VBCC November 2013

NOVEMber 2013 VOL 4 NO 9

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com ASCO Quality Care Symposium

Need for Innovative Strategies for Quality Care Will Continue to Grow Oncology reimbursement requires new approaches, says Lee Newcomer

By Charles Bankhead

Such an impossible situation will mean that providers at every level will have to get by with less. “No one will be exempt from having less money available to take care of even more patients,” said Dr Newcomer.

“It won’t matter whether you’re a Continued on page 13

Bronchial/Nasal Gene-Expression Tests for Early Detection of Lung Cancer Novel assay expected in 2014 using bronchial airway biomarker

By Wayne Kuznar Boston, MA—Diagnosing lung cancer by swabbing a patient’s nose may be possible in the not-too-distant future. Changes in nasal gene expression in patients with lung cancer have been found to correlate with changes in gene expression in the bronchus, opening the door to the possi©2013 Engage Healthcare Communications, LLC

Funding healthcare is crucial to improving cancer outcomes

By Audrey Andrews Amsterdam, The Netherlands—The more a European Union (EU) country spends on health, the fewer the cancer-related deaths occur in that country, and there is a great disparity between Western and Eastern EU countries, according to research presented at the 2013 European Cancer Congress.

Greater wealth and higher health expenditures were strongly associ-

San Diego, CA—Current economic trends mandate the development of innovative strategies to affect quality and efficiency in cancer care, applying the same rigor as used in clinical trials, according to Lee N. Newcomer, MD, MHA, Senior Vice President, UnitedHealthcare, who addressed cost issues and barriers in provider reimbursement at the 2013 ASCO Quality Care Symposium.

Less Money for Patient Care Within 2 to 3 years, consumers’ out-of-pocket costs will consume half of the average household income, Dr Newcomer said. Another 10 or 15 years down the road, healthcare costs will require the entire household income, according to a study published in 2012 (Young RA, et al.

Ann Fam Med. 2012;10:156-162).

Health Disparities in Oncology: Western Europe Spends More, Achieves Better Patient Survival Outcomes than Eastern Europe

bility of nasal gene expression as an early diagnostic biomarker of lung cancer, said Avrum Spira, MD, MSc, Director, Translational Bioinformatics Program, Boston University Clinical and Translational Science Institute.

“What’s in the nose may be a very

Continued on page 41

ated with decreased cancer mortality, as well as with increased cancer incidence, according to Felipe Ades, MD, a member of the Breast European Adjuvant Studies Team (BrEAST), a clinical trials unit and data center in Belgium.

The higher cancer incidence in Western Europe, and lower death rates, Continued on page 19

Rising Costs of Cancer Survivorship a Growing Concern First national analysis of survival-related medical costs and lost productivity

By Neil Canavan

Gery P. Guy, Jr, PhD, MPH

S

urvival is not cheap. In fact, according to the results of a new study, cancer survivors have ongoing annual medical expenditures averaging

$17,000 per patient in the first year after diagnosis, or $6400 per patient at least 1 year postdiagnosis (Guy GP Jr, Continued on page 27

inside FDA UPDATE . . . . . . . . . . . . . . . . . .

Gazyva approved for CLL Imbruvica approved for MCL

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FROM THE EDITOR . . . . . . . . . . . .

The cost-of-end of life care

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VALUE PROPOSITIONS . . . . . . . . . 7 1-dose HPV vaccine protective, saves costs

PERSONALIZED MEDICINE . . . . . 42 Benefits of next-generation sequencing DRUG UPDATE . . . . . . . . . . . . . . . 44 Gilotrif for NSCLC and EGFR mutation OVARIAN CANCER . . . . . . . . . . . . 48 Oral VEGF inhibitor improves survival

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VALUE-BASED CARE . . . . . . . . . .

10 steps to achieving value at Mayo Clinic

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ECONOMICS OF CANCER CARE . .18 Cost-effective strategy for NSCLC

CONTINUING EDUCATION . . . . . .

Advances in the treatment of CML

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QUALITY CARE SYMPOSIUM . . .

Integrating PROs into cancer care

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

NOW AVAILABLE

GRANIX is a new option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines.

The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com.

Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

©2013 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. FIL-40190 October 2013.

FDA Update Gazyva, First Breakthrough Therapy to Receive FDA Approval, Indicated for Chronic Lymphocytic Leukemia

Using its priority review pathway, the US Food and Drug Administration (FDA) approved the monoclonal

antibody obinutuzumab (Gazyva; Genentech) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have not previously received treatment for CLL. Obinutuzumab is approved to be used in combination with chlorambucil.

Obinutuzumab, which works by

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture.

5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain.

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

GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92).

In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a nonUS-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the

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DIGITAL

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helping immune system cells to attack cancer cells, is the first drug with a “breakthrough therapy” designation to receive FDA approval; other breakthrough therapies are currently under FDA review for different types of cancers.

“Today’s approval represents an

recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product).

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined.

7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed.

Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day.

8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates.

8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established.

8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients.

8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment.

8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment.

10 OVERDOSAGE No case of overdose has been reported.

©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved.

GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Sicor Biotech UAB Vilnius, Lithuania U.S. License No. 1803 Distributed by: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Product of Israel FIL-40045 July 2013 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

NOVEMber 2013

CMYK Vers

important new addition to the treatments for patients with CLL,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval reflects the promise of the Breakthrough Therapy Designation program, allowing us to work collaboratively with companies to expedite the development, review and availability of important new drugs.”

Obinutuzumab also has an orphan drug designation, because CLL is categorized as a rare disease. According to the National Cancer Institute, 15,680 Americans are expected to be diagnosed with CLL in 2013 and 4580 will die from it.

Obinutuzumab’s approval was based on an open-label multicenter trial of 356 treatment-naïve patients with CLL who were randomized to obinutuzumab in combination with chlorambucil or to chlorambucil alone. The combination of obinutuzumab plus chlorambucil demonstrated a significant, 2-fold improvement in progression-free survival compared with chlorambucil alone, for an average of 23 months with the combination versus 11.1 months in the monotherapy cohort.

The most common adverse events in patients receiving obinutuzumab were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain, and fever.

Gazyva was approved with a boxed warning regarding the risk for hepatitis B virus (HBV) reactivation and progressive multifocal leukoencephalopathy, a rare brain disorder; these are known risks with other monoclonal antibodies. Patients should be advised of these risks and be assessed for HBV risk and reactivation risk. (November 1, 2013)

Imbruvica, Second Breakthrough Therapy Drug, Gets FDA Approval for Mantle-Cell Lymphoma

A few days after the first drug with a breakthrough therapy designation was approved by the US Food and Drug Administration (FDA), ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech)—the second drug with such a designation—received an accelerated FDA approval for the treatment of patients with mantle-cell lymphoma (MCL), a rare form of non-Hodgkin lymphoma (NHL). MCL represents approximately 6% of all cases of NHL in the United States.

This aggressive type of cancer is usually diagnosed when it has already spread to the lymph nodes, bone marrow, and other organs.

Ibrutinib is an oral Bruton’s tyrosine

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From the Editor

The Cost of End-of-Life Care in Oncology

By Craig Deligdish, MD

Hematologist/Oncologist, Oncology Resource Networks, Orlando, FL, and Editor-in-Chief, Value-Based Cancer Care

T

he recent Institute of Medicine report “Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis” addressed the important issues of delivering high-quality cancer care, including end-of-life care.1 Given that for many patients cancer can be a terminal illness, the cost of end-of-life care in oncology has recently been a significant focus for public and private payers.

Communication and shared decision-making are important components of high-quality cancer care. The adoption of advance care directives, palliative care, and hospice care as necessary components of end-of-life care is crucial, and can help to address the medical and psychosocial needs of patients, caregivers, and their families.

For more than 30 years, the costs associated with dying have been recognized as significant components of the overall healthcare spending. Medical care at the end of life may be responsible for as much as 20% of the overall Medicare budget.2 Despite efforts to address these costs, the expenses associated with the treatment of cancer at the end of life are significant. There are concerns that patients with cancer are hospitalized and visit emergency departments at a higher frequency than is necessary, and that many of these visits are avoidable. Many members of the healthcare and payer communities believe that the expenditures associated with end-of-life care are at times unnecessary, because some of the treatments that are administered to patients with cancer at the end of life may be futile. For example, patients

with poor performance status are less likely to respond to chemotherapy.

Many also believe that hospitalization in an intensive care unit (ICU) is inappropriate for patients with cancer, yet a recent brief from the Dartmouth Atlas reported that 28.8% of Medicare beneficiaries with cancer are hospitalized in an ICU during the last month of life.3 Furthermore, this brief reported that in 2010, 24.7% of Medicare beneficiaries with cancer died in the hospital.3 Despite the ongoing efforts to educate physicians, providers, and patients about hospice care, some still believe that end-of-life care, specifically hospice care, is underutilized.

Although several studies have demonstrated significant decreases in the cost of care at the end of life as a result of advanced illness programs and hospice care, other reports suggest that hospice care may be overutilized and is more costly than is necessary.

A 2010 study by Jennifer Temel, MD, and colleagues published in the New England Journal of Medicine demonstrated that early palliative care for patients with metastatic non–smallcell lung cancer (NSCLC) improved the quality of life and the survival of patients who were studied.4 In a subsequent publication, early palliative care administered to patients with metastatic NSCLC was shown to lower hospital utilization, by reducing inpatient visits and chemother­ apy administration at the end of life.5 The mean cost-savings was $2282 per patient compared with a cohort of patients that did not receive early palliative care.5 This study was performed at a single tertiary care center, with access to palliative care physicians, who are not typically available in many community hospitals or practices.5 A

number of studies, however, have suggested that the cost-savings reported in palliative care settings may be a function of one’s proximity to death.6 Despite the focus of end-of-life care, specifically hospice care, there are concerns that this focus has led to a boom in hospice care. Today, numerous for-profit and not-for-profit hospices exist, and the number of patients in hospice care has increased 10-fold in the past decade. In the same period, the number of hospices has increased by more than 50%.

The goals of hospice care include assisting terminally ill patients and supporting the families of terminally ill patients and other caregivers throughout the end-of-life process. In 1989, Medicare paid only $205 million for hospice care, but by 2011, Medicare paid $13.7 billion to cover 1.2 million beneficiaries. Of this money spent, Medicare paid an excess of $1.1 billion for inpatient hospice care.

The Affordable Care Act (ACA) requires the Centers for Medicare & Medicaid Services (CMS) to reform the hospice payment system. The ACA also requires CMS to develop quality measures for hospices, and requires hospices to report quality data. CMS is currently using 2 quality measures— one related to pain management, and a second related to the way hospices track patient care.7 During the past decade, an increasing number of hospices have been alleged to have submitted false claims to the federal government.8 In 2011, an article in Bloomberg reported that there were multiple pending or settled lawsuits against hospice companies that provided enrollment-based incentives that had led to admitting patients who did not qualify for hospice care.9 In 2009, a report from the Office

of Inspector General about Medicare claims for hospice patients living in nursing homes found that as many as 82% of such claims failed to meet Medicare requirements.10 As the oncology community faces further pressure to reduce the cost of care, improve the quality of care, and, ultimately, improve the value of cancer care and end-of-life care, it will be important to better define quality parameters and the appropriate costs for palliative care and hospice care, as necessary components of end-of-life care. n References

1. Institute of Medicine. Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis. September 10, 2013. www.iom.edu/ reports/2013/delivering-high-quality-cancer-carecharting-a-new-course-for-a-system-in-crisis.aspx.

Accessed November 13, 2013.

2. Emanuel EJ, Emanuel LL. The economics of dying.

The illusion of cost savings at the end of life. N Engl J Med. 1994;330:540-544.

3. Goodman DC, Morden NE, Chang CH, et al. Trends in cancer care near the end of life: a Dartmouth Atlas of Health Care brief. September 4, 2013. www. dartmouthatlas.org/downloads/reports/Cancer_ brief_090413.pdf. Accessed November 13, 2013.

4. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742.

5. Greer JA, McMahon PM, Tramontano A, et al. Effect of early palliative care on health care costs in patients with metastatic NSCLC. J Clin Oncol. 2012;30(suppl).

Abstract 6004.

6. Chochinov HM, Kristjanson L. Dying to pay: the cost of end-of-life care. J Palliat Care. 1998;14:5-15.

7. Medicare Payment Advisory Commission. Report to the Congress: Medicare Payment Policy. March 2012. www.medpac.gov/documents/Mar12_EntireReport. pdf. Accessed November 13, 2013.

8. Frantz D. Hospice boom is giving rise to new fraud. New York Times. May 10, 1998. www.nytimes. com/1998/05/10/us/hospice-boom-is-giving-rise-tonew-fraud.html?pagewanted=all&src=pm. Accessed November 13, 2013.

9. Waldman P. Aunt Midge not dying in hospice reveals $14B market. Bloomberg. December 6, 2011. www.bloomberg.com/news/2011-12-06/hospicecare-revealed-as-14-billion-u-s-market.html. Accessed November 13, 2013.

10. Office of Inspector General. Semiannual Report to Congress, April 1, 2009-September 30, 2009. Fall 2009. https://oig.hhs.gov/publications/docs/semiannal/ 2009/semiannual_fall2009.pdf. Accessed Novem­ ber 13, 2013.

FDA Update Imbruvica, Second...

kinase inhibitor that blocks the acti­ vity of malignant B-cells.

Ibrutinib is indicated for use in patients with MCL who have received at least 1 previous therapy with bortez­ omib (Velcade) or with lenalidomide (Revlimid), the only 2 other drugs approved by the FDA for the treatment of patients with MCL. Ibrutinib was approved under the FDA’s priority review path, and has received an orphan drug designation,

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by demonstrating its safety and efficacy in the treatment of MCL, which is considered a rare disease.

“Imbruvica’s approval demonstrates the FDA’s commitment to making treatments available to patients with rare diseases,” said Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

The FDA’s accelerated approval of ibrutinib for MCL was based on a mul-

ticenter, single-arm trial of 111 patients who were previously treated for MCL; they received ibrutinib therapy daily until their disease progressed or their side effects became intolerable.

The results showed an overall response rate of 65.8% (95% confidence interval, 56.2-74.5); of these, 17% of the patients achieved complete response and 49% achieved partial response.

The median duration of response was 17.5 months. The trial did not demonstrate an improvement in overall sur-

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vival or in MCL-related symptoms.

The most common side effects reported included thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, edema, upper respiratory infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, and reduced appetite. Other clinically significant side effects include bleeding, infections, kidney problems, and the risk for developing other types of cancers. n

www.ValueBasedCancerCare.com

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In This Issue FDA UPDATE

Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 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.

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

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Value-Based Cancer Care

3RD CONFERENCE

Gazyva approved for chronic lymphocytic leukemia More…

Surveys emphasize oncology practice challenges More…

FROM THE EDITOR

Barriers to personalized medicine in oncology More…

PERSONALIZED MEDICINE

The cost of end-of-life care in oncology

IN THE LITERATURE

Gemcitabine increases survival in resected pancreatic cancer More…

ASCO QUALITY CARE SYMPOSIUM

Integrating patient-reported outcomes into cancer care Development of quality measures should address current limitations More…

ECONOMICS OF CANCER CARE

New study warns of rising costs of cancer survivorship Can FDA approval keep pace with current research?

More…

DRUG UPDATE

Gilotrif for NSCLC and EGFR mutation

RADIOTHERAPY IN FOCUS

Expanded radiotherapy improves breast cancer control More…

OVARIAN CANCER

Oral VEGF inhibitor improves survival

VALUE-BASED CARE

10 steps to achieving value at Mayo Clinic More…

CONTINUING EDUCATION

Advances in the treatment of CML

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Linda D. Bosserman, MD, FACP President, Wilshire Oncology Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

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

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

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

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

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

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

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

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

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

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

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

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

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

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

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

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

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 John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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

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

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NOVEMber 2013

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No. 9

Advance Care Planning

VALUE PROPOSITIONS New Technique Selectively Enables Cancer Drugs to Target Malignant Cells while Sparing Healthy Cells

Researchers led by Nobuhide Ueki, PhD, Assistant Research Profes­ sor, Department of Molecular Genetics & Microbiology, Stony Brook University, have found a new way to get targeted cancer drugs to selectively affect only the cancer cells of a patient and not the healthy cells that are also normally affected by the drug (and cause its toxicity), thereby removing many of the potential side effects of the drugs, which would of course greatly enhance the value of cancer drugs.

Dr Ueki and his Stony Brook team found a way to selectively target cancer cells with prodrugs (ie, precursors of the target drug) that are activated by 2 enzymes, histone deacetylase (HDAC) and a protease called cathepsin L (CTSL). The HDAC and CTSL enzymes have proved to increase their activity in cancer cells, becoming a potential goal for a selective targeted therapy to kill cancer cells.

“We wondered if we could develop drugs to target those 2 enzymes to make a better anticancer drug,” Dr Ueki said. They tested this approach by adding puromycin to HDAC and CTSL, thereby creating a masked cytotoxic agent, which then selectively kills cancer cell lines with the enhanced activity of HDAC and CTSL. “This cancer-selective cleavage of the masking group is a promising strategy for the next generation of anticancer drug development, and could be applied to many other cytotoxic agents,” Dr Ueki said.

He hopes that this technique could help pharmaceutical companies to continue the development of drugs that were previously discontinued because of their severe toxicities. If drug companies “can use this technique, they might be able to use their drug again. The more new drugs are developed, the more chances of successful treatment are increased.

That’s our purpose.” The results of this study were recently published (Ueki N, et al. Nat Commun. 2013;4:2735). The study was funded by the National Cancer Institute and the Stony Brook Institute for Clinical and Translational Sciences. Stony Brook University; November 4, 2013

1-Dose HPV Vaccine Sufficient to Protect from Cervical Cancer, Save Costs

A simplified administration schedule of only 1 dose, instead of the current standard of 3 doses, of the human papillomavirus (HPV) vaccine appears to be all women need to be protected from cervical cancer, according to new data from a study funded by the National Cancer Institute (NCI) and recently published (Safaeian M, et al. Cancer Prev Res [Phila]. 2013;6:1242-1250).

“The latest Morbidity and Mortality Weekly Report from the Centers for Disease Control and Prevention on vaccination coverage indicates that in 2012, only 53.8% of girls between 13 and 17 years old initiated HPV vaccination, and only 33.4% of them received all 3 doses,” said Mahboobeh Safaeian, PhD, Division of Cancer Epidemiology and Genetics at NCI. “We wanted to evaluate whether 2 doses, or even 1 dose, of the HPV 16/18 L1 VLP vaccine [Cervarix] could induce a robust and sustainable response by the immune system.”

In their study, Dr Safaeian and her team found that 100% of the women who received 1, 2, or 3 doses of the HPV vaccine (Cervarix) had antibodies in their blood against HPV 16 and HPV 18 for up to 4 years, regardless of the dosing schedule.

“We found that both HPV 16 and HPV 18 antibody levels in women who received one dose remained stable 4 years after vaccination. Our findings challenge previous dogma that protein subunit vaccines require multiple doses to generate long-lived responses,” Dr Safaeian said.

In addition, the team found that although antibody levels were lower among women who received only 1 dose of the vaccine than in women who received the 3 doses, the antibody levels were stable in the former cohort, suggesting that these responses endure and can provide sufficient protection. These findings may change the practice of HPV vaccination, according to Dr Safaeian.

“Our findings suggest promise for simplified vaccine administration

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schedules that might be cheaper, simpler, and more likely to be implemented around the world,” said Dr Safaeian. “Vaccination with 2 doses, or even 1 dose, could simplify the logistics and reduce the cost of vaccination, which could be especially important in the developing world, where more than 85% of cervical cancers occur, and where cervical cancer is one of the most common causes of cancer-related deaths,” she predicted.

American Association for Cancer Research; November 4, 2013

Translating Cancer Genetics into Patient Care Focus of New Joint Center for Precision Medicine

A new collaborative initiative among Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Boston Children’s Hospital, and the Broad Institute of MIT and Harvard has been established to create treatment pathways based on precision (or personalized) medicine for patients with advanced cancer and to try to accelerate the development of personalized therapies.

“This center will allow us to be optimally positioned to answer the big questions in cancer genetics, especially as they affect clinical decision-making,” said Levi Garraway, MD, PhD, Associate Professor of Medicine at Dana-Farber and the Joint Center’s Director. “We seek to understand which genetic and other molecular alterations predict how tumors will respond to targeted drugs, why some patients become resistant to drugs, and what that means about the treatments that should be tried next.”

The mission of the Joint Center “is to accelerate the development of personalized therapies that achieve long-term disease control and, eventually, the cure of many patients with advanced cancer,” Dr Garraway said. Acknowledging the substantial expertise within these 4 institutions, the heads of these institutions reflected on this new effort to speed up the integration of personalized medicine into patient care.

Edward Benz, Jr, MD, President of Dana-Farber, said, “The center is creat­ ing a new capability to use these huge resources in sequencing and pathology and making sure the data gets to caregivers to help customize treatment.”

“This exciting collaboration will allow the life-giving breakthrough of advanced genetic analysis of cancer to be translated into clinical care,” said Betsy Nabel, MD, President of Brigham and Women’s Hospital.

“Patients will benefit from having the latest genetic discoveries applied to an individual treatment plan,” she added.

“This is an extraordinary moment,” said Eric Lander, PhD, President and Director of the Broad Institute. “By learning from genomic information obtained in the course of clinical care of patients, this remarkable new center will be poised to make critical discoveries, and to ensure that those discoveries get translated back to the clinic.”

Neal Lindeman, MD, Director of the Center for Advanced Molecular Diagnostics at Brigham and Women’s Hospital, added, “This information can be used to design treatments that are more effective from the beginning and can be used to anticipate the changes each cancer will make during treatment.” Dana-Farber Cancer Institute; November 12, 2013

Empire Genomics to Launch New CLIA-Approved Tests in 2014 for Myeloma, Prostate Cancer

Empire Genomics, an emerging molecular diagnostics company focused on cancer diagnostics, has recently received approval from the New York State Department of Health for its diagnostic test facility. In addition, its laboratory has received the Clinical Laboratory Improvements Amendments (CLIA) certification from the Centers for Medicaid & Medicare Services.

“This permits our expansion of complete genomic testing services to our clients,” said Anthony Johnson, President and CEO of Empire Genomics. The company is launching a full-service CLIA-certified laboratory for tests and companion diagnostics in oncology, and will start to offer 2 new biomarker tests for myeloma and for prostate cancer in 2014.

Empire Genomics; November 12, 2013

NOVEMber 2013

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www.ValueBasedCancerCare.com

7

NOW INDICATED

ABRAXANE® is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas (mPAC), in combination with gemcitabine.

ignite survival in first-line mPAC Important Safety Information WARNING - NEUTROPENIA • Do not administer ABRAXANE therapy to

patients who have baseline neutrophil counts of less than 1500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE

• Note: An albumin form of paclitaxel may

substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS

CONTRAINDICATIONS Neutrophil Counts • ABRAXANE should not be used in patients who have baseline neutrophil counts of <1500 cells/mm3 Hypersensitivity • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug WARNINGS AND PRECAUTIONS Hematologic Effects • Bone marrow suppression (primarily neutropenia) is dosedependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer • Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 for pancreatic cancer

• Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1500 cells/mm3 • In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended Nervous System • Sensory neuropathy is dose- and schedule-dependent • The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification • If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 followed by a dose reduction for all subsequent courses of ABRAXANE Sepsis • Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine • Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis • If a patient becomes febrile (regardless of ANC), initiate treatment with broad-spectrum antibiotics • For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥1500 cells/mm3, then resume treatment at reduced dose levels Pneumonitis • Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine • Monitor patients for signs and symptoms and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis

• Permanently discontinue treatment with ABRAXANE and gemcitabine upon making a diagnosis of pneumonitis Hypersensitivity • Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported • Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug Hepatic Impairment • Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution • For pancreatic adenocarcinoma, ABRAXANE is not recommended for patients with moderate or severe hepatic impairment Albumin (Human) • ABRAXANE contains albumin (human), a derivative of human blood Use in Pregnancy: Pregnancy Category D • ABRAXANE can cause fetal harm when administered to a pregnant woman • If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus • Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE Use in Men • Men should be advised not to father a child while receiving ABRAXANE ADVERSE REACTIONS • Among the most common (≥20%) adverse reactions in the phase III study, those with a ≥5% higher incidence in the ABRAXANE/gemcitabine group compared with the gemcitabine group are neutropenia (73%, 58%), fatigue (59%, 46%), peripheral neuropathy (54%, 13%), nausea (54%, 48%), alopecia (50%, 5%), peripheral edema (46%, 30%), diarrhea (44%, 24%), pyrexia (41%, 28%), vomiting (36%, 28%), decreased appetite (36%, 26%), rash (30%, 11%), and dehydration (21%, 11%)

Significant and clinically meaningful survival in first-line mPAC ABRAXANE + gemcitabine significantly increased overall survival vs gemcitabine alone

Median OS

1.0

ABRAXANE + gemcitabine (n=431)

0.9

Proportion of survival

0.8 0.7 0.6

Gemcitabine (n=430)

0.5

8.5

months (95% CI: 7.9-9.5)

6.7

months (95% CI: 6.0-7.2)

0.4 0.3

HR: 0.72 (95% CI: 0.62-0.83) a

0.2

P<0.0001b

0.1 0.0 0

3

6

9

12

15

18

21

24

27

30

33

36

39

357 340

269 220

169 124

108 69

67 40

40 26

27 15

16 7

9 3

4 1

1 0

1 0

0 0

Time (months)

Patients at risk

A+G: 431 G: 430

A+G=ABRAXANE + gemcitabine; G=gemcitabine; HR=hazard ratio; KPS=Karnofsky Performance Status; OS=overall survival. a

metastasis (yes vs no).

b

STUDY DESIGN The multinational, randomized, phase III MPACT trial compared ABRAXANE (125 mg/m2) + gemcitabine (1000 mg/m2) on Days 1, 8, and 15 of each 28-day cycle vs gemcitabine alone (1000 mg/m2 administered weekly for 7 weeks, followed by a 1-week rest, then on Days 1, 8, and 15 of each subsequent 28-day cycle) in 861 patients with mPAC. The primary end point was OS.

• Of these most common adverse reactions, those with a ≥2% higher incidence of Grade 3-4 toxicity in the ABRAXANE/ gemcitabine group compared with the gemcitabine group, respectively, are neutropenia (38%, 27%), fatigue (18%, 9%), peripheral neuropathy (17%, 1%), nausea (6%, 3%), diarrhea (6%, 1%), pyrexia (3%, 1%), vomiting (6%, 4%), decreased appetite (5%, 2%), and dehydration (7%, 2%) • Thrombocytopenia (all grades) was reported in 74% of patients in the ABRAXANE/gemcitabine group vs 70% of patients in the gemcitabine group • The most common serious adverse reactions of ABRAXANE (with a ≥1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%), and vomiting (4%) • The most common adverse reactions resulting in permanent discontinuation of ABRAXANE were peripheral neuropathy (8%), fatigue (4%), and thrombocytopenia (2%) • The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%) • The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%), and diarrhea (5%) • Other selected adverse reactions with a ≥5% higher incidence for all-grade toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group, respectively, are asthenia (19%, 13%), mucositis (10%, 4%), dysgeusia (16%, 8%),

headache (14%, 9%), hypokalemia (12%, 7%), cough (17%, 7%), epistaxis (15%, 3%), urinary tract infection (11%, 5%), pain in extremity (11%, 6%), arthralgia (11%, 3%), myalgia (10%, 4%), and depression (12%, 6%) • Other selected adverse reactions with a ≥2% higher incidence for Grade 3-4 toxicity in the ABRAXANE/gemcitabine group compared to the gemcitabine group are thrombocytopenia (13%, 9%), asthenia (7%, 4%), and hypokalemia (4%, 1%)

USE IN SPECIFIC POPULATIONS Nursing Mothers • It is not known whether paclitaxel 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, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother

Postmarketing Experience With ABRAXANE and Other Paclitaxel Formulations • Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied • There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs • There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration DRUG INTERACTIONS • Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4

Pediatric • The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated

Please see Brief Summary for ABRAXANE, including Boxed WARNING, on following pages.

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

ABRAXANE® is a registered trademark of Celgene Corporation. © 2013 Celgene Corporation 09/13 US-ABR130068a

Geriatric • Diarrhea, decreased appetite, dehydration, and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old who received ABRAXANE and gemcitabine in adenocarcinoma of the pancreas Renal Impairment • The use of ABRAXANE has not been studied in patients with renal impairment DOSAGE AND ADMINISTRATION • Withhold ABRAXANE if bilirubin ≥1.26 x ULN or if AST >10 x ULN • Dose reductions or discontinuation may be needed based on severe hematologic, neurologic, cutaneous, or gastrointestinal toxicity • Monitor patients closely

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) The following is a brief summary for metastatic adenocarcinoma of the pancreas; refer to full prescribing information for complete product information.

WARNING: NEUTROPENIA • Do not administer ABRAXANE therapy to patients who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE [see Contraindications (4), Warnings and Precautions (5.1) and Adverse Reactions (6.3)].

• Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. 1 INDICATIONS AND USAGE 1.3 Adenocarcinoma of the Pancreas ABRAXANE is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.

2 DOSAGE AND ADMINISTRATION 2.3 Adenocarcinoma of the Pancreas The recommended dose of ABRAXANE is 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle. Administer gemcitabine immediately after ABRAXANE on Days 1, 8 and 15 of each 28-day cycle [see Clinical Studies (14.3)].

2.4 Dosage in Patients with Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Withhold ABRAXANE if AST >10 x ULN or bilirubin > 5 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 1.

Monitor patients closely [see Warnings and Precautions (5.6), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Table 1: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Bilirubin ABRAXANE Dosea Levels Levels Pancreaticc Adenocarcinoma Mild < 10 x ULN AND > ULN to ≤ 1.25 x ULN 125 mg/m2 Moderate < 10 x ULN AND 1.26 to 2 x ULN not recommended Severe < 10 x ULN AND 2.01 to 5 x ULN not recommended > 10 x ULN OR > 5 x ULN not recommended a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. c Patients with bilirubin levels above the upper limit of normal were excluded from clinical trials for pancreatic cancer 2.5 Dose Reduction/Discontinuation Recommendations Adenocarcinoma of the Pancreas Dose level reductions for patients with adenocarcinoma of the pancreas, as referenced in Tables 4 and 5, are provided in Table 3.

Table 3: Dose Level Reductions for Patients with Adenocarcinoma of the Pancreas Dose Level

ABRAXANE (mg/m2)

Gemcitabine (mg/m2)

Full dose

125

1000

1st dose reduction

100

800

2nd dose reduction

75

600

Discontinue

Discontinue

If additional dose reduction required

Recommended dose modifications for neutropenia and thrombocytopenia for patients with adenocarcinoma of the pancreas are provided in Table 4.

Table 4: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or within a Cycle for Patients with Adenocarcinoma of the Pancreas Cycle Day Day 1 Day 8

ANC Platelet count ABRAXANE / Gemcitabine (cells/mm3) (cells/mm3) < 1500 OR < 100,000 Delay doses until recovery 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were reduced or given without modification: 500 to < 1000 OR 50,000 to < 75,000 Reduce 1 dose level from Day 8 < 500 OR < 50,000 Withhold doses Day 15: IF Day 8 doses were withheld: ≥ 1000 OR ≥ 75,000 Reduce 1 dose level from Day 1 500 to < 1000 OR 50,000 to < 75,000 Reduce 2 dose levels from Day 1 < 500 OR < 50,000 Withhold doses Abbreviations: ANC = Absolute Neutrophil Count Recommended dose modifications for other adverse drug reactions in patients with adenocarcinoma of the pancreas are provided in Table 5.

Table 5: Dose Modifications for Other Adverse Drug Reactions in Patients with Adenocarcinoma of the Pancreas Adverse Drug Reaction ABRAXANE Gemcitabine Withhold until fever resolves and ANC ≥ 1500; resume at next Febrile Neutropenia: Grade 3 or 4 lower dose level Peripheral Neuropathy: Withhold until improves to Grade 3 or 4 ≤ Grade 1; resume at No dose reduction next lower dose level Cutaneous Toxicity: Reduce to next lower dose level; discontinue treatment Grade 2 or 3 if toxicity persists Gastrointestinal Toxicity: Withhold until improves to ≤ Grade 1; resume at next Grade 3 mucositis lower dose level or diarrhea

4 CONTRAINDICATIONS • ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

• Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Effects Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In a clinical study, Grade 3-4 neutropenia occurred in 38% of patients with pancreatic cancer.

Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Days 1, 8, and 15 (for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3.

In patients with adenocarcinoma of the pancreas, withhold ABRAXANE and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended [see Dosage and Administration (2.5)].

5.2 Nervous System Sensory neuropathy is dose- and schedule-dependent [see Adverse Reactions ( 6.3)]. The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification. If ≥ Grade 3 sensory neuropathy develops, withhold ABRAXANE treatment until resolution to ≤ Grade 1 for pancreatic cancer followed by a dose reduction for all subsequent courses of ABRAXANE [see Dosage and Administration (2.5)].

5.3 Sepsis Sepsis occurred in 5% of patients with or without neutropenia who received ABRAXANE in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis. If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics.

For febrile neutropenia, interrupt ABRAXANE and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels [see Dosage and Administration (2.5)].

5.4 Pneumonitis Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving ABRAXANE in combination with gemcitabine. Monitor patients for signs and symptoms of pneumonitis and interrupt ABRAXANE and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with ABRAXANE and gemcitabine.

5.5 Hypersensitivity Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be re-challenged with this drug.

5. 6 Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

5.7 Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.

No cases of transmission of viral diseases or CJD have ever been identified for albumin.

5.8 Use in Pregnancy ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryofetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

There are no adequate and well-controlled studies in pregnant women receiving ABRAXANE. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE [see Use in Specific Populations (8.1)].

5.9 Use in Men Men should be advised not to father a child while receiving ABRAXANE [see Nonclinical Toxicology (13.1)].

6 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.

In a randomized open-label trial of ABRAXANE in combination with gemcitabine for pancreatic adenocarcinoma [see Clinical Studies (14.3)], the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of ABRAXANE are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration. The most common serious adverse reactions of ABRAXANE (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%). The most common adverse reactions resulting in permanent discontinuation of ABRAXANE are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%). The most common adverse reactions resulting in dose reduction of ABRAXANE are neutropenia (10%) and peripheral neuropathy (6%). The most common adverse reactions leading to withholding or delay in ABRAXANE dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).

6.3 Clinical Trials Experience in Adenocarcinoma of the Pancreas Adverse reactions were assessed in 421 patients who received ABRAXANE plus gemcitabine and 402 patients who received gemcitabine for the first-line systemic treatment of metastatic adenocarcinoma of the pancreas in a multicenter, multinational, randomized, controlled, open-label trial. Patients received a median treatment duration of 3.9 months in the ABRAXANE/gemcitabine group and 2.8 months in the gemcitabine group. For the treated population, the median relative dose intensity for gemcitabine was 75% in the ABRAXANE/gemcitabine group and 85% in the gemcitabine group. The median relative dose intensity of ABRAXANE was 81%.

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Table 9 provides the frequency and severity of laboratory-detected abnormalities which occurred at a higher incidence for Grades 1-4 (≥ 5%) or for Grade 3-4 (≥ 2%) toxicity in ABRAXANE plus gemcitabine-treated patients.

Table 9: Selected Hematologic Laboratory-Detected Abnormalities with a Higher Incidence (≥ 5% for Grades 1-4 or ≥ 2% for Grades 3-4 Events) in the ABRAXANE/Gemcitabine Arm ABRAXANE(125 mg/m2)/Gemcitabined Gemcitabine Grades 1-4 Grade 3-4 Grades 1-4 Grade 3-4 (%) (%) (%) (%) Neutropeniaa,b 73 38 58 27 Thrombocytopeniab,c 74 13 70 9 a 405 patients assessed in ABRAXANE/gemcitabine-treated group b 388 patients assessed in gemcitabine-treated group c 404 patients assessed in ABRAXANE/gemcitabine-treated group d Neutrophil growth factors were administered to 26% of patients in the ABRAXANE/gemcitabine group.

Table 10 provides the frequency and severity of adverse reactions which occurred with a difference of ≥ 5% for all grades or ≥ 2% for Grade 3 or higher in the ABRAXANE plus gemcitabine-treated group compared to the gemcitabine group.

Table 10: Selected Adverse Reactions with a Higher Incidence (≥5% for All Grade Toxicity or ≥2% for Grade 3 or Higher Toxicity) in the ABRAXANE/Gemcitabine Arm ABRAXANE (125 mg/m2) and gemcitabine (N=421) System Organ Class General disorders and administration site conditions

Gemcitabine (N=402)

Adverse Reaction

All Grades

Grade 3 or Higher

All Grades

Grade 3 or Higher

Fatigue

248 (59%)

77 (18%)

183 (46%)

37 (9%)

Peripheral edema

194 (46%)

13 (3%)

122 (30%)

12 (3%)

Pyrexia

171 (41%)

12 (3%)

114 (28%)

4 (1%)

Asthenia

79 (19%)

29 (7%)

54 (13%)

17 (4%)

Mucositis

42 (10%)

6 (1%)

16 (4%)

1 (<1%)

Nausea

228 (54%)

27 (6%)

192 (48%)

14 (3%)

Diarrhea

184 (44%)

26 (6%)

95 (24%)

6 (1%)

Vomiting

151 (36%)

25 (6%)

113 (28%)

15 (4%)

Skin and subcutaneous tissue disorders

Alopecia

212 (50%)

6 (1%)

21 (5%)

0

Rash

128 (30%)

8 (2%)

45 (11%)

2 (<1%)

Nervous system disorders

Peripheral neuropathya

227 (54%)

70 (17%)

51 (13%)

3 (1%)

Dysgeusia

68 (16%)

0

33 (8%)

0

Headache

60 (14%)

1 (<1%)

38 (9%)

1 (<1%)

Decreased appetite

152 (36%)

23 (5%)

104 (26%)

8 (2%)

Dehydration

87 (21%)

31 (7%)

45 (11%)

10 (2%) 6 (1%)

Gastrointestinal disorders

Metabolism and nutrition disorders

Hypokalemia

52 (12%)

18 (4%)

28 (7%)

Respiratory, thoracic and mediastinal disorders

Cough

72 (17%)

0

30 (7%)

0

Epistaxis

64 (15%)

1 (<1%)

14 (3%)

1 (<1%)

Infections and infestations

Urinary tract infectionsb

47 (11%)

10 (2%)

20 (5%)

1 (<1%)

Musculoskeletal and connective tissue disorders

Pain in extremity

48 (11%)

3 (1%)

24 (6%)

3 (1%)

Arthralgia

47 (11%)

3 (1%)

13 (3%)

1 (<1%)

Myalgia

44 (10%)

4 (1%)

15 (4%)

0

Depression

51 (12%)

1 (<1%)

24 (6%)

0

Psychiatric disorders a

Peripheral neuropathy is defined by the MedDRA Version 15.0 Standard MedDRA Query neuropathy (broad scope). b Urinary tract infections includes the preferred terms of: urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, and urinary tract infection enterococccal.

Additional clinically relevant adverse reactions that were reported in < 10% of the patients with adenocarcinoma of the pancreas who received ABRAXANE/gemcitabine included: Infections & infestations: oral candidiasis, pneumonia Vascular disorders: hypertension Cardiac disorders: tachycardia, congestive cardiac failure Eye disorders: cystoid macular edema

Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 17% of patients who received ABRAXANE/gemcitibine compared to 1% of patients who received gemcitabine only; no patients developed grade 4 peripheral neuropathy. The median time to first occurrence of Grade 3 peripheral neuropathy in the ABRAXANE arm was 140 days. Upon suspension of ABRAXANE dosing, the median time to improvement from Grade 3 peripheral neuropathy to ≤ Grade 1 was 29 days. Of ABRAXANE-treated patients with Grade 3 peripheral neuropathy, 44% resumed ABRAXANE at a reduced dose.

Sepsis Sepsis occurred in 5% of patients who received ABRAXANE/gemcitabine compared to 2% of patients who received gemcitabine alone. Sepsis occurred both in patients with and without neutropenia. Risk factors for sepsis included biliary obstruction or presence of biliary stent.

Pneumonitis Pneumonitis occurred in 4% of patients who received ABRAXANE/gemcitabine compared to 1% of patients who received gemcitabine alone. Two of 17 patients in the ABRAXANE arm with pneumonitis died.

6.4 Post-Marketing Experience with ABRAXANE and other Paclitaxel Formulations Unless otherwise noted, the following discussion refers to the adverse reactions that have been identified during post-approval use of ABRAXANE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. In some instances, severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hypersensitivity Reactions Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

Cardiovascular There have been reports of congestive heart failure and left ventricular dysfunction with ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving ABRAXANE and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.

Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with ABRAXANE. Neurologic Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.

Vision Disorders Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage. These may also be observed with ABRAXANE. Reduced visual acuity due to cystoid macular edema (CME) has been reported during treatment with ABRAXANE as well as with other taxanes. After cessation of treatment, CME improves and visual acuity may return to baseline.

Hepatic Reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Gastrointestinal (GI) There have been reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis following ABRAXANE treatment. There have been reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, occurring in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction There have been reports of extravasation of ABRAXANE. Given the possibility of extravasation, it is advisable to monitor closely the ABRAXANE infusion site for possible infiltration during drug administration.

Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.

Other Clinical Events Skin reactions including generalized or maculopapular rash, erythema, and pruritus have been observed with ABRAXANE. There have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia.

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.

There have been reports of conjunctivitis, cellulitis, and increased lacrimation with paclitaxel injection.

6.5 Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

7 DRUG INTERACTIONS The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.9)].

There are no adequate and well-controlled studies in pregnant women using ABRAXANE. Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving ABRAXANE. Administration of paclitaxel protein-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

8.3 Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

8.5 Geriatric Use Of the 431 patients in the randomized study who received ABRAXANE and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older.

No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of ABRAXANE did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.

8.6 Patients with Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment, the administration of ABRAXANE should be performed with caution in patients with hepatic impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)]. Abraxane has not been studied in combination with gemcitabine for the treatment of pancreatic cancer in patients with a bilirubin greater than the upper limit of normal.

8.7 Patients with Renal Impairment The use of ABRAXANE has not been studied in patients with renal impairment.

In the Literature Denosumab Improves Bone Metastasis–Free Survival in Patients with CRPC

In a recently reported phase 3 trial of men with nonmetastatic castration-resistant prostate cancer (CRPC) and high risk for disease progression based on baseline prostate-specific

antigen (PSA) ≥8 ng/mL and/or PSA doubling time of 10 months or less, denosumab (Xgeva)—an anti-RANK ligand monoclonal antibody—significantly increased bone metastasis–free survival (BMFS)B:7.5” and delayed time to first metastasis, but did not imT:7” prove overall survival (OS) or proS:6.5”

gression-free survival compared with placebo. In a new exploratory analysis, researchers evaluated the relationship between PSA doubling time and BMFS, time to first bone metastasis, and OS in recipients of denosumab and placebo (Smith MR, et al. J Clin Oncol. 2013;31:3800-3806).

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) 10 OVERDOSAGE There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Product No.: 103450 NDC No.: 68817-134-50 100 mg of paclitaxel in a single-use vial, individually packaged in a carton.

16.2 Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

16.3 Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see References (15)]. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling • ABRAXANE injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving ABRAXANE [see Warnings and Precautions (5.8) and Use in Specific Populations (8.1)].

• Advise men not to father a child while receiving ABRAXANE [see Warnings and Precautions (5.9)].

• Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection. [see Warnings and Precautions (5.1), (5.3)].

• Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.

• Patients must be informed that sensory neuropathy occurs frequently with ABRAXANE and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities [see Warnings and Precautions (5.2)].

• Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with ABRAXANE • Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal. [see Warnings and Precautions (5.5)].

• Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath [see Warnings and Precautions (5.4)].

Manufactured for:

Celgene Corporation Summit, NJ 07901

ABRAXANE® is a registered trademark of Abraxis BioScience, LLC. ©2005-2013 Abraxis BioScience, LLC. All Rights Reserved.

Abraxis BioScience, LLC is a wholly owned subsidiary of Celgene Corporation.

U.S. Patent Numbers: See www.celgene.com.

ABR_PANC_HCP_BSv006 9_2013

T:10”

B:10.5”

S:9.5”

This randomized, phase 3, double-blind, placebo-controlled study included 1432 men with nonmetastatic CRPC. The patients were randomized in a 1:1 ratio to monthly subcutaneous denosumab 120 mg or to placebo. The time of survival without bone metastasis was analyzed according to PSA doubling times of ≤10 months, ≤6 months, and ≤4 months. At baseline, median PSA was 12.3 ng/mL, PSA doubling time was 5.1 months, and doubling duration time was 47.1 months.

An analysis of the placebo arm demonstrated a shorter BMFS time as PSA doubling time decreased to less than 8 months. Compared with placebo, treatment with denosumab was associated with median BMFS increases of 6 months (28.4 vs 22.6 months, respectively; hazard ratio [HR], 0.84) in patients with a PSA doubling time of ≤10 months, 7.2 months (25.9 vs 18.7 months; HR, 0.77) among patients with a PSA doubling time of ≤6 months, and 7.5 months (25.8 vs 18.3 months; HR, 0.71) in patients with a doubling time of ≤4 months.

The median time to first bone metastasis was significantly reduced with denosumab in patients with a PSA doubling time of ≤6 months (26.5 vs 22.1, respectively; HR, 0.80) and ≤4 months (26.4 vs 18.5 months; HR, 0.71). No difference was found in OS between the 2 treatment arms for the overall study population or for PSA doubling time subsets.

These findings demonstrate that faster PSA doubling time is associated with a shorter BMFS in this patient population. Denosumab significantly increased BMFS time and time to first bone metastasis in the overall study population, and the drug has shown the greatest treatment effects in men who are at high risk for disease progression.

Although the study results show that denosumab improves BMFS in patients with nonmetastatic CRPC at high risk for developing bone metastasis, an accompanying editorial by Garraway suggests that denosumab is not approved by the US Food and Drug Administration for the prevention of bone metastasis, in part because of its effect on patient survival, pain metrics, and other quality-of-life measurements (Garraway IP. J Clin Oncol. 2013;31:3838-3840). It is possible that the development of rational therapeutic combinations to prevent bone metastasis, combined with further molecular and genetic classification of prostate cancer, will provide greater clarity regarding who gets treatment and at what point in disease progression, Garraway suggests.

Continued on page 24

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Need for Innovative Strategies for Quality Care Will Continue to...

Continued from cover

social worker or a nurse or a physician, a hospital, a pharmacy institute, or a payer. We will all have less money to work with,” he emphasized.

“One of the things we have to learn to do is to eliminate all of the waste.

The things that don’t make as much difference to us as quality-of-life money. We have to figure out how to deliver the best outcome with the limited resources we have available.”

Currently, approximately 22% of every UnitedHealthcare oncology dollar goes to pharmaceuticals, the cost of which is increasing by approximately 10% to 15% annually. Hospital costs account for 54% and are also increasing at a rate of approximately 10% annually. Physicians—all physicians, not just oncologists—account for the remaining 24% of the cost, and their costs are in a negative-inflation status, said Dr Newcomer.

Innovation in Reimbursement Innovation in payment strategies focuses on 3 basic models: the pay-for-performance model, bundling or episodic payment, and capitation.

Pay-for-performance is by far the most popular strategy, and is usually tied to clinical pathway adherence. At UnitedHealthcare, currently 80% of the patients with cancer are treated based on predetermined pathways, according to Dr Newcomer.

Measuring the performance and outcome of various payment strategies faces several barriers, he says.

The first relates to enrollment of a sufficient number of patients to conduct quality-of-care studies. The majority of patients do not qualify as “typical” patients that would be needed for a study of different reimbursement models. Related to study enrollment is the time required to conduct studies, which require several years to complete.

Identifying an appropriate control or comparison group can also be problematic, including the decision to compare outcomes and costs on a year-toyear basis, or to use a control group followed over the same duration of time as the study group.

Finally, the funding of clinical trials is complicated because everyone wants a share of the savings that result from improved care efficiency and lower costs. Moreover, most healthcare organizations already have relatively slim margins from which to trim additional costs.

“One of the things we have to learn to do is to eliminate all of the waste. The things that don’t make as much difference to us as qualityof-life money. We have to figure out how to deliver the best outcome with the limited resources we have available.”

but we need to get results that are proportionate to the payment,” said Dr Newcomer.

Measuring Quality and CostEffectiveness The difficult realities associated with the pay-for-performance approach have led Dr Newcomer, and possibly others, to reconsider the approach to measuring quality and cost-effectiveness. Specifically, he questions whether payers have had the wrong focus in their efforts to achieve cost-efficiency and good outcomes.

Payers can easily compare chemotherapy regimens, he continued. As part of preauthorization, detailed clinical information can be obtained, and then a payer can initiate an intendto-treat study, specifying the regimen during preauthorization. Within a couple of years, a large organization can accrue hundreds, if not thousands, of patients using various chemotherapy regimens for different types of cancer.

“This would give us a very good start toward comparative effectiveness studies, comparing regimens against each other,” said Dr Newcomer.

Such studies could help fill the void that has resulted from the disappearance of phase 3 cooperative-group trials that compared chemotherapy regimens in various types of cancer.

—Lee N. Newcomer, MD, MHA “It’s very difficult to find a lot of money to fund pay-for-performance programs,” said Dr Newcomer.

As another example of the difficulties involved in finding reward money for pay-for-performance initiatives, he described an oncology practice that performed better than the national average for virtually all types of cancer; however, that practice already received a 33% premium on payments as a result of a higher fee schedule, and the group’s performance was only slightly better than the national average.

“For pay-for-performance to work, we not only need to get good results,

If you value

“That is something payers can do and can do effectively, and with a large enough volume that we could start parsing out those regimens that are ineffective, and lowering cost in the process.”

—Lee N. Newcomer, MD, MHA

Quality Care Research To reduce costs, payers need to know which regimens provide the best re-

at a glance ➤ At UnitedHealthcare, approximately 22% of every oncology dollar is spent on drugs; 54% for hospital costs; and all physicians, not just oncologists, account for 24% of the cost, and their costs are going down ➤ Pay-for-performance is by far the most popular reimbursement strategy, and is usually tied to clinical pathway adherence in oncology ➤ Measuring the performance and outcome of various payment strategies faces several barriers: enrolling sufficient patients to conduct studies, identifying a control group, and funding such trials ➤ Payers can easily compare chemotherapy regimens using preauthorization: getting detailed clinical information, then initiating an intend-to-treat study, specifying the regimen during preauthorization

sults at the lowest cost and lowest toxicity. “That is something payers can do and can do effectively, and with a large enough volume that we could start parsing out those regimens that are ineffective, and lowering cost in the process,” Dr Newcomer said.

Moving forward, he concluded, quality care researchers must continue to test solutions, because the need for better quality and efficiency will always be relevant. At the same time, payers, clinicians, researchers, and other interested parties must be realistic about the financial results that can be expected from improvements in quality and efficiency.

Finally, quality care researchers must apply the same rigor as clinical researchers use in clinical trials.

“The scientific method applies to business applications as well,” said Dr Newcomer. n

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ASCO Quality Care Symposium

Integrating Patient-Reported Outcomes into Cancer Care

By Charles Bankhead

San Diego, CA—The Patient-Reported Outcomes Measurement Information System (PROMIS) tool can inform clinical care delivery for patients with cancer, according to the initial results of a National Institutes of Health (NIH)-funded project.

The integration of the PROMIS tools into oncology clinical care has provided actionable information about cancer-related symptoms. The information is fed into patients’ electronic medical records (EMR) in real time to aid clinical care decision-making and delivery, reported Lynne I. Wagner, PhD, Associate Professor of Medical Social Sciences, Northwestern University, Chicago, IL, at the 2013 ASCO Quality Care Symposium.

patients can report their symptom status, which is automatically captured by the EMR.

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For more information, please call 800-843-8197 or visit www.GILOTRIF.com

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“Clinical application of PROMIS computer adaptive tests has provided an assessment center platform for electronic patient-reported outcomes (ePRO) assessment,” said Dr Wagner.

“Integration with the patient’s electronic health record triggers ePRO assessment through a patient communication portal and populates the EMR with results of the assessment. When an assessment shows a patient has severe symptoms, clinicians receive notifications through their EMR in-basket.

Integration also facilitates automatic triage for supportive oncology services,” she pointed out.

Patients with cancer often have a significant symptom burden that can interfere with treatment and adversely affect quality of life. However, clinical practices often face multiple barriers to obtaining meaningful symptom assessments, said Dr Wagner.

50

—Lynne I. Wagner, PhD

ported outcomes and their integration into clinical management. By means of an online communication portal,

NOW AVAILABLE

50

“Integration with the patient’s electronic health record triggers ePRO assessment through a patient communication portal and populates the EMR with results of the assessment.

When an assessment shows a patient has severe symptoms, clinicians receive notifications through their EMR in-basket.”

The NIH has supported the development of the PROMIS network to improve the assessment of patient-re-

Copyright © 2013. Boehringer Ingelheim Pharmaceuticals, Inc.

All rights reserved.

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GF582706PROF

36643_VB_CANCER_CARE 1

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ASCO Quality Care Symposium If a patient has a score in the “severe” range for fatigue, pain, or physical functioning, a message is generated automatically and sent to the patient’s oncologist and to the nursing messaging system. The portal can be accessed by a home computer or tablet computer.

Dr Wagner described the imple-

mentation of the PROMIS system in the gynecologic oncology outpatient clinic. Patients receive e-mail notices 72 hours before scheduled visits with their doctors, and are asked to complete the online symptom assessment.

Patients provide information related to 5 domains—pain, fatigue, physical

function, depression, and anxiety.

If scores for depression or anxiety are in the severe range, messages are sent to the oncologists, nursing pool, and psychosocial services. Social work needs, informational needs, and nutrition status are also assessed. If patients’ responses reflect potential

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• Patient support kit • Nurse support • 24-hour specialty pharmacy support‡ • GILOTRIF Dose Exchange™§

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• Coverage and reimbursement support • Financial support • Distribution options* • GILOTRIF Pledge™†

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➤ The Patient-Reported Outcomes Measurement Information System can inform clinical care delivery for patients with cancer ➤ Information is added to patients’ EMR in real time to help clinical care decisionmaking ➤ This provides cancer-related symptoms to the provider directly during treatment ➤ In addition, patients can report their symptom status through an online portal, which is automatically captured in the EMR ➤ Providers can respond to the patient’s concerns and needs using this interface ➤ This process facilitates automatic triage for supportive oncology services

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at a glance

*GILOTRIF is available through our specialty pharmacy partner, Accredo, as well as through select on-site pharmacies. † GILOTRIF Pledge provides patient and payer refund for first month of therapy if eligible patients (commercially insured through participating health plans and serviced through Accredo) discontinue before first refill. ‡ For patients serviced through Accredo. § GILOTRIF Dose Exchange offers replacement drug and eliminates an additional co-pay for the replacement drug. It is offered for up to 2 dose adjustments for patients serviced through Accredo who are exchanging ≥9 pills.

Copyright © 2013. Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (8/13) GF572109PROF

problems in any of the areas, messages are sent to the appropriate services.

The system can also link patients to an online health resource library, which contains cancer-related information, symptom management, and psychosocial resources, among others.

Moreover, members of specific services can respond to concerns or informational needs expressed by patients, using the interface between the EMR and the assessment center.

Dr Wagner presented findings for the first 558 patients who completed an initial assessment. Approximately 75% of the patients were white (mean age, 56 years). The majority of cancer types included ovarian (37.1%), uterine (28.7%), and cervical (6.9%) cancers.

The majority of the assessment (87%) was done from home, showing that: • 1 patient had severe anxiety • 1 had depression • 11 had severe fatigue • 11 had significant pain • 22 had significant problems related to physical functioning.

In addition, 43% of the initial assessments triggered social work triage, 23% health education center triage, 16% sought information about advance directives, and 9% requested information about financial resources.

Preliminary analysis of follow-up assessments showed that the proportion of patients with psychosocial concerns declined to 20.6% on the second assessment, 13% on the third, and 8.2% on the fourth. n

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ASCO Quality Care Symposium

Development of Quality Measures Should Address Current Limitations

By Charles Bankhead

San Diego, CA—A new sense of urgency surrounds the need to improve quality measurement, even as major gaps persist in existing measures, said Jennifer L. Malin, MD, PhD, Medical Director, Oncology, WellPoint, at the 2013 ASCO Quality Care Symposium.

The recently released Institute of Medicine (IOM) report on the status of cancer care has called for a national quality reporting system with meaningful measures that incorporate patient-reported outcomes. The report further calls for reimbursement based on providers’ ability to deliver affordable, patient-centered, high-quality care.

The Challenge of Quality Measures To meet the challenges set forth by the IOM report, providers and payers must work together to address the limitations of current quality measures, “Many of the National Quality Forum–endorsed measures of quality lack variability, which limits their utility for public reporting or developing pay-for-performance strategies,” said Dr Malin. “They don’t allow us to discriminate variations in quality.”

Many measures lack specificity, making it difficult to determine whether a patient received the most efficacious or cost-effective therapy.

Low scores on quality assessments may reflect data problems. Public reporting of the data could lead to inappropriate expenditure of resources to improve the data infrastructure.

Few existing outcome measures

have been validated, Dr Malin continued, and few measure overuse, which is as important as underuse. A final limitation of current measures is their failure to include the patient experience.

“Many of the National Quality Forum–endorsed measures of quality lack variability, which limits their utility for public reporting or developing pay-forperformance strategies. They don’t allow us to discriminate variations in quality.”

—Jennifer L. Malin, MD, PhD

Patient-Centered Care

Efforts to address the limitations should begin with the need for pa-

tient-centered care. Borrowing from another IOM report, Dr Malin enumerated qualities of patient-centered care.

“This can involve many different domains, but I think the key aspects involve collaboration, sensitivity to nonmedical aspects of care, and respect for patient needs and preferences, as well as free flow and accessibility of information,” she said.

The feedback loop of patient-centered healthcare begins with quality measurement, which is critical to improvement in the delivery system. To make measurement meaningful, payment systems should be aligned with quality, not necessarily with volume or other outcomes traditionally rewarded by payment systems. The feedback should lead to accessible, affordable, high-quality care, said Dr Malin.

The development of meaningful quality measures in oncology can benefit from incorporating oncology-related contributions to the American Board of Internal Medicine Foundation’s Choosing Wisely campaign, which focuses on identifying widely used practices that have little or no supporting evidence. ASCO contributed 5 recommendations in 2012 and another 5 in 2013 (see article below).

Dr Malin illustrated the relevance of the Choosing Wisely campaign to quality improvement. ASCO’s Top Five recommendations for 2013 include not using positron-emission tomography (PET) or PET–computed tomography (CT) imaging for routine follow-up after curative treatment of

ASCO’s “Choosing Wisely” Top 5 List: Inappropriate Tests, Imaging, and Targeted Therapies San Diego, CA—Unnecessary treatment, imaging, and testing all came into focus in the American Society of Clinical Oncology (ASCO)’s 2013 choices for the Choosing Wisely campaign to eliminate the overuse and misuse of medical care resources.

At the 2013 ASCO Quality Care Symposium, Lowell E. Schnipper, MD, Medical Director, Beth Israel Deaconess Medical Center Cancer Center, Boston, Chair of ASCO’s Cost of Cancer Care Task Force, cited in-

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appropriate use of antiemetics, combination chemotherapy for metastatic breast cancer, routine follow-up imaging with positron-emission tomography (PET) or PET–computed tomography (CT), prostate-specific antigen (PSA) testing, and targeted therapies.

2012 Top 5 List ASCO released its first “Top Five” list in 2012 and received considerable positive feedback from the oncology community, said the task force.

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“The exercise we went through to identify the top five items was viewed by our professional colleagues in ASCO as very, very helpful to them, because [the recommendations] all were quite evidence-based,” said Dr Schnipper. “They provided substantial support in difficult conversations the doctors might have been having with their patients as they were negotiating management plans with them.”

Initiated by the American Board

Continued on page 18

a malignancy. Dr Malin cited a 2012 study that raised questions about the appropriateness of PET-CT use for 6 types of cancer, including lymphoma.

“It seems that with some tumor types, 50% to 70% of the time patients have multiple imaging studies in a very short period of time,” said Dr Malin. “We think about this in terms of cost, but I would argue that this is not very patient centered, because there’s a burden on patients to go back and forth for imaging studies. It usually requires their caregivers to take time off from work. There might be some complications with intravenous contrast. It’s not patient centered to perform testing that’s not necessary and that’s not going to change the management of the patient.”

Outcome Measures

One ASCO Top Five for 2012 involved the appropriate use of growth factors during chemotherapy. Dr Malin presented data from WellPoint showing wide variation in the use of colony-stimulating factors, from <5% to ≥65% cycles of chemotherapy.

Dr Malin’s list of potential recommendations to improve measurement began with the admonition to ensure that quality measures are specific enough to distinguish high-quality care from mediocre or bad care.

For surgery and other therapies with meaningful short-term outcomes, outcome measures should be included in quality measurement.

Interim outcomes of importance should be addressed, such as treatment-related hospitalizations and emergency department visits. Quality measures should reflect the recognition that overuse is as important as underuse, Dr Malin said. As emphasized in the new IOM report, quality measures should capture patient experience.

Because efficiency is a key component of quality, quality-improvement efforts should devote time to the development of meaningful measures of efficiency. Quality measures should be relevant to all healthcare stakeholders, including patients and payers. Finally, data on quality-improvement efforts should be readily accessible to stakeholders.

“Transparency is critical,” said Dr Malin. “For quality measurement to change the healthcare delivery system, key stakeholders, especially patients, need access to the data.” n

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SHOULDN’ T A PATIENT SUPPORT PROGRAM BE EASY TO NAVIGATE?

Connecting your patients who are prescribed Jakafi® (ruxolitinib), and who are eligible for the program, to ongoing support and resources during their treatment ACCESS AND REIMBURSEMENT SERVICES

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• Educational information to help teach your patients about their condition • Patient packet Visit www.IncyteCARES.com or call 1-855-4-JAKAFI (1-855-452-5234) Monday–Friday, 8 AM–8 PM ET, to learn more about how to connect your patients to IncyteCARES. Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1227d 05/13

ASCO Quality Care Symposium

ASCO’s “Choosing Wisely” Top 5 List: Inappropriate Tests... Continued from page 16 of Internal Medicine Foundation, the Choosing Wisely campaign has provided a vehicle for leading medical organizations to identify and publicize practices that are widely used but have no supporting evidence and likely add nothing to aid clinical care. The 2012 inappropriate practices included: • Use of cancer therapy in poor performance • Poor-prognosis patients • PET, CT, or radionuclide bone scans for staging low-risk early prostate cancer • PET, CT, or radionuclide bone scans for staging low-risk early breast cancer • Surveillance tests or imaging for asymptomatic patients with breast cancer treated with curative intent • Use of growth factors for the pri­ mary prevention of febrile neutropenia in patients at low risk of the complication.

2013 Top 5 List Dr Schnipper reviewed the 2013 Top Five and discussed the rationale for the choices: 1. Antiemetics designed to reduce the risk of nausea and vomiting associated with highly emetogenic chemotherapy regimens in patients treated with regimens that have a low or moderate risk of nausea or vomiting.

The agents are extremely effective when given with highly emetogenic regimens, but also are “phenomenally expensive.”

“We thought it very important to emphasize that antiemetic use guide-

lines—guidelines that ASCO itself has promulgated—suggesting ways in which antinausea drugs be utilized, should be adhered to,” said Dr Schnipper.

“If the biomarker predicts response to the drug, we suggest strongly that that is the only circumstance in which that particular targeted therapy should be utilized.”

—Lowell E. Schnipper, MD Agents developed for use with highly emetogenic regimens should be given to patients treated with those regimens, recognizing the high cost, he added. On the other hand, ASCO encourages the use of lower cost but effective antiemetics in association with regimens that have a moderate or low emetogenic potential.

2. Do not use combination chemotherapy instead of a single drug in patients with metastatic breast cancer, except when a rapid response is required to relieve tumor-related symptoms.

“The concept at the outset of clinical trials that have utilized combination chemotherapy agents is that more is better,” said Dr Schnipper. “It turns out that, when we look at the outcome, bringing multiple drugs together, for the majority of women who have met-

astatic breast cancer, does not add to their survival and sometimes, because of the side effects or toxicities, actually detracts from the quality of their life.”

Single-agent therapy, even when used sequentially, also saves money, Dr Schnipper added. However, the judicious use of single agents serves to support the primacy of the patient and is a time-tested, effective approach for most patients with metastatic breast cancer.

3. Avoid PET or PET-CT imaging for routine follow-up of asymptomatic patients who have finished curative therapy, except when high-level evidence suggests that the imaging will change the outcome.

“We do not believe there is any evidence to say that routine use of CT scans or PET scans or PET-CT scans provides any strong evidence that we can keep patients alive longer or maintain their health better,” said Dr Schnipper. “In fact, the concern we have is that too much testing will uncover abnormalities that are not related to cancer, that don’t even need to be identified because they are harmless.”

4. Do not perform screening PSA tests in asymptomatic men who have a life expectancy of less than 10 years.

“Studies have been done looking at the impact of prostate cancer diagnosis in men, particularly men over 70, and the majority of studies do not show that treating this prostate cancer affects their mortality at all,” said Dr Schnipper. “There is a very small increase over time in mortality related to prostate cancer in these in-

dividuals, but overall mortality is not affected at all.”

Members of the task force were quite affected by the impact of therapy for localized prostate cancer, Dr Schnipper added. Surgery, radiation therapy, and hormonal therapy all can substantially and adversely affect a man’s quality of life.

5. Do not use targeted therapy unless a patient’s tumor produces a biomarker that predicts response to the therapy.

“If the biomarker predicts response to the drug, we suggest strongly that that is the only circumstance in which that particular targeted therapy should be utilized. We think that will control the use of these expensive, but very valuable, target agents and restrict them to the indicated population, assuming this is an adhered to element without promiscuous use in populations of patients who are not likely to derive benefit.”

These Top Five are not intended as “legislated dicta. They are evidence-based suggestions that are presented as a foundation for discussion between the doctor and the patient,” Dr Schnipper concluded. “Of course, there will be individual circumstances in which patients and their doctors may decide in ways that would not be consistent with the guidelines….What we are trying to do is make recommendations that adhere to evidence and encourage our colleagues to do so.”

The list was published simultaneously online (Schnipper LE, et al. J Clin Oncol. Epub 2013 October 29).—CB n

Economics of Cancer Care

Cost-Effective Strategy for Early NSCLC Hinges on Operability of the Disease

By Charles Bankhead Atlanta, GA—Surgery and stereotactic body radiotherapy (SBRT) proved cost-effective strategies for stage I non–small-cell lung cancer (NSCLC) when applied to specific patient populations, according to a study reported at the 2013 American Society for Radiation Oncology meeting.

SBRT had the advantage for older patients with marginally operable disease, whereas lobectomy offered the

18

most cost-effective option for patients with clearly operable disease.

“These findings were robust over a wide range of assumptions, including treatment efficacies, toxicities, costs, and health state utilities,” said Anand Shah, MD, MPH, Resident in the Department of Radiation Oncology, Columbia University Medical Center, New York.

Surgery has a long-standing histo-

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ry as the treatment for patients with clearly operable stage I NSCLC. For patients with marginally operable disease, wedge resection and SBRT have been employed with no clear evidence of superiority for one approach over the other.

Recent advances in the diagnosis of lung cancer will likely increase the population of patients with stage I disease, said Dr Shah. As a result,

determining the cost-effectiveness of various treatment options is essential.

To address the cost-effectiveness issue, investigators used Markov modeling to compare treatment options for 2 hypothetical patient cohorts. For patients with marginally operable stage I NSCLC, they compared SBRT and wedge resection.

For clearly operable disease, the comContinued on page 19

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Economics of Cancer Care

Health Disparities in Oncology: Western Europe Spends More, Achieves Better Patient Survival...

Continued from cover

may result from greater access to cancer screening, coupled with more effective treatments, Dr Ades suggested.

—Felipe Ades, MD

percentage of GDP invested in healthcare and health expenditure per person annually with their own estimates of the proportion of patients dying after a cancer diagnosis.

“We have observed that the more spent on health, the fewer the deaths after a cancer diagnosis, and this is specially marked in breast cancer. We have also noticed that, despite all the initiatives to standardize public health policies, there is significant variation between health expenditure and cancer incidence and mortality in the 27 EU member states. This disparity is more glaring between the Western and Eastern European countries,” Dr Ades reported.

He and his colleagues obtained information on populations, cancer incidence, and mortality from the World Health Organization, the International Monetary Fund, and the World Bank Group. They compared the countries’ gross domestic product (GDP) and the

East/West Divide Although the population of Western Europe is approximately 4 times larger than that of Eastern Europe, the western countries’ total GDP is more than 10-fold higher than that of Eastern Europe. These 2 regions also have significantly different health expenditures.

“The more spent on health, the fewer the deaths after a cancer diagnosis….There is significant variation between health expenditure and cancer incidence and mortality in the 27 EU member states.”

The cutoff point between Eastern and Western European countries for health expenditure per person annually is approximately $2600. For example, among the Western European countries, Portugal has the lowest per-

“Cancer is a leading cause of mortality in Europe, and yet there is an important deficit between the resources needed to control it and those deployed to do so.”

—José M. Martín-Moreno, MD, PhD, MPH

capita expenditure at $2690, whereas in Eastern Europe, Slovenia has the highest per-capita expenditure at $2551. In the West, Luxembourg spent the most per person annually—$6592—where-

Cost-Effective Strategy for Early NSCLC... Continued from page 18 parison was SBRT versus lobectomy.

SBRT efficacy was assumed to be the same in both comparisons, but the toxicity of SBRT was assumed to be greater in patients with marginally operable disease.

The investigators extracted disease,

at a glance ➤ SBRT is cost-effective for patients with marginally operable stage I NSCLC, with a mean cost of $42,094 and a mean QALY of 8.03 compared with $51,487 and 7.93, respectively, for wedge resection ➤ For the clearly operative subgroup, SBRT had a mean of 8.21 QALYs versus a mean of 8.89 QALYs with lobectomy for an additional cost of $13,200, which is well within the definition of cost-effectiveness ➤ Therefore, for patients with clearly operative NSCLC, lobectomy is the most costeffective treatment

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treatment, and toxicity data from the medical literature and these varied in sensitivity analyses. The investigators assumed a Medicare payer perspective and that all patients were treated at the same institution.

“In the sensitivity analysis for the marginally operable cohort, SBRT was nearly always the dominant, and thus cost-effective, strategy. For the clearly operable cohort, lobectomy was the cost-effective treatment in every sensitivity analysis.”

—Anand Shah, MD, MPH

The surgical case mix was derived from 2011 data for the 18-county Philadelphia media market. The average surgery payment was a weighted

average of payments for the case mix.

The costs were adjusted to reflect 2012 US dollars, as determined from the Consumer Price Index. The costs and quality-adjusted life-years (QALYs) were discounted at 3% annually.

The analysis of the marginally operable cohort yielded a mean cost of $42,094 and a mean QALY of 8.03 for SBRT compared with $51,487 and 7.93, respectively, for wedge resection, demonstrating dominance for SBRT. For the clearly operable cohort, SBRT was associated with a mean cost of $40,107 and a mean QALY of 8.21, whereas lobectomy resulted in a mean cost of $49,093 and 8.89 QALYs. The difference translated into an additional cost of $13,200 per QALY, which fell well within the definition of cost-effectiveness, and with additional QALYs, which rendered lobectomy the most cost-effective strategy for the clearly operable cohort.

“In the sensitivity analysis for the marginally operable cohort, SBRT was nearly always the dominant, and thus cost-effective, strategy,” said Dr Shah.

“For the clearly operable cohort, lobectomy was the cost-effective treatment in every sensitivity analysis.” n

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at a glance ➤ The higher cancer incidence in Western European countries and lower death rates may result from greater access to screening and more effective treatments ➤ In countries spending $4000 per person on healthcare, <40% of the patients die after a cancer diagnosis ➤ In countries spending $2500 to $3500 per person, 40% or 50% of patients die after a cancer diagnosis ➤ In countries that spend <$2000 per person, nearly 60% of patients die after a cancer diagnosis

as in the East, Romania spent the least—$818.

Proportionally, Eastern Europe has a lower cancer incidence and a higher cancer mortality, whereas the opposite is the case in Western Europe. This pattern is strongly associated with health expenditure—the more a country spends on health, the less likely its patients will die after a cancer diagnosis, Dr Ades said.

“In countries spending less than $2000 per capita on healthcare, like Romania, Poland, and Hungary, around 60% of the patients die after a cancer diagnosis. In those spending $2500 to $3500, this figure is around 40% and 50%, as in the case of Portugal, Spain, and the United Kingdom. When countries spend $4000, less than 40% of the patients die, as in the case of France, Belgium, and Germany,” he noted.

José M. Martín-Moreno, MD, PhD, MPH, University of Valencia, Spain, commented on the study. “Cancer is a leading cause of mortality in Europe, and yet there is an important deficit between the resources needed to control it and those deployed to do so,” he said.

The study confirms that funding for health systems is crucial to ensuring good patient outcomes, Dr MartínMoreno said. “Public health expenditure, along with adequate governance and accountability mechanisms, evidence-based guidelines, and proper capacity-building, are all essential ingredients for a strong health system and for a better society.” n

www.ValueBasedCancerCare.com

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Help give your patients a chance for response Overall response rate (ORR) of 29.2% was achieved with all-oral POMALYST + low-dose dex ORR (≥PR)

100%

Patients, %

80%

95% CI for ORR: POMALYST: 3.3% to 14.1% POMALYST + low-dose dex: 21.0% to 38.5%

60% 40% 20% 0%

ORR 7.4% (n=8) POMALYST (N=108)

PR 7.4% (n=8) CR 0% (n=0)

ORR 29.2% (n=33)

PR 28.3% (n=32) CR 0.9% (n=1)

POMALYST + low-dose dex (N=113)

CI, confidence interval; CR, complete response; Dex, dexamethasone; PR, partial response. Endpoint based on responses assessed by IRAC, based on EBMT criteria.

Study design: A Phase II, multicenter, randomized open-label study in patients who were refractory to their last myeloma therapy and had received lenalidomide and bortezomib. The safety and efficacy of POMALYST 4 mg 21/28 days until disease progression was evaluated alone and in combination with low-dose dex: 40 mg per day (patients ≤75 years) or 20 mg per day (patients >75 years) only on Days 1, 8, 15, and 22 for each 28-day cycle. Patients in the POMALYST alone arm were allowed to add low-dose dex upon disease progression.

7.4-month median duration of response (n=33; 95% CI, 5.1 to 9.2) vs NE for POMALYST + low-dose dex and POMALYST, respectively NE, not established (the median has not yet been reached).

ORR did not differ based on type of prior anti-myeloma therapy

For more information visit www.pomalyst.com or use your smartphone to scan this code.

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning EMBRYO-FETAL TOXICITY • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe life-threatening birth defects • For females of reproductive potential: Exclude pregnancy before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception POMALYST is available only through a restricted program called the POMALYST REMS program.

VENOUS THROMBOEMBOLISM • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST

CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female. POMALYST is contraindicated in females who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity • Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious

adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported

Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

• In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. © 2013 Celgene Corporation 04/13 US-POM120033a

In the Literature Continued from page 12

Gemcitabine Increases Survival for Patients with Resected Pancreatic Cancer

The prognosis for patients with pancreatic cancer is poor, even for patients with surgically resectable tumors.

Gemcitabine (Gemzar) is the standard chemotherapy for advanced pancreatic cancer. Despite the lack of a clear con-

sensus, gemcitabine has also become the mainstay of adjuvant treatment for this deadly disease, even though its effects on survival after surgery have not been demonstrated. Now, findings from the extended follow-up of the Charité Onkologie 001 (CONKO-001) trial of patients with pancreatic cancer who underwent surgery provide sup-

port for the use of gemcitabine in the adjuvant setting (Oettle H, et al. JAMA. 2013;310:1473-1481).

CONKO-001 was a multicenter, open-label, parallel-group, randomized, phase 3 trial that compared gemcitabine with observation alone in the adjuvant setting in 368 adults who had undergone complete, curative-

intent resection of pancreatic cancer at 88 medical centers in Germany and Austria. In the intent-to-treat analysis, the investigators randomized 354 eligible patients to adjuvant gemcitabine (N = 179) or to observation alone (N = 175). Gemcitabine was administered at 1 g/m2 on days 1, 8, and 15 every 4 weeks for 6 months.

S:7”

This brief summary does not include all the information needed to use POMALYST® (pomalidomide) safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy.

POMALYST is a thalidomide analogue.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

Toxicity

Dose Modification

Neutropenia • ANC* < 500 per mcL Interrupt POMALYST or Febrile neutropenia treatment, follow CBC (fever more than or weekly. equal to 38.5°C and ANC < 1,000 per mcL) • ANC return to more than or equal to 500 per mcL

Resume POMALYST at 3 mg daily.

• For each subsequent drop < 500 per mcL

Interrupt POMALYST treatment

• Return to more than or equal to 500 per mcL

Resume POMALYST at 1 mg less than the previous dose

Dose Modification

Thrombocytopenia • Platelets < 25,000 per Interrupt POMALYST mcL treatment, follow CBC weekly • Platelets return to > 50,000 per mcL

Resume POMALYST treatment at 3 mg daily

• For each subsequent drop < 25,000 per mcL

Interrupt POMALYST treatment

• Return to more than Resume POMALYST at or equal to 50,000 per 1 mg less than previous mcL dose. *Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females who are pregnant.

Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)].Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)].Males Pomalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions

(5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors.

5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia.

Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia.

Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)].

5.5 Hypersensitivity Reactions. Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity.

5.6 Dizziness and Confusional State. In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state.

Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy.

There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)]

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1 INDICATIONS AND USAGE 1.1 Multiple Myeloma POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib 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 (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities

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In the Literature The enrollment period ran from July 1998 to December 2004, and the follow-up period ended September 2012. During a median follow-up of 11 years, pancreatic cancer recurred in 308 patients—145 in the gemcitabine group and 163 in the observation group. The primary end point was disease-free survival (DFS). The

secondary end points included overall survival (OS).

The results show that the median DFS was significantly greater with gemcitabine than with observation alone (13.4 vs 6.7 months, respectively). Furthermore, the rates of DFS were significantly better with gemcitabine than with observation at 5 years

(16.6% vs 7.0%, respectively) and 10 years (14.3% vs 5.8%, respectively).

At the end of the follow-up, 316 of the 354 patients (89.3%) had died.

The median OS was 22.8 months in the gemcitabine group versus 20.2 months in the observation group. The difference in OS between the 2 groups was significant. OS in the gemcitabine

group at 5 years was 20.7% versus 10.4% in the observation group, and at 10 years it was 12.2% versus 7.7%, respectively. These treatment benefits occurred across all subgroups of patients, regardless of tumor stage and nodal status at the time of resection.

The significant differences in DFS

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(6%, 10%), Lymphopenia (2%, 7%); Infections and infestations: Pneumonia (16%, 23%), Urinary tract infection (2%, 8%), Sepsis (6%, 3%); Metabolism and nutritional disorders: Hypercalcemia (9%, 1%); General disorders and administration site conditions: Fatigue and asthenia (11%, 13%); Investigations: Blood creatinine increased (6%, 3%); Respiratory, thoracic and mediastinal disorders: Dyspnea (7%, 13%); Musculoskeletal and connective tissue disorders: Back pain (12%, 9%), Muscular weakness (6%, 4%); Renal and urinary disorders: Renal failure (9%, 6%).

Serious adverse events were reported in 67% of patients treated with POMALYSTa (72/107) and 62% with POMALYST + Low dose Dex (69/112).

Serious Adverse Reactions in 2 or more patients in either arm, respectively, included: Infections and infestations: Pneumonia (14%, 19%), Urinary tract infection (0%, 5%), Sepsis (6%, 3%); Respiratory, Thoracic and mediastinal disorders: Dyspnea (5%, 6%); General disorders and administration site conditions: Pyrexia (3%, 5%); General physical health deterioration (0%, 2%); Cardiac Disorders: Atrial fibrillation (2%, 3%), Cardiac failure congestive (0%, 3%); Renal and urinary disorders: Renal failure (8%, 6%), Gastrointestinal disorders: constipation (1%, 3%); Blood and Lymphatic system disorders: Febrile neutropenia (5%, 1%); Metabolism and nutrition disorders: Dehydration (5%, 3%), Hypercalcemia (5%, 2%); Musculoskeletal and connective tissue disorders: Back pain (4%, 2%) aPOMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided.

7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction.

Patients should be advised that smoking may reduce the efficacy of pomalidomide.

Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)]

Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects.

Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels.

There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day.

Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption.

8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established.

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• Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions.

The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

In the clinical trial of 219 patients who received POMALYST alonea (n=107) or POMALYST + Lowdose Dex (n=112), all patients had at least one treatment-emergent adverse reaction.

Adverse reactions ≥10% in either arm, respectively, included: General disorders and administration site conditions: Fatigue and asthenia (55%, 63%), Pyrexia (19%, 30%), Edema peripheral (23%, 16%), Chills (9%, 11%), Pain (6%, 5%); Blood and lymphatic system disorders: Neutropenia (52%, 47%), Anemia (38%, 39%), Thrombocytopenia (25%, 23%), Leukopenia (11%, 18%), Lymphopenia (4%, 15%); Gastrointestinal disorders: Constipation (36%, 35%), Diarrhea (34%, 33%), Nausea (36%, 22%), Vomiting (14%, 13%); Infections and infestations: Pneumonia (23%, 29%), Upper respiratory tract infection (32%, 25%), Urinary tract infection (8%, 16%); Musculoskeletal and connective tissue disorders: Back pain (32%, 30%), Musculoskeletal chest pain (22%, 20%), Muscle spasms (19%, 19%), Arthralgia (16%, 15%), Musculoskeletal pain (11%, 15%), Pain in extremity (5%, 14%), Muscular weakness (12%, 12%), Bone pain (12%, 5%); Respiratory, thoracic and mediastinal disorders: Dyspnea (34%, 45%), Cough (14%, 21%), Epistaxis (15%, 11%); Metabolism and nutritional disorders: Decreased appetite (22%, 18%), Hyperglycemia (12%, 15%), Hyponatremia (10%, 13%), Hypercalcemia (21%, 12%), Hypocalcemia (6%, 12%), Hypokalemia (10%, 11%); Skin and subcutaneous tissue disorders: Hyperhidrosis (6%, 16%), Rash (22%, 16%), Night sweats (5%, 13%), Dry skin (9%, 11%), Pruritus (15%, 11%); Nervous system disorders: Dizziness (20%, 17%), Tremor (9%, 13%), Headache (13%, 8%), Neuropathy peripheral (10%, 7%); Investigations: Blood creatinine increased (15%, 11%), Weight increased (1%, 11%), Weight decreased (14%, 8%); Psychiatric disorders: Insomnia (7%, 14%), Confusional state (10%, 13%), Anxiety (11%, 7%); Renal and urinary disorders: Renal failure (15%, 10%).

Grade 3/4 adverse reactions reported in 90% of patients treated with POMALYSTa alone (96/107) and 88% with POMALYST + Low dose Dex (99/112).

Grade 3/4 Adverse Reactions ≥ 5% in either arm, respectively, included: Blood and lymphatic system disorders: Neutropenia (47%, 38%), Anemia (22%, 21%), Thrombocytopenia (22%, 19%), Leukopenia

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In the Literature Gemcitabine Increases Survival for Patients with...

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and OS between the treatment groups support the use of gemcitabine in clinical practice and as the backbone for future studies of adjuvant therapy after the resection of pancreatic cancer. These findings are likely to be representa-

tive of general clinical practice in other countries, because CONKO-001 was a community-based trial that involved academic centers and community-based oncologists without uniform standards for surgery. The researchers are currently testing gemcitabine monotherapy against gemcitabine combination therapy in similar patients.

Long-Term Cetuximab Therapy Shows Early Tumor Shrinkage in Colorectal Cancer

Although colorectal tumors with a mutation in the KRAS gene generally do not benefit from epidermal growth factor receptor (EGFR)-targeted therapy such as cetuximab (Erbitux), there

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13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Studies examining the carcinogenic potential of pomalidomide have not been conducted. One of twelve monkeys dosed with 1 mg/kg of pomalidomide (an exposure approximately 15-fold of the exposure in patients at the recommended dose of 4 mg/per day) developed acute myeloid leukemia in a 9-month repeat-dose toxicology study. Pomalidomide was not mutagenic or clastogenic in a battery of tests, including the bacteria reverse mutation assay (Ames test), the in vitro assay using human peripheral blood lymphocytes and the micronucleus test in orally treated rats administered doses up to 2000 mg/kg/day.

In a fertility and early embryonic development study in rats, drug-treated males were mated with untreated or treated females. Pomalidomide was administered to males and females at doses of 25 to 1000 mg/kg/day. When treated males were mated with treated females, there was an increase in post-implantation loss and a decrease in mean number of viable embryos at all dose levels. There were no other effects on reproductive functions or the number of pregnancies. The lowest dose tested in animals resulted in an exposure (AUC) approximately 100-fold of the exposure in patients at the recommended dose of 4 mg/day. When treated males on this study were mated with untreated females, all uterine parameters were comparable to the controls. Based on these results, the observed effects were attributed to the treatment of females.

17 PATIENT COUNSELING INFORMATION See FDA- approved Patient labeling (Medication Guide).

Embryo-Fetal Toxicity Advise patients that POMALYST is contraindicated in pregnancy [see Contraindicatons (4)]. POMALYST is a thalidomide analog and may cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)].

• Advise females of reproductive potential that they must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy.

• Initiate POMALYST treatment in females of reproductive potential only following a negative pregnancy test.

• Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during POMALYST therapy, during therapy interruption and for 4 weeks after she has completely finished taking POMALYST. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap.

• Instruct patient to immediately stop taking POMALYST and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant.

• Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

• Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy.

• Advise male patients taking POMALYST that they must not donate sperm [see Warnings and

Precautions (5.1) and Use in Specific Populations (8.6)].

• All patients must be instructed to not donate blood while taking POMALYST and for 1 month following discontinuation of POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

POMALYST REMS Program Because of the risk of embryo-fetal toxicity, POMALYST is only available through a restricted program call POMALYST REMS [see Warnings and Precautions (5.2)].

• Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive POMALYST. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)].

• POMALYST is available only from pharmacies that are certified in POMALYST REMS program. Provide patients with the telephone number and website for information on how to obtain the product.

Venous Thromboembolism Inform patients of the potential risk of developing venous thromboembolic events and discuss the need for appropriate prophylactic treatment. Hematologic Toxicities Inform patients on the risks of developing neutropenia, thrombocytopenia and anemia and the need to report signs and symptoms associated with these events to their health care provider for further evaluation.

Hypersensitivity Inform patients of the potential for a severe hypersensitivity reaction to POMALYST if they have had such a reaction in the past to either THALOMID® or REVLIMID®. Dizziness and Confusional State Inform patients of the potential risk of dizziness and confusion with the drug and to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. Neuropathy Inform patients of the risk of neuropathy and report the signs and symptoms associated with these events to their health care provider for further evaluation. Second Primary Malignancies Inform the patient that the potential risk of developing acute myelogenous leukemia during treatment with POMALYST is unknown.

Dosing Instructions Inform patients on how to take POMALYST [see Dosage and Administration (2.1)] • POMALYST should be taken once daily at about the same time each day • POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

• The capsules should not be opened, broken, or chewed. POMALYST should be swallowed whole with water.

• Instruct patients that if they miss a dose of POMALYST, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take POMALYST at the usual time. Warn patients not to take 2 doses to make up for the one that they missed.

Other Information Advise patients who smoke to stop because smoking may reduce the efficacy of pomalidomide [see Drug Interactions (7.2)].

Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

POMBSv.001a 02/13

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8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over. No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm.

8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies.

Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)]. The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. 10 OVERDOSAGE No specific information is available on the treatment of overdose with pomalidomide, and it is unknown whether pomalidomide or its metabolites are dialyzable.

are no current biomarkers to select patients who are more likely to respond to EGFR therapy. In a new study, researchers analyzed data from 2 trials to determine if early tumor shrinkage was associated with long-term outcomes in patients with colorectal cancer receiving first-line treatment with cetuximab (Piessevaux H, et al. J Clin Oncol. 2013;31:3764-3775).

The researchers combined data from the CRYSTAL and the OPUS trials. CRYSTAL was a randomized, open-label, multicenter, phase 3 trial comparing fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI alone.

OPUS was a randomized, open-label, multicenter, phase 2 trial comparing fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) plus cetuximab with FOLFOX-4 alone. The analysis included 1289 patients whose tumors could be analyzed for KRAS mutation status. Patients were followed for a median of 45 months and 32 months in the CRYSTAL and OPUS trials, respectively. Response was assessed every 8 weeks until disease progression or withdrawal.

Both trials showed that a more robust tumor response at 8 weeks after the start of therapy was associated with improved progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild-type tumors.

Early tumor shrinkage of ≥20% could identify patients who were receiving chemotherapy plus cetuximab with longer PFS and OS. In the CRYSTAL and OPUS trials, respectively, the cutoff value of early tumor shrinkage of ≥20% versus <20% for median PFS was 14.1 versus 7.3 months and 11.9 versus 5.7 months, and median survival was 30 months versus 18.6 months and 26 months versus 15.7 months.

The interaction between early tumor shrinkage and the treatment group (with cetuximab) was significantly associated with PFS (P = .027 and P = .004 for CRYSTAL and OPUS data, respectively), but not for survival (P = .573 and P = .546, respectively).

These results suggest that tumor shrinkage can be used as a prognostic biomarker.

In their accompanying editorial, Oxnard and Schwartz state that the study suggests several potential applications, including a response-guided treatment approach in which patients without early tumor response to chemotherapy plus cetuximab are switched to another therapeutic agent (Oxnard GR, Schwartz LH. J Clin Oncol. 2013;31:3739-3741). The findings also have the potential to improve tissue and biomarker discovery, they say. n

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Economics of Cancer Care

Rising Costs of Cancer Survivorship a Growing Concern...

Continued from cover

et al. J Clin Oncol. 2013;31:3749-3757).

Considered in aggregate, this comes to a nationwide expense of approximately $41 billion for patients younger than age 64 years—and for older patients, the figures are even higher.

“Our study demonstrates that cancer survivorship is associated with a considerable economic impact on society,” lead investigator Gery P. Guy, Jr, PhD, MPH, of the Centers for Disease Control and Prevention’s Division of Cancer Prevention and Control, told Value-Based Cancer Care. “Although the economic burden is greatest shortly after diagnosis, we also found that the burden remains high years after a cancer diagnosis.”

The Cost of Surviving Cancer Getting a handle on survivorship costs is of rapidly increasing importance. As of 2012, an estimated 13.7 million Americans are now cancer survivors, and this number is expected to quickly rise as novel treatments, combined with early detection strategies, greatly enhance the life expectancy of the average patient with cancer.

Gains in survival time, if not outright cures, are inevitably associated with a variety of long-term downsides, including cardiotoxicity, sexual dysfunction, incontinence, ongoing pain, fatigue, and so on. Furthermore, survivorship is associated with an ongoing loss of productivity, at work or in the home. Until now, there have been no coordinated analyses of both costs.

“This is the first study to quantify both medical expenditures and lost productivity as a result of cancer survivorship in adults of all ages at the national level,” explained Dr Guy. “We used the same data source for all of our estimates, allowing for important comparisons between groups (older and younger patients) and by type of burden.”

The analysis used data from the Medical Expenditure Panel Survey for the period from 2008 through 2010, comparing responses from 4960 patients with cancer versus more than 60,000 individuals without cancer.

Direct medical costs were assessed by source of payment and service type.

Indirect costs, namely loss of productivity, were estimated by the consideration of employment disability, missed workdays, and lost household productivity.

Aggregate Expenditures in the Billions The results of the analysis show

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“Our study demonstrates that cancer survivorship is associated with a considerable economic impact on society. Although the economic burden is greatest shortly after diagnosis, we also found that the burden remains high years after a cancer diagnosis.”

—Gery P. Guy, Jr, PhD, MPH that recently diagnosed (ie, first-year) cancer survivors (ages 18-64 years) have annual medical costs averaging $17,170 compared with $6485 for longer-term survivors, and $3611 for those who have never had cancer.

For patients aged >64 years, firstyear survivors are paying an average of $23,441 annually compared with

$12,357 for long-term survivors, and $8724 for the control group. For the older patients with cancer, extrapolated aggregate costs exceed $48 billion nationwide.

For the younger patients with cancer cohort, the most common source of payment was private health insurance, whereas the largest payer for older patients was Medicare.

Regarding the general services provided, ambulatory care accounted for the greatest expenditure in the younger cohort, whereas costs for inpatient care accounted for the greater share overall for older patients. Considering the loss of productivity, younger firstyear survivors (ages 18-64 years) took a hit to their paychecks on average of $4694 annually compared with $3593 for longer-term survivors, and $2040 for those without cancer.

For individuals aged >64 years, the average loss of productivity was $6133 for newly diagnosed patients, and $5295 for previously diagnosed patients. In aggregate, lost productivity for both age-groups combined is estimated to be in excess of $26 billion.

The largest share of aggregate loss in productivity for both age-groups came from employment disability ($19 billion), followed by missed workdays ($4 billion), and lost household productivity ($3 billion).

Underestimated Costs?

Dr Guy is quick to point out that

these estimates are still on the low side. For instance, the costs for patients who die within 1 year of a cancer diagnosis were not included, nor were the more nebulous expenses, such as those incurred by the caregivers of cancer survivors.

“We likely underestimated the burden of cancer survivorship among adults by not including caregivers’ productivity losses and the intangible costs associated with pain and suffering….

[However], studies are currently under way to examine the additional costs associated with cancer survivorship.”

In the meantime, is there anything to be done, beyond cancer prevention, to reign in cancer survival costs?

Dr Guy focuses on productivity.

“Efforts to reduce the health and economic burden caused by cancer are important given the burden of cancer survivorship. Cancer survivors may face challenges with returning to, or functioning in work after a cancer diagnosis,” he noted. “Additional research is needed to identify appropriate educational and work modifications to aid in the transition and retention of cancer survivors in the workplace. Such interventions could help maximize employment opportunities and workplace productivity. In addition, ensuring access to lifelong risk-based follow-up care and adherence to survivorship care plans are important components in improving the quality of life among cancer survivors.” n

Panel Recommends Major Changes for Cutting Down Cancer Overdiagnosis and Overtreatment

By Eileen Koutnik-Fotopoulos

F

or the past 30 years, awareness and screening have led to an emphasis on the early diagnosis of cancer. The goals were to get screened and to catch cancer early to reduce the rate of late-stage disease and to decrease cancer mortality. However, improved screening has resulted in the overdiagnosis and overtreatment of cancers that are not life-threatening, without significantly decreasing the death rate from the disease. In March 2012, the National Cancer Institute (NCI) convened a meeting to review the evidence on overdiagnosis.

In a recently published article, a working group has issued a call for major changes in the way the medical profession classifies and thinks about cancer, and in the way screening programs are designed (Esserman LJ, et al. JAMA. 2013;310:797-798).

The working group outlined 5 major recommendations for the NCI to consider.

1. The first is for physicians, patients, and the general public to recognize that overdiagnosis is common and occurs frequently with cancer screening. Overdiagnosis is com-

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mon in breast, lung, prostate, and thyroid cancers. Whenever screening is used, the fraction of tumors in this category increases. “By acknowledging this consequence of screening, approaches that mitigate the problem can be tested,” wrote the working group.

2. The second recommendation is to reserve the term “cancer” for describing lesions with reasonable likelihood of lethal progression if left untreated. For example, premalignant conditions should not be Continued on page 28

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Economics of Cancer Care

PET Use for NSCLC Management Has Altered Resource Utilization, Increased Cost

By Charles Bankhead

Atlanta, GA—The adoption of positron emission tomography (PET) imaging for the management of patients with non–small-cell lung cancer (NSCLC) has had a mixed impact on clinical and economic outcomes, according to findings from a large retrospective cohort study.

The use of PET was associated with upstaging of early-stage disease and a reduction in “futile” attempts to control occult metastatic disease. As the adoption of PET increased, the use of radiotherapy and surgery declined, as did short-term inpatient costs. The use of chemotherapy increased, which was associated with higher overall costs.

“The ability of PET to affect patient management, healthcare resource use, and costs remains an important area of ongoing research,” Michaela A. Dinan, PhD, Medical Instructor, Department of Medicine, Duke University School of Medicine, Durham, NC, said at the 2013 American Society for Radiation Oncology annual meeting.

The study represented an extension of previous work by Dr Dinan and colleagues to ascertain changes in the use of imaging in Medicare patients with cancer. That analysis showed that from 1999 to 2006, the use of PET in Medicare patients with cancer increased substantially (Dinan MA, et al. JAMA. 2010;303:1625-1631). The overall cost of cancer care increased by 2% to 5% annually during the study period, but the cost of imaging

increased by 5% to 10% annually.

The greatest increase in PET utilization occurred in patients with NSCLC. At the start of the study, few, if any, patients underwent PET imaging. By the end, more than 50% of patients had PET imaging at some point. “We found that no matter which subgroup of patients we looked at, all patients experienced large increases in PET use during the study period,” said Dr Dinan.

“No matter which subgroup of patients we looked at, all patients experienced large increases in PET use during the study period….This study suggests that PET has played a role in the upstaging of early-stage NSCLC and a corresponding reduction in futile attempts at local control of occult metastatic disease.”

—Michaela A. Dinan, PhD

The team also found that increasing the use of PET was associated with the identification of more patients with advanced disease, which led to

a closer look at resource utilization.

“The presumption that appropriate detection of occult metastatic disease should reduce associated healthcare costs remains an open question at the population level,” said Dr Dinan.

The Study Results To address the question, the team used the National Cancer Institute’s Medicare-linked Surveillance, Epide­ miology, and End Results database to identify patients with NSCLC between 1996 and 2005, examining treatment utilization and the associated costs accrued within the first year after diagnosis.

Dr Dinan and colleagues hypothesized that the increasing use of PET would be associated with a decreased use of radiotherapy and surgery and lower short-term and total healthcare costs in the management of NSCLC. Patients were grouped by years according to the evolution of PET use, resulting in cohorts of 9638 patients in the pre-PET era (1996-1997), 9551 patients in the initial-PET era (20002001), and 11,814 patients in the postPET era (2004-2005).

The proportion of patients with NSCLC who underwent PET increased from 0.2% in the pre-PET period to 17.5% during initial PET use to 53.5% in the post-PET period (P <.001 for trend). This increased use was not associated with significant improvements in 2-year survival (28.7% in 1996-1997 and 29.9% in 2004-2005).

Panel Recommends Major Changes... labeled as cancers, nor should “cancer” be in the name. Diagnostic tools that identify indolent or low-risk cancers also need to be adopted and validated.

Another change is to reclassify such cancers as indolent lesions of epithelial origin (IDLE) conditions. The writing group suggests that “multidisciplinary effort across the pathology, imaging, surgical, advocate, and medical communities could be convened by an independent group (eg, the Institute of Medicine) to revise the taxonomy of lesions now called cancer and to create reclassification for IDLE conditions.”

3. The third recommendation is to create observational registries for le-

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sions with low malignant potential.

This would improve information about related disease progression and help patients and clinicians decide on a treatment plan.

4. The fourth recommendation is to mitigate overdiagnosis by developing strategies to reduce the detection of indolent disease, such as reducing low-yield diagnostic evaluations, reducing the frequency of screening examinations, focusing screening on high-risk populations, and raising thresholds for recall and biopsy.

5. The final recommendation is to expand the approaches to cancer progression and treatment. “Future research should include controlling

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the environment in which precancerous and cancerous conditions arise, such as an alternative to surgical incisions,” wrote the working group.

The panel noted that these recommendations are only initial approaches. Policies that prevent or reduce the chances of overdiagnosis and overtreatment are needed. Physicians and patients are urged to have open discussions about these complex issues.

The media also must begin to better comprehend and communicate these messages to the public about the potential hazard of overdiagnosis and overtreatment of cancer to ensure that the approach to screening for cancer can be improved. n

at a glance ➤ PET imaging upstages earlystage NSCLC, reduces futile attempts to control occult metastatic disease ➤ As PET use increased, radiotherapy and surgery declined, as did short-term inpatient costs ➤ A new study shows that inpatient costs averaged $28,924 per patient in the pre-PET period and $26,944 in the post-PET period ➤ Outpatient costs increased from $18,411 to $25,266, and PET use increased from $0 to $741 ➤ PET use was associated with more patients identified with advanced NSCLC

As hypothesized, the use of radio­ therapy declined from 49.4% of patients in the pre-PET era to 42.9% in the post-PET period; the use of any type of surgical resection decreased from 29.1% to 24.7%; and the proportion of patients who received no treatment increased from 22.0% to 24.7% (P <.001 for all).

Inpatient costs averaged $28,924 per patient in the pre-PET period and $26,944 in the post-PET period. Outpatient costs increased from $18,411 to $25,266, and costs associated with PET use increased from $0 to $741, resulting in a net increase in total costs from $47,335 to $52,209 (P <.001 for all).

Using 1996 to 1997 as the reference point, the rate of surgical resection was significantly lower each year from 2001 (odds ratio [OR], 0.87) to 2004 (OR, 0.72). The proportion of patients receiving radiation therapy declined significantly starting in 2002 (OR, 0.85), and was 19% lower in 2004 (OR, 0.81).

In contrast, the growth in use of chemotherapy for NSCLC began in the first year after the reference period (OR, 1.30), increasing by more than 2-fold by 2003 (OR, 2.08) and 2004 (OR, 2.52).

“Consistent with previous research, this study suggests that PET has played a role in the upstaging of early-stage NSCLC and a corresponding reduction in futile attempts at local control of occult metastatic disease,” Dr Dinan concluded. n

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Now enrolling

Investigating ABT-199 (GDC-0199) in Chronic Lymphocytic Leukemia Phase II Open-Label Study of the Efficacy and Safety of ABT-199 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia Harboring the 17p Deletion N=100

ABT-199 is an investigational agent that has not been approved by regulatory agencies for the use under investigation in this trial.

Primary Endpoint

Secondary Endpoints

• Overall response rate

• • • • • • • •

Complete remission rate Partial remission rate Duration of response Progression-free survival Time to progression Overall survival Percentage of patients who move on to stem-cell transplant Safety and tolerability of ABT-199

Key Inclusion Criteria • Adult patients ≥18 years of age • Diagnosis of CLL that meets 2008 IWCLL NCI-WG criteria (relapsed/refractory after receiving ≥1 prior line of therapy and 17p deletion) • ECOG performance score of ≤2 • Adequate bone marrow function • Adequate coagulation, renal, and hepatic function, per laboratory reference range

NCT#01889186 Reference: ClinicalTrials.gov.

@ 2013 Genentech USA, Inc. All rights reserved. BIO0001961500 Printed in USA.

To learn more about this study, please visit www.ClinicalTrials.gov.

Economics of Cancer Care

Can FDA Drug Approval Keep Pace with Translational Research?

By Audrey Andrews

Amsterdam, The Netherlands—With the development of targeted therapies, there has been a clear evolution in the pathway to the approval of drugs by the US Food and Drug Administration (FDA), and a rapid approval of a drug after phase 1 clinical trials, which show definitive proof of activity and safety, and “breakthrough” designation, are now possible.

“We are ready for a significant acceleration in the pace of drug approvals,” said Bruce A. Chabner, MD, Professor, Department of Medicine, Harvard Medical School, Boston, who described the new FDA approval algorithm at the 2013 European Cancer Congress.

gefitinib (Iressa) proved ineffective in the third-line treatment of unselected patients with non–small-cell lung cancer (NSCLC) “in a poorly designed trial,” Dr Chabner said, and bevaciz­ umab (Avastin) failed in the first-line setting of HER2-negative breast cancer.

Accelerated FDA Approval The possibility of faster drug approval started with the targeted drug trastuzumab (Herceptin) around 2000.

Because targeted molecular agents are directed at treating the patients who are the most likely to benefit, activity emerges early in the trial process, making it probable that the drug will show benefit in later-phase trials.

Between 2003 and 2010, some 15 targeted agents received accelerated FDA approval, although not all panned out in the long-run: 2 ultimately failed—

“These are important new compounds that are producing significant responses and clinical benefits in difficult-to-treat situations. They are likely to get accelerated approval.”

at a glance ➤ The FDA’s drug approval process is changing to meet the ever-smaller patient subpopulations of cancer-related targeted therapies ➤ The possibility of a faster approval track began with the introduction of targeted molecular agents, starting with trastuzumab ➤ The new designation of “breakthrough therapy” has changed the drug development paradigm ➤ Rather than waiting for phase 3 trial data, an accelerated approval of targeted agents can occur if the phase 1 clinical trials show conclusive evidence of efficacy and safety ➤ The pace of accelerated approvals will increase if trials are done well and have good patient selection

30

Changing the Paradigm: “Breakthrough Therapy” Designation The value of accelerated drug approval was shown with the “game-changing” drug crizotinib (Xalkori) in patients with EML4 ALKpositive NSCLC. Approximately 4%

—Michaela A. Dinan, PhD of patients have the ALK translocation, and crizotinib showed striking results in this subpopulation. “Virtually all patients experienced tumor shrinkage, lasting about 8 months on average,” Dr Chabner said. “This is remarkable in the context of NSCLC.” Accelerated approval was granted within 3 years of development, based on phase 1 and phase 2 trials.

Crizotinib was also effective in patients with the rare ROS1 kinase mutation, which is confined to 1% of patients with NSCLC. In a phase 1 study of 35 ROS1-positive patients, the overall response rate was 60%, and 80% of the patients achieved disease control; these results will likely lead to FDA approval of crizotinib for this subset of patients, Dr Chabner predicted.

Crizotinib is a good example of how the drug approval process must change to meet the needs of eversmaller patient subpopulations, he said. The ability of crizotinib to show such clear efficacy in phase 1 trials triggered a change and opened the door to drug approvals after phase 1 trials when “the evidence is sufficient,” Dr Chabner said.

In 2012, Congress established the breakthrough therapy designation to

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expedite access to drugs that show substantial improvement on a clinical

“The pace of FDA approvals in cancer is accelerating.

If you do a trial well and have good patient selection, getting rapid approval after phase 1 trials is very likely.”

—Bruce A. Chabner, MD end point or improved safety compared with available therapies. The designation creates an early and intensive FDA guidance during the drug development process, a rolling New Drug Application (NDA) process, and an expedited development and review.

Since 2012, the FDA has received 64 breakthrough therapy designation requests; 21 were granted, 22 are under consideration, and 21 were denied.

“Breakthrough” Cancer Drugs in the Pipeline The list of current cancer drugs designated as “breakthrough therapy” includes 2 “new and better” ALK inhibitors, Dr Chabner said, a Bruton’s tyrosine kinase (BTK) inhibitor for hematologic malignancies, a cyclin-dependent kinase (CDK) 4/5 inhibitor for breast cancer, and a programmed death (PD)-1 inhibitor for solid tumors.

LDK378, the drug most likely to be approved first on this list, is a potent and selective oral ALK inhibitor that provides durable responses in mouse models, including models of crizotinib resistance. In a study of 78 patients, the overall response rate was 60%, with no differences among patients who had received or were naïve to crizotinib therapy. Only 2 patients discontinued the drug, because of adverse events.

“These are quite impressive re-

sults,” Dr Chabner noted. “Virtually all patients have tumor regression, both in previously treated and untreated groups.”

An NDA for LDK378 has been submitted, confirmatory phase 2 studies are recruiting, and phase 3 studies are planned with LDK378 versus chemotherapy in previously crizotinib-treated and untreated patients.

“My hope is that patients will not be denied the better drug for the sake of testing it versus chemotherapy,” Dr Chabner commented.

To date, more than 500 patients have received LDK378. Although fewer patients have used AF802, the other ALK inhibitor with a breakthrough therapy designation, this is also a very promising agent that is active in crizotinib-naïve and previously treated patients, Dr Chabner said.

Because most patients with ALKpositive NSCLC develop resistance to crizotinib within 2 years, these new, potent ALK inhibitors will be important. Both drugs are also active in patients with brain metastases, and visual abnormalities are less frequent than with crizotinib.

The BTK inhibitor ibrutinib has been studied in chronic lymphocytic leukemia, Waldenström’s macroglobulinemia, and in non-Hodgkin lymphoma (NHL), with a 90% progression-free survival rate seen in patients with NHL. Palbociclib, the CDK 4/5 inhibitor, is active in metastatic breast cancer, and lambrolizumab, the PD-1 inhibitor, is active in renal and lung cancers and melanoma.

“These are important new compounds that are producing significant responses and clinical benefits in difficult-to-treat situations. They are likely to get accelerated approval,” Dr Chabner predicted.

“Indeed, the pace of FDA approvals in cancer is accelerating,” he said. In 2011, there were 15 approvals, with 2 accelerated approvals, and 8 drugs were new chemical entities. In 2012, there were 23 cancer drug approvals, 5 accelerated approvals, and 12 new chemical entities. The pace has continued in 2013, with several accelerated approvals.

Dr Chabner suggested that accelerated approvals will only increase. “If you do a trial well and have good patient selection, getting rapid approval after phase 1 trials is very likely,” he concluded. n

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Recent Surveys Highlight Ongoing Challenges for Oncology Practices 72% of practices plan to send Medicare patients to hospitals or refuse to treat them

By Caroline Helwick Hollywood, FL—Many current forces are colliding to challenge community oncology, according to David Eagle, MD, Immediate Past President of Community Oncology Alliance (COA), Lake Norman Oncology, Mooresville/ Huntersville, NC. At the 3rd Annual Conference of the Association for ValueBased Cancer Care, Dr Eagle described the seriousness of the plight faced by community oncology practices.

Approximately 1250 oncology practices have been affected by changes in cancer care over the past 5 years, either closing, struggling financially, sending patients elsewhere for chemotherapy, or merging with other entities. “This picture’s worth a thousand words and it recaps where we are today,” Dr Eagle said (Figure 1).

With the Medicare Modernization Act (MMA) of 2003, reimbursement shifted to the average sales price (ASP) + 6%. The problem is that this was never tested through demonstration or pilot projects, but purely through financial modeling “on the fly,” Dr Eagle said.

The MMA did create payment for infusion services, but the payment amounts for these infusion codes have been cut significantly since then.

These cuts are becoming more obvious from surveys conducted by COA and others. Based on data from 499 physicians in 2008, COA, in partnership with Avalere Health, documented that Medicare covered only 57% of the cost of drug administration.1 “If we are paid for what we do, but it does not match up with the expense component, this creates a problem,” Dr Eagle said.

Current Impact Over the past few years, private payers have gradually migrated to the ASP payment system, and the cross subsidy for underpayments has been disappearing. “I think that explains why the MMA of 2003 has taken several years to fully surface,” Dr Eagle suggested.

Oncology practices are doing all they can to adjust to these changes, including seeing more new patients— an estimated 345 annually now, up from 235 approximately 10 years ago.

“We’re adjusting as much as we possibly can,” Dr Eagle said.

Cuts related to the sequester have aggravated the situation. The Centers for Medicare & Medicaid Services applied a 2% cut to the entire 106%

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of chemotherapy payments, which reduced ASP + 6% to ASP + 4.3%.

Consequently, a recent COA survey showed that 72% of practices plan to send Medicare patients to the hospital, or to not see Medicare patients at all.2 “This has become a prominent national and even international story, and we welcome that,” Dr Eagle commented.

In Dr Eagle’s state of North Carolina, Congresswoman Renee Ellmers introduced H.R. 1416, the Cancer Patient Protection Act of 2013, which now has 102 cosponsors. The bill aims to terminate the application of sequestration to payments for physician-administered chemotherapy drugs under Part B of the Medicare program. Currently, the sequestration cut is applied to these drugs, forcing many physicians to refer patients to hospitals for treatment, because Medicare payments are less than their costs. The bill is currently in the House Subcommittee on Health.

The referral of patients receiving chemotherapy to hospitals impacts all stakeholders. The 2011 Milliman Client

Report from US Oncology used a limited Medicare data set for the years 2006 to 2009, and calculated the per-member per-month cost of chemotherapy. They figured this at $4361 for chemothera-

py delivered in the physician’s office versus $4981 for that delivered in the hospital outpatient setting. The annual costs were $47,500 versus $54,000, and the annual patient out-of-pocket ex-

Figure 1 Where Are We? Community Oncology Practice Impact Report

• Clinics closed • Practices struggling financially • Practices sending patients elsewhere • Hospital agreement/purchase • Merged/acquired by another entity Source: Community Oncology Alliance Practice Impact Tracking Database.

Figure 2 Medicare Payment Reform for Oncology Ensuring the Delivery of Quality and Value-Based Cancer Care—Working Draft v7 (2-3-13) Phase 1

Phase 2

Phase 3

Phase 4

Drugs at ASP + 6% E&M Oncology/ hematology services Quality reporting

Drugs at ASP + 6% E&M Oncology/hematology services Quality and value Performance

Drugs at ASP + 6% E&M Oncology/hematology services Shared savings

Episode of care (Drugs and services) Shared savings

Implement within 1 year

Implement within 2 years

Implement within 3 years

Implement within 5 years

Current FFS payment structure for drugs and services (E&M and oncology/hematology specific codes)

Current FFS payment structure for drugs and services (E&M and oncology/hematology specific codes)

Current FFS payment structure for drugs and services (E&M and oncology/hematology specific codes)

Additional payment tied to measures reporting and OPS reporting—0%-2% QVA based on formula

Additional payment or decrease tied to relative measures performance and OPS performance: –2% to 5% QVA based on a specific formula; any increases from phase 1 built into formula such that phases 1 and 2 are revenue neutral

Additional 50/50 shared savings benchmarked against national or regional comparison group

Practice is paid based on a predetermined episode of care (by cancer type; adjuvant and metastatic) that combines services and drugs; a demonstration project will be fielded by CMS at least 3 years before national implementation in order to develop/ refine episode payments

Compliance with measures/OPSa reporting qualifies practice to receive MEI increase

Compliance with measures/OPSb reporting qualifies practice to receive MEI increase

Savings quantified relating to emergency department utilization and hospitalizations, and overall treatment costs including drugs.

Imaging and radiation costs also included in the shared savings calculation. Practices must hit established quality measures/ OPSb targets to qualify for any savings Compliance with measures/OPSb reporting qualifies practice to receive MEI increase

Shared savings benchmarked against comparison group as in phase 3, but increases to 60/40 (practice/Medicare) for greater risk assumption by providers MEI increase applied to episodeof-care payments Measures are stage I, II, and III (III if feasible), to-be-developed outcomes measures, and full OPS reporting

Measures are stage I (see following pages) and full OPS reporting.

Measures are stage I and II and full OPS reporting.

NOTE: Assumes suspension of the SGR for oncology/hematology.

Oncology/hematology services include infusion, imaging, radiation, and others provided.

ASP indicates average sales price; CMS, Centers for Medicare & Medicaid Services; E&M, evaluation and management; FFS, fee-for-service; MEI, Medicare Economic Index; OPS, oncology patient satisfaction; QVA, quality/value adjustment; SGR, sustainable growth rate. a

b

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3rd Conference

Recent Surveys Highlight Ongoing Challenges for... pense differential was $650.3 In another study, COA and Avalere examined data from private payers from 2008 to 2010 for patients receiving 12 or fewer months of chemotherapy, measuring all costs of medical and pharmacy services in 30-day increments at the start of each episode.4 The average cost of an episode was $28,200 in the physician’s office versus $35,000 in the hospital outpatient department.4 This amounted to a 24% difference, adjusted for age, previous cancer history, and sex, and even greater in the absence of these adjustments, Dr Eagle reported.

Of note, the rate of hospitalizations per 100 patients was 14 among hospital-managed patients versus 11 for office-managed patients.

Draft Model for Medicare Payment Reform COA has drafted a model for Medicare payment reform (Figure 2).

The first phase ties additional payments to patient satisfaction. “If you do that successfully, you get cost of living increases, medical economic index adjustments in your payments,” Dr Eagle said.

“The second phase is similar, but you can get a decrease or an increase, depending on how you perform,” he said. “In the third phase, you move to a shared savings model that is benchmarked against regional or national comparison groups. The final phase bases most of the payments around the episodic care payment model.”

“bottom-up” strategies, such as clinical pathways, episode-of-care models, and so forth, whose foundation is the oncologist.

“Our organization is spending a lot of time on the oncology medical home model,” he said. “The strength of this model is that it doesn’t just focus on one thing, but puts together multiple

“The strength of this [oncology medical home] model is that it doesn’t just focus on one thing, but puts together multiple opportunities for coordination of care, open access, and so forth.”

—David Eagle, MD

Actionable Programs Although there are “top-down” strategies for improving value in oncology, such as accountable care organizations, Dr Eagle is interested in

opportunities for coordination of care, open access, and so forth.”

Such a model incorporates concepts such as same-day evaluation and treatment to help patients avoid the

Continued from page 31

emergency department, standardized processes for patient evaluation, measurement of performance and compliance to pathways, and monitoring of costs.

Finally, Dr Eagle stressed the importance of oncologists working as part of a multistakeholder team, bringing together providers, patients, industry, payers, and nursing and pharmacy representatives “to have the conver­ sation about what oncology should look like.” n References

1. Community Oncology Alliance, Avalere Health.

Providing high quality care in community oncology practices: an assessment of infusion services and their associated costs. February 2010. www.communityon cology.org/pdfs/avalere-coa-components-of-carestudy-final-report.pdf.

2. Community Oncology Alliance. Sequestration started; countdown to cancer care cuts. March 4, 2013. www.communityoncology.org/site/blog/ detail/2013/03/04/sequestration-started-count down-to-cancer-care-cuts.html.

3. Fitch K, Pyenson B. Site of service cost differences for Medicare patients receiving chemotherapy.

Milliman Client Report. October 19, 2011. http:// publications.milliman.com/publications/health-pub lished/pdfs/site-of-service-cost-differences.pdf.

4. Community Oncology Alliance. Studies document efficiency of community oncology, but threats from consolidation. July 31, 2012. www.community oncology.org/site/blog/detail/2012/07/31/break ing-news-studies-document-efficiency-of-communi ty-oncology-but-threats-from-consolidation.html.

Community Oncology Care Improves Outcomes, Adds Value in the New Models of Cancer Care Multidiscipline involvement is crucial

By Caroline Helwick Hollywood, FL—As new models of oncology care evolve, they should not dismiss the importance of multi­ discipline involvement, Thomas A. Marsland, MD, President, Integrated Community Oncology Network, Orange Park, FL, maintained in his talk at the 3rd Annual Conference of the Association for Value-Based Cancer Care. Dr Marsland is also Past President of the Florida chapter of the American Society of Clinical Oncology.

Many specialists are involved in the diagnosis, treatment, and follow-up care for cancer. Dr Marsland envisions a multidisciplinary practice that brings together, within a cancer center model, disparate groups using ancillary-type revenue from radiation, imaging, laboratory services, and so forth to provide incremental revenue to practitioners that may entice them to stay independent.

Multidisciplinary specialties could

32

be a viable model for cancer care in the future, Dr Marsland said. The trend in alternative payment models, such as accountable care organizations and medical homes, is to foster a multidis-

the true integration of clinical care, he emphasized.

“The key thing is, it will not be ‘one size fits all,’” Dr Marsland added.

“Markets are going to be different,

“The key thing is, it will not be ‘one size fits all.’ Markets are going to be different, and you will have to be a dominant player in your market. You don’t have to be the dominant player, but you have to be big enough that you can’t necessarily be excluded or frozen out of a system that’s looking to provide cancer care.”

—Thomas A. Marsland, MD

ciplinary team approach—to get rid of fragmentation and duplication for better coordination of care. This requires

Value-Based Cancer Care

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NOVEMber 2013

and you will have to be a dominant player in your market. You don’t have to be the dominant player, but you

have to be big enough that you can’t necessarily be excluded or frozen out of a system that’s looking to provide cancer care.”

Value Has Always Been There, in the Community Care Model Dr Marsland takes exception to the idea that there has not been value in oncology. “I think the oncology care in the United States is the best in the world. Deaths rates have declined 20% in the last 20 years. I think part of this is due to this whole world of practice that I grew up in—the buy-and-bill, fee-for-service, community-based, infusion-model therapy. Access to quality care in the community has had an impact on survival,” he insisted.

The ability to provide most cancer care in a community setting has been a big part of the value proposition, Dr Marsland suggested. “But now we are Continued on page 37

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No. 9

SHOULDN’T A PATIENT SUPPORT PROGRAM BE EASY TO NAVIGATE?

• REIMBURSEMENT SERVICES

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An uncommon condition requires a common solution— IncyteCARES IncyteCARES helps connect your patients with intermediate or high-risk myelofibrosis (MF), who qualify for the program, to ongoing support and resources during their treatment with Jakafi® (ruxolitinib).

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

•Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are

each dose-related effects, with the most frequent being thrombocytopenia and anemia • Monitor CBCs, and in patients with cytopenias, consider dose reductions, temporarily withholding Jakafi, or transfusions, as clinically indicated Please see additional Important Safety Information and the Brief Summary of Full Prescribing Information within this ad.

HELPING PATIENTS RECEIVING JAKAFI ® (ruxolitinib) STAY CONNECTED TO CARE

Patients living with intermediate or high-risk MF face many challenges. IncyteCARES is a program created by Incyte to connect patients who qualify for the program to ongoing support and resources during their treatment with Jakafi.

IncyteCARES HELPS PEOPLE BEING TREATED WITH JAKAFI ACCESS AND REIMBURSEMENT SERVICES

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Visit www.IncyteCARES.com or call 1-855-4-JAKAFI (1-855-452-5234), Monday–Friday, 8 AM –8 PM ET, to learn more about how to connect your patients to IncyteCARES.

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Enrollment sent to

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86% of commercially insured patients had co-pays of less than $100/month

Information is based upon 1421 patients enrolled in IncyteCARES between April 1, 2012 and April 1, 2013.

91% of patients referred to the IncyteCARES commercial co-pay assistance program were eligible for assistance Important Safety Information (continued)

•Risk of Infection: Assess patients for signs and symptoms of infection and initiate

appropriate treatment promptly. Serious infections should have resolved before starting therapy with Jakafi • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache Please see additional Important Safety Information and the Brief Summary of Full Prescribing Information within this ad.

Jakafi is a registered trademark of Incyte Corporation. © 2013, Incyte Corporation. All rights reserved. RUX-1227e 07/13

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 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 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pretreatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur.

Active serious infections should have resolved before starting therapy with Jakafi. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected [see Adverse Reactions].

ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.

Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discontinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; however, it has not been established whether discontinuation of therapy contributed to the clinical course in these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.

Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled Study During Randomized Treatment Jakafi Placebo (N=155) (N=151) Adverse All All Grade 3 Grade 4 Grades Grade 3 Grade 4 Reactions Gradesa (%) (%) (%) (%) (%) (%) Bruisingb 23.2 0.6 0 14.6 0 0 Dizzinessc 18.1 0.6 0 7.3 0 0 Headache 14.8 0 0 5.3 0 0 Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 Weight Gaine 7.1 0.6 0 1.3 0.7 0 Flatulence 5.2 0 0 0.7 0 0 Herpes Zosterf 1.9 0 0 0.7 0 0 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 hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain f includes herpes zoster and post-herpetic neuralgia

Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern was observed in patients regardless of whether they had received transfusions during therapy. In the randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.

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% versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Grade 4 (%) 0 3.3 1.3

a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0

Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transaminase (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 with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations.

DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent administration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacodynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.

Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses 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 teratogenicity. 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 the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).

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 reactions in nursing infants from Jakafi, a decision should be made 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 Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differences 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 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) 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 normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full Prescribing Information].

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

U.S. Patent No. 7,598,257 © 2011-2013 Incyte Corporation. All rights reserved.

Issued: June 2013 RUX-1216

Personalized Medicine

Practical Problems Must Be Overcome to Move Personalized Medicine Forward in Oncology

By Wayne Kuznar

Boston, MA—Incorporating personalized medicine into everyday oncology clinical practice will require new paradigms in an effort to match patients with cancer with the appropriate therapies, as well as attempts to treat solid tumors at an earlier stage with targeted agents, said Razelle Kurzrock, MD, Director, Center for Personalized Cancer Therapy, University of California, San Diego (UCSD) Moores Cancer Center, at the Second Global Biomarkers Consortium annual conference.

“In a very real way, it’s very hard to institute personalized medicine both in clinical trials and in the community,” Dr Kurzrock said.

A practical problem to implementing personalized medicine is that common cancers are difficult to treat, especially in the metastatic setting, because each tumor may embody more than 100 different diseases, and multiple subtypes of each tumor exist. “Even if some of these tumors have things in common, the individual landscape of each patient may be very distinct,” said Dr Kurzrock.

Molecular Testing and Clinical Trials Molecular testing of tumors can make a difference in early clinical trials. “The old way of thinking was that we need-

the drugs with the right patient is crucial to the future of oncology, and maybe to all of medicine.”

Although the tools to match patients with target-based agents are becoming

“The old way of thinking was that we needed new drugs to treat patients. We do need new drugs, no question about it, but very fundamentally, it doesn’t matter how good your drug is: if you don’t give it to the right set of patients, it’s not going to work.”

—Razelle Kurzrock, MD

ed new drugs to treat patients,” she said. “We do need new drugs, no question about it, but very fundamentally, it doesn’t matter how good your drug is: if you don’t give it to the right set of patients, it’s not going to work. Matching

available, “in a practical way, this is hard to do.”

Even in early-phase clinical trials, matching patients to targeted agents can produce high response rates, even in difficult-to-treat populations.

The Profile-Related Evidence De­ termining Individualized Cancer Thera­py (PREDICT) study used a histology-independent targeted approach in which multiple molecular aberrations were assessed and were used to match patients with targeted agents.

When the study started in 2008, molecular profiling was primitive, and single-gene assays were used to identify 12 genetic mutations. Conventional therapy had failed in all 1144 patients who were enrolled in PREDICT. Molecular aberrations were found in up to 73% of patients, and did not segregate by tumor histology. Most of the molecular aberrations that were identified were “actionable.”

Patients for whom a matched therapy was available in a phase 1 setting had a complete or partial response rate of 27%, whereas patients who did not have a matching therapy had a response rate of only 5%.

Progression-free survival improved with the phase 1 matched therapy but not with the unmatched therapy

Continued on page 40

3rd Conference

Community Oncology Care Improves Outcomes, Adds Value in...

Continued from page 32

being asked to provide better-quality care and attain higher survival rates, at a reduced cost. What they are asking for is a relative value increment,” he said.

Rising healthcare costs cannot continue indefinitely. Costs are rising because more patients are living longer using costly therapies delivered amid systemic inefficiencies, Dr Marsland suggested.

The new models stress patient-centric quality outcomes that will be measured and rewarded. Across the models there are some consistent elements. One important component is that patients and physicians are integral to the development and testing of the models. Unfortunately, this was not done for the Medicare Modernization Act of 2003, when average sales price + 6% was instituted, Dr Marsland noted.

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Who Will Chart the Value Course?

“The question again is, who gets to decide? Who will be charting the future?” Dr Marsland continued. “I think it’s partly the role of organized

The main driver will be data, he said, “but what data, and data collected by whom?” Although physicians, payers, and industry are all collecting data, it is important that these data are

“I think the oncology care in the United States is the best in the world….Access to quality care in the community has had an impact on survival.”

—Thomas A. Marsland, MD

medicine to drive these changes and be involved in defining what value and quality really are.”

shared, Dr Marsland emphasized.

“I think that’s been part of the problem in the past, with some of the pay-

NOVEMber 2013

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ers not always sharing cost data. They were asking us to help to control costs, but we didn’t really always know what those costs were,” he pointed out.

That enlarging database now includes genomics and proteonomics. This will increasingly impact drug development, clinical trial design, and drug usage, including treatment off label.

Finally, one of the biggest tasks will be to establish the best means of compensating for the attainment of “value,” Dr Marsland concluded. “We live in a relative value unit (RVU) world, based on CPT [Current Procedural Terminology] and ICD-9 [International Classification of Diseases, Ninth Revision] codes. Compensation is often based on RVUs, yet for many of these new things, there are no RVUs assigned. How will we address these issues? These are challenges that we face going forward in all of this.” n

www.ValueBasedCancerCare.com

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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 $1,544 per 3.5-mg vial as of July 2013 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.

Personalized Medicine

Practical Problems Must Be Overcome... compared with previous conventional therapy. Overall survival improved with the matched treatment (RAF/ MEK inhibitor) compared with the unmatched treatment.

The Challenge of Relapsed Disease Another practical problem with personalized medicine in oncology is that patients withB:7”metastatic disease

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.

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NEPA3X0007_Payer_Ad_TABLOID_r6.indd Value-Based Cancer3

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usually relapse. Chronic myelogenous leukemia (CML) is a fatal disease that has been transformed with imatinib (Gleevec) therapy, with median survival extended to 20 to 25 years, but

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 © 2013, Millennium Pharmaceuticals, Inc. V-12-0306 All rights reserved.

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such success is rare with solid tumors.

The conventional wisdom is that solid tumors are more complex than CML, and elucidating combinations of therapies to treat solid tumors is a herculean task because of this complexity, Dr Kurzrock said.

The conventional wisdom, however, does not account for the precipitous decline in response rates with advancing disease in patients with CML. In the blast crisis, median survival is only approximately 12 months, and patients develop resistance. “That sounds a little bit like solid tumors to me,” said Dr Kurzrock.

“In the future, we’ll have to train oncologists in genomics.”

—Razelle Kurzrock, MD The transformation in CML outcomes was made possible by treating newly diagnosed disease. “We have not done that in solid tumors,” Dr Kurzrock said. “Comparing metastatic solid tumors to newly diagnosed CML is not an apt comparison.” A practical solution to enhancing outcomes with personalized medicine in solid tumors, therefore, is to treat newly diagnosed patients.

B:10”

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.

Continued from page 37

Host Individual Differences The future of personalized medicine in oncology is actionable cancer gene sequencing, but a practical problem is host individual differences. “The host reaction may be critical to how the tumor responds and also critical to toxicity,” Dr Kurzrock pointed out.

Tumor microheterogeneity is another practical problem. The molecular profile can differ even within a single lesion. A potential solution is liquid biopsy to obtain cell-free or circulating DNA from patients with tumors, and performing gene sequencing on this DNA. The technology is moving rapidly.

A lack of training in genomics is a barrier to personalized cancer therapy trials and treatment. “In the future, we’ll have to train oncologists in genomics,” Dr Kurzrock noted.

Another challenge is proving the concept of personalized medicine. To this end, the Worldwide Innovative Networking in Personalized Cancer Medicine trial has been initiated as a signature global trial with genomics and transcriptomics used to navigate patients with end-stage cancer to clinical trials. n

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Personalized Medicine

Bronchial/Nasal Gene-Expression Tests for Early Detection of Lung...

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good surrogate for what’s going on deeper within your lung,” Dr Spira said at the Second Global Biomarkers Consortium annual conference.

Evolving Biomarkers for Lung Cancer Diagnosis Because the discovery of molecular biomarkers has not yet resulted in cures with the use of targeted therapies, efforts should be directed toward early detection and screening.

Currently, fewer than 1 of 5 patients with lung cancer is diagnosed at stage I, a potentially curable stage, and a similarly small proportion is alive 5 years after their diagnosis, Dr Spira said.

The vast majority of lung cancers occur in persons with a history of tobacco smoke exposure, but only 10% to 15% of smokers will develop lung cancer during their lifetime. The challenge, said Dr Spira, is how to identify the high-risk subset.

The National Lung Screening Trial (NLST) was a landmark study that found that annual computed tomography (CT) scans of the lung in asymptomatic smokers reduced lung cancer mortality by 20%. By the inclusion criteria used in the NLST (ie, age >50 years, >30 pack-years of smoking), approximately 9 million individuals in the United States would be eligible

at a glance ➤ Many bronchoscopies are nondiagnostic for diagnosing lung cancer, because their sensitivity is only 50% to 60%, and even lower in early-stage disease ➤ Molecular biomarkers for lung cancer have yet to result in a cure with targeted therapies ➤ Changes in nasal gene expression in patients with lung cancer correlate with changes in the bronchus; therefore, nasal gene expression may be an early diagnostic biomarker of lung cancer ➤ Annual lung CT scans in asymptomatic smokers can reduce lung cancer mortality by 20% ➤ A bronchial airway geneexpression biomarker will be available as a CLIA test in 2014

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for screening; however, only 50% of lung cancers occur in this population, Dr Spira said, creating a need for molecular biomarkers to personalize lung cancer screening decisions.

“I would argue that the second and more urgent need right now is developing biomarkers that can distinguish a benign lesion from a malignancy that’s found on routine CT screening,” said Dr Spira. “CT screening is incredibly sensitive, but has a very high false-positive rate… leading to a lot of unnecessary invasive procedures.”

Numerous molecular biomarkers are in development. “In the next 3 to 5 years, a number of them are going to be emerging in the clinic to guide both screening and diagnostic decisions in this setting,” Dr Spira said.

A bronchial airway gene-expression biomarker will be available as a Clinical Laboratory Improvement Amendments (CLIA) test in early 2014.

“We’re in the process of extending that same type of biomarker into nasal epithelium so that we have less invasive sampling and the ability to go into the screening setting,” Dr Spira said.

“Field of Injury” Paradigm The bronchial biomarkers are based on the “field of injury” paradigm that smoking alters epithelial gene expression through the respiratory tract, and that variability in airway epithelial-cell genomic response to and damage from smoking are linked to lung cancer.

The sensitivity of bronchoscopy for diagnosing lung cancer is only 50% to 60%, and is even lower in the early stages of lung cancer. Many bronchoscopies are therefore nondiagnostic, in which case gene-expression information can be used to select patients for biopsy and patients who can be noninvasively monitored with repeat imaging studies.

In Dr Spira’s work as founder of Allegro Diagnostics, an 80-gene biomarker profile was identified that could distinguish between smokers who do and do not have lung cancer.

The 80 gene-expression biomarker has been validated in 2 independent cohorts, with an 80% sensitivity and specificity for lung cancer. “More important, if we combine our gene-expression biomarker with the routine cytology collected at bronchoscopy, you get 95% sensitivity and 95% negative predictive value,” Dr Spira said.

“So we can almost, not quite but al-

“What’s in the nose may be a very good surrogate for what’s going on deeper within your lung….If we combine our gene-expression biomarker with the routine cytology collected at bronchoscopy...we can almost, not quite but almost, rule out lung cancer.”

—Avrum Spira, MD, MSc most, rule out lung cancer.”

Based on successful validation, the BronchoGen gene-expression test will be launched as a CLIA assay in 2014.

A clinical validation study of smokers undergoing bronchoscopy for suspected lung cancer is ongoing. Data from the first 350 patients show an area under the curve (AUC) of 0.77 in distinguishing cancer from noncancerous nodules, and a negative predictive value of approximately 90%. The sensitivity of BronchoGen for nodules that are <3 cm and for stage I disease was 88% compared with 66% for bronchoscopy, and the sensitivity for stage I and II diseases was 86% compared with only 40% for bronchoscopy. When the biomarker test was combined with bronchoscopy, the sensitivities increased to 96% and 93%, respectively.

Early data suggest that airway gene-expression alterations precede the development of lung cancer in high-risk smokers with dysplasia, making intervention in the preventive setting a possibility. In a phase 1 che-

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moprevention trial, P13K gene-expression alterations were reversible with the administration of myo-inositol.

Further research has extended the field of injury to the upper airway.

RNA obtained from nasal mucosal brushings has been used to demonstrate that the gene-expression changes in the nasal epithelium reflect the changes observed in the bronchial epithelium in smokers. In a diagnostic trial funded by Allegro, cells are being collected from the bronchus and nasal epithelium; microarray analysis is being performed to identify biomarkers in the nose in an attempt to diagnose lung cancer. From the first 100 patients, 60 genes were found to be altered in patients with lung cancer compared with patients without lung cancer.

“Those genes that change in your nose when you have lung cancer change in almost the identical matter in your bronchus,” said Dr Spira.

A nasal gene-expression biomarker has since been developed. From a training set of 100 patients, a 5-gene nasal biomarker yielded the maximum AUC (ie, 0.74). The biomarker was tested on 84 independent samples, achieving a 0.71 AUC. “It’s not quite as good as what we’ve seen in the bronchial airways, but there’s still a relatively good signal-to-noise ratio for lung cancer diagnosis,” Dr Spira said.

“In the next 3 to 5 years, a number of them [biomarkers] are going to be emerging in the clinic to guide both screening and diagnostic decisions in this setting.”

—Avrum Spira, MD, MSc In the clinical workflow, he envisions the nasal test being used in patients who have a very small lung lesion on CT that would not undergo bronchoscopy. “A more impor­ tant place for the nasal testing is as a screening tool, upstream of CT,” Dr Spira said. “It might be used to decide who should get annual CTs of their chest. The most exciting potential unmet need is to stratify high-risk smokers, not simply to a CT screening protocol, but also into chemoprevention trials.” n

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Personalized Medicine

Next-Generation Sequencing Identifies “Actionable” Genomic Alterations in Solid Tumors

By Wayne Kuznar

Boston, MA—Next-generation sequencing is a valuable tool to identify actionable genomic alterations that may be present in a tumor sample, said Gary A. Palmer, MD, JD, MBA, MPH, Senior Vice President of Medical Affairs and Commercial Development, Foundation Medicine, Cambridge, MA, at the Second Glob­al Biomarkers Consortium annual conference.

Next-generation sequencing techniques can overcome many of the shortcomings associated with conventional sequencing of clinical cancer samples, and routine use of next-generation sequencing in the clinic could potentially aid clinical trial enrollment and off-label drug treatment.

Matching the correct targeted therapy to the patient is diagnostically challenging as the number of clinically relevant genomic alterations (ie, base substitutions, mutations, short insertions and deletions, focal amplification, homozygous deletion, gene fusion) increases. Performing multiple tests may exhaust the biopsy material. “NGS [next-generation sequencing] can find all of these different types of alterations,” said Dr Palmer.

There are many potentially target­ able alterations in any particular tumor type, “so I think that the days

of panel testing, where you only test for 3 or 4 alterations in lung cancer and a different 3 or 4 in colon cancer, are probably rapidly coming to a close, because alterations tend to be shared across different solid tumors,” Dr Palmer said.

“I think that the days of panel testing, where you only test for 3 or 4 alterations in lung cancer and a different 3 or 4 in colon cancer, are probably rapidly coming to a close, because alterations tend to be shared across different solid tumors.”

—Gary A. Palmer, MD, JD, MBA, MPH

Many of the alterations are found in a small percentage of cancer cells, so a high degree of sensitivity is needed to find actionable alterations in a tumor sample. Sanger sequencing has a level of sensitivity of only approximately 20%, “so if you have a mutated allele that’s less than 20% of the tumor DNA, you’re not likely to

Table Distribution of 116 ErbB2 Alterations in 2200 Solid Tumors Tumor type, %

ErbB2 alteration

Breast, 37

8S, 31A, 1T, 1R

Lung, 21

17S, 5A, 1T

Esophagus, 7

8A

Uterus, 7

4S, 4A

Colon, 4

1S, 4A

Unknown, 4

2S, 2A

Bladder, 3

1S, 2A

Duodenum, 3

2S, 1A

Ovary, 3

1S, 2A

Skin, 3

1S, 2T

Stomach, 3

1S, 3A

Pancreas, 2

1S, 1A

Appendix, 1

1A

Peritoneum, 1

1A

Soft tissue, 1

1R

A indicates amplification; R, fusion/rearrangement; S, substitution/indel; T, truncation.

Source: Miller VA, et al. J Clin Oncol. 2013;31(suppl). Abstract 11020.

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find it with Sanger sequencing,” said Dr Palmer. In the first 107 cases of non–small-cell lung cancer for which next-generation sequencing was used at Foundation Medicine, 55% of biologic driver alterations were present in <20% of tumor DNA.

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With next-generation sequencing, alterations can be found using small amounts of tissue in a clinically relevant time frame (approximately 2 weeks).

Foundation Medicine is looking at 236 genes. “You want a comprehensive list of genes you’ll be able to pick up in any particular solid tumor, those genes that have alterations that are clinically significant,” Dr Palmer said.

“These alterations are not restricted to 1 tumor type.” HER2 alterations have been found in more than 15 types of solid tumors, for example.

The keys to making next-generation sequencing work routinely are the availability of tissue that has viable DNA and issuing relevant results to oncologists, “the biologic drivers of the particular tumor.” A high degree of specificity is also desirable.

Foundation Medicine’s report to the clinician includes the biologic drivers that are found and a table of “actionable” alterations. It also lists any US Food and Drug Administration (FDA)-approved drugs for the alteration that is found, as well as FDAapproved drugs for a different tumor type, potentially supporting the offlabel use of a drug, and relevant clinical trials based on genomic alterations that are identified.

The initial experience with next-generation sequencing at Foundation

at a glance ➤ Next-generation sequencing can identify actionable genomic alterations ➤ The keys to this new and valuable tool include using tissue that has viable DNA, a high degree of sensitivity, and providing relevant results to oncologists ➤ Each genetic alteration can be found in many tumor types, so a high degree of specificity is needed ➤ With next-generation sequencing, genetic alterations can be found within 2 weeks, using small amounts of tissue ➤ New techniques can overcome many of the shortcomings associated with conventional sequencing of tumor samples ➤ Routine use of nextgeneration sequencing in the clinic could also aid clinical trial enrollment and off-label drug use

Medicine consists of 2200 solid tumor cases in which gene alterations have been found.

The most frequently altered gene in cases in which alterations have been found is p53, which is present in approximately 50% of cases with alterations. Approximately 75% of specimens harbored ≥1 actionable gene.

No 2 patients had the same findings, although many had similar alterations, Dr Palmer said. “That gives credence to this whole idea of personalized medicine.”

Of the 2200 cases, 116 had ErbB2 alterations (Table). “We’re up to 18 solid tumors in which we found what we feel are biologically important ErbB2 alterations,” he said. The majority have been found in breast cancer, but a sizable number of ErbB2 alterations have been found in lung cancer as well. In the lung tumors, 17 have been activating point mutations, “the great majority postamplification,” Dr Palmer said. Whether anti-HER2 agents will work in solid tumors other than breast cancer will need to be determined, he added. n

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When it comes to oncology, reliable supply is critical

That’s one reason why Pfizer Injectables focuses on the production of quality oncology products. Pfizer Injectables is committed to supplying the products you need, when you need them.

Scan this code with your smartphone or visit pfizerinjectables.com/products to learn more about the products we offer.

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July 2013

Drug Update

Gilotrif: Second-Generation Tyrosine Kinase Inhibitor Indicated for the First-Line Treatment of Patients with Non–Small-Cell Lung Cancer and EGFR Mutation

By Lisa A. Raedler, PhD, RPh

L

ung cancer is one of the most frequently diagnosed cancers, as well as the leading cause of cancer-related mortality in the United States.1 The American Cancer Society has estimated that more than 159,000 Americans will die from lung cancer in 2013, representing approximately 27% of all cancer deaths.1 Non–small-cell lung cancer (NSCLC), the most common form of the disease, accounts for 85% to 90% of all cases of lung cancer.2 NSCLC encompasses a number of histologies, including adenocarcino­ ma, nonsquamous carcinoma, largecell car­ cinoma, sarcomatoid carcinoma, and adenosquamous carcinoma.2 Data from a 2005 retrospective case-control cohort study of more than 2000 patients with lung cancer show that, as can be expected, the cost burden associated with lung cancer is substantial.3 In this study, patients with lung cancer had significantly greater healthcare utilization and costs for hospitalization, emergency department visits, outpatient office visits, radiology procedures, laboratory procedures, and pharmacy-dispensed medications compared with controls (ie, people without any cancer). Approximate adjusted average costs of care across the study period—from diagnosis to death or to a maximum of 2 years— were $45,000 for patients with lung cancer and $2900 for controls.3 A more recent analysis of claims data from an oncology registry associated with a large US commercial health plan has further demonstrated the substantial cost burden associated with NSCLC.4 This study, which was published in 2013, assessed the total cost of treatment for more than 300 patients with advanced NSCLC who were continually enrolled in the plan from diagnosis until death. The average total healthcare costs ranged from approximately $19,000 to more than $167,000 for first-line treatment of NSCLC and from approximately $35,000 to more than $135,000 for second-line treatment. In this analysis, systemic therapy represented 20% to 55% of total costs of first-line treatment, and 22% to 68% of total costs for second-line treatment.4 Traditionally, patients with metastatic NSCLC have been treated with combinations of cytotoxic agents. Although the use of platinum-based “doublet” chemotherapy has improved median

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overall survival (OS) for patients with advanced NSCLC from 4 or 5 months (for untreated patients) to 8 to 10 months, these doublet therapies are limited by significant toxicities, including myelosuppression, nausea and vomiting, and severe fatigue.5-7 With enhanced knowledge of lung cancer tumor cell biology, targeted agents now offer the opportunity to treat patients with NSCLC using a personalized approach.8 Among North American patients with NSCLC, approximately 10% express mutations in the epidermal growth factor receptor (EGFR).7 Approximately 90% of these EGFR mutations express a deletion at exon 19 or an L858R substitution at exon 21.9,10 Patients whose tumors include either of these 2 classes of EGFR mutations have similar clinical characteristics; they are typically female Asian never-smokers with adenocarcinomas that display bronchioloalveolar features.10 Researchers continue to identify and evaluate medications that target EGFR and other relevant NSCLC mutations.

In May 2013, the US Food and Drug Administration (FDA) expanded the indication of erlotinib (Tarceva) to include patients who have not previously received treatment for metastatic NSCLC and whose tumors have a deletion in exon 19 or exon 21 L858R substitution mutations in the EGFR gene as detected by the cobas EGFR Mutation Test.11 The cobas EGFR test was also approved in May 2013. Other novel kinase inhibitors that are being investigated in clinical trials for patients with EGFR mutation–positive NSCLC include dacomitinib, neratinib, pelitinib, and canertinib.8,12 Afatinib: A New Treatment Option for NSCLC In July 2013, the FDA approved afat­ inib (Gilotrif; Boehringer Ingelheim), a tyrosine kinase inhibitor, for the firstline treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA-approved test.13 This test, known as the therascreen EGFR RGQ PCR Kit (Qiagen, Manchester, United Kingdom), is a companion diagnostic used to determine if a patient’s tumor cells express relevant EGFR mutations.13 The approval of afatinib for the treatment of patients with NSCLC

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and EGFR mutation was based on the demonstration of efficacy, specifically progression-free survival (PFS), in a phase 3 multicenter clinical trial known as the LUX-Lung 3 trial.13,14 In a recent interview regarding the use of afatinib in patients with metastatic NSCLC, Corey Langer, MD, Director of Thoracic Oncology at the University of Pennsylvania’s Abram­ son Cancer Center, stated, “Afatinib, which is an irreversible EGFR inhibitor targeting both human epidermal growth factor receptor 1 (HER1) and HER2, may ultimately have an advantage over erlotinib….Based on my own experience with both agents, I could give one or the other equally to a newly diagnosed [metastatic NSCLC] patient with an EGFR mutation.”15 Mechanism of Action Afatinib is a pan-HER inhibitor that irreversibly blocks tyrosine kinase autophosphorylation. This results in downregulation of signaling from EGFR1, HER2, ErbB4, and other dimers in the ErbB family.16,17 Dosing and Administration For first-line patients with NSCLC and EGFR exon 19 deletion mutations or exon 21 (L858R) substitution mutations, the recommended dose of afatinib is 40 mg orally once daily until disease progression or until the drug is no longer tolerated. Afatinib should be taken at least 1 hour before or 2 hours after a meal. Missed doses of afatinib should not be taken within 12 hours of the next dose.16 LUX-Lung 3: A Phase 3 Clinical Trial In the multicenter LUX-Lung 3 trial that served as the basis for the FDA approval of afatinib, 345 patients with EGFR mutation–positive stage IIIB or IV lung adenocarcinoma were randomly assigned to treatment with afatinib or with the combination of cisplatin plus pemetrexed.14 Patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before 2:1 random assignment to 40-mg oral afatinib once daily or up to 6 cycles of cisplatin plus pemetrexed at standard doses administered every 21 days.

Maintenance chemotherapy was not permitted. Treatment with afatinib or with cisplatin plus pemetrexed continued until disease progression was

observed by the investigators. The trial’s primary end point was PFS as determined by an independent review.

Secondary end points included tumor response, OS, adverse events, and patient-reported outcomes.14

Patient Population

In the LUX-Lung 3 trial, patient dem­ographics and clinical characteristics were balanced between the treatment arms. The patients’ median age was approximately 61 years, and more than 85% of the patients were diagnosed with stage IV adenocarcinoma.14 The majority of patients with EGFR mutation–positive disease enrolled in this trial were East Asian (72%), never-smokers (68%), and women (65%).

EGFR mutations were predominantly exon 19 deletions (49%) and L858R point mutations (40%).14

Efficacy

The phase 3 study demonstrated that afatinib is active and safe in newly diagnosed patients with EGFR mutation– positive advanced NSCLC. At the time of data cutoff for the primary end point analysis, patients had been followed for a median of 16.4 months.14 Over that period, 221 disease progression or death events were observed by an independent review.14 As shown in the Figure, the median PFS was significantly prolonged for patients receiving afatinib compared with patients receiving cisplatin and pemetrexed (11.1 vs 6.9 months, respectively; P <.001).14 The difference in PFS outcomes was even more pronounced for patients whose tumors had deletion 19 or L858R EGFR mutations. In those patients, PFS was nearly doubled with afatinib compared with chemother­ apy (13.6 vs 6.9 months, respectively; P <.001).14 The PFS findings and other key efficacy end point analyses are summarized in Table 1.14,16

Safety

In the phase 3 trial, afatinib was administered for a median of 11 months (16 cycles).14 As assessed on a per-patient basis, the mean overall compliance with afatinib was 98%. Dose reductions to less than 40 mg daily were necessary for 120 patients (52%). A total of 16 patients (7%) opted to increase the daily dose of afatinib from 40 mg to 50 mg after the first cycle.14 Altogether, 112 patients (49%) re-

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Drug Update Afatinib for the Treatment of EGFR Mutation–Positive NSCLC

Median (months) 0.8 Afatinib Cisplatin/pemetrexed (N = 230) (N = 115) 0.6 Cisplatin/pemetrexed Afatinib Events, N (%) 152 (66) 69 (60) (n = 230) Median, months 11.14 (n = 115) 6.90 Events, n (%) 152 (66) 69 (60) 0.4

Progression-Free Survival Progression-free survival (probability) (probability)

A

1.0 1.0 0.8 0.8

Median (months)

0.6 0.6

B

11.14

0.2

0.4 0.4 0.2 0.2

Afatinib Afatinib Cisplatin/pemetrexed Cisplatin/pemetrexed

No. at risk Afatinib 230 115 HR, 0.58; CI,CI, 0.430.43-0.78; to 0.78;Cisplatin/pemetrexed P<P .001 HR, 0.58;95% 95% <.001

3 180 72

6

9

12

15

151 41

120 21

77 11

C

50 7

No. of Patients

Factors Time (months) Time, months

No. at risk Patients at risk, N Afatinib 230 180 151 120 Total 77 50 31 10 3 0 Afatinib 180 151 120 77 50 31 10 3 00 Cisplatin/pemetrexed 230 115 72 41 21 11 7 3 2 0

121

Male

Table

Sex E fficacy of Afatinib 1 Male LUX-Lung 3 Female

versus

Age at baseline, years Efficacy <end 65 point ≥ 65 Progression-free survival14

Race Deaths orstratification progressions,factor N (%) Non‐Asian Median progression-free survival Asian

EGFR mutation category Hazard ratio Del19/L858R (common) Stratified log-rank testa Del19 14 Overall survival L858R

Deaths, N (%) Baseline ECOG score Median 0 overall survival 1

Afatinib Asian (N = 230) 211

(N = 115)

Del19 152 (66.1) 69 (60.0) 96(95% CI, L858R 11.1 months 6.9 months (95% 249 ECOG score 9.6-13.6) 5.4-8.2) Baseline 0 0.58 (95% CI, 0.43-0.78) 1 308 P <.001 170 history Smoking 138smoked Never

308 170 CI,138 133 211 236

116 (51.2) < 15(50.4) packet years + stop > 159 year 30 28.1 months (95% CI, 28.2 months (95% CI,79 133 Other current/ex‐smoker 24.6-33.0) 20.7-33.2) 211

Hazard ratio history Smoking Never smoked Stratified log-rank testa < 15 packet years + stop > 1 year response rate (CR + PR)16 Other current/ex‐smoker

Overall Percent per independent review Median duration of response

3 Study,

211 134

96 Cisplatin/pemetrexed 249

EGFR mutation category 134 Del19/L858R (common)

0.91 (95% CI, 0.66-1.25) 236 P = .55 30 79

0.8

(N = 229)

(n = 204)

130 (64) 0.4 13.60

Median (months)

Diarrhea

96

Stomatitis 0.6

71

b

Cheilitis

12

0.4 21 18 Skin and

24 27 tissue disorders subcutaneous

0.2

Dry skin 0

3

1/16

6

9

Infections and infestations

31

12

15

61 (59) 6.90

15

23

143 35

115 17

9

6

13

3

6

9

Decreased appetite

18

0 21

24

30 2

2

95% CI

29

0

1

Rhinorrhea Investigations Weight decreased

0.61 0.54

17

0.37 to 1.01 11 0.38 to 0.78

Eye disorders

0.85

0.53 0.64

0.36 to 0.76 17 0.39 to 1.03

1.58

0.68 0.54

0.39 to 1.19 12

0

0.38 to 0.76

0 0.58 0

4

General disorders and administration site conditions Pyrexia

27

0.61 0.54 P Interaction

0

.65

12

0 15

115 75 1 17 9

HR

11 10 3

0.43 to 0.78 0.58 Respiratory, thoracic, and mediastinal disorders

Epistaxis

1 18

21

24

27

3 0

0 0

Time (months) 0 11

16

Metabolism and nutrition disorders HR

2

Afatinib Cisplatin/pemetrexed 9 15 HR, 0.47; 95% CI, 0.34 to 1 0.65; P < .001 0

Time (months) 58 75 49

All grades, % Grade 3,a %

(n = 104)

0

6.90

(N = 111)

0.2 Cisplatin/pemetrexed Afatinib 204 31 10 3 0 169 143 21 0 Pruritus 104 3 2HR, 0.47;0 95% CI,0 0.34 to 0.65;Cisplatin/pemetrexed 62 35 P < .001

Cystitis

C confidence interval; HR, hazard ratio.No. of CI indicates Female 224 Factors Adapted with permission from Sequist LV, YangPatients JC, Yamamoto N, et al. J Clin Oncol.

Age at baseline, years 2013;31:3327-3334.

Median (months) 13.60 Pemetrexed/cisplatin

0.6%Cisplatin/pemetrexed Afatinib All grades, Grade 3,a %

Gastrointestinal disorders Events, n (%)

No. at risk d Paronychia Afatinib 204 169 345 Cisplatin/pemetrexed 104 62

Cisplatin/pemetrexed 115 72 41 21 11 7 3 2 0 0 Sex

345 < 65 ≥ 65 Cisplatin/Pemetrexed in the Phase Race121 stratification factor 224 Non‐Asian

0.8 Afatinib

Afatinib acneiformc 90 Time (months)Rash/dermatitis No. at risk

0 0 0 3 6 9 12 15 18 21 24 3 6 9 12 15 18 21 24 27 27

Total

6.90

Adverse reaction 1.0

HR, 0.58; 95% CI, 0.43 to 0.78; P < .001

0 Afatinib Cisplatin/pemetrexed

6.90

11.14

Progression-Free Survival (probability)

Progression-Free Survival (probability)

Progression-Free Survival (probability)

Afatinib Cisplatin/pemetrexed Cisplatin/pemetrexed 1.0 for All Randomly Review dverse Reactions Afatinib in (nthe A B Reported1.0in ≥10% of Patients Receiving (nAfatinib Figure P rogression-Free Survival by Independent (n = 230) = 204) = 104) Table 2 (n = A115) Assigned Patients Afatinib for the Treatment of EGFR Mutation–Positive NSCLC LUX-Lung 3 Study Events, n (%) 152 (66) 69 (60) Events, n (%) 130 (64) 61 (59)

49 6

2

30 10 0 2 2

0

95% CI

P Interaction

0

0

5

0

0.43 to 0.78

0.37 to 1.01 0.38 to 0.78

55

.85

4

0.36 to 0.76 0.53 0.39 to 1.03 0.64 2 1 0.68 0.54

6

.58

0

0.39 to 1.19 0.38 to 0.76

14

.65

1

0.34 to 0.65 0.47 0.18 to 0.44 0.28 0.46 to 1.17 0.73 6 0

.01

0.31 to 0.82 0.50 11 0 0 0.34 to 0.65 0.47 0.43 to 0.91 0.63 3 0.18 to 0.44 0.28 a None of the adverse reactions in this table were grade .014 in severity. to 1.17 mucosal inflammation, b 0.33 to 0.67 0.47 Includes stomatitis,0.73 aphthous0.46 stomatitis, mouth ulceration, oral

Conjunctivitis

.60

mucosa erosion, mucosal erosion, mucosal ulceration. 0.50 0.19 to 1.34 c Includes group of rash 0.31terms, to 0.82acne, acne pustular, 0.50 preferred 0.54acneiform. to 1.98 1.04dermatitis .60 d Includes paronychia, nail bed infection.

0.43 to 0.91 0.63nail infection, 1/4 1 16 Source: Gilotrif (afatinib) tablets prescribing information; 4July 2013.

.09

reduction.

0.33 to 0.67 0.47 Favors afatinib Favors cisplatin plus pemetrexed to 1.34 0.50 .09 Patients should0.19 self-adminInterstitial Lung Disease 0.54 toRatio 1.98 1.04 Hazard

ister an antidiarrheal agent, such as Interstitial lung disease or interstitial 56% 23% 5.5 months survival1 (PFS) loperamide, at the diarrhea disease–like reactions, in- analysis 1/111.1 6 2. months 1/4Progression-free 4 onset 16 lung Fig Primary analysis. (A) by independent review for allof randomly assigned patients.

At the timeadverse of data cutoff for primary

and should continue sucharmtherapy infiltration, pneumonitis, of PFS, 45 patients (3%) in the chemotherapy were known cluding to be alivelung and progression free.

(B) PFS by independent P (20%) = .001in the afatinib arm and three patients review in patients with common mutations (del19/L858R; nFavors loose 308).cisplatin (C) Forest plotpemetrexed of subgroups patients showing PFS by independent HR, hazard ratio; Favors afatinib plus until bowel movements ceaseoffor acute respiratory distressreview. syndrome, race.

ECOG, Eastern Cooperative Oncology Group.

16

Stratified by EGFR mutation status and 12 hours. or allergic alveolitis, were observed in Hazard Ratio CI indicates confidence interval; CR, complete response; EGFR, epidermal growth factor 1.5% of the 3865 patients who received receptor; PR, partial response.

Fig 2. Primary analysis. (A) Progression-free survival (PFS) by independent review for all randomly assigned patients. At the time of data cutoff for afatinib primary analysis Bullous/Exfoliative Skin Disorders across clinical trials.16 The inSources: Sequist LV, Yang JC, Yamamoto N, et al.

J Clin Oncol.

2013;31:3327-3334; 26,28,29 of PFS, 45 patients (20%) in the afatinib arm and three patients (3%) in theby chemotherapy armthat were known to be aliveby and progression free.

(B) PFSfor by shorter independent mutation predicts with EGFR analysis, any events reported investigators were nonevents Of the 3865 patients who received cidence of PFS interstitial lung TKIs. disease wasAfatinib Gilotrif (afatinib) tablets prescribing information; July 2013. review in patients with common mutations (del19/L858R; n 308). (C) Forest plot of subgroups of patients showing PFS by independent review. HR, hazard ratio;

a

review were censored at the time ofafatinib discrepancy; therein vitro activityhigher against in theAsian T790M variant10 and improved PFS across clinicalhad trials, 6 had patients (2.1%) comceiving afatinib and 53 patients (48%) fore,Warnings and Precautions grade 3 cutaneous characpared non-Asian patients the true treatment effect could have been underestimated, as was reactions compared with placebo in with a randomized phase III trial(1.2%). in an NSCLC 30 receiving chemotherapy experienced shown Diarrhea terizedanalyses by bullous, andclinically ex- Among these 0.4% were fatal.

In in several preplanned sensitivity and subgroup using blistering, population enriched for cases, the presence of such mutations.

16 treatment-related adverse events (AEs) investigator-generated Diarrhea secondary to afatinib has foliating lesions. In the LUX-Lung 3 the trial,selective grade ≥3 interstitial progression mayphase inhibit3 the expansion of T790M mutation predicts for shorter PFS Therefore, with EGFRafatinib TKIs.26,28,29 analysis, any events reported by investigators that were nonevents by events.

Afatinib that were grade ≥3 in severity.14 Among resulted in dehydration with orand withstudy, 90% had skin reactions (rash, lung disease developed in 1.3% of pa-19 dele10 Despite the high response rate prolonged PFS of patients clones and prolong PFS. Afatinib-treated patients with exon independent werethe censored the time of discrepancy; therehad activity against the T790M variant and improved PFS afatinib, and resulted patients receivingreview afatinib, most at out renal impairment, as well as in inorvitro erythema, and acneiform rash), of tients receiving with EGFR mutations treated with gefitinib erlotinib, there are still tion and L858R mutations had a prolonged PFS of 13.6 months. fore, the true treatment effect been underestimated, as was 3 trial, compared with placebo in a grade randomized phase III trialin in an NSCLC 16 common treatment-related AEs could were have fatalities.

In the LUX-Lung diwhich 16% were 3.

Of the total death for 1%toofPFS patients.

Afatinib major clinical obstacles.

Approximately half of those with EGFR mu- for the presence An important accompaniment gains with a genotype30 shown in several preplanned sensitivity and subgroup analyses population clinically enriched mutations. diarrhea, rash, and dryness or irritation arrhea occurred in 96%using of the patients patients, 7% experienced grade 1 toof3suchshould be withheld while patients 31 tations will develop the T790M resistance mutation when their tudirected therapeutic strategy is improvement in PROs. We progression Therefore, afatinib may inhibit the selective expansion ofsuspected T790M interstitial lung diseasedemonof theinvestigator-generated skin, mucosa, and nails (Tableevents. receiving afatinib (N = 229).16 For 15% hand-foot syndrome (palmar-plantar with 23-25 mors are rebiopsied after treatment with erlotinib or gefitinib. strated clinically meaningful delays in worsening of lung cancer– 16 Despite the high response rate and PFS of patientswas clones prolong PFS. Afatinib-treated patients withundergo exon 19 dele2). Of these, diarrhea (1.3%) and parof prolonged these patients, diarrhea grade anderythrodysesthesia syndrome). evaluation, and should be related symptoms in afatinib-treated compared with those T790M mutations may already be present in EGFR TKI treatment– 16 with(0.9%) EGFR mutations treated with gefitinib erlotinib, there are still tion mutations a prolonged PFS of 13.6discontinued months. onychia resulted in treatment 3 in or severity.

Renal impairment asand a L858R Patients whohad develop life-threatenif a patients diagnosis of intersti26,27 treated with chemotherapy.

The AE profile of afatinib was manageable naive patients, and the presence of a detectable de novo T790M 14 discont­ inuation.

Among re- consequence of diarrhea occurred in ing bullous, blistering, or lung disease is confirmed.16 major clinical obstacles.patients Approximately half of those with EGFR muAn important accompaniment to exfoliating PFS gains withtial a genotypeindependent ECOG, Eastern Cooperative Oncology Group.

ceiving cisplatin plus pemetrexed, 6.1%mutation of patients treated lesions should using af- 31 We demontations will develop the T790Mderesistance when their with tu- afatinib, directed therapeutic strategydiscontinue is improvement in PROs. 16 23-25 www.jco.org 2013

by American Society of Clinical Oncology creased appetite, fatigue, nausea, vom- with of which 3 (1.3%) were grade 3. strated clinically atinib. meaningful In patients delays who have grade 2 of Hepatic Toxicity mors are rebiopsied after treatment erlotinib or gefitinib. in worsening lung ©cancer– iting, T790M and myelosuppression were the patients develop grade 2 symptoms skin AEsinthat last for more patients than 7 days, test abnormalities occurred related afatinib-treated comparedLiver with those mutations may already be presentFor in EGFR TKIwho treatment– most naive common AEs. Therapy was disdiarrhea that lasts more than 48 hours intolerable grade 2 skin reactions, or in 10.1% of the 3865 patients who re26,27 treated with chemotherapy. The AE profile of afatinib was manageable patients, and the presence of a detectable de novo T790M continued secondary to treatment-re- or diarrhea that is grade ≥3, afatinib grade 3 skin reactions, afatinib should ceived afatinib across clinical trials.16 lated AEs in 8% of patients receiving should be withheld until diarrhea re- be withheld until the reaction resolves In 7 patients, this toxicity was fatal. www.jco.org © 2013 by American Society of Clinical Oncology 3331 afatinib and in 12% of patients receiving solves to grade ≤1. Afatinib can then to grade ≤1. Afatinib can be resumed In the LUX-Lung 3 trial, liver test Continued on page 46 cisplatin plus pemetrexed.14 be resumed with appropriate dose with appropriate dose reduction.16

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3331

Bladder Cancer

Hispanics More Likely than Caucasians to Develop Major Complications after Radical Cystectomy

By Rosemary Frei, MSc

Vancouver, Canada—The odds of having a major complication after a radical cystectomy, which is performed as part of the treatment for bladder

at a glance ➤ The odds of having a major complication after a radical cystectomy are considerably higher for Hispanics than for Caucasians ➤ Hispanics are a minority of patients undergoing radical cystectomy in the United States, but they have the highest odds of having a major complication compared with all other races ➤ Being aged >65 years and being uninsured or underinsured may be responsible for some, although not all, of the racial disparity

cancer, are higher for Hispanics than for Caucasians, researchers have found. They calculated that the rate of such complications was 23.53% for Hispanic Americans compared with 16.09% for Caucasian Americans.

“In the United States, Hispanic patients represent a minority of patients undergoing radical cystectomy but are associated with the highest odds of having a major complication compared to all other racial groups,” concluded Chenchen Feng, MD, Research Fellow in Medicine, Brigham and Women’s Hospital, Boston, and colleagues in a poster presented at the 2013 annual congress of the Société Internationale d’Urologie.

Dr Feng’s team analyzed data from the Perspective Rx Comparative Database, which includes information from 600 nonfederal hospitals across the country. They captured data on men who had a radical cystectomy between 2003 and 2010.

The study included 38,903 Cau­

“In the United States, Hispanic patients represent a minority of patients undergoing radical cystectomy but are associated with the highest odds of having a major complication compared to all other racial groups.”

—Chenchen Feng, MD casians; 2343 African Americans; 875 Hispanics; and 8864 men from other races. A lower percentage of men aged ≥75 years was found in the Hispanic and African-American groups versus the other 2 groups, among other differences, such as a larger percentage of Hispanic patients who had surgery in hospitals with more than 600 beds.

Besides the higher rate of major complications after cystectomy in Hispanic patients, significant differences were also seen in surgical characteristics, such as a higher percentage of African-American patients not having lymph node dissection compared with Caucasian and Hispanic patients.

The odds ratio (OR) for major complications was 1.88 for Hispanic patients relative to Caucasians in a multivariate analysis (95% confidence interval [CI], 1.08-3.27; P = .02).

This OR difference remained significant when the analysis included only older patients (aged ≥65 years), at 1.82 (95% CI, 1.05-3.16; P = .03), but the OR difference lost its significance when only Medicare beneficiaries were included. The researchers believe that this indicates that being aged >65 years and being uninsured or underinsured (ie, not being covered

by Medicare) may be responsible for some, although not all, of the racial disparity. n

Drug Update

Gilotrif: Second-Generation Tyrosine Kinase Inhibitor... ab­normalities of any grade were observed in 17.5% of afatinib recipients.16 Periodic liver testing should be conducted during treatment with afatinib.

Afatinib should be withheld in patients who develop worsening of liver function and in patients who develop severe hepatic impairment.16

Keratitis

Keratitis (ie, acute or worsening eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain, and/or red eye) occurred in 0.8% of 3865 afat­inib recipients across clinical trials.16 Of the patients in the phase 3 afatinib trial, 5 developed keratitis, with 1 patient experiencing grade 3 severity.16 Afatinib should be withheld while patients with suspected keratitis are evaluated. If ulcerative keratitis is confirmed, afatinib treatment should be interrupted or discontinued. Afatinib should be used with caution in patients with a history of keratitis, ulcerative keratitis, or severe dry eye, as well as in patients who wear contact lenses.16

46

Embryofetal Toxicity

Based on its mechanism of action, afatinib can cause fetal harm when administered during pregnancy. Patients who become pregnant while taking afatinib should be warned about the potential hazard to the fetus.16 Females of reproductive potential should use very effective contraception during treatment with afatinib, and for at least 2 weeks after the last dose of afatinib. Patients taking afat­ inib should contact their healthcare providers if they become pregnant or if pregnancy is suspected.16 Conclusion Lung cancer remains the main cause of cancer-related death in the United States for men and women. The disease is still diagnosed mainly at advanced stages, such that prognosis is poor and long-term survival is rare. Afatinib, the second oral kinase inhibitor approved for the initial treatment of EGFR mutation–positive metastatic NSCLC, has demonstrated improved efficacy with manageable side effects relative to doublet chemotherapy. Afatinib joins erlo-

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tinib as the only FDA-approved agents for this subset of patients with NSCLC, offering them another effective alternative to cytotoxic therapy.

As a pan-HER inhibitor, afatinib may confer clinical value in other cancers that overexpress EGFR and HER2. In addition to further exploration in NSCLC, investigators are evaluating afatinib monotherapy, as well as combinations with various cytotoxic and biologic agents, in breast, prostate, head and neck, and esopha­ gogastric cancers.18 n References

1. American Cancer Society. Lung cancer (non-small cell): what are the key statistics about lung cancer? Revised July 12, 2013. www.cancer.org/cancer/lungcancernon-smallcell/detailedguide/non-small-cell-lung-cancerkey-statistics. Accessed September 23, 2013.

2. American Cancer Society. Lung cancer (non-small cell): what is non-small cell lung cancer? Revised July 12, 2013. www.cancer.org/cancer/lungcancer-non-smallcell/detailedguide/non-small-cell-lung-cancer-what-isnon-small-cell-lung-cancer. Accessed September 23, 2013.

3. Kutikova L, Bowman L, Chang S, et al. The economic burden of lung cancer and the associated costs of treatment failure in the United States. Lung Cancer. 2005;50: 143-154.

4. Henk HJ, Ray S. Treatment patterns and healthcare costs among patients with advanced non-small-cell lung cancer. Lung Cancer Manag. 2013;2:189-197.

5. Azzoli CG, Giaccone G, Temin S. American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non–Small-Cell Lung Cancer. J Oncol Pract. 2010;6:39-43.

6. American Cancer Society. Lung cancer (non-small

Continued from page 45

cell): chemotherapy for non-small cell lung cancer. Revised July 12, 2013. www.cancer.org/cancer/lungcancernon-smallcell/detailedguide/non-small-cell-lung-cancertreating-chemotherapy. Accessed September 23, 2013.

7. Villaflor VM, Salgia R. Targeted agents in non-small cell lung cancer therapy: what is there on the horizon?

J Carcinog. 2013;12:7.

8. Hirsh V, Melosky B, Goss G, et al. A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. Curr Oncol. 2012;19:78-90. Erratum in: Curr Oncol. 2012;19:e228.

9. Politi K, Zakowski MF, Fan PD, et al. Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors.

Genes Dev. 2006;20:1496-1510.

10. Uramoto H, Mitsudomi T. Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? Br J Cancer. 2007;96:857-863.

11. US Food and Drug Administration. Drugs: erlotinib. Updated May 15, 2013. www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm352317. htm. Accessed September 24, 2013.

12. Landi L, Cappuzzo F. Irreversible EGFR-TKIs: dreaming perfection. Transl Lung Cancer Res. 2013;2:40-49.

13. US Food and Drug Administration. Drugs: afatinib.

Updated July 12, 2013. www.fda.gov/drugs/infor mationondrugs/approveddrugs/ucm360574.htm. Accessed September 24, 2013.

14. Sequist LV, Yang JC, Yamamoto N, et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327-3334.

15. OncLive TV. Dr. Corey Langer discusses afatinib in EGFR-positive NSCLC. YouTube. August 13, 2013. www. youtube.com/watch?v=Q0Cwcfv0W58. Accessed September 23, 2013.

16. Gilotrif (afatinib) tablets [prescribing information].

Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; July 2013.

17. Solca F, Dahl G, Zoephel A, et al. Target binding properties and cellular activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. J Pharmacol Exp Ther. 2012;343:342-350.

18. ClinicalTrials.gov. Afatinib. Search results. http:// clinicaltrials.gov/ct2/results?term=afatinib&Search= Search. Accessed September 24, 2013.

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A Global Collaboration dedicated to improving the lives of patients with B-Cell Malignancies

Š Pharmacyclics, Inc. 2013 Š Janssen Biotech, Inc. 2013 08/13 K08BR13002C

Ovarian Cancer

Oral VEGF Inhibitor, Cediranib, Improves Survival in Recurrent Ovarian Cancer

By Charles Bankhead

Amsterdam, The Netherlands—Treat­ ment with the oral angiogenesis inhibitor cediranib led to significant improvements in overall survival (OS) and progression-free survival (PFS) in patients with recurrent ovarian cancer, according to new data reported at the European Cancer Congress 2013.

48

The median PFS improved by 2.4 months, from 8.7 to 11.1 months, in patients receiving conventional chemotherapy plus cediranib followed by cediranib maintenance. OS, a secondary end point of the trial, was 6 months longer with the cediranib regimen compared with chemotherapy and placebo.

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“I think the evidence is pretty strong that antiangiogenics have a very important role in ovarian cancer, and I think there are opportunities to use different antiangiogenic drugs,” said Jonathan A. Ledermann, MD, BSc, Head, Cancer Research UK and UCL (University College London) Cancer Trials Centre, United Kingdom. “I don’t think bev-

acizumab [Avastin] is the only one.

Certainly, in the setting of recurrent ovarian cancer, there is quite a lot of space for different types of antiangiogenics other than bevacizumab.”

Dr Ledermann reported the findings from the initial efficacy of the ICON6 Gynaecologic Cancer InterGroup trial, sponsored by the British Medical Research Council. The trial was the

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Ovarian Cancer

Oral VEGF Inhibitor, Cediranib, Improves Survival... first to examine the activity of an oral inhibitor of vascular endothelial growth factor (VEGF) in combination with platinum-based chemotherapy and as maintenance therapy in recurrent ovarian cancer.

The trial included 456 patients with relapsed, platinum-sensitive ovarian cancer, who were randomized in a 2:3:3 ratio to platinum-based chemotherapy plus placebo and placebo maintenance therapy, chemotherapy plus cediranib followed by placebo maintenance, or to chemotherapy plus cediranib and cediranib maintenance.

The primary end point was PFS, and the primary analysis compared the chemotherapy plus placebo arm and the chemotherapy plus cediranib and cediranib arm.

The difference in PFS translated into a 43% reduction in the hazard for progression in favor of the cediranib maintenance arm (P = .001). To account for nonproportional hazards between 2 treatment groups, the investigators performed a restricted means analysis, which yielded a median PFS of 9.4 months with chemotherapy alone and 12.5 months with chemotherapy and cediranib.

The uncorrected analysis of OS showed a median of 20.3 months for chemotherapy alone versus 26.3 months for the cediranib maintenance arm (P = .042). A restricted means analysis reduced the difference to 2.7 months (20.3 with cediranib maintenance and 17.6 with chemotherapy alone).

The adverse events reported with cediranib were consistent with previous trials of VEGF inhibitors (hypertension, fatigue, diarrhea, and nausea) and were controlled with dose reduction or treatment interruption. “The addition of cediranib did not compromise the delivery of chemotherapy,” said Dr Ledermann. “In the maintenance phase, most patients were able to tolerate prolonged oral therapy.”

Although seemingly modest, the improvements in PFS and OS were clinically meaningful, as well as statistically significant, said Dr Ledermann.

“We’ve made progress in cancer therapy in small increments,” he said.

“This is an increment, and I think most people would accept an increment of 2 to 3 months in overall survival as a worthwhile increment to have.”

Having more than 1 effective antiVEGF option could prove valuable in the management of patients with recurrent ovarian cancer, said Cora N. Sternberg, MD, Chief, Department of Medical Oncology, San CamilloForlanini Hospital, Rome, Italy.

“A patient might become resistant

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to bevacizumab, a monoclonal antibody, and then respond to a tyrosine kinase inhibitor that has several different mechanisms of action,” said Dr Sternberg. “I could actually see use of one tyrosine kinase inhibitor after an-

other in different populations.”

Despite these favorable results, cediranib has an uncertain future: its manufacturer (AstraZeneca) has suspended its clinical development, according to Dr Ledermann. “It is a drug

that has been tested in a number of tumor types,” he said. “All of those trials did not reach the end point that [the manufacturer] required to take forward for licensing, so the company decided to stop developing the drug.” n

GE Healthcare Clarient Diagnostic Services

Things aren’t always what they seem. Get the complete picture.

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You know that biomarker expression matters.

Did you know that context and relationship matter, too?

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Introducing a Clarient validated lab-developed test using MultiOmyx to assess 9 antibodies on a single slide at a single cell – maximizing the molecular data from precious patient samples

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Aids the pathologist’s diagnosis of CD30-positive lymphoma cases with difficult morphology or otherwise insufficient tissue for adequate evaluation

•

Leverages imaging data technology to visualize disease and the relationship between different biomarkers and the tumor environment

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•

Helps pathologists diagnose previously undiagnosable lymphoma cases and may help prevent rebiopsy for additional diagnostic material

www.MultiOmyx.com www.Clarient.com www.gehealthcare.com © 2013 General Electric Company — All rights reserved.

GE, the GE Monogram, and imagination at work are trademarks of General Electric Company.

GE Healthcare, a division of General Electric Company.

Clarient Diagnostic Services, Inc. is a division of General Electric Company.

MultiOmyx is a trademark of General Electric Company.

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JB15955US

www.ValueBasedCancerCare.com

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Value-Based Care

Physician-Focused Improvement in Patient Satisfaction at the Cleveland Clinic

By Rosemary Frei, MSc

Phoenix, AZ—The degree of patient satisfaction with healthcare is becoming paramount in the new era of value-based care, according to James Merlino, MD, Chief Experience Officer, and Associate Chief of Staff, Patient Experience Office, Cleveland Clinic Health System (CCHS), OH, who discussed high-value healthcare at the American Medical Group Association 2013 Institute for Quality Leadership conference.

Dr Merlino said that the proliferation of ratings by government agencies and internet sites of physicians’ outcomes, behavior, and interactions with patients is here to stay, and institutions would therefore do well to understand the importance of positive patient interactions.

“Hospital leaders need to ‘create the burning platform’ and to inform physicians that they will be increasingly held accountable for their actions around outcomes, behavior, complaint, and patient-experience metrics, and provide them with information on how to be successful at the human side of healthcare,” Dr Merlino told Value-Based Cancer Care.

“At our organization, we expect phy-

“Hospital leaders need to…inform physicians that they will be increasingly held accountable for their actions around outcomes, behavior, complaint, and patient-experience metrics.”

—James Merlino, MD

sicians to develop good relationships with patients and communicate well with both patients and other members of the healthcare team, primarily nurses.”

A 12-member Physician Conduct Committee is in place at the Cleveland Clinic. The committee “conducts comprehensive and fair evaluations of reported incidents” of disruptive behavior, said Robert W. Coulton, Jr, MD, MBA, Executive Director of the CCHS’s

Office of Professional State Affairs. It “encourages employees to come forward with concerns,” but it is “not intended to restrict healthy criticism [that has] the intention of improving patient care,” Dr Coulton noted.

A total of 80 complaints have been filed in the 3 years since the committee was set up; 35% did not reach the level of an incident. Having the committee in place has been “viewed as overwhelmingly positive by both physician staff and employees,” Dr Coulton said.

Communicating with Patients A very effective way members of the CCHS have staved off a proliferation of complaints has been an emphasis on communication-skills training, explained Adrienne Boissy, MD, MA, Medical Director, Center of Excellence in Healthcare Communication, CCHS. Approximately half of the responses to the question on the Hospital Consumer Assessment of Healthcare Providers and Systems are negative comments, whereas 43% are positive, and 8% are mixed, noted Dr Boissy.

It has also been documented that physicians who are given only “fair”

or “poor”/“very poor” ratings by patients are disproportionately sued and lose those cases in court.

“Just because a clinician knows that he or she cares or is trying to be caring, it doesn’t matter,” Dr Boissy told Value-Based Cancer Care. “What matters is his or her ability to communicate this verbally and whether the patient walks away feeling it.”

The Center of Excellence in Health­ care Communication has been using a 4-pronged program since 2011 to help physicians achieve this, including a communication course for groups of 10 to 12 physicians, one-on-one coaching, faculty development, and research on other ways to optimize provider–patient communication.

Immediately after this 4-pronged approach was implemented, the CCHS’s outpatient surveys and physician-communication ratings by the Centers for Medicare & Medicaid Services skyrocketed, and the CCHS now stands above many other major hospitals in the country, concluded Dr Boissy.

“Everyone can change something, and in aggregate, this makes a significant difference,” she said. n

Ten Steps to Achieving Value-Based Care at the Mayo Clinic Phoenix, AZ—The staff at the Mayo Clinic are working to “bend the cost curve” and optimize resource utilization efficiency while continuing to provide high-quality care to their large population of patients, said Kari Bunkers, MD, Chief Medical Information Officer, Mayo Clinic Health System, and Medical Director, Mayo Clinic Office of Population Health Management (OPHM) at the American Medical Group Association 2013 Institute for Quality Leadership conference.

The OPHM is aiming to transform the approach to care from fee-for-service to value-based care within the next 2 or 3 years. The Mayo Clinic is focusing on a data-driven, teambased approach to coordinate care for its patients based on each individual’s needs, she said. These efforts are not specific to cancer care, but the majority of them also apply to oncology.

“Team members will practice to the fullest extent of their licensure, which frees up providers to concen-

50

trate on the most complex patients,” said Dr Bunkers. “Analytical systems will help us stratify the population to identify what level of care is appropriate for which patients. And care coordinators can spend time following up with the patients that are most at risk for complications, and intervene to optimize their care and reduce their likelihood of hospitalization.”

Dr Bunkers, together with her Mayo Clinic colleagues Robert J. Stroebel, MD, Medical Director, Midwest Office of Population Health Management, and James Yolch, Administrator, OPHM, provided information about the central parts of their plan to transition to value-based care.

The Mayo Clinic’s approximately 4000 physicians care for nearly 1.2 million patients annually in the Midwest, Southwest, and Southeast.

“Our current model has some proactive disease management…but in general, it is an acute care system that sees a patient when they schedule a visit or show up in the emer-

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gency department or hospital,” said Dr Bunkers. “It relies on patients to manage their disease and follow-up, which is often confusing, especially to our frail elderly population and our underserved members who require the most care and are at the highest risk for adverse outcomes.”

Efficiently meeting the complex care needs of these individuals is one of the central goals of the Mayo Clinic’s new model. Mr Yolch noted that these needs represent an opportunity to implement the Institute for Healthcare Improvement Triple Aim Initiative of improving patients’ experience of care, and reducing the per-capital cost of healthcare.

Key Steps to Transforming Patient Care The 10 key components identified by the Mayo Clinic include prevention, community engagement, wellness, team-based care, patient engagement, access optimization, care coordination, smooth care transi-

tions, and effective chronic condition management and palliative care.

They also have aligned 3 key principles—partnering, caring for patients every day, and additional services for high-risk groups—with the programs led by a physician and administrative partner to outline their population health management framework. The focus, said Dr Bunkers, is on a gradual shift and adoption of the 10 elements in the framework.

“For example, we are introducing the concept of team-based care by having a nurse and a provider share an office, and also by identifying team members who will gradually start sharing a panel of patients and assume overall accountability for that panel,” she observed.

“We are determined to deliver better-coordinated care for patients, with a better overall experience, through engaging them in ways that work for them, and by focusing on health, wellness, and outcomes,” noted Dr Bunkers.—RF n

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Interview with the Innovators

Utilizing a Personalized Diagnostic in a Class of Hodgkin Lymphoma Patients: An Interview With Dr Lawrence Weiss

Lawrence M. Weiss, MD, of Clarient Diagnostic Services, Inc.

C

larient Diagnostic Services, Inc, a GE Healthcare Company, combines innovative diagnostic technologies with pathology expertise to assess and characterize cancer.

Their stated mission is to “become the leader in cancer diagnostics by dedicating ourselves to collaborative relationships with the healthcare community to translate cancer discovery and research into better patient care.”

The rise of individualized medicine as the new direction in oncology has created the need for innovative diagnostic technologies. Clarient is meeting this need by commercializing new lab-developed tests and companion diagnostic markers for therapeutics in breast, prostate, lung, and colon cancers and leukemia/lymphoma.

Most recently, they have introduced the Hodgkin Lymphoma Profile by MultiOmyx™, an aid to a pathologist’s

diagnosis of CD30-positive lymphoma cases with difficult morphology or otherwise insufficient tissue to adequately evaluate the case. This test utilizes a new pathology platform that uses proprietary methodology to assess multiple proteins from a single tissue section at a single-cell level. If you have a small amount of tissue, you do not have to sacrifice or choose between important markers. You can assess them all.

Personalized Medicine in Oncology (PMO) had the pleasure of meeting with Dr Lawrence Weiss in his Aliso Viejo, California, office to talk about his definition of personalized medicine, the implications of costs to a burdened healthcare system, and the venues in which MultiOmyx is best used. To view the interview in its entirety, please go to www.PersonalizedMedOnc.com/ videolibrary.

PMO Thank you so much for speaking with us, Dr Weiss. As a hematopathologist, how do you define personalized medicine in oncology?

Dr Weiss Personalized medicine is different things to different people.

As a hematopathologist, I think it’s matching the person’s cancer to the best diagnosis and the best treatment modalities.

PMO Personalized medicine remains sporadic and occurs mainly at well-funded academic medical centers or prompted by physicians who really understand the genetic principles behind molecular biomarkers and how to assess them appropriately. How can this situation change so that personalized medicine in oncology can be made available broadly to patients managed by the community caregivers?

Dr Weiss Clarient’s objective has always been to deliver reliable information to the community cancer caregivers, to help keep cancer care local.

Bringing personalized medicine to the community and individual patients is a difficult issue – the biggest driver is cost. We’re talking about expensive

diagnostic and treatment procedures.

We not only have to provide innovative diagnosis and treatment, but we have to do it at a cost that is affordable to our healthcare system. Juggling the two is a difficult proposition.

PMO What are the barriers and opportunities for this to actually occur, bringing these types of molecular biomarkers and genetic principles into the community?

Dr Weiss The basic barrier is cost.

The medical profession needs to convince the payers – government and private payers – that the diagnostic modalities and the treatment modalities that we want to bring to individual patients will have benefit to those patients. But just by virtue of it being individualized therapy, it may be hard to prove in clinical studies, at least in clinical studies as we provide them today. As a result, we have to invest in resources to prove to payers that our innovative therapies and treatments are going to be effective, and try to do it at a reasonable cost so that when it translates to reimbursable procedures and treatments, it’s still within the bounds of the healthcare budget.

Lawrence M. Weiss, MD, is Medical Director of Clarient Diagnostic Services. He is Chairman Emeritus of the Department of Pathology at the City of Hope National Medical Center. He received his BS summa cum laude and his MD summa cum laude from the University of Maryland. He completed a residency in anatomic pathology at the Brigham & Women’s Hospital in Boston and a fellowship in surgical pathology at Stanford University Medical Center. He was previously an Assistant Professor at Stanford and Director of Surgical Pathology at the City of Hope. Dr Weiss’ interests lie in surgical pathology, hematopathology, and immunohistochemistry.

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PMO The Hodgkin Lymphoma Profile by MultiOmyx is being launched as a Clarient-validated lab-developed test which uses a new proprietary methodology to aid pathologists and oncologists in delivering a genomic profile they can use as a guide in the treatment of difficult lymphoma cases. Please explain the differentiating factors of this test as opposed to other laboratory-developed tests.

Dr Weiss When we speak of personalized medicine, we usually talk about the therapy side being personalized. But in this particular case, MultiOmyx is a personalized diagnostic. It will be utilized in lymphoma – but not every case. It will be utilized in certain types of biopsies showing particular findings as a way of making a more precise and accurate diagnosis of Hodgkin lymphoma so people can get the correct therapies that they deserve.

PMO Issues raised regarding genomic profiling include the accuracy, sensitivity, and reproducibility of results. If the right drug is to be delivered to the right patient at the right time, we have to have confidence in the results of molecular biomarker analyses. Can you please compare MultiOmyx’s tests versus genomic tests and also as opposed to proteomic tests?

Dr Weiss As of this time, genomic tests are really not helpful in the accurate diagnosis of Hodgkin lymphoma. Currently, Hodgkin lymphoma is diagnosed by having a pathologist look down a microscope, supplemented by protein studies – immunohistochemical analyses – performed in sections taken from paraffin-embedded blocks. MultiOmyx offers a superior way of looking at multiple antigens in tissue.

First, in immunohistochemistry it’s 1 antibody, 1 section; with MultiOmyx you can get numerous proteins looked at in 1 section. Therefore, if you have small biopsies, you will never run out of tissue. In fact, you’ll preserve the tissue that’s there for additional studies if they’re needed, whereas with immunohistochemistry you’re very limited.

Second, immunohistochemistry has the limitation that proteins are being examined on different tissue sections; you never quite look at the same cell. Hodg­ kin lymphoma has

a unique morphologic appearance in which the neoplastic element is only about 1% of the infiltrate that you see. So when you look at antibody studies you’ll see, for example, some CD30-positive cells, you’ll see some CD15-positive cells. Both are characteristics of Hodgkin lymphoma, and when you see them on the same cell it helps you toward that diagnosis.

But when you look on the typical immunohistochemistry studies, you’re never quite sure whether it’s the same cell expressing both antigens or it’s 2 separate cell populations that express those antigens.

With MultiOmyx, you can look at your CD30 or other antigen stain and see how those positive cells are stained with other markers so you have a direct comparison, whereas with immunohistochemistry there’s a little bit of guesswork in indirect comparison.

PMO Incorporating a molecular biomarker profile in the management plan for all cancer patients is an extremely expensive undertaking.

How should patients be selected for biomarker analysis?

Dr Weiss There are 2 ways to select patients for biomarker analysis. First, there has to be effective therapy. If there’s no effective therapy, you can do all the analysis that you want, and it really won’t help the individual patient. There has to be something on the treatment end that one could be offered. It could be 1% of patients, it could be 70% of patients, it could be 0.1% of patients, but there has to be some benefit should a certain profile be obtained.

But I look at it another way as well. I look at it from the standpoint of whether there is something in the patient’s cancer that will benefit in diagnosis as well from a particular modality.

Hodgkin lymphoma is generally a difficult diagnosis. First of all, it’s not a very common lymphoma, and many pathologists have limited ex­ perience with the diagnosis, so that makes it hard right from the start.

Second, quite often the differential diagnosis of Hodg­ kin versus something else, even benign conditions, can be quite difficult even for a very experienced hemato­pathologist. So if you have a treatment modality for

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those small subsets of hard cases, I think that’s personalized medicine as well.

PMO Should the Hodgkin Lymphoma Profile by MultiOmyx be added to the management plan for all patients with Hodgkin lymphoma and if so, how can the added cost be justified?

Dr Weiss At this point in time I don’t think that MultiOmyx should be included in the diagnostic regimen for all patients with Hodgkin lymphoma. I think it should be included when the pathologist thinks there is a chance it may help the diagnosis.

So where may it help? Currently excisional biopsies represent the most common diagnostic medium because Hodgkin or any lymphoma diagnosis is a difficult one, and an important one, and you do not want to skimp on tissue. But sometimes you have to do needle biopsies; for example, a biopsy of a large mediastinal mass. Cracking the chest would be an awful lot of money as well as morbidity for the patient. If MultiOmyx can help you by more frequently obtaining diagnoses on small pieces of tissue, this actually is going to be very cost-effective.

I had a case the other day where the diagnosis in the referring pathologist’s mind, and in my mind as well, was Hodgkin versus non-Hodgkin lymphoma. We threw this on MultiOmyx and were able to get a definitive diagnosis. That’s going to save a lot of money for the system by preventing a second excisional biopsy.

Where will MultiOmyx be in the future? I think we may go away from more excisional biopsies for possible patients with lymphoma and go more to core needle biopsies to make the diagnosis, and I think MultiOmyx is going to help with that. It may be more expensive than routine immunohistochemistry, but when you factor in the cost of an excisional biopsy versus the cost of an easy outpatient needle biopsy, you may find that going the latter route is going to be the more cost-effective, and from a quality standpoint, the better way.

PMO How will MultiOmyx help cancer patients who either do not respond to therapy or acquire resistance to standard therapy?

Dr Weiss Currently for Hodgkin lymphoma, patients with favorable low-stage disease have about a 90% cure rate. For those with a higher stage or more unfavorable features, the cure rate is still relatively high, but on the order of 75% to 80%.

Typically at some point during the treatment of a patient with Hodgkin lymphoma, some radiologic studies are performed, perhaps a PET-CT

©GE Healthcare

Interview with the Innovators

Multiplexed fluorescence microscopy and image acquisition (MultiOmyxTM) was performed using the 9 stains in the Hodgkin Lymphoma Profile. The hallmark Reed-Sternberg cell (center of image) shows expression patterns of both CD30 and CD45. The antigen illustrated can be changed by moving the vertical divider left or right.

scan to see if the patient is responding. In a small percentage of the cases, the patient may not respond to therapy. Is it because the patient had the correct diagnosis of Hodgkin lymphoma and is just not responding to therapy, or is there a possibility that it was an incorrect diagnosis?

Hodgkin is a tough diagnosis.

We’ve made a lot of progress in terms of pathology and diagnoses, but I’d still estimate that perhaps 5% of diagnoses may be incorrect, even by expert hematopathologists who don’t always agree with each other.

So it could be that if a patient is found not to respond, or have an unusual occurrence, that this is a mandate to implement this better technology and either definitively confirm that the original diagnosis is right or that this is 1 of the 5% of cases in which you are treating the wrong disease.

PMO Education of providers, pharmacists, payers, and patients is vital in achieving personalized medicine in oncology. How is GE Healthcare positioning itself in personalizing medicine and oncology as a whole?

Dr Weiss I think GE Healthcare is very interested in personalized medicine and wants to be part of the solution. They want to bring innovative diagnostic modalities that will help guide individualized therapies.

PMO What do you foresee as the future clinical application of personalized medicine when sequencing the entire human genome will hopefully cost less than $1000 within the next several years, and how is GE Healthcare positioned for next-generation sequencing?

Here the very same Reed-Sternberg cell as pictured on the previous page is evaluated for expression patterns of CD15 and CD79a. The antigen illustrated can be changed by moving the vertical divider left or right.

Dr Weiss I think there’s an unlimited potential for next-generation sequencing, particularly when the costs do come down to a reasonable point. Clarient recently acquired SeqWright Genomic Services, a DNA sequencing service organization that is well poised to be part of this revolution.

PMO What could be offered to patients without a biomarker that directs a targeted therapy, especially if this impacts a significant percentage of patients?

Dr Weiss I don’t think we ought to be giving individualized treatments without detecting the biomarkers, because we could be overtreating a segment of the population and giving them morbidity, mortality, without any benefits. I’m a big believer that for any personalized medicine therapy there ought to be a corresponding diagnostic that will give some probability whether patients will or will

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not respond to that therapy. I see the two as a yin-yang going together. The diagnostic has to come with the individualized therapy, otherwise it’s not individualized therapy.

PMO Do you foresee a future in which pharmaceutical and biotech companies will not develop new therapeutic agents for oncology if the agent isn’t linked to a biomarker that identifies the patient population most likely to benefit?

Dr Weiss I agree, I don’t see pharmaceutical companies or other biotech companies developing therapies without accompanying biomarkers. I think patients want it, I think payers want it, and it’ll bring cost down, and it’ll prevent morbidity in patients who don’t need that therapy. So I think the two go hand in hand, the diagnostic and the therapeutic.

PMO Thank you so much for your time and insights today.

Dr Weiss My pleasure. n

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Radiotherapy in Focus

Expanded Radiotherapy Improves Breast Cancer Control

By Charles Bankhead

Amsterdam, The Netherlands— Expanded radiotherapy led to significantly better disease-free survival (DFS) and metastasis-free survival (MFS) rates in women with early breast cancer, according to the results of a large study reported at the European Cancer Congress 2013.

Irradiation of the internal mamma­ ry and medial supraclavicular lymph nodes was associated with a 10-year DFS rate of 72.1% compared with 69.1% in patients with stage I to III breast cancer. An identical absolute difference of 3% was observed in favor of expanded irradiation for MFS. The 10-year overall survival (OS) favored expanded radiotherapy.

“Our results make it clear that irradiating these lymph nodes gives a better patient outcome than giving radiation therapy to the breast and thoracic wall only,” Philip Poortmans, MD, PhD, Radiation Oncologist, Instituut Verbeeten, Tilburg, The Netherlands.

“Not only have we shown that such treatment has a beneficial effect on

locoregional disease control, but it also improves distant metastasis-free survival and overall survival.”

“Irradiating these lymph nodes gives a better patient outcome than giving radiation therapy to the breast and thoracic wall only…[and] it also improves distant metastasis-free survival and overall survival.”

—Philip Poortmans, MD, PhD

The results addressed a long-standing debate about the potential benefits of irradiating secondary lymphatic pathways after surgery for early breast cancer. Although irradiation of axillary lymph nodes has become

standard practice, the need to treat the internal mammary nodes and the supraclavicular nodes remained unresolved.

This randomized trial was conducted at 43 European centers and involved 4000 patients with newly diagnosed stage I to III breast cancer.

Approximately 75% of the patients had breast-conserving surgery, and 85% of those had a radiation boost to the primary tumor bed. Among patients who underwent mastectomy, 75% received chest wall irradiation.

The patients were randomized to expanded radiotherapy that included the internal mammary and medial supraclavicular lymph nodes or to standard radiotherapy limited to the axillary lymph nodes. The primary end point was OS, and the trial had the power to detect an improvement in 10-year OS from 75% to 79%.

After a median follow-up of 10.9 years, the results showed a trend toward better OS with irradiation of the secondary lymphatic pathway, but

the difference did not achieve significance (82.3% vs 80.7%; P = .056).

“The lack of a significant difference in overall survival can be explained by the better-than-expected survival among patients who received standard irradiation,” said Dr Poortmans.

Irradiation of the internal mammary and supraclavicular nodes was associated with significant improvement in DFS (P = .044) and in MFS (78% vs 75%; P = .020). The benefits of expanded irradiation did not vary by the number of involved lymph nodes, Dr Poortmans reported. The stage at diagnosis also did not affect the beneficial effect.“This is likely to be related to the positive interaction of the [radiation] treatment with systemic treatment—chemotherapy, hormonal therapy, and targeted therapy,” Dr Poortmans said.

These investigators had previously reported that additional exposure to radiotherapy did not significantly increase the incidence of adverse events. n

Sulfasalazine Fails to Prevent Radiotherapy-Induced Diarrhea Atlanta, GA—Patients with cancer treated with pelvic radiation did not have fewer bouts of diarrhea when treated prophylactically with the anti-inflammatory drug sulfasalazine (Azulfidine), a randomized trial showed. Patients receiving sulfasalazine had radiation-associated severe diarrhea almost 3 times as often as patients receiving placebo.

at a glance ➤ Sulfasalazine has often been used empirically to prevent diarrhea in patients with cancer to prevent pelvic irradiation– induced diarrhea ➤ But new data show that prophylactic use of this drug does not reduce the bouts of diarrhea in this setting ➤ Patients receiving sulfasalazine had almost 3-fold more radiation-associated severe diarrhea events than the placebo arm

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The trial ended prematurely when an interim analysis showed that treatment with sulfasalazine was unlikely to demonstrate a benefit, reported Robert C. Miller, MD, Professor of Radiation Oncology, Mayo Clinic, Rochester, MN, at the 2013 American Society for Radiation Oncology meeting.

“The toxicity did not meet the a priori stopping-rule requirements,” said Dr Miller. “A futility analysis showed that the trial would not be positive if all future toxicities—based on the frequency of toxicity to date in both arms—were in the placebo arm. As a result, the data safety and monitoring board halted recruitment and active-agent use.”

Available for more than 70 years, sulfasalazine has often been used empirically to prevent diarrhea in patients with cancer who are treated with pelvic irradiation. The evidence to support this use consisted of a small, phase 3, placebo-controlled trial in 2001 showing a significantly lower incidence of grade ≥2 diarrhea in patients randomized to sulfasalazine.

Despite the limited supporting evidence, sulfasalazine received a recom-

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mendation for mucositis prevention and treatment in a clinical guideline published in 2007 in Cancer.

To confirm the only published report of efficacy in 2001, Dr Miller and colleagues conducted a phase 3, randomized, placebo-controlled trial of sulfasalazine for the prevention of diarrhea in patients undergoing pelvic

“We were very surprised to find that patients receiving sulfasalazine experienced worse diarrhea than those receiving placebo.”

—Robert C. Miller, MD radiotherapy. Eligible patients were receiving a >45-Gy dose of radiation once daily, with or without chemotherapy.

Patients were randomized to sulfasalazine 1000 mg twice daily or to matching placebo during radiation therapy and continuing for 4 weeks afterward. The primary end point was

the maximal grade of treatment-associated diarrhea.

Patients were assessed weekly for their maximum severity of diarrhea, rectal bleeding, abdominal cramping, tenesmus, and constipation. Patients also completed weekly bowel function questionnaires during radiation and for 6 weeks afterward, and then at 12 and 24 months postradiation.

The trial had an accrual target of 140 patients, with 73 enrolled patients who were evaluable at the interim data analysis. At that point, 4 of 38 patients in the placebo arm had grade ≥3 diarrhea (≥7 stools daily) compared with 10 of 35 in the sulfasalazine arm.

“We were very surprised to find that patients receiving sulfasalazine experienced worse diarrhea than those receiving placebo,” said Dr Miller. “For the prevention of radiotherapy-related diarrhea, we now know that sulfasalazine will not benefit patients.”

“This trial clearly illustrates the necessity for large, phase 3, randomized controlled trials to understand which drugs and therapies will relieve the more negative side effects of patients receiving radiation therapy,” he said.—CB n

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Partner Health Policy Strategies, LLC

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael Kolodziej, MD

National Medical Director, Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Navigation, and Advocacy Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

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

www.AVBCConline.org AVBCC2014chairs Ksize_91313

NEW FOR 2014! Principles in Value and Market Access Educational Session for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.

CONTINUING EDUCATION

Faculty Perspectives

NOVEMBER 2013 • VOLUME 4 • NUMBER 3

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ADVANCES IN THE TREATMENT OF CHRONIC MYELOID LEUKEMIA LETTER

PUBLISHING STAFF Group Director, Sales & Marketing John W. Hennessy john@greenhillhc.com

FROM THE

EDITOR

Progress in the treatment of hematologic malignancies has been remarkable over the past decade, primarily due to the introduction of targeted agents, a better understanding of prognostic indicators, and new data on biomarker analysis. There is no doubt that these advances have great potential for improving outcomes; however, hematologists and oncologists who seek to provide state-of-the-art therapy for their patients may be challenged by the rapidly shifting paradigm of care. In 2013, a wealth of new data regarding the treatment of chronic lymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, myelodysplastic syndromes, myelofibrosis, and multiple myeloma has been presented at major scientific meetings throughout the world. In this “Faculty Perspectives” newsletter series, we will continue to feature highlights from these meetings, along with perspectives from highly respected thought leaders in the field, which will provide valuable practice implications for the management of your patients with hematologic malignancies.

Editorial Director Susan A. Berry susan@coexm.com Senior Copy Editor BJ Hansen Copy Editors Dana Delibovi Rosemary Hansen The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris

Sincerely,

Vice President of Finance Andrea Kelly

Paul Richardson, MD RJ Corman Professor of Medicine Harvard Medical School Clinical Director Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Boston, Massachusetts

Director, Human Resources Blanche Marchitto Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede

FACULTY

Director, Creative & Design Robyn Jacobs

Jerald P. Radich, MD Member and Professor Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington

Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean

David P. Steensma, MD, FACP Leukemia Program, Dana-Farber Cancer Institute Associate Professor of Medicine Harvard Medical School Boston, Massachusetts

Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston

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

Project Coordinators Deanna Martinez Jackie Luma Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen

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

Center of Excellence Media, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512

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FACULTY PERSPECTIVES Sponsors This activity is jointly sponsored by Medical Learning Institute Inc and Center of Excellence Media, LLC. Commercial Support Acknowledgment This activity is supported by educational grants from Millennium: The Takeda Oncology Company, Celgene Corporation, and Incyte Corporation.

Target Audience The activity was developed for physicians, nurses, and pharmacists involved in the treatment of patients with chronic myeloid leukemia (CML).

Purpose Statement The purpose of this activity is to enhance competence of physicians, nurses, and pharmacists concerning the treatment of CML. Physician Credit Designation The Medical Learning Institute Inc designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™.

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

Registered Nurse Designation Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 1.25 contact hours.

Registered Pharmacy Designation The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this applicationbased activity provides for 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is 0468-9999-13-025-H01-P.

Learning Objectives Upon completion of this activity, the participant will be able to: • Discuss emerging data and recent advances in the personalized treatment of patients with CML, and integrate key findings into clinical practice • Outline contemporary prognostic and predictive biomarkers and patient characteristics for CML and apply the results to create an individualized approach to managing each patient

Paul Richardson, MD, is on the Advisory Board for Bristol-Myers Squibb, Celgene Corporation, Genmab, Johnson & Johnson, Millennium: the Takeda Oncology Company, Novartis, and Onyx.

He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

David P. Steensma, MD, FACP, is a stockholder for Ariad. He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

Disclosures Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships.

Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute Inc for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

Disclaimer The information provided in this CME/CPE/CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred.

The associates of Medical Learning Institute Inc, the accredited provider for this activity, and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CPE/CE activity for any amount during the past 12 months.

Planners’ and Managers’ Disclosures Karen Cooksey, Medical Writer, has nothing to disclose. She does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

William J. Wong, MD, MLI Reviewer, has nothing to disclose.

Nancy Nesser, JD, PharmD, MLI Reviewer, has nothing to disclose.

Pamela Vlahakis, RN, MSN, CBCN, MLI Reviewer, has nothing to disclose.

Faculty Disclosures Jerald P. Radich, MD, is on the Speaker’s Bureau and is a Consultant for Amgen, Ariad, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer, and has a research contract for laboratory supplies with Novartis. He does not intend to discuss any non-FDA-approved or investigational use of any products/devices.

Instructions for Credit There is no fee for this activity. To receive credit after reading this CME/CPE/CE activity in its entirety, participants must complete the pretest, posttest, and evaluation. The pretest, posttest, and evaluation can be completed online at www.mlicme.org/P13005C.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute Inc at 609-333-1693 or cgusack@mlicme.org.

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Estimated time to complete activity: 1.25 hours Date of initial release: November 14, 2013 Valid for CME/CPE/CE credit through: November 14, 2014

Highlights from EHA 2013 Introduction Chronic myeloid leukemia (CML) accounts for 15% of all adult leukemias. The median age of disease onset is 67 years; however, CML occurs in all age groups.1 In 2013, an estimated 5920 cases (3420 men and 2500 women) will be diagnosed in the United States, and 610 patients will die from the disease.2 CML is characterized by a consistent chromosomal abnormality (the Philadelphia [Ph] chromosome), which carries a unique fusion gene, termed BCR-ABL1.3 Three tyrosine kinase inhibitors (TKIs) are currently approved by the US Food and Drug Administration (FDA) as frontline therapy for chronic-phase (CP) CML: imatinib, dasatinib, and nilotinib.4-6 Dasatinib and nilotinib are also approved for the treatment of patients resistant or intolerant to imatinib.5,6 Two other TKIs, bosutinib and ponatinib, were also recently approved for the treatment of patients with resistance or intolerance to prior TKI therapy.7,8 Several presentations at the 18th Congress of the European Hematology Association (EHA), held in Stockholm, Sweden, on June 13-16, 2013, discussed novel treatments and strategies for CML. In this supplement, Jerald P. Radich, MD, from the Fred Hutchinson Cancer Research Center, and David P. Steensma, MD, FACP, from the Dana-Farber Cancer Institute, offer their perspectives on key data from these presentations.

A NOVEL METHOD FOR DETECTING RESIDUAL DISEASE IN PATIENTS WITH DURABLE REMISSION

Imatinib, an adenosine triphosphate analog, selectively inhibits the enhanced tyrosine kinase activity of the BCR-ABL1 oncoprotein and induces a complete cytogenetic response (CCyR; defined as a state in which the Ph chromosome is no longer detectable) in the majority of patients.3,9,10 However, patients who achieve CCyR can still carry as many as 109 leukemic cells.11 Therefore, in patients who achieve CCyR, BCR-ABL1 transcript levels are monitored using quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to assess the amount of residual leukemia.12,13 A consensus standardized measurement scale, known as the BCR-ABL International Scale (BCR-ABL[IS]) is used to allow direct comparison of BCR-ABL RNA levels (measured by qRT-PCR) from one laboratory to another.14 Using this scale, a major molecular response (MMR) is defined as a BCR-ABL(IS) transcript level of ≤0.1%.15

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An MMR is defined as a ≥3-log reduction in BCR-ABL1 mRNA.15 However, laboratories that are running at the IS sensitivity use equipment that is capable of higher sensitivities—up to 4.0-log and 4.5-log reductions—and thus can assess deeper, more durable molecular responses. With the increased sensitivity of PCR testing equipment, molecular responses are "graded" as MR3.5, MR4.0, and MR4.5: An MR4.0 is defined as BCR-ABL(IS) transcripts of ≤0.01%, and an MR4.5 is defined as BCR-ABL(IS) transcripts of ≤0.0032%.15 A complete molecular response (CMR) occurs when there is no detectable BCR-ABL mRNA as assessed

by PCR using IS with a sensitivity of ≥4.5-log reduction or more from the standardized baseline.1 Studies indicate that approximately 40% of patients with CML who achieve a stable CMR on imatinib for at least 2 years are able to stop imatinib treatment and remain in molecular remission after drug discontinuation for at least 2 years, suggesting the possibility of an “operational cure.”16 However,

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Figure 1. Percentage of Patients Newly Diagnosed With Philadelphia Chromosome–Positive CML Reaching MMR With Nilotinib vs Imatinib: 24 Months and 4 Years.18,19 100

76% 71%

Nilotinib 400 mg BID

Nilotinib 300 mg BID

Imatinib 400 mg QD

Nilotinib 400 mg BID

73%

67% 60

Imatinib 400 mg QD

80

56%

44% 40

20

Percentage of patients with MR

Percentage of patients with MMR

100

Nilotinib 300 mg BID

80

60

56% 50% 40%

40

37%

32% 23% 20

0 24 Months

4 Years

BID indicates twice daily; CML, chronic myeloid leukemia; MMR, major molecular response; QD, once daily.

the safe introduction of a TKI withdrawal policy would require a reliable and cost-effective method of identifying patients with the lowest likelihood of relapse, which is likely to be related to presence of residual disease. At EHA 2013, Alikian and colleagues described a novel method for detection of residual disease.17 This method, based on targeted next-generation sequencing (NGS), allows identification of BCR-ABL1 breakpoints from enriched genomic BCR and ABL1 DNA, followed by rapid generation of DNA-based qPCR assays. In clinical samples from 9 patients in CMR, the new method detected residual disease in 3 of 9 patients, demonstrating that DNA-based qPCR assays can detect residual disease in patient samples in which CML cells persist below the detection threshold of qRT-PCR. The authors noted that their results also demonstrated the variation in residual disease levels that can be found among patients who have achieved a CMR: While 3 of 9 patients had detectable residual disease, disease levels in the remaining 6 were presumed to be exceedingly low or completely absent. The authors concluded that NGS-facilitated DNA-qPCR may prove valuable for the stratification of patients with low levels of residual disease and, therefore, in the identification of patients for whom TKI therapy could be safely reduced or discontinued.

Perspectives Since approximately half of all patients with CML relapse shortly after discontinuation of therapy, investigators are striving to develop more sensitive tests to detect residual disease. A common hypothesis for why certain patients relapse is that they have a slightly higher level of disease than those who stay in remission. One approach to identifying patients who are likely to relapse is to look at genomic DNA via next-generation sequencing. This method basically uses multiple probes to go over hundreds of thousands of kilobases and target the BCR-ABL at the DNA level.

Although this type of sequencing is becoming faster and less expensive, it still requires an enormous amount of work and commitment. Therefore, I would say that while this is an interesting approach, it is certainly not ready for “prime time.”

-Jerald P. Radich, MD

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Figure 2. Percentage of Patients Newly Diagnosed With Philadelphia Chromosome–Positive CML Reaching MR4.0 and MR4.5 With Nilotinib vs Imatinib.19

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0

MR4.0

MR4.5

An MR4.0 is defined as BCR-ABL(IS) transcripts of ≤0.01%, and an MR4.5 is defined as BCR-ABL(IS) transcripts of ≤0.0032%.

BID indicates twice daily; CML, chronic myeloid leukemia; MR, molecular response; QD, once daily.

This study looked at a new genomic DNA sequencing method for identifying whether patients who appear to be in molecular remission using current RT-PCR assays are truly free of BCR-ABL1. The context of this investigation is that some patients who are in a CMR for an extended period on TKI therapy will remain in CMR following discontinuation of therapy, whereas others experience a recurrence of their disease, and we currently don’t know how to predict which patients will relapse if we stop treatment.

Although this is a very early study, it is still exciting and has the potential to be instrumental for determining which patients can avoid unnecessary treatment and the related toxicities that extended treatment incurs.

-David P. Steensma, MD, FACP

4-YEAR FOLLOW-UP FROM THE ENESTnd STUDY

Nilotinib is a second-generation oral TKI that has been shown to be significantly more potent than imatinib.1 In the phase 3, multicenter, open-label, randomized Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) trial (N=846), nilotinib demonstrated greater efficacy than imatinib in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) CML in CP after a minimum follow-up of 24 months.18 Nilotinib showed superior MMR rates, defined as BCR-ABL transcript levels on the BCR-ABL(IS) of ≤0.1%; deeper molecular responses (MR4.0, BCR-ABL[IS] ≤0.01%; MR4.5, BCR-ABL[IS] ≥0.0032%); and reduced rates of progression to accelerated phase (AP) or blast phase (BP), compared with imatinib.

At EHA 2013, Hochhaus and colleagues presented follow-up data from the ENESTnd study.19 With 4 years of follow-up, nilotinib continued to demonstrate significantly higher rates of MMR (Figure 1). Molecular responses obtained using increased sensitivity PCR testing equipment, showing 4.0-log (MR4.0) and 4.5-log (MR4.5) reductions, were consistently higher with nilotinib versus imatinib (Figure 2).

Patients in both nilotinib cohorts had significantly lower rates of progression to AP or BP on study (including follow-up after discontinuation of treatment) compared with patients in the imatinib cohort (3.2%, 2.1%,

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FACULTY PERSPECTIVES and 6.7% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib groups, respectively). Of the patients who progressed on core study treatment (0.7%, 1.1%, and 4.2% in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib groups, respectively), the majority never achieved CCyR. No patient who had achieved MR4.5 had progressed. The 4-year overall survival (OS) rates were 94.3%, 96.7%, and 93.3% for nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib, respectively. Treatment-emergent BCR-ABL mutations were less common in patients on nilotinib versus imatinib; only 2 patients had newly emergent mutations in year 4.

The long-term safety profiles of both drugs were consistent with those previously reported. By 4 years, peripheral arterial occlusive disease (PAOD) was reported in 4, 5, and 0 patients, and ischemic heart disease was reported in 11, 14, and 3 patients in the nilotinib 300 mg BID, nilotinib 400 mg BID, and imatinib arms, respectively. The annual frequency of these events has not increased with longer follow-up. Seven of the 9 patients with a PAOD event on nilotinib were at high risk for this toxicity at baseline, based on a combination of baseline risk factors.

The authors concluded that with 4 years of follow-up, nilotinib continued to demonstrate significantly higher rates of molecular response, lower rates of progression to AP/BP, and fewer treatment-emergent BCR-ABL mutations versus imatinib.

Perspectives This study shows that the results reported at 12 months in the ENESTnd trial hold true even after 4 years. Specifically, we are seeing more and deeper molecular responses with nilotinib compared with imatinib. However, this update still shows no difference in OS between the nilotinib and imatinib arms. One issue that I find slightly concerning is that at 4 years, the investigators reported more cases of PAOD with nilotinib than with imatinib.

Although the incidence of this toxicity hasn’t increased significantly over time, it should still be noted in light of recent reports of arterial disease associated with the use of ponatinib.

-Jerald P. Radich, MD

Although nilotinib was shown in the ENESTnd study to produce more rapid and deeper molecular remissions in newly diagnosed patients, the question that has been asked is whether imatinib will eventually catch up with time. The bottom line from this study was that even after 4 years of follow-up, nilotinib was still better than imatinib in terms of inducing both higher rates of molecular remission and also a lower incidence of progression to AP or BP. Although there was not a large difference such that imatinib is still reasonable initial therapy for some patients (eg, older patients with lower Sokal scores), these results suggest that the benefit of nilotinib is sustained.

-David P. Steensma, MD, FACP

5-YEAR FOLLOW-UP RESULTS OF THE PHASE 2 GIMEMA CTs CML0307 STUDY

Gugliotta and colleagues from the GIMEMA CML Working Party presented updated results of a multicenter, investigator-initiated, phase 2 study (GIMEMA CML0307) designed to evaluate the long-term (5-year minimum follow-up) efficacy of frontline treatment with nilotinib, with particular focus on the stability of the deep molecular response (MR4.0).20 Seventy-three patients (median age, 51 years; 45% low, 41% intermediate, and 14% high Sokal risk) enrolled in the study; median follow-up presented at EHA 2013 was 55 months (range, 50-62 months). Two patients never achieved an MR3.0; 1 of these patients progressed to AP/BP, and the other was in stable and confirmed CCyR at 48 months. Only 3 patients had a confirmed loss of MR3.0 due to poor adherence (all 3 remained on nilotinib).

The overall estimated probability of MR4.0 was 82%, with a median time to MR4.0 of 18 months. Overall, 19/73 patients (26%) showed a stable MR4.0 during the third and fourth year of therapy.

Only 1 patient progressed at 6 months to AP/BP and subsequently died (high Sokal risk, T315I mutation). The estimated probability of OS, progression-free survival, and failure-free survival was 97% at 5 years; the estimated probability of event-free survival (EFS) was 83% at 5 years. The authors

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concluded that after 5 years of follow-up, the great majority of patients are still on nilotinib, and a significant proportion have a stable deep molecular response (MR4.0) and may potentially enter into TKI-free remission trials.

Perspective This Italian study evaluated deep molecular responses in patients who were given 400 mg of nilotinib twice daily. The updated results showed that 82% of patients reached an MR4.0 from baseline; 26% had stable MR4.0, which means that they stayed at that level or better for at least a few years, which is very good. Amazingly, only 1 patient progressed to AP/BP. Even more impressive is the fact that only 15% of patients discontinued treatment due to toxicity or lack of efficacy; this rate is lower than in most studies, including those conducted in the United States. The OS and EFS rates of 97% and 83% confirm that second-generation TKIs are very effective in CML. -Jerald P. Radich, MD

24-MONTH RESULTS FROM THE PHASE 3 ENESTcmr STUDY

At EHA 2013, Cervantes and colleagues presented the 24-month follow-up results from the ENESTcmr study, an open-label, randomized, prospective, multicenter, phase 3 study that is evaluating the potential benefit of switching patients with persistent residual disease on long-term imatinib therapy to nilotinib.21 ENESTcmr includes patients with Ph+ CML-CP who achieved a CCyR but had detectable BCR-ABL transcripts after ≥2 years of imatinib therapy. Patients were randomized to continue their imatinib dose (400 or 600 mg once daily [QD; n=103]) or switch to nilotinib 400 mg twice daily (BID; n=104). Molecular response (including MMR, BCR-ABL[IS] ≤0.1% and MR4.5, BCR-ABL[IS] ≤0.0032%) was determined by qRT-PCR. Confirmed undetectable BCR-ABL was achieved if 2 consecutive samples (with sensitivity of ≥4.5 logs) had negative qRT-PCR results.

Treatment-emergent BCR-ABL mutations were less common in patients on nilotinib versus imatinib; only 2 patients had newly emergent mutations in year 4.

With 24 months of follow-up, confirmed undetectable BCR-ABL was achieved by significantly more patients who switched to nilotinib versus patients continuing imatinib (22.1% vs 8.7%, respectively; P=.0087). Twice as many patients achieved and maintained undetectable BCR-ABL on 3 consecutive assessments on nilotinib versus imatinib (n=10 vs 5, respectively). In patients without MR4.5 at study start, significantly more patients in the nilotinib arm than in the imatinib arm achieved MR4.5 by 24 months than in the imatinib arm (42.9% vs 20.8%, respectively; P=.0006). Rates of MR4.5 were superior on nilotinib regardless of response at study start, but the difference between the treatment arms was particularly pronounced in patients without MMR at study start (MR4.5 achieved in 29.2% vs 3.6% of patients on nilotinib vs imatinib; P=.016). No patient without MMR at study start who continued on imatinib achieved confirmed MR4.5 or undetectable BCR-ABL (on 2 consecutive assessments). No patient progressed to AP/BP since the 12-month follow-up.

Events were experienced by 3 patients on nilotinib (confirmed loss of MMR, n=2; death, n=1) and 7 on imatinib (confirmed loss of MMR, n=4; confirmed loss of CCyR, n=3). Prior interferon therapy (with vs without) and length of prior imatinib therapy (≤36 vs >36 months) did not significantly affect the rate of MR4.5 in either treatment arm. The safety profiles of nilotinib and imatinib were consistent with previous studies. The authors concluded that in patients with detectable residual disease on long-term imatinib therapy, nilotinib induced deeper molecular responses than continued imatinib, and these responses were more frequently maintained in consecutive assessments. The difference between arms in rates of MR4.5 and undetectable BCR-ABL increased between 12 and 24 months. These deeper molecular responses achieved after the switch to nilotinib may increase eligibility for TKI-free remission studies.

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Figure 3. Probability of Cumulative Progression/Death at 24 Months: MCyR vs No MCyR.22

Figure 4. Probability of OS at 24 Months: MCyR vs No MCyR.22 MCyR

No MCyR P=.049

P=.018

100

P=.026

42% 39%

40 P=.002

P<.001

28%

27%

25%

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21%

20 14%

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0 3 Months

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Probability of OS at 24 months

Probability of cumulative progression/death at 24 months

No MCyR

MCyR

60

P=.005 98%

P=.011 97%

88%

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P=.009

P=.232

P=.027

96% 89%

88%

95%

92% 86%

P=.022

88%

84%

80

60

40

20

Bosutinib as third-/ fourth-line therapy 0

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

Perspective

One of the questions that investigators have tried to answer is whether adding a next-generation TKI can benefit patients on imatinib who have achieved a response but who still have detectable disease. The results of this study show that, in fact, such patients can be pushed into a lower molecular burden by adding a more potent drug, namely, nilotinib. This approach may be especially beneficial for certain populations, such as younger patients and those who are looking to get pregnant, as it may allow them to get to a CR status where they would be eligible for a discontinuation trial.

-Jerald P. Radich, MD

EARLY RESPONSE TO BOSUTINIB AS A PREDICTOR OF LONG-TERM OUTCOMES

Bosutinib is a third-generation, oral, dual Src/Abl TKI that was approved by the FDA in 2012 for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy.7 At EHA 2013, Cortes and colleagues presented results of a phase 1/2, open-label study investigating early response to bosutinib as a predictor of long-term outcomes in patients with CML-CP who were receiving bosutinib as second-line therapy (after imatinib only) or third-/fourth-line therapy (after imatinib plus dasatinib and/or nilotinib).22

The authors concluded that early attainment or maintenance of an MCyR by second-line therapy patients was associated with a decreased likelihood of on-treatment progression/death and better OS. A total of 288 patients were receiving bosutinib as second-line therapy and 119 patients were receiving bosutinib as third-/fourth-line therapy.

Among 266 evaluable second-line therapy patients, a major cytogenic response (MCyR; defined as having the Ph chromosome detectable in ≤35% of cells) was newly attained or maintained from baseline by 157 (59%) patients, including 128 (48%) patients with a CCyR (ie, Ph chromosome undetectable). An MCyR was attained/maintained by 45/110 evaluable third-/fourth-line therapy patients, including 35 (32%) patients with a CCyR. The Kaplan-Meier probability of maintaining a MCyR at 2 years

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Bosutinib as second-line therapy

3 Months

6 Months

9 Months

Bosutinib as third-/ fourth-line therapy

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

OS indicates overall survival.

was 77% (95% CI, 69-83) for second-line therapy patients and 71% (95% CI, 54-83) for third/fourth-line therapy patients. An MMR was achieved by 69/200 (35%) evaluable second-line therapy patients and 17/106 (16%) evaluable third/fourth-line therapy patients.

In second-line therapy patients, attaining/maintaining an MCyR by Months 3, 6, 9, and 12 on bosutinib versus no MCyR was significantly associated with a lower cumulative incidence of on-treatment progression/death (Figure 3) and longer OS (Figure 4). Similar results were observed when the analysis separately evaluated patients attaining/maintaining a CCyR versus partial cytogenetic response versus no MCyR. In third-/fourth-line therapy patients, a borderline significant association between attaining/maintaining an MCyR versus no MCyR by Month 3 was found for on-treatment progression/death, but not OS; however, both analyses achieved significance at later response time points. Achievement of an MMR by Month 3 versus no MMR was not predictive of on-treatment progression/death in second- and third-/fourth-line therapy patients, although a numerically lower cumulative incidence was observed (second-line therapy, 5% [95% CI, 1-34] versus 20% [95% CI, 15-28]; third-/fourth-line therapy, 11% [95% CI, 2-71] vs 35% [95% CI, 26-48]). There was also no significant association between response by Month 3 and OS in the second-line therapy group (100% [not estimable to 100] vs 90% [95% CI, 84-93]) and third-/ fourth-line therapy cohorts (75% [95% CI, 32-93] vs 88% [95% CI, 79-93]).

The authors concluded that early attainment or maintenance of an MCyR by second-line therapy patients was associated with a decreased likelihood of on-treatment progression/death and better OS. Among third-/ fourth-line therapy patients, association with long-term outcomes was borderline for MCyR by Month 3, but significant for MCyR by Months 6, 9, and 12. Achievement of MMR by Month 3 was not predictive of long-term outcomes in either cohort, perhaps due to the fewer number of patients with MMR, thus increasing variability in the long-term estimates.

Perspectives In this study, patients who had disease progression after 1 or more lines of prior TKI therapy were given bosutinib as salvage. The investigators found

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FACULTY PERSPECTIVES that at the 3-month mark, patients who had a major cytogenetic response to this drug also experienced longer OS. The same was true at the 6- and 9-month marks. However, in patients who were the most heavily pretreated (those who had received 3 TKIs prior to bosutinib), early responses were not as predictive of overall outcomes. It is not surprising that at 3 months, there were no fast responders in this trial. However, by the time you get out to 9 months, it becomes easier to separate those who have had a better response from those who haven’t. The real money is on this longer term data.

-Jerald P. Radich, MD

We know that with up-front therapy with nilotinib and imatinib, early robust response (ie, less than 10% BCR-ABL RT-PCR level by 3 months) predicts better long-term clinical outcomes. In this study, the investigators looked at whether early attainment of molecular remission was associated with better outcomes in patients receiving bosutinib in the second- or third-line settings. In the second-line setting, the answer was a clear “yes,” although in the third-line setting, the benefit was a little less clear. I think these results are potentially helpful for telling us how to look at landmarks of response with bosutinib, although we don’t know yet what to do if the patient doesn’t achieve a rapid remission (should we switch the drug?) if the landmarks are not achieved.

-David P. Steensma, MD, FACP

EVALUATION OF CROSS-INTOLERANCE BETWEEN BOSUTINIB AND PRIOR TKI THERAPY

As mentioned above, bosutinib is indicated for the treatment of patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior TKI therapy. The bosutinib toxicity profile is characterized primarily by hematologic adverse events (AEs), gastrointestinal toxicities, and rash.7

The authors concluded that hematologic cross-intolerance between bosutinib and recent imatinib or dasatinib therapy was relatively low, although many patients experienced the same grade 3/4 cytopenia on bosutinib.

At EHA 2013, Cortes and colleagues presented the results of a phase 1/2 study evaluating the potential for cross-intolerance between bosutinib and prior TKI therapy.23 Patients were evaluated for cross-intolerance (ie, AEs leading to permanent treatment discontinuation of both bosutinib and prior TKI therapy), and subsequent occurrence of these AEs on bosutinib therapy. Intolerance to prior imatinib therapy was reported for 122 CP-CML patients. The most common AEs associated with imatinib intolerance were cytopenias (Table 1). Fifty-one percent (29/57) of CP-CML patients with imatinib intolerance due to cytopenias experienced the same grade 3/4 AE on bosutinib, while cross-intolerance (ie, discontinuation of bosutinib due to the same AE) due to cytopenias occurred in 12/57 (21%) of CP-CML patients. Although diarrhea is the most frequently reported AE on bosutinib, only 4/10 (40%) CP-CML patients with imatinib intolerance due to diarrhea subsequently experienced grade 3/4 diarrhea on bosutinib, and 2/10 (20%) CP-CML patients experienced true cross-intolerance (ie, discontinued bosutinib due to diarrhea).

Intolerance to prior dasatinib (after imatinib) was reported for 21 CP-CML patients. The most common AEs associated with dasatinib intolerance were pleural effusion (n=19) and thrombocytopenia (n=8).

In patients with dasatinib intolerance due to thrombocytopenia, grade 3/4 thrombocytopenia was experienced by all patients on bosutinib; however, cross-intolerance was observed in 4/8 (50%) patients. Pleural effusion occurred in (3/19) 16% of patients on bosutinib; however, there was no cross-intolerance. Neither of the 2 patients with dasatinib intolerance due to diarrhea experienced cross-intolerance.

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Table 1. Common AEs Associated With Imatinib Intolerance23 Grade 3/4 AEs Associated With Imatinib Intolerance

Percentage of Patients Who Experienced the Same Grade 3/4 AE on Bosutinib

Thrombocytopenia (n=29)

66% (19/29)

Neutropenia (n=19)

32% (6/19)

Rash (n=18)

11% (2/18)

Anemia (n=14)

21% (3/14)

Edema (n=12)

0

Diarrhea (n=10)

40% (4/10)

Bone marrow failure (n=7)

71% (5/7)

Fatigue (n=7)

0

AE indicates adverse event.

An additional 2 CP-CML patients had intolerance to prior nilotinib (after imatinib), including intolerance due to rash (n=3), thrombocytopenia (n=2), neutropenia (n=1), and headache and pleural effusion (n=1); however, none of these patients experienced cross-intolerance and discontinued bosutinib due to the same AE. No deaths due to the AEs leading to prior TKI discontinuation were reported on bosutinib in patients with cross-intolerance.

The authors concluded that hematologic cross-intolerance between bosutinib and recent imatinib or dasatinib therapy was relatively low, although many patients experienced the same grade 3/4 cytopenia on bosutinib.

Cross-intolerance due to nonhematologic AEs, including diarrhea, was rare.

These results suggest that most patients intolerant to prior TKI therapy will tolerate long-term therapy with bosutinib.

Perspective There is not much cross-intolerance between TKIs. In other words, if patients develop an AE with a specific TKI and they are switched to a different TKI, they will often not have that same AE. In this study, the investigators wanted to see whether patients who had intolerance to other TKIs would have the same problems if they were switched to bosutinib. Interestingly, results varied depending on their original intolerance. For most AEs related to other TKIs, patients could be given bosutinib and tolerated it very well.

The exception was hematologic toxicities, especially thrombocytopenia.

For example, if patients developed thrombocytopenia while on dasatinib, they had the same problem on bosutinib.

-Jerald P. Radich, MD

RESISTANCE TO TKI THERAPY

Point mutations in the BCR-ABL kinase domain (including T315I, V299L, T315A, F317L/V/I/C, Y253H, E255K/V, and F359V/C/I) are emerging as the most frequent mechanism of resistance to TKI therapy.1,24 The emergence of resistance to imatinib25 prompted the development of next-generation agents, including dasatinib, nilotinib, and bosutinib, which are active against several imatinib-insensitive mutant forms of BCR-ABL.1 However, the presence of the T315I mutation, which results in an amino acid substitution at position 315 in BCR-ABL1 (from a threonine to an isoleucine), confers resistance to these agents as well.26-29 Ponatinib is a multikinase inhibitor approved in 2012 by the FDA for the treatment of adult patients with chronic, accelerated, or blast phase CML that is resistant or intolerant to prior TKI therapy.8 Evidence suggests that ponatinib is active against many of the BCR-ABL kinase domain mutations, including T315I.30,31 At the 2011 annual meeting of the American Society of Hematology, Cortes and colleagues presented initial findings from an international, single-arm, open-label, phase 2 study (PACE; Ponatinib Ph+ ALL and CML Evaluation) of ponatinib in patients with CML or Ph+ acute lymphoblastic leukemia who are resistant to or intolerant of dasatinib or nilotinib, or who harbor the T315I mutation.32 Results showed that among the 23 CML patients with T315I, 13/23 (57%) had an MCyR and 11/23 achieved a CCyR.

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CONTINUING EDUCATION

Table 2. MCyR Rates Against Mutations Other Than T315I33 Mutation

MCyR Rate

E459K

3/3 (100%)

G250E

7/8 (88%)

E255K

6/8 (75%)

F359I

3/4 (75%)

T315I

45/64 (70%)

M244V

3/5 (60%)

V299L

3/5 (60%)

F317L

11/22 (50%)

E355A

1/2 (50%)

L248V

1/2 (50%)

Y253H

1/2 (50%)

E255V

1/2 (50%)

F359V

6/13 (46%)

F359C

1/4 (25%)

H396R

1/5 (20%)

Major cytogenic response (MCyR) is defined as having the Ph chromosome detectable in ≤35% of cells.

At EHA 2013, Hughes and colleagues presented results of an analysis of the impact of baseline mutations on response to ponatinib treatment in the PACE study, as well as an analysis of the mutations present at the end of treatment in the study.33 At baseline, no mutations were detected in 136 (51%) patients, 1 mutation was detected in 105 (39%) patients, ≥2 mutations were detected in 26 (10%) patients; 27 unique mutations were observed. Responses were observed regardless of baseline mutation status.

MCyR rates were as follows: 56% overall, 49% in patients with no mutations, 64% in patients with 1 mutation, 62% in patients with ≥2 mutations, 57% in patients with mutation(s) other than T315I (n=67), 74% in patients with T315I only (n=50), and 57% in patients with T315I + other mutation(s) (n=14). Although higher response rates were observed in patients with T315I, multivariate analyses showed that T315I is not an independent predictor of response. Responses (MCyR) were seen against each of the 15 mutations present in >1 patient at baseline (Table 2) Ninety-nine patients discontinued treatment, including 35 due to AEs, 20 due to progressive disease, and 11 due to lack of efficacy; 56 of these patients had end-of-treatment mutations assessed. Results showed that 5 patients had lost a mutation, 46 had no change, and 5 had gained mutations. Overall, 11 patients lost MCyR (none with T315I at baseline); 6 of the 11 discontinued, and 4 had end-of-treatment mutations assessed and no changes from baseline that were observed. The authors concluded that responses to ponatinib were observed regardless of baseline mutation status. No single mutation conferring resistance to ponatinib in CP-CML was observed.

Perspectives This study asks the question: What is the efficacy of ponatinib across the different mutation spectrums in heavily pretreated patients? The investigators reported that this drug was effective regardless of a patient’s mutation status. The fact that a high percentage of patients with the T315I mutation had a MCyR response to ponatinib is very impressive. However, the FDA currently has temporarily halted ongoing trials, as well as the sale and marketing of this drug, due to an increasing amount of treatment-related arterial events. Therapy may be continued for appropriate patients under an Emergency-Use Investigational New Drug application.

-Jerald P. Radich, MD

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One of the important aspects of this study is that the investigators really didn’t find any specific mutation that conferred resistance to ponatinib.

This included T315I, which confers resistance to all of the other tyrosine kinase inhibitors that are FDA approved for CML, and which is very problematic when it develops. We have a number of patients with T315I who are back in a deep remission on ponatinib. Therefore, this drug appears to be very effective across various mutations in CML. The problem, of course, is that the drug was recently taken off the market based on data regarding a high incidence of cardiovascular and thromboembolic events, and that is an important safety signal, so we will have to wait and see how that plays out in the future.

-David P. Steensma, MD, FACP

CONCLUSION

The approval of imatinib in 2001 changed the way CML is treated and induced CCyRs in the majority of patients, although many of these patients became resistant to or intolerant of imatinib. Second- and third-generation TKIs are now available for the treatment of patients refractory to prior TKI therapy, and some second-generation TKIs are also approved for first-line therapy—and are demonstrating improved efficacy over imatinib. Point mutations in the BCR-ABL kinase domain (eg, T315I) are emerging as the most frequent mechanism of resistance to TKI therapy, and ponatinib—the most recently approved TKI—is active against many of the BCR-ABL kinase domain mutations, including T315I. Some patients who achieve a stable CMR on TKI therapy may be able to discontinue therapy, and research is under way to identify patients in whom TKI treatment could be safely reduced or discontinued.

References

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2. American Cancer Society. Cancer Facts & Figures. 2013. http://www.cancer.org/acs/ groups/content/@epidemiologysurveilance/documents/document/acspc-o36845.pdf.

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11. Vigil CE, Griffiths EA, Wang ES, Wetzler M. Interpretation of cytogenetic and molecular results in patients treated for CML. Blood Rev. 2011;25:139-146.

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13. Löwenberg B. Minimal residual disease in chronic myeloid leukemia. N Engl J Med. 2003; 349:1399-1401.

14. Müller MC, Cross NC, Erben P, et al. Harmonization of molecular monitoring of CML therapy in Europe. Leukemia. 2009;23:1957-1963.

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phase (CML-CP): ENESTnd 4-year follow-up (F/U). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P712.

20. Gugliotta G, Castagnetti F, Breccia M, et al. High rate of deep molecular response after 5 years of nilotinib 400 mg BID in early chronic phase chronic myeloid leukemia – update of the GIMEMA CML WP Trial CML0307. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P141.

21. Cervantes F, Hughes T, Etienne G, et al. Continued deeper molecular response with nilotinib in patients with chronic myeloid leukemia in chronic phase (CML-CP) with detectable disease on long-term imatinib: ENESTcmr 24-month results. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P133.

22. Cortes J, Gambacorti-Passerini C, Kantarjian H, et al. Assessment of early cytogenetic response as a predictor of long-term clinical outcomes in a phase 1/2 study of bosutinib in chronic phase (CP) chronic myeloid leukemia (CML). Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P148.

23. Cortes J, Lipton J, Kantarjian H, et al. Evaluation of cross-intolerance between bosutinib and prior tyrosine kinase inhibitor therapy in patients with Philadelphia chromosome-positive (Ph+) leukemia. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P151.

24. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208-1215.

25. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876-880.

26. Soverini S, Colarossi S, Gnani A, et el. Resistance to dasatinib in Philadelphia-positive

leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007;92:401-404.

27. Lange T, Ernst T, Gruber FX, et al. The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia. Haematologica. 2013;98:714-717.

28. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567-4576.

29. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood.

2012;119:3403-3412.

30. O’Hare T, Shakespeare WC, Zhu X, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401-412.

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

32. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Initial findings from the PACE trial: a pivotal phase 2 study of ponatinib in patients with CML and Ph+ ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. Blood (ASH Annual Meeting Abstracts) 2011;118:Abstract 109.

33. Hughes T, Cortes J, Kim D, et al. Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with Philadelphia chromosome-positive (Ph+) leukemias. Presented at: 18th Congress of EHA; June 13-16, 2013; Stockholm, Sweden. Abstract P134.

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