participate in their clinical treatment pathways programs. Nearly half of oncologists note that the adoption of pathways has had little impact on patient outcomes and the percentage supporting clinical pathways has steadily decreased since the winter of 2011.

Conclusions: Similar to their use of other management interventions, payers intend clinical pathways to reduce inappropriate utilization and to control costs. The jury is still out on these programs’ success. A majority of payers indicate pathways, thus far, are not meaningfully efficacious in either reducing inappropriate utilization or in reducing costs.

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Kinsman L, Rotter T, James E, Snow P, and Willis J. What is a clinical pathway?

Development of a definition to inform the debate. May 27, 2010. BMC Medicine. 8:31.

Available at http://www.biomedcentral.com/1741-7015/8/31. Accessed 2/26/13.

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Category: Guideline/Pathway Impact

Anemia-Related Costs and Adverse Event Rates in Cancer Patients Who Do Not Respond to Erythropoietin Stimulating Agents

Allicia Girvan; Gerhardt Pohl; Yiu-Keung Lau; Pamela Landsman-Blumberg; Nianwen Shi; Helen Varker; Paul Juneau; Lee Bowman Background: While broadly utilized for treatment of anemia in cancer patients, treatment with erythropoietin stimulating agents (ESA) is not recommended in patients who fail to respond within 6-8 weeks.

Objective: This study examined the rate of adverse events (AE) and costs of continued exposure to ESAs in the absence of clinical response compared to those responding to ESA treatment.

Methods: Electronic medical records of breast, head & neck, cervical, non-small cell lung cancer, and multiple myeloma patients initiating ESAs during 1/1/2007 7/1/2011 were extracted (ACORN, Memphis, TN). Patients with ESA use ≥8 weeks, valid Hemoglobin (Hb) values ≤28 days before and 43-70 days after ESA start were retained. Following the ASCO/ASH guidelines, “responders” had Hb increase ≥1 g/ dL from start to between days 43 to 70. Non-responders were then divided into “continuing” or “discontinuing” based on presence of ESA treatment after the 43-70 day window. Days on ESA, anemia-related costs (ESA, laboratory, visits), and AE rates were analyzed. ESA costs were estimated by 2011 Wholesale Acquisition Cost (WAC) dose billed and other anemia-related costs by applying Current Procedural Terminology (CPT) pay proxies, derived from the 2011 MarketScan Databases.

Results: Compared to responders, continuing non-responders had significantly longer mean ESA treatment (+17 days; P = 0.023) and significantly higher median anemia-related costs (+$3,385; P <.001) during post-response period and for entire ESA treatment period (+$2,927; P <.001). Discontinuing non-responders incurred significantly lower median anemia-related costs than responders during ESA treatment (–$2,368; P <.001). Additionally, continuing non-responders experienced a higher number of AEs compared to discontinuing non-responders (9.4% vs 3.4%, respectively).

Outcomes Days on ESA, mean (SD) Anemia-related costs, median (IQR) Post-ESA response

Continuing Discontinuing Responders (A) Non-Responders Non-Responders P value: P value: N=458 (B1) N=458 (B2) N=149 A vs B1 A vs B2 120 (137) 137 (86) 63 (10) 0.023 <.0001

$1,824 $5,209 ($0, $5,795) ($2,804, $9,724) Entire ESA period $8,451 $11,378 ($6,253, $14,895) ($7,781, $17,250) Adverse event, N (%) 47 (9.7%) 43 (9.4%)

$647 ($0, $1,958) $6,082 ($4,663, $8,650) 5 (3.4%)

<0.001

<0.001

<0.001

<0.001

0.867

0.014

Conclusion: For every one non-responding cancer patient who discontinued treatment according to recommendations, there were three non-responders who continued treatment. The treatment duration for non-responding patients who continued ESAs was longer even than for those responding to ESA treatment. Treatment costs were significantly higher for non-responders continuing ESA treatment than the other two cohorts. It was not clear from these data whether the increased AE rate in non-responders who continued ESAs, compared to those who discontinued, was offset by other positive outcomes for the patients.

Category: Health Policy

Evaluating Payer Restrictions on Prostate Cancer Treatments Melinda C. Haren; Kati Sadiwnyk; Joseph Tucciarone

Background: According to the National Institutes of Health, medical expenditures are projected to reach $158 billion by the year 2020. This represents a 27% increase from 2010 costs. Prostate cancer is in the top 5 contributors of this cost, and is projected to reach $12 billion. Advancements in drugs, surgery, and radiation therapy have all contributed to an increase in costs. Payers are feeling increased pressure to make cost-effective choices among these agents.

Objective: To assess how payers are currently managing the biologic agents for prostate cancer.

Methods: The Zitter Group collected and evaluated payer policies from 202 commercial payers representing 183.7 million lives. The payer policies were entered into a database based on strict rules of entry and interpretation. Each payer policy for Zytiga, Provenge, Jevtana, and Xtandi were categorized into 6 categories: drug covered without a prior authorization (PA), PA required no criteria, managed to the prescribing information (PI) with off-label indications, managed to the PI, managed

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AVBCC Third Annual Conference Abstracts more than PI, and not covered. Payer policies were evaluated over a period of 2 years.

Results: More than 80% of all commercial payers require PA for most drugs in the category. Although Xtandi’s policies are still developing after its recent approval, it appears that payers will be managing it with PA as well. Most payers manage the drugs to their labels, articulating lines of therapy, and concomitant therapies, with larger payers more likely than smaller payers to have robust policies articulating full label indication statements. Two payers manage Provenge with guidelines more strictly than label, whereas 1 payer does the same with Zytiga.

Conclusions: Most payers are still managing prostate cancer agents to their labels.

However, some sequencing of agents is occurring based on the differences in firstline and second-line agents’ labels. This is likely short-term until Xtandi receives approval as a first-line agent.

Category: Health Policy

Knowledge Gaps and Value-Based Oncology Coverage Related Findings from the 2012 National Employer Survey

F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare; Cheryl Larson, BA, Vice President, Midwest Business Group on Health; Margaret Rehayem, MA, Senior Director of Strategic Initiatives and Communications, Midwest Business Group on Health; Larry Boress, MPA, CEO and President, Midwest Business Group on Health Background: Healthcare costs are a continued concern among employers and other purchasers, and extend especially to biologics 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. The costs of biologics are also hard to track, because they show up in medical as well as pharmacy expenditures.

Objective: To assess the change in level of knowledge and benefit design gaps of employer plan sponsors in the area of specialty pharmacy and biologic products for conditions such as cancer 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 spring 2012. The survey was disseminated to 15 business coalitions across the United States during the second half of 2012, and was completed in January 2013. Results were analyzed by the Midwest Business Group on Health and the Institute for Integrated Healthcare.

Results: A total of 68 employers of varying size and representative Standard Industrial Classification types completed the survey. Results in 2012 indicated that larger-size companies have a higher knowledge base versus the 2011 survey findings, which indicated that 25% of small- to mid-size employers had little to no understanding of specialty or biologics, and 53% had a moderate understanding of these covered products. Similar to 2011, the 2012 results showed that many companies did not know whether their company’s claim costs for specialty drugs had increased over the past 3 to 5 years. Again in 2012, most employers were using traditional benefit design (eg, tiered formularies, copayments, and coinsurance) instead of innovative (ie, value-based) benefit designs that may be more appropriate for biologic and specialty pharmacy medications. Vendor performance was again highly valued, yet the majority of benefit designs continue to omit an incentive to ensure proper adherence to medication or compliance with treatment.

Conclusion: There remains a knowledge gap among commercial plan sponsors that is important to those who manage oncology services or risk, among other specialty drug categories. The 2012 survey findings demonstrate employers’ relatively low knowledge of biologic drugs, appropriate support technologies, and vendor contracting options available to their plan. Employers who improve their understanding of the many challenges in managing this area will be able to more effectively manage costs and the related patient outcomes.

Category: Patient Navigation

Onyx Pharmaceuticals 360™: A Support Program for Patients with Multiple Myeloma and Their Caregivers

Vicki Kennedy, LCSW;1 Joanne Buzaglo, PhD;1 Jennifer Sharretts, MBA2 1 Cancer Support Community, Washington, DC; 2Onyx Pharmaceuticals, Inc, South San Francisco, CA Background: In 2007, the Institute of Medicine’s Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs outlined a framework to integrate psychosocial health services into routine care for patients with cancer. Building off this report, the Onyx Pharmaceuticals 360™ (Onyx 360) program was developed and subsequently introduced in 2012 following the approval of carfilzomib in the United States for the treatment of relapsed and refractory multiple myeloma with the goal of delivering an innovative program to integrate biopsychosocial care and serve as a model for industry-sponsored patient access programs. Herein we describe the key features of this

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program with emphasis on the integration of patient navigation and supportive resources.

Objective: To describe the key features of Onyx 360, an industry sponsored patient access program that emphasizes patient-centered navigation to personalized support services.

Methods: Onyx Pharmaceuticals convened focus groups with patients, caregivers, oncology nurses, oncology social workers, and practice managers, the results of which informed the design and development of the program. To assess the impact of Onyx 360, participants were asked to complete a satisfaction survey.

Results: Onyx 360 was established for patients and caregivers to receive reimbursement and financial support and to navigate other concerns that could impact patients’ capacity to receive treatment and maintain quality of life. Oncology nurse advocates act as the primary source of contact and collaborate with healthcare professionals, payers, and community organizations on patients’ behalf. Unique features of the program include transportation assistance, clinical support, and realtime referrals to key resources including the Chronic Disease Fund, the International Myeloma Foundation, the Multiple Myeloma Research Foundation, and the Cancer Support Community (CSC). Consenting patients and caregivers are transferred to CSC whose licensed mental health professionals conduct distress screening and offer patients and caregivers free supportive counseling, resource referral, group support, and treatment decision counseling. Early results from a survey demonstrate that patients, caregivers, and providers (N=241) are “highly satisfied” (89%) and value the integrated approach to meeting patients’ medical, emotional, and everyday needs.

Conclusions: The Onyx 360 program is unique from standard reimbursement support programs in that it partners with a patient’s healthcare team to expand upon, and provide efficient access to, a support network. By assisting patients with everyday challenges, this program is establishing a seamless delivery of care between patients, caregivers, healthcare professionals, and community organizations to ease the burden of the treatment journey. Preliminary results from an initial participant survey are encouraging.

Category: Patient Navigation

Building a Successful Navigation Program Lori McMullen, RN, MSN, OCN

Background: Dealing with a cancer diagnosis is emotional and overwhelming; patients are suddenly faced with the difficult task of making healthcare decisions as an ensuing barrage of tests and consultations present them with treatment decisions which are often complex and confusing. Further complicating this process are potential barriers to care such as being under- or un-insured, or having issues with transportation, health literacy, eldercare, childcare, cultural differences, or psychosocial concerns. The American College of Surgeons Commission on Cancer (ACoS CoC) recognizes that patient navigation is an important component in the ability to deliver patient-centered care and has added Standard 3.1 to its Cancer Program Standards. Patient navigation has been identified as a process to address healthcare disparities and barriers to obtaining optimal care.

Objective: To fulfill the ACoS CoC Standard 3.1, close the gaps on fragmented care, and address potential barriers to care, the Matthews Center for Cancer Care introduced the position of a Senior Oncology Nurse Navigator (ONN). The position requirements included licensure as a Registered Nurse, Bachelors Degree, OCN certification, and experience in oncology nursing.

Methods: Building the program began with establishing referral pathways for staff and physicians. The ONN accomplished this by attending staff meetings, medical and section meetings, and administrative leadership meetings. Using the nursing process, the ONN works with cancer patients throughout the disease trajectory to assess for barriers to care, provide resources, and diagnosis specific education.

Guidance is provided by the ONN to encourage informed decision making.

Continuity of care and communication are supported as the ONN ensures pertinent documents and test results travel across the care continuum to members of the patient’s interdisciplinary team.

Results: The overarching goal of delivering patient centered care while addressing barriers to care has been observed. While providing navigation to oncology patients, the ONN has promoted increased referrals to ancillary services and community resources. Outcome measures will be documented following a six month period to evaluate for success and identify areas for process improvement. Antidotal results have shown a decrease in the time from diagnosis to treatment as well as improved patient and physician satisfaction.

Conclusions: The implementation of a navigation process provides patients with seamless and efficient patient-centered care. The ONN works collaboratively with the multidisciplinary care team and functions to improve communication; provide patient advocacy; assess for and address barriers to care: create links to resources; reduce anxiety and fear by supporting patient self-efficacy and preparedness; and facilitate patient decision making.

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Making

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

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment benefits in clinical trials.2,3 Use of a PRO instrument can evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement.

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

Myelofibrosis (MF) is a life-threatening, progressive disease characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, double-blind placebo-controlled study, COMFORT-I, for Jakafi. Spleen reduction, as measured by imaging (MRI or CT), was the primary and biologic endpoint, and a reduction in total symptom score (TSS), the PRO measure, was a key secondary endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

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

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

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

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

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

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

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patient’s response.

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

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

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

10. Data on File, Incyte Corporation.

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

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

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

RUX-1130A 05/12

In the Literature HER2, which is associated with shortened survival. The combination of cytotoxic chemotherapy and HER2targeted agents is an effective therapy Approximately 20% of patients with for these patients. The recently ap1INC007advanced JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1 proved antibody-drug conjugate trasbreast cancer exhibit amplification of the epidermal growth factor tuzumab emtansine (T-DM1) includes

T-DM1 Significantly Prolongs Survival in Patients with HER2 Advanced Breast Cancer

anti-HER2–targeted antitumor properties with the cytotoxic activity of DM1, a microtubule-inhibitor agent. The phase 3 clinical trial known as EMILIA compared the impact of T-DM1 on survival of patients with advanced HER2-positive breast cancer compared

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

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

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

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

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

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

Issued: November 2011 RUX-1040

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with conventional cytotoxic chemotherapy with lapatinib plus capecitabine (Verma SL, et al. N Engl J Med. 2012;367:1783-1791).

This international trial randomized 991 patients with advanced HER2positive breast cancer in a 1:1 ratio to T-DM1 3.6 mg/kg intravenously every 21 days or to 1250 mg of oral lapatinib plus oral capecitabine. Dose adjustments for lapatinib plus oral capecitabine, including reductions and delays, as well as discontinuation because of adverse events, were done per protocol. All patients had previously received trastuzumab and a taxane. The primary end points were progression-free survival (PFS) and overall survival (OS). The secondary end points were objective response rate and time to symptom progression.

The median PFS (as assessed by an independent review) was 9.6 months with T-DM1 compared with 6.4 months with the combination of lapatinib and capecitabine, with a hazard ratio (HR) for disease progression or death of 0.65 (95% confidence interval [CI], 0.55-0.77; P <.001). At the second interim analysis, the median OS was 30.9 months with T-DM1 versus 25.1 months for the combination of lapatinib plus capecitabine (HR for all-cause death, 0.68; 95% CI, 0.55-0.85; P <.001).

The objective response rate was also higher with T-DM1 than with the combination (43.6% vs 30.8%, respectively; P <.001). All of the results for the other secondary end points also favored T-DM1. Overall, the new agent was less toxic than the combination of lapatinib and capecitabine in this setting. Grade 3 or 4 adverse events were more frequent with the combination of lapatinib and capecitabine than with T-DM1.

T-DM1 is the first immunoconjugate drug to be approved by the US Food and Drug Administration for the treatment of any cancer. Emtansine, a maytansine-like agent and a very potent cytotoxic drug, is linked to the targeted drug trastuzumab. This immunoconjugate is approved for HER2-positive metastatic breast cancer in patients who were previously treated with trastuzumab or with a taxane alone or in combination. This pivotal randomized trial of T-DM1 versus the second-line combination of lapatinib plus capecitabine produced a very impressive 50% prolongation of PFS, a 5-month improvement in OS, and a 32% reduction in mortality. The toxicity profile of T-DM1 was significantly better than the cytotoxic combination. This new drug may now be considered a firstline treatment for recurrent advanced HER2-positive breast cancer.

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AVBCC Third Annual Conference Abstracts Continued from page 21

Category: Practice Management Outcomes

Impact of a Cancer Management Program

J. Russell Hoverman, MD, PhD; Ira Klein, MD; Deb Harrison, MS, RN; Jad Hayes, MS, ASA, MAAA; Greg C. Nelson; Jody S. Garey, PharmD; Jean Stratton; Maria Sipala; Scott Houldin; John Ciaglo; Cynthia Taniguchi, RN, BSN, OCN; Melissa Jameson, RN, BSN, OCN; Mitra Abdullahpour, RN, BSN, OCN; Jessica McQueen; Diana K. Verrilli, MS; Roy Beveridge, MD Background: US Oncology, Inc. and Aetna are engaged in a pilot program, Innovent Oncology (IOP) to evaluate clinical and financial impacts of Pathways (PW), a nursing call intervention for chemotherapy patients (patient support services [PSS]), and an advanced care planning (ACP) initiative. We report quality initiatives, PW compliance, and ACP, from the program at 18 months, and inpatient (IP) and emergency department admissions at 12 months.

Methods: Eligible Aetna patients with PW diagnoses, treated by Texas Oncology (TxO) were enrolled. PW compliance was tracked. PSS calls occurred at regular intervals during chemotherapy. Symptoms, quality of life, and depression were screened with each call with referrals to TxO as needed for management. ACP was initiated in month 2 of IOP. To support IOP, a leadership team comprising physicians, pharmacists, and nurses was established. IP and emergency department data on predefined subgroups were compared to diagnosis-adjusted rates from the baseline prior year.

Results: The program enrolled 184 patients from 6/1/10 to 12/30/11 with 278 regimens ordered. Pathway adherence improved from 67% to 75%. 81% enrolled in PSS; of these, 83% were introduced to ACP, with 11% (n=16) completing a full ACP discussion. PSS made 906 calls to patients and assessed pain at 80% of contacts. IP and emergency department utilization rates after 12 months of IOP are reported (Table).

Conclusions: This is a preliminary evaluation with small numbers. Results suggest: cancer patients can be identified pretreatment, a proactive nurse call system is feasible and well received, a symptom assessment tool can be systematically implemented, communication on ACP can be initiated, and a pathways program can be enhanced. A reduction of emergency department visits by 39.8%, IP admits by 16.5%, and inpatient days per member by 35.9% are very promising trends. A bootstrap shows 97% of scenarios with IP utilization reduction, and 96% with emergency department utilization reduction.

IOP

Bre 18-50 Bre 51+ CRC 51+ Lun 51+ Total

Baseline

Bre 18-50 Bre 51+ CRC 51+ Lun 51+ Total Total

Percent change Per member.

Emergency departmenta 0.00 0.19 0.15 0.16 0.13

0.14 0.24 0.2 0.25 0.21 –39.8%

Admissionsa 0.11 0.19 0.55 0.42 0.32

0.15 0.29 0.5 0.58 0.38 –16.5%

Inpatient, daysa 0.39 1.05 1.95 1.9 1.33

0.88 1.61 2.9 2.87 2.08 –35.9%

Average length of stay, days 3.5 5.5 3.55 4.5 4.16

5.76 5.5 5.8 4.96 5.42 –23.2%

a

Category: Practice Management Outcomes

Low Incidence of Treatment-Induced Peripheral Neuropathy (PN) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM) Treated with Single-Agent Carfilzomib

Thomas Martin;1 Ravi Vij;2 Ashraf Z. Badros;3 Leanne McCulloch;4 Sundar Jagannath5 1 University of California-San Francisco, San Francisco, CA, USA; 2Washington University School of Medicine, St. Louis, MO, USA; 3Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA; 4Onyx Pharmaceuticals, South San Francisco, CA, USA; 5Mount Sinai Medical Center, New York, NY, USA Background: Treatment of patients with RRMM can be challenging because of debilitating PN caused by the disease itself or by MM treatments. Neuropathy at diagnosis is prevalent (20–54%, depending on evaluation type [Richardson PA, et al.

J Clin Oncol. 2009]) and can commonly be exacerbated by MM treatments (eg, bortezomib- or thalidomide-induced PN; BIPN or TIPN). PN reduces quality of life and leads to increased PN-related healthcare expenditures (eg, diagnostic testing and pharmaceutical and non-pharmaceutical interventions [Snowdon JA, et al. Br J Haematol. 2011]). One group has estimated that a single event of treatment-related Grade 3/4 PN costs more than $1,000 (Durie B, et al. J Med Econ. 2013; Epub).

Carfilzomib is a selective proteasome inhibitor recently approved in the US for RRMM that, in preclinical models, does not induce neurodegeneration as seen with bortezomib and, in clinical studies, is associated with low rates of PN. Objectives: An analysis of the PN safety profile for single-agent carfilzomib was

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performed in a cross-trial safety analysis of 526 patients from 4 phase 2 studies.

Methods: AEs were analyzed from the following studies: PX-171-003-A0, PX-171003-A1, PX-171-004, and PX-171-005 (NCT00511238, NCT00530816, NCT00721734), in which carfilzomib was dosed at 20−27 mg/m2 in 28-day cycles for all studies except 005 (15−27 mg/m2). Patient assessments included neuropathy history and baseline neuropathy status. An aggregate of PN terms including peripheral neuropathy, neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy were used in the analysis of PN. Results: The majority of patients in these studies (84.8%) had a history of PN due to previous therapy (42.6% due to bortezomib, 43.3% thalidomide, and 5.9% lenalidomide), with 71.9% of patients having active PN just prior to study entry (all Grade 1 or 2). During treatment with carfilzomib, PN worsened or emerged in only 13.9% overall. Among the 526 patients, 41 (7.8%) experienced Grade 1 PN, 25 (4.8%) Grade 2 PN, and 7 (1.3%) Grade 3 PN. Notably, no ≥Grade 4 PN was reported. In response to a PN-related AE, only 1 patient (0.2%) discontinued treatment and 4 (0.8%) required a dose modification. Of significance, 330/378 (87.3%) of the patients with baseline PN had stable or improved neuropathy during study treatment and did not report any PN-related AEs within 30 days of their last dose of carfilzomib.

Conclusions: In contrast to currently approved MM therapies, carfilzomib is associated with a low rate of treatment-emergent PN, even in patients with a history of PN, and does not exacerbate PN in patients with pre-existing neuropathy.

Additionally, there was a low rate of dose reductions or discontinuations due to PN. Future findings from comparative trials will determine whether complications and costs associated with BIPN and TIPN can be minimized with carfilzomib treatment.

Category: Practice Management Outcomes

Effects of 5-Hydroxytryptamine-3 Receptor Antagonists (5-HT3 RAs) in Lung Cancer Patients with Multiple Risk Factors

Claudio Faria; Xuan Li; Russell Knoth; Annette Powers. Eisai, Inc. Woodcliff Lake, NJ 07677 Background: Chemotherapy induced nausea and vomiting (CINV) is a major adverse effect of cancer treatment. The 5-HT3 RAs are indicated for the prevention of CINV. Certain factors such as age <50 years, female gender, prior CINV, anxiety, no or minimal alcohol use, history of motion sickness, and emetogenicity of chemotherapy have been associated with increasing the likelihood of a CINV event. We examined the impact of palonosetron vs. other 5-HT3 RAs on incidence of delayed CINV at cycle 1 based on presence of certain risk factors in patients with Lung Cancer.

Methods: A retrospective claims analysis was conducted using OptumInsight database from December 1, 2005, to June 30, 2011. Continuously enrolled (±6 months) lung cancer patients over 18 years of age initiated on their first chemotherapy (index date) were included in this analysis. Patients with a previous cancer diagnosis in the pre-index period or receiving multi-day chemotherapy were excluded. The study population was then examined for differences in CINV rates by each 5-HT3 RA stratified by number of risk factors (female gender, age <50, previous anxiety, vomiting pre-index, and highly emetogenic chemotherapy. CINV was identified using ICD9CM codes for nausea, vomiting, or related events, and use of rescue medication within 5 days after chemotherapy.

Results: Final analysis included 3863 patients. Overall the percentage of patients experiencing CINV increased as the number of risk factors increased—13.5%, 16.8%, 23.4%, and 26.7% for 0, 1, 2, and 3 or more risk factors, respectively. High-risk patients (3 or more risk factors) receiving palonosetron had less CINV events compared to ondansetron, granisetron, and dolasetron. Odds Ratios (OR) 95% CI vs palonosetron were 1.683 (0.625, 4.530), 2.775 (1.101, 6.995), and 2.254 (0.684, 7.434), respectively.

Conclusion: In patients with Lung Cancer the probability of a CINV event increased with the accumulation of identified risk factors. Palonosetron demonstrated a favorable OR vs all other 5-HT3 RA in the patients at the highest risk of developing a CINV event.

Category: Practice Management Outcomes

Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients Receiving 5-HT3-RA Therapy throughout Chemotherapy Cycles

Faria C; Nagl N; Li X; Powers A. Eisai, Inc. 100 Tice Blvd. Woodcliff Lake, NJ 07667 Objective: Current guidelines support the use of 5-HT3-RAs for chemotherapy-induced nausea and vomiting (CINV). Controlling CINV upon chemotherapy initiation is important as the likelihood of CINV in future chemotherapy cycles increases if a patient experiences CINV in the first/previous chemotherapy cycle. The purpose of this study was to evaluate the overall rate of CINV, and compare the odds of CINV per chemotherapy cycle in patients with lung cancer receiving the same 5-HT3-RA throughout chemotherapy cycles.

Methods: A retrospective database analysis was conducted utilizing medical and pharmacy claims from 2005-2011 in a commercial (96%) and Medicaid (4%) popula-

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tion. Continuously enrolled patients (6 month pre-period, 6 month post-period) with a diagnosis of lung cancer receiving single-day chemotherapy regimens were eligible.

Patients were required to remain on the initial 5-HT3-RA therapy and same level of emetic potential of chemotherapy throughout. CINV was defined as a primary or secondary diagnosis of nausea, vomiting, or dehydration or use of rescue antiemetic medication. Overall rates of CINV were calculated, and odds for CINV for each chemotherapy cycle were calculated by 5-HT3-RA agent. Patients without CINV in the previous cycle or who switched 5-HT3-RA therapy were excluded from subsequent calculations.

Results: A total of 3,863 patients were included in the analysis. Average age was 61 years, and mean Charlson Comorbidity score was 5.3. The overall CINV rate regardless of 5-HT3-RA was 17% at Cycle 1, and more than doubled for Cycle 2 and Cycle 3 (39.0% and 71.8%, respectively). Multivariate analysis showed patients receiving ondansetron, granisetron, or dolasetron had significantly higher odds of developing CINV at Cycle 2 vs palonosetron (Cycle 2 OR: 2.02; 95% CI: 1.23, 3.32 for ondansetron, OR: 2.79; 95% CI: 1.73, 4.49 for granisetron, OR: 1.85; 95% CI: 1.03, 3.32 for dolasetron; p<0.05 for all comparisons) and significantly higher odds for ondansetron and granisetron vs palonosetron at Cycle 3 (Cycle 3 OR: 3.36; 95% CI: 1.22, 9.24 for ondansetron, OR: 2.65; 95% CI: 1.07, 6.57 for granisetron; p<0.05 for each).

Conclusions: CINV rates increased in subsequent chemotherapy cycles for patients who experienced CINV and maintained therapy with the same 5-HT3-RA. For patients receiving palonosetron, the odds of experiencing CINV in subsequent cycles was lower than patients receiving one of the other 5-HT3-RAs.

Category: Practice Management Outcomes

An Assessment of Racial Differences in Toxicities and Supportive Care in Patients with Metastatic Breast Cancer (MBC) George Dranitsaris; Nancy Beegle; Traci Kalberer; Zhixiao Wang; Claudio Faria; Sibel Blau

Background: Racial disparities in clinical outcomes between Caucasian and African American (AA) MBC patients have been identified. Some of these disparities may be attributed to differences in toxicities and access to supportive care interventions. In this study, treatment toxicities and use of supportive care were compared between Caucasian and AA MBC patients treated in 15 community oncology practices across the United States.

Methods: Between 2009 and 2010, 264 MBC patients (198 Caucasians, 66 AAs) met the inclusion criteria. Data collection included baseline patient and disease characteristics, biochemistry, hematology, type of cytotoxic therapy by line of treatment (for the first three lines), use of supportive care drugs and incidence of dose limiting toxicities. Results were presented only descriptively. Socioeconomic data were not collected in this population.

Results: AA patients had significantly lower hemoglobin levels at baseline (12.5 vs 11.5 g/dL) and the levels remained lower throughout the first three lines of therapy. This resulted in significantly higher use of erythropoietin stimulating agents (28.8% vs 15.2%) and blood products (13.6% vs 7.6%) in AA. In contrast, neutropenia (33.9% vs 23.4%), G-CSF use (32.3% vs 28.8%) and diarrhea (21.3% vs 8.5%) were more common in Caucasian patients. The incidence of emesis (12.6% vs 8.5%) and anti-emetic support was similar between Caucasian and AA patients (77.3% vs 78.8% during 1st line chemotherapy). However, chemotherapy dose reductions and delays due to toxicity were higher in Caucasians than AA patients during 1st line and 3rd line chemotherapy (32.8% vs 21.2% and 43.2% vs 28.1%, respectively) and correspondingly, more medical interventions to treat toxicities were observed in Caucasian patients.

Conclusions: In this exploratory analysis, differences in the incidence of dose limiting toxicities such as anemia, neutropenia and diarrhea as well as supportive pharmacotherapy and blood products were identified between groups. Research in larger populations is warranted to better understand cancer treatment toxicities and outcomes across racial groups.

Category: Practice Management Outcomes

Impact of Treatment Modification on Treatment Duration in Metastatic Breast Cancer Patients Treated with Eribulin Mesylate Faria C;1 Belk K;2 Craver C;2 McBride A3

Eisai Inc. Woodcliff Lake, NJ; 2MedAssets, Inc., Charlotte, NC; 3Ohio State University, Columbus, OH

1

Introduction: EM is a microtubule inhibitor shown to improve overall survival in metastatic breast cancer patients who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. There are side effects of EM, including neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. While some physicians discontinue treatment due to side effects, others manage side effects using dose delays/skipped doses and/or dose modifications. The purpose of this retrospective study is to analyze the impact of EM

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treatment modifications (dose modification) on therapy duration.

Description: This study examined dosing and treatment patterns during EM treatment. The study population included MBC pts in the MedAssets health system database treated with EM in the hospital inpatient or outpatient setting from December 2010 to September 2012. Treated pts, dosing and dosing changes were identified administratively using hospital charge records which include drug description, quantity given and frequency of administration. Treatment patterns were discerned using service dates for each charge record. Adverse events were identified using diagnosis codes and/or the presence of charge codes for common treatments during the EM treatment period. Between group differences were tested using ANOVA for continuous variables and Chi-Square for categorical variables. A negative binomial generalized linear regression model was used to estimate the effect of dose modification on the number of EM treatments. The model was adjusted for common treatment side effects (neutropenia, anemia, fatigue, nausea, constipation, diarrhea, peripheral neuropathy and alopecia), cancer type (ER+ and HER+) and age >65 years. Due to limitations of administrative data HER2- and triple negative cancer pts could not be identified; therefore their effects on treatment could not be measured.

Summary: Of 510 pts in the cohort 34.1% had either a dose decrease (23.3%) or treatment delay/missed (20.2%) during EM treatment. Approximately 30% of pts with a dose decrease subsequently increased their dose. More than 80% of the treatment modifications occurred in the first (21.3%), second (48.3%) or third (11.5%) cycle. The most common side effects (>15%) in this population were nausea (60.0%), neutropenia (41.0%), anemia (25.1%) and fatigue (15.1%). Pts with neutropenia (40.7% vs 29.6%, p<.001), fatigue (46.8% vs 31.9%, p<.05), nausea (39.2% vs 26.5%, p<.001) and constipation (47.9% vs 32.7%, p<.05) were more likely to have a dose modification as were hormone positive pts (58.6% vs 48.5%, p<.05). No difference was seen in HER2 positive pts (19.0% vs 17.0%, p = 0.57) or in age ≥65 (28.7% vs 26.2%, p = 0.540) between the two cohorts. After adjusting for other factors, pts with a dose modification were estimated to have more treatments (1.90, p<.0001) compared to those who did not.

Conclusion: Patients who had a dose modification, a common strategy to handle adverse events, were able to stay on therapy longer.

Reference: Cortes J, Montero AJ, Glück S. Eribulin mesylate, a novel microtubule inhibitor in the treatment of breast cancer. Cancer Treatment Reviews. 2012;38(2):143-151.

Category: Practice Management Outcomes

Impact of Granulocyte Colony-Stimulating Factor and Treatment Modification on Eribulin Mesylate Therapy in Metastatic Breast Cancer Patients with Neutropenia

Gluck S;1 Yardley D;2 Belk K;3 Craver C;3 Cox D;4 Faria C4 University of Miami, Leonard M. Miller School of Medicine, Miami, FL; 2Tennessee Oncology, PLLC, Nashville, TN; 3MedAssets, Inc., Charlotte, NC; 4Eisai Inc., Woodcliff Lake, NJ 1

Background: Eribulin mesylate (EM) is a microtubule inhibitor shown to improve survival in patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. A common grade 3/4 toxicity of EM is neutropenia which may result in dose adjustments and dose delays. To minimze neutropenic complications, granulocyte colony-stimulating factor (GCSF or GMCSF) may be utilized, as well as dose modifications or treatment discontinuation. The purpose of this analysis is to examine the impact of treatment modifications and/or GCSF administration in patients experiencing EM mediated neutropenia on treatment duration.

Methods: A retrospective, cross-sectional claims database analysis was conducted in the MedAssets health system database on EM treated MBC patients experiencing neutropenia in the inpatient or outpatient setting between December 2010 and September 2012. EM dosing and dosing changes identified 110 EM treated MBC patients using hospital charge records which consist of drug description, quantity administered, and frequency of administration. Treatment patterns were discerned using service dates for each charge record. Adverse events, including neutropenia, were identified using diagnosis codes and/or presence of charge codes for common treatments during the EM treatment period. Patients were classified into those administered GCSF anytime during EM treatment (N = 24) and those who were not (N = 86). A negative binomial generalized linear regression model was used to estimate the effect of GCSF use and dose modification on the total number of EM treatments during a patient’s course of treatment. The model was adjusted for common treatment side effects (anemia, fatigue, nausea, constipation, diarrhea, peripheral neuropathy and alopecia), cancer type (ER+ and HER+) and above 65 years of age.

Due to limitations in administrative data certain molecular subtypes, line of therapy, and grade and duration of neutropenia could not be identified.

Results: Approximately 22% of EM MBC patients with neutropenia were treated with GCSF. Among patients with EM related neutropenia 38.1% experienced either a dose adjustment (23.7%) or treatment delay (26.8%) with 81.4% of these modifications occurring in the first three cycles. After controlling for age, molecular subtype, and side effects—EM treated MBC patients also receiving concomitant GCSF admin-

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AVBCC Third Annual Conference Abstracts istered during EM treatment were estimated to have a higher number of EM infusions (1.5 infusions, p<0.05) as compared to those EM treated MBC pts who were not administered GCSF. In addition, patients experiencing treatment modifications were estimated to have more EM infusions (1.8 infusions, p<0.0001) than those without modifications.

Conclusion: EM treatment related neutropenia managed with GCSF and/or dose modification facilitated the ability to continue EM administrations in MBC patients.

Category: Practice Management Outcomes

Category: Practice Management Outcomes

Julia Whiteker; Ann Bredensteiner

Say Ahh! Making Sense of Oral Assessments for Mucositis

Joanne Growney, MA, RN, ANP-BC, OCN; Rebecca Martin, BSN, RN, OCN; Phyllis McKiernan, RN, MSN, APN-BC; Joan Collela, RN, DNP, APN-BC, NP-C; Claudia Douglas, RN, MA, CNN, APN-C Background: Chemotherapy and radiation therapy, the mainstays of current cancer treatment, often result in devastating side effects involving the oral cavity.

Mucositis, an inflammatory and/or ulcerative lesion of the oral and/or gastrointestinal tract is a common therapy-related toxicity. Mucositis significantly impacts patients’ overall physical and functional well-being, as well as quality of life. There is strong evidence suggesting that the implementation of preventive strategy, such as patient and family education on the importance of oral hygiene practices, can lower the incidence of mucositis. The evidence also suggests that mucositis can be prevented or managed by performing rigorous oral hygiene, leading to lower occurrence in severity and in progressive symptoms. Research suggests that the implementation of preventive strategies such as patient and family education can lower the severity of mucositis symptoms, and the nurse plays a unique role in performing this patient and caregiver education at every opportunity of point of care.

Objective: To develop a standardized patient education booklet for oral assessment, oral hygiene practices, and symptom management of mucositis in populations with cancer.

Methods: The evidence-based practice (EBP) project was initiated using the Johns Hopkins model for the question development and project management. The EBP project will be carried out in phases. The first phase is to standardize an oral assessment tool for mucositis across populations and settings and the development of a practice policy. The mucositis EBP workgroup developed a pilot to gather data on the selected oral assessment tool to show evidence that the tool was endorsed by the staff nurses who were using it. In addition, the workgroup brought the project through the appropriate hospital councils to incorporate the oral assessment guide (OAG) into the daily shift assessment. Included in phase 1, the nurse educator completed the education of all of the nursing staff on oral assessment, oral hygiene, and chart documentation.

Next, phase 2 included the development of a standardized patient education and a nursing policy that governs when and how education and assessment are performed.

We are now approaching phase 3, in which the mucositis workgroup will be developing standards of treatment based on OAG score, known as the mucositis protocol.

Results: A patient-centered education program on the identification of the signs and symptoms of mucositis and on oral hygiene practices will be accomplished by developing a transdisciplinary EBP team, inclusive of advanced-practice nurses, staff nurses, pharmacists, dieticians, oncologists, dentists, and patient and caregiver representation. This EBP team will identify best educational practices and will incorporate patient preferences for education content, and assure collaborative decision-making among team members. The focus of this project will be the implementation of a patient-centered cancer education program related to oral hygiene practices and the identification of the signs and symptoms of mucositis. Comprehensive oral assessment conducted by the nurse will lead to earlier identification of the signs and symptoms of mucositis. Rapid detection of the onset of mucositis by the patient and the nurse will lead to implementation of interventions that will promote improved patient outcomes. The project goals include patient and caregiver early recognition of the symptoms of mucositis and improved quality of life patient outcomes in the areas of pain, dehydration, and weight loss. Therefore, with the identification, selection, and implementation of the OAG with oral hygiene practices, earlier recognition of mucositis symptoms and early initiation of the appropriate treatment will result. The EBP project has completed phase 1. During this phase, a pilot study was completed on 492 oral assessments. These assessments included 24 registered nurses and 5 advanced-practice nurses. The results of this pilot showed that 82% of users agreed on utilizing the OAG as the assessment tool, because it was thorough. In addition, 86% of the participants felt the tool was user-friendly. In phase 2, the Mucositis EBP workgroup is standardizing the patient education booklet; the nursing policy on performing oral assessment; and oral hygiene practices. A follow-up chart audit performed after the initial nursing staff education on oral assessment documentation showed a 64% increase and was occurring in a policy-compliant manner. Phase 2 included having the workgroup present the new OAG to be placed in the electronic medical record to the hospital informatics council.

Conclusions: At the conclusion of this EBP project, patients and caregivers will be able to demonstrate and articulate an oral assessment, the signs and symptoms of mucositis, and oral hygiene practices. The oncology nurses’ role is intended to

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enhance cancer care for symptom management. This EBP project of standardizing oral assessment skills, oral hygiene practices, and intervening with a mucositis protocol will become part of the oncology nurses’ armament to aid the patient through the treatment process, thus resulting in enhanced cancer care.

Wait Time and Patient Satisfaction—Improving Outcomes Can Be as Easy as Child’s Play Background: Breast Care at IU Health North Hospital is a multidisciplinary clinic comprised of breast surgeons, medical and radiation oncologists, plastic surgeons and geneticists. It has consistently achieved excellent patient satisfaction scores; however, one area needing improvement was in office wait time. Patient responses to the Clinician and Group Consumer Assessment of Healthcare Providers and Systems (CGCAHPS) survey question “During your most recent visit, did you see this provider within 15 minutes of your appointment time?” had been ranked in the 3rd, 38th and 63rd percentile consecutively for the first three quarters (Q) of 2012 by the National Research Corporation (NRC) Picker data.

Objective: To improve patient satisfaction on wait time.

Methods: Wait time for the first patient of each clinic session (morning/afternoon) for each provider was measured each day. Team members (providers, registration staff, medical assistants and nurses) were rewarded with incentives if the patient was seen within 15 minutes of their scheduled appointment time regardless of patient arrival time. On time starts were tracked in full view of the team. Rewards started October 1, 2012, with a communication to all providers and staff in our program.

Total cost of implementation was $50 per quarter for incentives.

Results: One week prior to the intervention, baseline wait time was measured. With an average wait time of 17 minutes, only 50% were seen on time. After initiation of the intervention, Q4 of 2012, 96 first starts were measured. The average wait time for all first starts after intervention was 9 minutes and 77% of the patients saw her provider within 15 minutes of her appointment time. In 14 of the 23 late start cases, the patient arrived more than 10 minutes after her appointment time. Patient satisfaction on the CGCAHPS recent wait time question was in the 100th percentile for Q4 2012.

Conclusions: Seeing a change on CGCAHPS recent wait time from the 63rd percentile in Q3 to the 100th percentile in Q4 represents an encouraging trend for this intervention. This project is ongoing to determine if this trend will continue. Patients do arrive late which in turn causes the clinic to run late. However, we realized the timeliness of the patients’ arrival was a much smaller factor than originally anticipated. Accountability played a key role. By setting our goal at 15 minutes, there was no room for excuses. It was much easier to address the problem when all team members realized their role in on time starts, not just the providers. This intervention also anecdotally improved team morale and a sense of efficiency.

Category: Practice Management Outcomes

Imatinib Can Still Be Used as 1st-Line for Treating Chronic Myelogenous Leukemia Wesley Wong, PhD

Background: The introduction of tyrosine kinase inhibitors (TKIs) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all patients with chronic myeloid leukemia (CML) in chronic phase. If properly managed, and if adherence is greater than 80%, the 10-year survival rate reaches 85% for patients treated with the 1st-generation (Gen) TKI, imatinib (Gleevec). Currently, there are five TKIs available for CML. Clinicians must weigh the relative advantages and toxicities of each when selecting a course of treatment. Three TKIs are approved for frontline therapy in CML—imatinib, nilotinib (Tasigna), and dasatinib (Sprycel). The 2nd-Gen TKIs (nilotinib, dasatinib) produce more rapid responses but have yet to show any overall survival advantage compared with long-term administration of imatinib. The 3rd-Gen TKI, ponatinib (Iclusig), looks promising but clinical data are still immature, and it is only approved for salvage therapy. Current practice is a 30-40% start with 2nd-Gen TKIs. Both nilotinib and dasatinib are more expensive than imatinib, a difference expected to become more dramatic once imatinib is no longer patent-protected in late 2015. Given its cost-effectiveness, it is still reasonable to initiate imatinib as 1st-line treatment for CML in appropriate patients. This would maximize the cost avoidance with respect to initiating CML therapy with a 2nd-Gen TKI. Objective: To determine the cost-avoidance of initiating patients with imatinib for chronic-phase CML compared to 2nd-Gen TKIs. Method: Chronic-phase CML patients will be started with imatinib where appropriate. Molecular testing was recommended at 90 days from day 1 of initiated TKI therapy to determine BCR-ABL transcript levels. The results would determine whether to continue with imatinib or switch to a 2nd-Gen TKI as was similarly done

by David Marin, et al. (Marin D, et al. JCO. 2012;30(3):232-238).

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

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

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

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

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

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost IF YOU DEFINE VALUE AS AN OVERALL SURVIVAL ADVANTAGE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage At 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

IF YOU DEFINE VALUE AS DEFINED LENGTH OF THERAPY: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

IF YOU DEFINE VALUE AS MEDICATION COST: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1,506 per 3.5-mg vial as of July 2012 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

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

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

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

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

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

In the Literature Adding Rituximab to Chlorambucil Improves Event-Free Survival in Patients with MALT Lymphoma

Approximately 8% of patients with non-Hodgkin lymphoma have extra­

nodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The condition can occur in any extranodal location, although the stomach is the most frequent site. There is currently no standardized treatment for advanced cases

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

VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

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

WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported.

Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%.

These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

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

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

Monitor patients closely and take appropriate precautions.

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

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of extranodal MALT lymphomas.

Although eradication of Helicobacter pylori has been shown to be successful in treating localized gastric involvement, no consensus exists about the optimal treatment for patients with extensive MALT lymphoma. A new

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

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

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

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%.

Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved.

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5-year study investigated the impact of adding rituximab to chlorambucil on event-free survival (EFS) in the treatment of patients with MALT lymphoma (Zucca E, et al. J Clin Oncol. 2013;31: 565-572).

The first phase of the IELSG-19 (Randomized Trial of Chlorambucil Versus Chlorambucil plus Rituximab Versus Rituximab in MALT Lympho­ ma), international, multicenter, phase 3 clinical trial, from January 2003 to October 2005, randomized 252 patients with MALT lymphoma in a 1:1 ratio to chlorambucil alone (arm A) or to chlorambucil plus rituximab (arm B). All patients had a diagnosis of CD20positive MALT lymphoma at any extranodal site. Patients did not receive any previous therapy other than for the purpose of H pylori eradication.

After October 2005, a third arm receiving rituximab therapy alone (arm C) was added. This report, however, is based on the results of the first phase only, with arms A and B only.

After a median follow-up of 62 months, the median EFS in the 2 arms combined had not been reached. At 5 years, the EFS in the patients receiving rituximab plus chlorambucil was significantly better than the patients receiving chlorambucil alone (68% vs 50%, respectively; P = .002). Adding rituximab to chlorambucil led to a significant improvement in EFS (HR, 0.52; 95% CI, 0.34-0.79). A total of 22 patients had an event, but it was not related to progression or to death.

Although the overall response rates were similar in the 2 arms, the group that received the combination of rituximab plus chlorambucil had a greater rate of complete remission compared with those receiving chlorambucil alone (78% vs 65%, respectively).

The 5-year OS rate was 89% in both arms. In addition, both treatments were well tolerated, and no unexpected toxicities were reported in any arm.

It will be interesting to see the results of the third arm of the IELSG-19 trial and whether combination therapy with chlorambucil plus rituximab is better than single-agent rituximab.

Screening Colonoscopy Reduces the Risk for Incident Late-Stage CRC in AverageRisk Persons

Evidence is lacking regarding the efficacy of colonoscopy screening in reducing the incidence of and death from colorectal cancer (CRC) in persons with average risk. By contrast, the evidence for the efficacy of sigmoidoscopy or fecal occult blood test (FOBT) has been established. Nevertheless, and despite the high cost of colonoscoContinued on page 42

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Results: From October 2011 to January 2013, 92% of CML patients in chronic phase were prescribed imatinib 1st-line compared to 8% of patients that were initiated with a 2nd-Gen TKI. Potential cost avoidance and need to switch to another TKI will be reported.

Conclusion: Second-generation TKIs are increasing utilization in frontline therapy for CML. To date, there is no survival benefit. Patients who fail imatinib can be salvaged effectively with 2nd-Gen TKIs. It is reasonable to initiate CML therapy with imatinib without compromising efficacy and long-term outcomes in appropriate patients.

Category: Value-Based Therapy

Cost Analysis of Bortezomib Retreatment Compared with Switching to Carfilzomib in Patients with Relapsed Multiple Myeloma Previously Treated with Bortezomib

Kevin B. Knopf, MD, MPH; Marie-Hélène Lafeuille, MA; Jonathan Gravel, MS; Patrick Lefebvre, MA; Liviu Niculescu, MD; Abbie Ba-Mancini, MBA; Esprit Ma, MPH; Mei Sheng Duh, MPH, ScD Background: In an era of multiple effective treatment options for relapsed/refractory multiple myeloma (MM), a recent meta-analysis has shown that retreatment with bortezomib continues to be an effective option in previously treated patients who relapsed. As economic pressures rise in oncology, it is important to evaluate the cost-effectiveness of newer therapies relative to standards of care. Carfilzomib was recently approved by the US Food and Drug Administration for the treatment of relapsed/refractory MM. Objective: This analysis estimates treatment-related costs for bortezomib retreatment versus carfilzomib in patients with relapsed MM previously treated with bortezomib.

Methods: A cost model was constructed from a US managed care payer’s perspective. Treatment-related costs included drug, medical (physician assessment and counseling, intravenous [IV] administration, hydration, laboratory tests), and adverse event (AE) costs. Drug costs were based on wholesale acquisition costs, and medical costs were based on Medicare published Current Procedural Terminology codes; AE costs were obtained from published literature. Pooled weighted average estimates from the 4 studies of IV bortezomib-dexamethasone retreatment were identified in the recent meta-analysis (0%-≥10% bortezomib-refractory patients) were used for treatment and efficacy inputs; the median duration of treatment (DOT) was 6.3 twenty one–day cycles; overall response rate (ORR) was 51.0%. Single-agent carfilzomib data were taken from the PX-171-003-A1 study (Siegel, et al. Blood. 2012; 100% bortezomib-exposed, 73% bortezomib-refractory patients; DOT, 3.2 28-day cycles; the ORR was 40.3% in bortezomib-exposed patients but not bortezomib-refractory patients).

Because of a lack of information regarding carfilzomib’s DOT in bortezomib-exposed but not bortezomib-refractory patients in PX-171-003-A1, the DOT was also estimated based on the PX-171-004 trial (bortezomib-naïve patients; seven 28-day cycles). The results were calculated as monthly costs and per course of treatment (ie, per median DOT).

Results: For bortezomib-dexamethasone retreatment, the monthly treatmentrelated cost was $11,919, including a drug cost of $8643, a medical cost of $1173, and an AE cost (including anemia, neutropenia, and thrombocytopenia) of $2103. The treatment-related cost per course was $52,311. For carfilzomib (DOT, 3.2 cycles for PX-171-003-A1), the monthly treatment-related cost was $21,899; including a drug cost of $10,659; a medical cost of $1295; and an AE cost (including anemia, neutropenia, and acute renal failure) of $9945. The treatment-related cost per course was $65,499. Using a carfilzomib DOT of 7 cycles (PX-171-004), the monthly treatment-related cost with carfilzomib was $16,511 and $107,578 per course. Progression-free and overall survival cannot yet be fully evaluated because of a lack of comparable data.

Conclusions: With a similar ORR and lower treatment-related costs, bortezomib-dexamethasone is a cost-saving treatment option compared with carfilzomib in bortezomib-relapsed patients.

Category: Value-Based Therapy

Cost Considerations for New Oral Therapies for Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC) Previously Lorie A. Ellis; Zoe Clancy; R. Scott McKenzie; Mekre’ Senbetta

Background: Two oral agents for mCRPC patients who previously received docetaxel were recently approved by the US Food and Drug Administration—abiraterone acetate plus prednisone (AA+p) and enzulatamide (EN). Phase 3 studies in this population showed median treatment duration of 8 months for AA+p1 and 8.3 months for EN,2 while median survival was 15.81 months and 18.42 months, respectively. The budgetary impact of these products to payers depends, in part, upon real world treatment duration and the proportion of mCRPC patients utilizing each product.

Objective: To model the expected pharmacy costs of treatment with AA+p or EN in mCRPC patients previously treated with docetaxel.

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Methods: Pharmacy costs of AA+p and EN were calculated by multiplying drug wholesale acquisition costs3 of a 30-day supply (AA 1,000 mg/d - $5,819.21, on 6/6/12; EN 1,000 mg/d - $7,450, on 8/31/12) by treatment duration (months) and number of post-docetaxel mCRPC patients receiving each therapy. The number of patients with prostate cancer at any stage was calculated by multiplying the age-adjusted rate of new prostate cancer cases (0.14%)4,5 by plan population size and proportion of males in the U.S. population (49.2%).6 Docetaxel-treated mCRPC population estimates were derived from a dynamic progression model.4 Two treatment durations, 8 months and 12 months, were modeled.

Results: In a 1,000,000 member plan, the model estimated 58 mCRPC patients with prior docetaxel chemotherapy. For an 8 month treatment duration, estimated cost of AA+p was $46,576 per patient and $59,600 per patient for EN, a difference of $13,024.

Modeling 12 month treatment duration,the cost of AA+p was $69,864 per patient and $89,400 per patient for EN or a difference of $19,536 per patient. The expected budget impact of an 8 month treatment duration in a 1,000,000 member plan with 25% of post-docetaxel mCRPC patients receiving AA+p and 25% receiving EN was $674,781 (AA+p) or $863,473 (EN), a difference of $188,692. Based on similar assumptions, the expected budget impact of a 12 month treatment was $1,012,172 (AA+p) and $1,295,209 (EN), a difference of $283,037.

Conclusions: In this cost model for the treatment of post-docetaxel mCRPC patients, AA+p was less costly than EN when treatment duration was held constant.

The higher modeled costs of EN therapy resulted in an additional $188,692 and $283,037 in plan spending for an 8 or 12 month course of therapy, respectively.

References: 1Zytiga® Prescribing Information; Janssen Biotech Inc. (12/2012).

2 Xtandi® Prescribing Information; Astellas Pharma US, Inc. (12/2012). 3Analysource/ First Data Bank. 4Solo K, et al. Presented at ASCO Annual Meeting, 2011. 5United States Census Bureau. http://www.census.gov/population/www/projections/ usinterimproj/. Accessed on 09/07/12. 6United States Census Bureau. http://www. census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed on 02/20/12.

Category: Value-Based Therapy

Is Oral Electrolyte Replacement More Effective than IV Replacement in the Oncology Population?

Rebecca Martin, RN, BSN, OCN; Joanne Growney, RN, MA, ANP-BC

Background: Electrolyte abnormalities are the most common laboratory findings in patients with malignancies. Clinical manifestations of several electrolyte deficiencies occur with frequency in malignancy (Hawthorne JL, Schneider SM, Workman ML). Patients who are admitted for chemotherapy regimens as well as for complications post chemo receive electrolyte replacements on a daily basis. Experience has shown consistent patient and staff nurse dissatisfaction with the current replacement protocol. From their skilled nursing judgment, oncology nurses have found that patients can receive up to 500 mL of excess fluids from IV electrolyte replacement, causing unnecessary fluid overload. Another issue that has been identified by oncology nurses with IV replacement is the potential for phlebitis and pain due to administration of IV potassium. Both of these occurrences can lead to increased costs and admission stays.

Objective: The objective of this evidence-based practice (EBP) project is to evaluate the efficacy of giving oncology patients oral electrolyte replacement (OER) as opposed to IV replacement. The expected outcome is that serum electrolyte values will normalize after being given OERs based on the protocol. The goal is to also increase patient satisfaction regarding unnecessary fluid overload, decrease discomfort from IV potassium given peripherally, decrease administration time leading to earlier discharge times, and reduce costs.

Methods: With a multidisciplinary team devised of an oncology physician, PharmD, APN, nurse educator, and staff RN, the original IV electrolyte protocol was revised to include oral options. The revised order set was presented to the hospital Pharmacy Review Committee for physician approval. Upon approval, a pilot study was initiated. Education of the nursing staff was key to the success of the pilot. Once the staff RN identified a decrease in the serum electrolyte value, they assessed the patient for the presence of nausea, vomiting, diarrhea, and mucositis. If all were negative, the nurse was able to proceed with the OER protocol. Data were gathered on a total of 73 instances of OER use regarding nurse compliance as well as the lab values following the replacement.

Results: Overall nurse compliance for using the OER protocol was 95.9%. For potassium, 65.4% of the occurrences using the OER met the target range for the serum level after repletion. For magnesium, 58% of the occurrences using the OER met the target range. For phosphorus, 100% of the occurrences using the OER met the target range.

Conclusions: The overall staff nurse compliance was extremely high. The reason for this is that the staff nurses were ready for the change in protocol. They identified the issues originally and the project team came together because of their requests. It was a smooth transition from using the IV protocol to the OER. Through staff nurse feedback, it was found that a potassium phosphate oral replacement does not exist on

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the hospital’s formulary, so only sodium phosphate replacement was used. This was vital information because it identified an unanticipated finding and a need to change the OER protocol. In addition to this, data showed that PO magnesium did not work as effectively for moderately low serum levels; however, oral repletion for mildly low serum magnesium levels was successful. Therefore, the parameters on the OER protocol were changed to reflect this finding and will be re-piloted. The PharmD had been gathering data regarding the usages of the original electrolyte protocol over the last five months. When substituting the amount of IV electrolyte replacement with the amount of OER, they were able to tabulate an overall savings of approximately $15,000.

Category: Value-Based Therapy

Perspectives of Quality Care in Cancer Treatment: A Review of the Literature Lisa M. Hess, PhD; Gerhardt Pohl, PhD

Background: Although information about quality care is increasingly available, there remains a gap in knowledge regarding stakeholders’ perceptions of quality cancer care. It is important to maintain high quality of patient care, but perspectives of quality may differ by stakeholder.

Objective: This systematic qualitative literature review was conducted to understand the current perceptions of key stakeholders about quality cancer care.

Methods: OVID/PubMed was searched using a predefined search strategy using specific medical subject headings (MeSH terms) encompassing each core concept:

cancer, chemotherapy, and quality of health care. Additional articles were obtained from the selected article bibliographies and from online searches informed by content from the selected articles. Eligible articles were required to focus on adults with cancer receiving chemotherapy, and must have presented perspectives obtained directly from a key stakeholder (patient, managed care, payer, health care provider, or caregiver) published from 2009-present. Thematic and descriptive analyses were conducted to assess the intersection of quality care issues from each stakeholder perspective.

Results: The search strategy identified 542 articles that were reviewed for eligibility. Of these, 15 articles were eligible, reporting perspectives from 4933 respondents (representing perspectives of patients, providers, caregivers, and thought leaders).

Cancer patient perspectives of quality care were primarily concerned with information needs (9 of 11 articles), psychosocial support and timeliness of care (each theme reported in 7 of 11 articles), responsibility for care (6 of 11 articles), and coordination of care (5 of 11 articles). Provider perspectives included information needs of patients, coordination of care, and psychosocial support needs (each theme reported in 3 of 4 articles), as well as the need to address equity in cancer care, reimbursement concerns, and the timeliness of care (each reported by 2 of 4 articles).

Conclusions: Thematic elements related to cancer quality were relatively consistent between patients and providers. The perspectives of these groups are important to consider as quality initiatives are being developed to ensure that provider and patient perspectives are reflected. Limitations of this work include the search strategy being limited to PubMed and work being limited to one reviewer. Despite these limitations, it is evident that the inclusion of perspectives of payers and managed care organizations are needed in the peer-reviewed medical literature.

Liver Cancer

Drug-Free Beads Match Chemoembolization for Hepatocellular Carcinoma

By Charles Bankhead

San Francisco, CA—Less proved to be the equivalent of more in a randomized comparison of empty versus chemotherapy-filled embolization beads for the treatment of patients with hepatocellular carcinoma (HCC), as shown in the results of a randomized study presented at the 2013 Gastro­ intestinal Cancers Symposium.

Treatment with the beads alone led to an overall response rate of 11% compared with 6% for patients who underwent hepatic arterial embolization with doxorubicin (Adriamycin)-elut­ ing beads. A similar proportion of patients in each treatment arm reached stable disease.

Progression-free survival (PFS) favored the drug-free beads, whereas chemoembolization had a small advantage in overall survival (OS).

Neither of the differences achieved statistical significance, reported Karen T. Brown, MD, FSIR, interventional radiologist in the Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York.

“This study brings into question the added benefit of chemotherapy for embolization of hepatocellular carcinoma,” said Dr Brown.

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Chemoembolization has an established role in the treatment of HCC, despite a paucity of evidence to support its use. According to Dr Brown, the rationale for the intervention rests largely on the results of 2 clinical studies, which were published approximately a decade ago, that suggested a

“This study brings into question the added benefit of chemotherapy for embolization of hepatocellular carcinoma.”

—Karen T. Brown, MD, FSIR

survival advantage for chemoembolization versus embolization alone.

One of the trials compared embolization and chemoembolization with conservative therapy. The trial design called for termination when either intervention achieved a significant advantage versus conservative care.

The difference occurred earlier in the chemoembolization arm, but

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that did not mean that the drugeluting beads were superior to the empty beads, which the investigators acknowledged.

“Over 10 years later, many people still interpret this study as showing a survival benefit for transarterial chemoembolization compared with embolization or best supportive care, and that is not the case,” Dr Brown said.

In this new study, the investigators randomized patients with Okuda stage I or stage II unresectable HCC to chemoembolization with doxorubicin or to embolization with the beads alone. The primary end point was an objective response rate, which was determined by computed tomography 3 weeks after treatment.

Of the 92 patients, 5 in the embolization arm and 3 in the chemoemboli­ zation arm met the Response Eval­ uation Criteria in Solid Tumors, Dr Brown reported. Another 40 (87%) patients achieved stable disease with the drug-free beads, as did 39 (85%) patients in the chemoembolization group.

The response by individual lesions showed that 58% of the lesions had a 100% decline in size in the emboliza-

tion arm versus 61% in the chemoembolization group. Approximately 25% of the lesions in each group decreased by 50%. A single lesion in each arm increased in size by >20%.

The PFS was 5.2 months with the drug-free beads and 4.6 months with the doxorubicin-containing beads. OS was 16.6 months versus 19.6 months, respectively, favoring chemoembolization, but not significantly.

Adverse events and serious adverse events occurred in a similar proportion of patients in the 2 groups.

The results provide “robust” evidence of the equivalence of the 2 treatment strategies, but they do not resolve all of the issues related to hepatic arterial embolization for the treatment of patients with HCC, said Françoise Mornex, MD, PhD, Head of the Department of Radiation Oncol­ ogy, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France. The outcome of the study does not exclude potential benefits from other embolization strategies. Moreover, the robust evidence came from a study involving fewer than 100 patients, so the need for a larger trial remains unclear, Dr Mornex concluded. n

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5/9/12 10:09 PM

Health Policy

Healthcare of Tomorrow: Digital, Genomic, and...

Continued from cover

Dr Topol shared his observations in a keynote address at the 2013 Health Information and Management Systems Society annual conference.

Dr Topol addressed 3 themes—the “digitalization” of medicine, the genomics revolution, and patient engagement and empowerment. These areas are fast becoming a medical reality, although current practice still largely fits the description posed by Voltaire: an era in which “doctors prescribe medicines of which they know little to cure diseases about which they know less in human beings about which they know nothing.”

The lightning-fast pace of digital technology will soon change this. In 2003, the world’s cumulative generation of data was estimated at 1 billion gigabytes. Just 10 years later, it’s in the trillions—zettabytes. “The digital revolution is accelerating innovation, driving connectivity, and irreversibly transforming our world…except, so far, in medicine,” Dr Topol said. “But it will hit medicine as well, because the digital infrastructure we are building is extraordinary.”

Drilling Down to the Level of the Individual The practice of medicine will shift from the “population level,” with general recommendations for all, to the level of the individual, thanks to tools that can help “define” who the individual is, he said. One benefit of this will be the avoidance of unnecessary harm and cost. Mass mammographic and prostate-specific antigen screenings cause harm to approximately 200 of 1000 screened persons and cost the United States $7 billion annually, plus another $33 billion for false-positive diagnoses and the harm associated with this, Dr Topol emphasized.

Treatment as well will become more targeted. Consider, he said, that atorvastatin—the highest-selling medication in history—reduces death and mortality by 36%, but in absolute terms it reduces the incidence of cardiovascular events from 3% to 2%. This means that for 99% of persons, a lifetime of statin medication results in nothing more than a better laboratory test.

“Can’t we do better than this?” Dr Topol asked. With the ability to make “Google maps” of each individual, and to employ omics, sensors, imaging, and the like, “we can get incredibly more precise,” he suggested.

Medical Apps: Coming Soon to Your Smartphone An impressive array of medical

34

“The digital revolution is accelerating innovation, driving connectivity, and irreversibly transforming our world…except, so far, in medicine. But it will hit medicine as well, because the digital infrastructure we are building is extraordinary.”

—Eric J. Topol, MD apps for Smartphones will mean instantaneous access to medical information on a patient level. Apps can already: • Produce continuous blood pressure readings and cardiograms • Monitor glucose levels and oxygen saturation • Digitize one’s voice, helping to diagnose neurologic conditions • Test for pulmonary and thyroid function • Assess medication compliance.

“You can get all your vital signs right on your wrist,” according to Dr Topol, who demonstrated how his own Smartphone is equipped for this.

“If you think that looking at your e-mail or browsing the internet is entertaining, how about looking at your vital signs.”

He predicted, “The Smartphone will evolve to become a ‘soul-mate’ device that knows your body better than you know yourself.”

Other handheld devices can produce images of the heart within minutes, can photograph the eardrum to help the diagnosis of otitis media, and can measure the eye’s refraction and thus eliminate the need for the optometrist.

Will Doctors Become Obsolete?

These patient-based devices represent “ways to bypass seeing a physician,” Dr Topol added. “We don’t

Value-Based Cancer Care

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need doctors so much when we have remarkable, innovative technology. As medicine becomes more of an information science, many tasks can be taken on by patients.”

Certainly, removing the physician from the equation would be incredibly cost-saving. A recent study from Indiana University evaluated an artificial intelligence framework for simulating clinical decision-making in 6700 patients, and found the cost per unit of outcome to be $189, versus $497 for traditional care (Artificial Intelligence in Medicine; January 2, 2013). The computer prescribed better treatment than the physicians, resulting in a 40% improvement in outcomes and a 50% reduction in costs.

Using innovative technology can also help keep patients out of the hospital, thus saving $17 billion alone by the avoidance of hospital-related medical errors (Classen DC, et al. Health Aff [Millwood]. 2011;30:581-589). “Keeping patients in their homes for monitoring would be safer, convenient and less expensive,” he suggested. Hospitaliza­ tion would be reserved for intensive care, surgery, and procedures.

“For that matter, when so much can be done remotely, why do we need office visits?” Dr Topol added. A recent study found that use of an “online clinic” for simple conditions delivered savings of $88 per episode, with high patient approval (Courneya PT, et al.

Health Aff [Millwood]. 2013;32:385-392).

The study was based on 4008 virtual visits and 17,678 regular visits, which costs $113 versus $208, respectively, per episode.

Scripps is undertaking a study of resource utilization and costs with “online care,” randomly assigning 200 patients with hypertension, diabetes, or atrial fibrillation—typically, high consumers of healthcare resources—to standard care or to care provided via Smartphone/apps/sensors.

“The idea of going to the doctor’s office is someday going to feel as foreign as going to the video store,” he predicted.

Genomics Will Change Care, Reduce Costs The burgeoning genomics landscape is also intersecting with infor­ mation technology, because genome sequencing can now be completed within hours using handheld devices.

In addition, the cost of individual whole-genome sequencing has steadily plummeted, from nearly $100 million in 2001 to $28 million in 2004 to <$4000 today.

“No technology has ever matched this degree of progress in what it can do, accompanied by a reduction in cost,” Dr Topol observed.

Whole-genome sequencing is iden­ tifying rare mutations in individuals with previously undiagnosed conditions, leading to treatments and, in some cases, cures, and is poised to greatly individualize cancer treatment based on mutation status. Last year, 11 newly approved oncology drugs each cost more than $100,000 for a course of treatment, emphasizing the importance of prescribing them only to patients who are likely to benefit. In addition, the use of pharmacogenomics to identify susceptibility to treatment-related toxicities will help guide treatment.

Power to the Patient Finally, the medical practice of the future will allow patients more access to their personal health information.

“Today’s doctor/patient relationship is based on asymmetry: the doctor has a lot more information while the patient has very little,” Dr Topol observed.

“The concept of the superiority of the physician over the patient has got to go.

We are moving the information across the board to produce parity.”

This change will be reflected by greater access to medical data by patients. In a 2012 survey by National Public Radio, 81% of respondents said they would want their genome sequenced, and 73% wished to have all of the information the test could provide. “We should not be suppressing direct-to-consumer access to data. It’s your DNA. You should be entitled to it,” he maintained.

The American Medical Association, on the other hand, disagrees, according to a February 2011 statement stating that genetic testing should be performed only under the guidance of a medical professional. “Talk about consumer engagement. This is antiengagement,” Dr Topol commented.

He stressed that physicians must also become more accepting of communication via e-mail, and must be more open to allowing patients access to physicians’ notes and to laboratory results. Some progressive healthcare systems are now changing their policies to allow such transparency.

The movement toward patient engagement can be summed up, Dr Topol said, in a mantra he proposed: “Nothing about me, without me.” He concluded, “In terms of real engagement and connectivity, this is where we want to be.” n

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Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

NOVEMBER 15-17, 2013 CONFERENCE CO-CHAIRS Lillie D. Shockney, RN, BS, MAS AONN Program Director University Distinguished Service Associate Professor of Breast Cancer Departments of Surgery and Oncology Administrative Director, Johns Hopkins Clinical Breast Programs Administrative Director, Johns Hopkins Cancer Survivorship Programs Department of Surgery and Oncology Associate Professor, JHU School of Medicine Departments of Surgery, Oncology, and Gynecology Associate Professor, JHU School of Nursing Johns Hopkins Avon Foundation Breast Center Baltimore, MD

Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

REGISTER TODAY

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Health Policy

What Does the Deficit Reduction Debate Mean for the Oncology Team?

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

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

F

irst it was the debt ceiling, then it was the fiscal cliff, and now we have sequestration. It seems that as the weeks go by, Washington is faced with one fiscal crisis after another, with little to no progress in making a meaningful dent in the ballooning deficit. No matter what your political leanings, this has been a frustrating process to watch unfold. For the oncology team (providers and payers alike), the process has also been filled with a fair amount of nail biting as Congress considers cost-cutting measures that could impact payment rates for oncologists, cancer hospitals, and manufacturers of oncology-related medications and diagnostics.

Although the sequestration deadline has passed, the deficit reduction debate is far from over. On March 27, 2013, the continuing resolution that has funded the current fiscal year will expire, resulting in another smaller sequestration of funds. Other significant dates loom nearby—Congress must pass a budget by April 15, and without further legislation, the current debt-ceiling limit will be reached on May 19. The real story for the oncology community, however, will not be in any short-term deficit package, but rather in larger, broader entitlement reform. In all likelihood, this “grand bargain” will not emerge in the next

6 months. But because any long-term deficit agreement must address entitlement cuts or reform, the oncology community would be wise to prepare.

In the near-term, sequestration means only minor pain for oncolo-

spective) of average sales price (ASP) plus 4.3%. Medicare beneficiaries are by and large protected. By the end of the year, Congress must once again address the long-delayed sustainable growth rate, because the physician

Ross D. Margulies

Jayson Slotnik

In the near-term, sequestration means only minor pain for oncologists. Looking beyond 2013, however, yields a much foggier and potentially painful picture for oncologists.

gists. Medicare cuts to providers and health plans are capped at 2%—or $11.495 billion—in 2013. The sequester will impact Medicare Part B drug payments, resulting in an effective payment rate (from the provider per-

payment fix was extended only until December 31, 2013.

Looking beyond 2013, however, yields a much foggier and potentially painful picture for oncologists. Medicare, Medicaid, and Social

Security—along with other entitlements—currently make up 62% of all federal spending, and so must be addressed to protect the solvency of these programs. Congress will address healthcare spending through a combination of structure reform and provider cuts. Many of these ideas have long sat on the table, and we are well aware of the devastating impact they could have on payment rates.

From the changes in payment rates for Medicare Part B drugs (from ASP + 6% to ASP + 4%) to moving entire classes of drugs (eg, anticancer and antiemetic drugs) from Part B to Part D, it is highly likely that providers will face cuts to their payment rates in the long-term. Broader structural reforms, such as the growth in bundled payments and accountable care organizations, pose both challenges and opportunities for the oncology community.

As the oncology community begins to position itself in an overall healthcare framework that will require its members to do more with less, bringing together the entire oncology team to have a real discussion about value-based care and delivery reform is essential. If oncologists can stay at the front of this debate, cuts will be less painful and opportunities will certainly emerge. n

Ochsner CEO Calls for Adding Value in Healthcare

By Caroline Helwick

New Orleans, LA—“We must start to think differently if we want to change the healthcare system,” said Ochsner Health System President and CEO Warner L. Thomas, CPA, MBA, FACHE, in a keynote address at the 2013 Health Information and Management Systems Society (HIMSS) annual conference. “We are seeing the most significant changes in healthcare in 30 years.”

Ochsner is a 71-year-old institution, with 8 hospitals and almost $2 billion in revenue. It is now 70% of the way toward an information technology (IT) conversion from a homegrown electronic health record to Epic systems software—in just 15 months— and 100% of its 900 physicians have met meaningful-use criteria.

36

Value-Based Cancer Care

The country’s fiscal situation, the unaffordability of healthcare for consumers, and the reductions in payments to

“We’ve got to shift from a volume mentality into value.

We’ve got to be thinking differently.”

—Warner L. Thomas, CPA, MBA, FACHE

providers and hospitals create a crisis that requires health systems to be more proactive than ever, he said. “What are we going to do about it?” Mr Thomas

I

march 2013

asked. “We’ve got to shift from a volume mentality into value. We’ve got to be thinking differently.”

Problem solving and coping with change is all about “perspective,” he suggested. “We control our perspective. If we’re not optimistic and energized, we will not be successful. We’re going to set the stage now for the next 10, 15, 20 years.”

Challenges and Solutions Ochsner’s mission, Mr Thomas noted, is to provide an experience for patients that makes them want to come back, to improve clinical outcomes, and to become more affordable for patients.

Success starts with the health IT leaders, he said, who should ensure

that systems provide better, safer patient experiences; optimize the use of systems to their full potential; be proactive and use systems to solve and improve on what patients want and need; and use IT to improve the productivity and efficiency of employees.

This requires that health IT be developed with the broad context in mind. For example, a successful “go live” is a very good start, rather than the end game. “I think we need to redefine what a good installation is,” Mr Thomas explained. “Does it provide higher quality healthcare cost-effectively? Are the physicians happier?

We don’t expect IT to drive all the change, but we expect it to be a driver….And I would add this advice to IT leaders: add value.” n

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No. 3

SECOND

ANNUAL CONFERENCE

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

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

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

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

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

Symposium/Product Theater

8:15 am - 8:30 am

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

8:15 am - 11:45 am

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

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

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

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

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

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

CONFERENCE OVERVIEW

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

TARGET AUDIENCE

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

LEARNING OBJECTIVES

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

DESIGNATION OF CREDIT STATEMENTS SPONSORS

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

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

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

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

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

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

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

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

GBCKsize20813

PMPMERSONALIZED EDICINE IN ONCOLOGY O

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

TM

Personalized Medicine

Personalized Immunotherapy plus Sunitinib Doubles... treatment of advanced RCC but is appropriate for “only about 10% of the entire population of patients with metastatic RCC,” because of its toxicities and the need for specialized centers to administer it, said Dr Amin.

At the 2013 Genitourinary Cancers Symposium, Dr Amin described the long-term survival of 21 patients with intermediate- or poor-risk meta­ static RCC who were treated with autologous dendritic-cell immunotherapy (ie, AGS-003) in combination with sunitinib. AGS-003 is produced from RCC antigens that are isolated and amplified from the patient’s tumor specimen. “To the best of our knowledge, this is the first such platform,” Dr Amin said. “At the time of nephrectomy, we get a little piece of the tumor and isolate the messenger RNA from the patient’s own tumor.

That is electroporated into the patient’s own dendritic cells. The hope is that those dendritic cells will then express the patient’s own tumor anti-

gens to the T-cells.”

In the phase 2 study, 21 patients with unfavorable-risk metastatic RCC

plus AGS-003, 5 doses given 3 weeks apart, and then every 12 weeks as maintenance.

“Sunitinib has been shown to modulate the immune system in a positive fashion by suppressing T-regulatory– cell activity and myeloid suppressor cells,” Dr Amin pointed out. “Using sunitinib made sense, because it’s an accepted first-line standard of care, and it actually may make the environment more appropriate for an immunotherapeutic to act.”

More than 150 doses of AGS-003 were administered; no grade 3 or grade 4 adverse events related to immunotherapy were reported. Grade 1 injection site reactions occurred in approximately 50% of the patients. Laboratory assessments for markers of autoimmune responses showed no evidence of emergent autoimmune disease.

“We have shown durability of responses,” Dr Amin said. For the overall study population, the median PFS was 11.2 months, and the final median

“At the time of nephrectomy, we get a little piece of the tumor and isolate the messenger RNA from the patient’s own tumor. That is electroporated into the patient’s own dendritic cells. The hope is that those dendritic cells will then express the patient’s own tumor antigens to the T cells.”

—Asim Amin, MD, PhD were treated. The treatment consisted of standard 6-week cycles of sunitinib

Continued from cover

OS was 30.2 months. An OS of more than 30 months was seen in 52% of the patients. Of the 21 patients, 7 are still alive nearly 4 years after registration.

When analyzed by baseline Heng risk status, the median PFS time was 19.4 months for intermediate-risk patients and 5.8 months for patients with poor-risk features at baseline.

The estimated median OS is 39.5 months for intermediate-risk patients and 9.1 months for patients with poor risk. By comparison, in a pivotal trial, treatment with sunitinib yielded a median OS of 5.3 months for poor-risk patients and of 20.7 months for intermediate-risk subjects. Only approximately 13% of patients with unfavorable-risk metastatic RCC and who receive sunitinib survive for more than 30 months.

The ongoing phase 3 ADAPT study is using this approach to personalized immunotherapy, with the goal of randomizing 450 patients from many sites. n

SNPs in Genes Affect Quality of Life Related to Radiation in Men with Prostate Cancer Orlando, FL—Novel candidate single nucleotide polymorphisms (SNPs) in genes that are associated with inflammation have been identified and will be explored further with regard to their role in long-term quality-of-life (QOL) effects of radiation in men with prostate cancer, according to new research presented at the 2013 Genitourinary Cancers Symposium. The investigators found 7 SNPs that were significantly associated with long-term QOL outcomes after radiation, but these SNPs did not retain statistical significance in a comparator group of men treated with radical prostatectomy.

“Men with prostate cancer have significant decrements in quality of life, which may be related to genetic differences. In particular, inflammationrelated genes may impact long-term toxicity following radiation therapy, including esophagitis and pneumonitis,” stated lead investigator Jonathan D. Schoenfeld, MD, MPH, a radiation oncology resident at Harvard Radia­ tion Oncology Program, Harvard Medi­cal School, Boston. “We have con­ firmed significant associations with SNPs and quality of life in men treated with radiotherapy, and these associations require prospective assessment

38

regarding their relationship to QOL.” The study was based on blood samples collected from men who were diagnosed with prostate cancer and were treated with radiation between 1982 and 2006. All men were enrolled in the prospective US Physicians’ Health Study (PHS), a randomized trial of aspirin and beta-carotene. Using the additive model, 43 SNPs in 10 inflammation-related genes (previously found to be associated with prostate cancer) were genotyped and analyzed.

A total of 264 men with confirmed cases of prostate cancer were given questionnaires at intervals between 2005 and 2007, at a median of 6 years after diagnosis. The questionnaires followed QOL outcomes about the symptoms that were experienced during the years since diagnosis and radiation, including decreased force of urinary stream, increased urinary frequency or urgency, rectal urgency, and impotence. In addition, medical records were obtained and reviewed.

The first cohort was specifically limited to men with nonmetastatic prostate cancer who were treated with definitive radiation. A second cohort of 337 men who were treated with definitive radical prostatectomy served

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Photo © ASCO/Todd Buchanan 2013

By Phoebe Starr

“Men with prostate cancer have significant decrements in quality of life, which may be related to genetic differences....We have confirmed significant associations with SNPs and quality of life in men treated with radiotherapy.”

—Jonathan D. Schoenfeld, MD, MPH as a comparison group.

“We limited excluded analysis to Caucasian men and excluded other races,” noted Dr Schoenfeld. The first cohort of 264 men (median age, 72 years) treated with radiation were predominantly low-risk patients. Of this cohort, 61% of the patients had Gleason scores of <7; 98% were in early clinical stage.

The investigators identified 13 SNPs that are significantly associated with

QOL. On multivariate analysis, 7 SNPs remained statistically significant and were found on the genes IL8 (1 SNP), NFKB (2 SNPs), RNase L (2 SNPs), CRP (1 SNP), and TLR 10 (1 SNP).

Between 20% and 29% of the patients reported severe urinary and rectal symptoms, and 72% reported severe impotence. Between 71% and 80% of the patients reported mild or nonexistent urinary and rectal symptoms, and 28% reported mild or nonexistent impotence.

In the second cohort of 337 men from the PHS who were treated with radical prostatectomy, 71% had Gleason scores of <7, and 95% were in early stage. The baseline characteristics and QOL results between the radiation and surgical patients were not comparable. Be­ tween 9% and 15% of the patients had urinary or rectal symptoms, and 82% had moderate-to-severe impotence.

“None of the 7 SNPs that were statistically significantly associated with the 4 parameters of QOL retained their statistical significance in men treated with radical prostatectomy,” Dr Schoenfeld pointed out. “The study is hypothesis generating. The mechanism of action of the selected genes is currently unknown. We performed incomplete sequencing of SNPs we tested.” n

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No. 3

Drug Update

Pomalidomide: A New Third-Generation Immunomodulatory Drug for Relapsed and/or Refractory Multiple Myeloma

By Lynne Lederman, PhD, Medical Writer

M

ultiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells that proliferate in the bone marrow, which typically produce large amounts of an abnormal immunoglobulin-like protein.1,2 The etiology of MM is unknown, but is associ­ ated with exposure to particular chemicals or to radiation and with being overweight or obese.3,4 MM is often preceded by monoclonal gammopathy of undetermined significance, an asymptomatic plasma-cell disorder, which may progress through asymptomatic smoldering MM before becoming symptomatic MM.2,5

The Burden of Myeloma Approximately 10% to 15% of all hematologic malignancies and 20% of deaths from hematologic cancers result from MM.2,5 The American Cancer Society estimates that in 2013, 22,350 Americans will be newly diagnosed with MM and 10,710 Americans will die from the disease.4 This represents an increase in the number of cases but not of deaths compared with in 2012.4,6 The frequent signs and symptoms of MM include fatigue, bone pain, osteolytic bone lesions, and/or compression fractures.7 Myeloma-related or­

Table 1

gan or tissue damage (eg, hyper­­­ calcemia, anemia, renal dysfunction, or bone lesions) is required to establish a diagnosis of symptomatic MM.1 The median survival for patients with MM has increased from <1 year before the introduction of alkylating agents in the 1960s, to almost 2 years after the development of high-dose chemotherapy and autologous stemcell transplant in the 1980s.2,8 Since approximately 2000, the development of novel, targeted thera­ pies, including the immunomodulatory drugs (IMiDs) thalidomide (Thal­ o­­­mid) and lenalidomide (Revlimid) and the proteasome inhibitor bortezomib (Velcade), have increased survival to a median of 5.4 years.8,9 However, a recent analysis shows that it is primarily patients aged >65 years who have benefited the most from novel agents, and there remains a need for additional new therapies for younger patients and to effect a cure.9 The Challenge of Relapsed, Refractory Myeloma Although MM may be initially sensitive to treatment, it remains incurable.2,8 MM almost always eventually relapses, the duration of remission

Registration Trial Results: Pomalidomide Alone and in Combination with Low-Dose Dexamethasone

Response ORR,b N (%)

95% CI for ORR, %

Complete response, N (%) Partial response, N (%) Duration of response Median, months

95% CI for DOR, months

Pomalidomidea (N = 108)

Pomalidomide plus low-dose dexamethasone (N = 113)

8 (7.4)

33 (29.2)

3.3-14.1

21.0-38.5

8 (7.4)

32 (28.3)

NE

7.4

0 (0.0)

NE

1 (0.9)

5.1-9.2

Results are before the addition of dexamethasone.

ORR = partial response plus complete response per European Group for Blood and Marrow Transplantation criteria.

CI indicates confidence interval; DOR, duration of response; NE, not established (the median has not yet been reached); ORR, overall response rate.

Source: Pomalyst (pomalidomide) capsules, for oral use. Prescribing information; February 2013. a

b

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shortens with each successive therapy,10 and it becomes more resistant to chemotherapy over time,2 indicating a need for additional salvage therapies.

The 2012 US Food and Drug Admin­ istration (FDA) accelerated approval of carfilzomib (Kyprolis), which is indicated for the treatment of relapsed and/or refractory MM, provides another treatment option,11 as does the continuing development of other antimyeloma agents.12

“I want to applaud the FDA. They moved very quickly with it, and they have been very proactive in meeting unmet medical needs.”

—Paul G. Richardson, MD

Pomalidomide: A Third-Generation Immunomodulatory Drug On February 8, 2013, the FDA approved pomalidomide (Pomalyst; Celgene Corporation), the most recent IMiD, for the treatment of patients with MM who have received at least 2 previous therapies, including lenalidomide and bortezomib, and have demonstrated disease progression within 60 days of the completion of the last therapy.12 The FDA accelerated the approval of pomalidomide based on a phase 2 clinical trial.

Value-Based Cancer Care discussed the FDA approval of pomalidomide with Paul G. Richardson, MD, Clinical Director, Jerome Lipper Center for Multiple Myeloma, and Professor of Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, who conducts clinical trials of pomalidomide, among other antimyeloma therapies.13-16 “I want to applaud the FDA. They moved very quickly with it, and they have been very proactive in meeting unmet medical needs,” said Dr Richardson. “Pomalidomide absolutely fills an unmet need for patients,” he emphasized. Of note, the approval is based on response rate, and any clinical benefit, such as increased survival or improvement of symptoms, has not been confirmed.17 Pomalidomide is an analog of tha-

lidomide and is the third agent in the immunomodulatory class that includes thalidomide and lenalidomide.12 Although thalidomide, particularly when combined with dex­ a­­ methasone, is very active against MM, it is associated with dose-limiting adverse effects, including somnolence, constipation, neuropathy, and thromboembolic events. Derivatives of thalidomide, including lenalidomide and pomalidomide, have been developed that have their own safety and efficacy profiles.

Like lenalidomide, pomalidomide is thought to act directly on myeloma cell adhesion and by decreasing factors that are required for myeloma cell survival, leading to cell death, and indirectly by modulating cells in the bone marrow microenvironment.18 According to Dr Richardson, for patients with MM whose disease is resistant to lenalidomide and to bortezomib, the orally available and generally well-tolerated pomalidomide provides a major step forward.

Phase 2 Registration Trial Results The FDA accelerated the approval of pomalidomide based on the results of an open-label, randomized phase 2 clinical trial that included 221 patients with relapsed MM refractory to the last therapy and who had received at least lenalidomide and bortezomib. Response rate was the primary objective.12,19 The patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone (pomalidomide 4 mg once daily for 21 of 28 days plus low-dose dexamethasone 40 mg daily for patients aged ≤75 years or 20 mg daily for patients aged ≥75 years on days 1, 8, 15, and 22 of each 28-day cycle; N = 113) or pomalidomide alone (N = 108) until disease progression.

Patients in the pomalidomide alone arm were allowed to add lowdose dexamethasone on disease progression.

For the efficacy analysis, 221 patients were evaluable for response; 219 patients were evaluable for safety, including 112 patients who received pomalidomide plus low-dose dexamethasone and 107 patients who received pomalidomide alone. Of those 107 patients, 61 had low-dose dexamethasone added during the treatment period.

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Drug Update

The overall response rate was 7.4% in the pomalidomide arm and 29.2% in the arm receiving pomalidomide plus low-dose dexamethasone (Table 1). The duration of response was 7.4 months in the arm receiving pomalidomide plus low-dose dexamethasone, and it was not reached in the pomalidomide-alone arm.17 Dosing Pomalidomide is administered orally at a starting dose of 4 mg once daily on days 1 to 21 of each 28-day cycle.

The cycles are repeated until disease progression. Pomalidomide capsules should be swallowed whole, with water, at least 2 hours before or 2 hours after a meal, and should not be taken with food.

Dexamethasone may be used in combination with pomalidomide, for example, at the doses administered in the registration phase 2 trial.

Important Safety Information for Pomalidomide The prescribing information for pomalidomide contains a Boxed Warning about serious adverse events that may occur with this drug, including17: • Pomalidomide is contraindicated in pregnancy, because it is an analog of the teratogen thalidomide, which can cause life-threatening birth defects. For women of childbearing age, pregnancy must be excluded before treatment, and pregnancy must be prevented during treatment by the use of 2 reliable contraceptive methods • Deep-vein thrombosis (DVT) and pulmonary embolism (PE) can occur in patients with MM who are treated with pomalidomide • Pomalidomide is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.

Although patients in the pomalidomide registration trial received mandated prophylaxis or antithrombotic agents (either aspirin [81%], heparin [21%], warfarin [16%], or clopidogrel [3%]), 3% of patients developed venous thromboembolism.17 Therefore, the risk for DVT and PE should be evaluated for each patient to decide on the use of prophylaxis against thrombolic events.17,20 Patients treated with pomalidomide should be monitored for hematologic toxicities, particularly neutropenia, which was the most frequent grade 3 or 4 adverse event reported (43% of

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Table 2

Clinically Important Adverse Reactions and Drug Interactions Associated with Pomalidomide

Adverse reaction/drug interaction

Comments

References

Dizziness

18% of patients (1% grade 3 or 4)

Neuropathy

18% neuropathy; 9% peripheral neuropathy

Confusional state Drugs that may increase pomalidomide plasma concentrations Drugs that may decrease pomalidomide plasma concentrations Cigarette smoking

12% of patients (3% grade 3 or 4)

CYP3A, CYP1A2, or P-gp inhibitors: coadministration of pomalidomide with drugs that are strong inhibitors of CYP1A2, CYP3A (eg, ketoconazole), or P-gp could increase exposure and should be avoided CYP3A, CYP1A2, or P-gp inducers: coadministration of pomalidomide with drugs that are strong inducers of CYP1A2, CYP3A (eg, rifampin), or P-gp could decrease exposure and should be avoided

May reduce pomalidomide exposure as a result of CYP1A2 induction and reduce the efficacy of pomalidomide

CY indicates cytochrome; P-gp, permeability glycoprotein.

Source: Pomalyst (pomalidomide) capsules, for oral use. Prescribing infor­ mation; February 2013. patients). The pomalidomide dose may be modified depending on the degree of neutropenia or thrombocytopenia.17 Other clinically significant adverse reactions and drug interactions are listed in Table 2.

“Pomalidomide is the most potent immunomodulatory drug we have tested so far….Because it is able to achieve a response in about a third of patients who are both resistant to lenalidomide and bortezomib, it has provided a major step forward and an excellent choice after lenalidomide and bortezomib fail.”

—Paul G. Richardson, MD

Restricted Distribution Program Because of the potential for embryonic and fetal toxicities, pomalidomide will only be available in the United States through a restricted dis-

tribution program called the Pomalyst REMS program.17,20 The Pomalyst REMS program requires that all patients be enrolled and agree to comply with its requirements before they can receive pomalidomide, both as an initial prescription and at each subsequent prescription refill. In addition, only certified prescribers can prescribe pomalidomide, and only certified pharmacies can dispense pomalidomide.20 Conclusions The FDA approval of pomalidomide adds a new treatment option for patients with myeloma whose disease has relapsed after treatment with other drugs or has developed resistance to the other options.

In his discussion with Value-Based Cancer Care, Dr Richardson said that “pomalidomide is the most potent immunomodulatory drug we have tested so far. Its efficacy is reflected by the fact that it is able to overcome resistance to both lenalidomide and bortezomib. Because it is able to achieve a response in about a third of patients who are both resistant to lenalidomide and bortezomib, it has provided a major step forward and an excellent choice after lenalidomide and bor­ tezomib fail.” Pomalidomide works very well with dexamethasone, as currently indicated, and it also “partners well” with other agents, includ-

MARCH 2013

ing bortezomib or carfilzomib.

Combination trials with pomalidomide are ongoing, and the results for efficacy and safety are promising. n

I

1. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol.

2003;121:749-757.

2. Laubach J, Richardson P, Anderson K. Multiple myeloma. Annu Rev Med. 2011;62:249-264.

3. American Cancer Society. Multiple myeloma overview. 2013. www.cancer.org/acs/groups/cid/docu ments/webcontent/003065-pdf.pdf. Accessed Febru­ ary 28, 2013.

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

5. Kyle RA, Rajkumar SV. Multiple myeloma. Blood.

2008;111:2962-2972.

6. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.

7. Rajkumar SV. Multiple myeloma. Curr Probl Cancer.

2009;33:7-64.

8. Kumar SK, Rajkumar SV, Dispenzieri A, et al.

Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-2520.

9. Kumar S, Dispenzieri A, Gertz MA, et al. Continued improvement in survival in multiple myeloma and the impact of novel agents. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 3972.

10. Rajkumar SV. Multiple myeloma: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. 2012;87:78-88.

11. Food and Drug Administration Drug Approvals and Databases. Carfilzomib. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm312945. htm. Accessed July 21, 2012.

12. FDA News Release. FDA approves Pomalyst for advanced multiple myeloma. Press release. February 8, 2013. www.fda.gov/NewsEvents/Newsroom/Press Announcements/ucm338895.htm. Accessed Febru­ary 12, 2013.

13. Richardson PG, Siegel D, Baz R, et al. Phase I study of pomalidomide MTD, safety and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2012 Dec 14 [Epub ahead of print].

14. Richardson PG, Jakubowiak A, Bahlis NJ, et al.

Treatment outcomes with pomalidomide (POM) in combination with low-dose dexamethasone (LoDex) in patients with relapsed and refractory multiple myeloma (RRMM) and Del(17p13) and/or t(4;14)(p16;q32) cytogenetic abnormalities who have received prior therapy with lenalidomide (LEN) and bortezomib (BORT). Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 4053.

15. Vij R, Richardson PG, Jagannath S, et al.

Pomalidomide with or without low-dose dexamethasone in patients with relapsed/refractory multiple myeloma: outcomes in patients refractory to lenalidomide and bortezomib. J Clin Oncol. 2012;30 (suppl):Abstract 8016.

16. Vij R, Hofmeister CC, Richardson PG, et al.

Pomalidomide (POM) with low-dose dexamethasone (LoDEX) in patients with relapsed and refractory multiple myeloma (RRMM): outcomes based on prior treatment exposure. Blood (ASH Annual Meeting Abstracts). 2012;120:Abstract 4070.

17. Pomalyst (pomalidomide) capsules, for oral use.

Prescribing information. Summit, NJ: Celgene Cor­ pora­tion; February 2013.

18. Latif T, Chauhan N, Khan R, et al. Thalidomide and its analogues in the treatment of multiple myeloma.

Exp Hematol Oncol. 2012;1:27-34.

19. Celgene Corporation. U.S. Food and Drug Administration approves Pomalyst (pomalidomide) for the treatment of patients with relapsed and refractory multiple myeloma. Press release. February 8, 2013.www.businesswire.com/news/home/ 20130208005889/en/U.S.-Food-Drug- AdministrationApproves-POMALYST%C2%AE-pomalidomide.

Accessed March 1, 2013.

20. Celgene Corporation. Prescriber guide to Pomalyst REMS. 2013. www.pomalystrems.com/pdf/POM_ Prescriber_Guide_2_6_13.pdf. Accessed February 28, 2013.

www.ValueBasedCancerCare.com

41

In the Literature Screening Colonoscopy Reduces the Risk...

Continued from page 30

py and the potential risks associated with this procedure, colonoscopy is rapidly replacing sigmoidoscopy and FOBT in the United States as the standard screening test for CRC. It is therefore important to better understand the ability of colonoscopy to diagnose incident CRC in low- or average-risk

persons. Late diagnosis is associated with increased risk for death from this disease.

A new case-control study investigated the link between screening colonoscopy and the risk for incident latestage CRC in persons at average risk for CRC (Doubeni CA, et al. Ann Intern Med. 2013;158:312-320). The study included a total of 1039 adults at average risk for CRC (aged 55-85 years) who were enrolled at a health plan for at

least 5 years. Persons with a history of total colectomy, a history of inflammatory bowel disease, or a strong family history of CRC were excluded from the study.

Of the 1039 enrolled persons, 498 patients (24 were excluded from the final analysis) were diagnosed with incident primary late-stage CRC between 2006 and 2008; the control group included 541 persons with no CRC diagnosis (3 of them were ex-

cluded from the final analysis). Of the final 474 case patients, 38 had stage IIB tumor, 279 had stage III tumor, and 157 had stage IV cancer; of these, 251 were right colon cancer, 206 were left colon cancer, and 17 had no specific location. Of the case patients, 13 (2.8%) had undergone screening colonoscopy compared with 46 (9%) in the control group, which corresponds to an adjusted odds ratio (OR) of 0.29 (95% CI, 0.15-0.58) for any late-stage CRC, 0.36 (95% CI, 0.16-0.80) for right colon cancer, and 0.26 (95% CI, 0.06-1.11; P = .069) for left colon/rectal cancer.

Furthermore, 92 (19.5%) case patients and 173 (34%) controls had screening sigmoidoscopy, which corresponds to an adjusted OR of 0.50 overall, 0.79 for late-stage right colon cancer, and 0.26 for left colon cancer.

These results indicate that colonoscopy screening is associated with a reduced risk of diagnosis of incident late-stage CRC, including right-sided colon cancer, in average-risk persons.

A significantly reduced risk for latestage left CRC is also seen with sigmoidoscopy, but not for late-stage right colon cancer.

This study confirms that the use of screening colonoscopy is associated with a significant reduction in the risk of diagnosis of late-stage incident CRC. n

The Burden of Colorectal Cancer Colorectal cancer (CRC) is the third most common cancer among men and women in the United States, which highlights the need for early diagnosis and treatment of CRC. Late diagnosis of this type of cancer is a main cause of CRCrelated mortality.

When looking at men and women separately, CRC is the third most common cause of cancer-related death among US men and among US women.

However, when combining cancer-related deaths in men and women as 1 group in the United States, CRC rises to the second most common cause of death among all types of cancer.

In 2013, an estimated 143,000 adults in the United States will be diagnosed with CRC. This number includes more than 103,000 new cases of colon cancer and more than 40,000 new cases of rectal cancer. In addition, it is estimated that more than 51,000 patients will die of CRCâ&#x20AC;&#x201D;colon and rectal cancers combinedâ&#x20AC;&#x201D;in the United States in 2013.

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2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

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

TM

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

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

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

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

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

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

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

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

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

www.CutaneousMalignancies.com

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

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

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

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

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

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

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

BREAK

1:15 pm – 4:30 pm

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

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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

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

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

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

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

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

BREAK

1:15 pm – 2:45 pm

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

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

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That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: • Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

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