TAP Vol 3 Issue 11 by Harborside Press LLC

ASCO Annual Meeting News 1, 3, 12, 14, 19, 25, 35

Acute Myeloid Leukemia

VOLUME 3, ISSUE 11

28 | Carcinoma of Unknown Primary 35

JULY 15, 2012

Editor-in-Chief, James O. Armitage, MD

2012 ASCO Annual Meeting

Second-line Treatments Tested in Patients with Non–Small Cell Lung Cancer

Reflections from the Old World

Docetaxel superior to erlotinib in wild-type EGFR setting, while maintenance pemetrexed prolongs survival in advanced disease

By John F. Smyth, MD

By Alice Goodman

esults of two lateTreatment Refinements in Non–Small Cell Lung Cancer breaking phase III trials presented at 2012 ■■ A large randomized phase III trial suggested that docetaxel ASCO Annual Meeting chemotherapy is superior to EGFR-targeted erlotinib as second-line add to the evolving untreatment of wild-type EGFR NSCLC tumors. derstanding of how best to ■■ The placebo-controlled PARAMOUNT trial found that maintenance treat non–small cell lung pemetrexed extends 2-year survival after induction therapy with cancer (NSCLC). The cisplatin/pemetrexed in advanced NSCLC. At 24 months, overall survival TAILOR trial suggested rates were 32% in the pemetrexed arm vs 21% in the placebo arm. the benefit of chemotherapy over plus best supportive care improved overall survival EGFR-targeted therapy as secondcompared with placebo plus best supportive care folline treatment of patients with lowing induction therapy with pemetrexed/cisplatin wild-type EGFR NSCLC.1 The PARAMOUNT trial found that in patients with advanced nonsquamous NSCLC.2 See Page 84 continued on page 10 maintenance pemetrexed (Alimta) Issues in Oncology

The Affordable Care Act Stands: Now What? By Ronald Piana

n March 23, 2010, President Obama signed the Patient Protection and Affordable Care Act into law—a hotly contested bill that enacted sweeping changes to the U.S. health-care system. The debate over the Affordable Care Act continued all the way to the Supreme Court, spearheaded by the case Florida v Department of Health and Human Services, which challenged the constitutionality of the individual mandate, the centerpiece of the law. On June 28, 2012, in a 5 to 4 vote, the Supreme Court rendered its

decision: The Affordable Care Act stands. Although the Court’s decision is conclusive, the political rancor over the legislation will undoubtedly be center stage in the upcoming battle for the White House. The oncology-related parts of the Affordable Care Act were addressed during an educational session at this year’s ASCO Annual Meeting. Presenter Beverly Moy, MD, MPH, Massachusetts General Hospital, stated, “Regardless of what happens politically, health-care reform has launched a series of irreversible changes that will affect the way we practice oncology. For instance, value-based purchasing, Regardless of what happens politically, payment bundling, and health-care reform has launched a series accountable care organizations are not going away.” of irreversible changes that will affect the

way we practice oncology. — Beverly Moy, MD, MPH

ASCOPost.com

few years ago, I was a key witness for a patent dispute at a trial in Delaware. Acting for the complainant, I was briefed that the opening gambit of the opposition lawyer would be to discredit my CV and, therefore, the value of my testimony. “So you are a full Professor at the University of Edinburgh,” stated the snide lawyer. “Is that a regular University?” Trying to sound as British as I possibly could, I replied, “Yes, sir, Edinburgh has been a regular University for the past 400 years.” The judge stifled a laugh, the lawyer looked confused, and we won the case! That said, medical oncology in Edinburgh is only 33 years old, and it was my responsibility to create the specialty locally when appointed as the first medical oncologist at the university continued on page 64

Dr. Smyth is Emeritus Professor of Medical Oncology at the University of Edinburgh, Scotland, United Kingdom.

MORE IN THIS ISSUE 2012 ASCO Annual Meeting Melanoma �� 3 Non–Small Cell Lung Cancer �� 12 Survivorship �� 14 Colorectal Cancer �� 19 Chronic Myelogenous Leukemia �� 25 Anthony L. Back, MD, on Communicating Bad News �� 23 Direct from ASCO �� 39 Health-care Disparities �� 43, 49

Access to Cancer Care Dr. Moy explained that a cornerstone of continued on page 8

A Harborside Press® Publication

The ASCO Post | JULY 15, 2012

PAGE 2

Journal Spotlight

Lung Cancer Death Rates Increase among White Women in Some States

Editorial Board James O. Armitage, MD Editor-in-Chief

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Associate Editors Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Douglas W. Blayney, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Philip D. Bonomi, MD Rush University Medical Center

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center

Richard Boxer, MD University of Miami

George W. Sledge, MD Indiana University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University

International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff

new study comparing lung cancer death rates among women by year of birth shows dramatic differences in trends between states, likely reflecting the success or failure of tobacco control efforts. The study, published early online in the Journal of Clinical Oncology,1 finds that while lung cancer death rates declined continuously by birth year for women born after the 1950s in California, rates in other states declined less quickly or even increased. In some southern states, lung cancer death rates among women born in the 1960s were approximately double those of women born in the 1930s.

Lung Cancer Mortality Trends Researchers led by Ahmedin Jemal, PhD, American Cancer Society Vice President of Surveillance Research, analyzed lung cancer death rates from 1973 through 2007 by age among white women for 23 states for which there was adequate data, using the NCI’s SEER mortality database. California has consistently led the U.S. in using public policies to reduce cigarette smoking. In California, age-specific lung cancer death rates by year of birth continued to decrease in all age groups younger than age 75 starting in the 1990s, with declines beginning earlier in younger age groups. In Alabama, in contrast, rates

continued to increase for those age 70 years or more, whereas rates for young and middle-aged women See Page 84 decreased for a short time, but are now increasing in the most recent time period, especially for women younger than age 50.

Increased Rate of Death In California, the lung cancer death rate for women born after 1950 is less than a third of that among those born in 1933, while in Alabama the death rate in women born after the 1950s is more than double that of women born in 1933. Similar increasing rates in women born after the 1950s were found in many southern states. “The dramatic rise in lung cancer death rates in young and middle-aged white women in several Southern states points to a lack of effective policies or interventions that deter initiation of smoking among teenagers and promote smoking cessation among adults,” Dr. Jemal said.

■

Reference 1. Jemal A, et al: Increasing lung cancer death rates among young women in southern and midwestern states. J Clin Oncol. June 25, 2012 (early release online).

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2012 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. For permission inquiries, contact permissions@harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Individual Domestic: $235; Individual International: $290; Institutional Domestic: $290; Institutional International $370. Contact subscriptions@harborsidepress.com.

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ASCOPost.com | JULY 15, 2012

PAGE 3

2012 ASCO Annual Meeting Dermatologic Oncology

Landscape for Treatment of Metastatic Melanoma Is Expanding By Alice Goodman

etastatic melanoma was long considered untreatable and incurable. The FDA approval of ipilimumab (Yervoy) and vemurafenib (Zelboraf ) ushered in a new era for this disease, and now additional treatment options are in late stages of clinical development. Dabrafenib, a novel oral BRAF inhibitor, and trametinib, a novel oral MEK inhibitor, achieved significant improvements in progression-free survival in patients with BRAF V600 mutation–positive metastatic melanoSee Page 84 ma in two separate phase III studies presented at the 2012 ASCO Annual Meeting.

BREAK-3 Trial Interim results of the BREAK-3 trial demonstrated a 70% decrease in risk of progression or death with dabrafenib compared with standard dacarbazine chemotherapy in patients with previously untreated BRAF V600E mutation–positive metastatic melanoma.1 Significant antitumor responses were observed in at least 50% of patients, whether assessed by independent review or investigators. Both dabrafenib

Axel Hauschild, MD

and dacarbazine resulted in few serious adverse events and treatment discontinuations. “We have had no new treatments for metastatic melanoma for decades, but now that is changing with the approval of ipilimumab and vemurafenib. Dabrafenib approval could be on the horizon,” stated principal investigator Axel Hauschild, MD, Professor of Dermatology at the University Hospi-

tal in Kiel, Germany. “This study forms the foundation for further studies of dabrafenib in combination with other drugs.” Adverse events of interest with dabrafenib included secondary squamous cell carcinoma/keratoacanthoma (7%) and phototoxicity (3%). This represents fewer skin cancers than are seen with vemurafenib, the first BRAF inhibitor to gain FDA approval for metastatic melanoma. The BREAK-3 study randomly assigned 250 patients with unresectable stage III or IV melanoma with or without central nervous system metastasis in a 3:1 ratio to dabrafenib at 150 mg twice daily or dacarbazine at 1,000 mg/m2 IV every 3 weeks; 68% of patients who were randomly assigned to standard dacarbazine crossed over at radiologically demonstrated disease progression. Investigator-assessed progression-free survival (the primary endpoint) was a median of 5.1 months with dabrafenib vs 2.7 months with dacarbazine (P < .0001). Best confirmed independently reviewed response (complete plus partial response) was 50% for dabrafenib vs 6% for dacarbazine. The benefit of dabrafenib was seen in all subgroups. Treatment discontinuation, dose reduction, and dose interruptions were almost identical for the two treatment arms. Dr. Hauschild noted that the survival data are not yet mature, but crossover will make it difficult to assess survival in the dabrafenib arm.

METRIC Trial Trametinib, a novel MEK inhibitor, delayed disease progression and prolonged survival compared with standard chemotherapy in patients with BRAF-mutated metastatic melanoma, according to an interim analysis of the phase III METRIC trial.2 This is the first phase III trial evaluating a MEK inhibitor. (See page 82 for more on this study.) Both BRAF and

Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

EXPERT POINT OF VIEW

t an Annual Meeting press conference, ASCO spokesperson Sylvia Adams, MD, said, “BREAK-3 confirms that BRAF targeting is effective in metastatic melanoma. The tumor shrinkage seen with dabrafenib is similar to results observed for the FDA-approved drug vemurafenib, with fewer side effects. We will want to study whether combination therapy with a MEK inhibitor can overcome resistance to BRAF inhibition.” Formal discussant at the oral presentation Sylvia Adams, MD of BREAK-3, Michael Atkins, MD, Director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC, commented, “This is a great trial with potentially practice-changing results. Treatment with dabrafenib was well tolerated, and tumor shrinkage was similar to what we see with vemurafenib. Dabrafenib [if approved] will mean competition in the BRAF inhibitor field, and competition is good for patients and physicians.” Michael Atkins, MD Commenting on the METRIC study, Dr. Adams said, “This trial shows that in metastatic melanoma, MEK pathway–targeted therapy is very effective, with good tumor shrinkage and a survival benefit. This study opens the landscape of treatment for BRAF-positive melanoma.” In 2012, the bar has been raised with data from BRAF inhibitors, Dr. Atkins added. “But metastatic melanoma is still a bad disease. We have postponed but not prevented death from this disease, and much work is needed to raise the bar even higher. Current strategies are being pursued to build on BRAF inhibitor data, such as combining immunotherapy with a BRAF inhibitor, either alone or in combination with a MEK inhibitor. With optimal BRAF inhibition and optimal immune therapy, and maybe with other strategies as well, we can raise the bar further and eliminate death from this disease.”

■

Disclosure: Dr. Adams is a consultant for GlaxoSmithKline Biologicals. Dr. Atkins serves on advisory boards for Genentech, Bristol-Myers Squibb, and Prometheus.

MEK are involved in the MAP kinase signaling pathway; MEK exerts its effect downstream from BRAF. “This study shows that targeting the MEK molecular pathway is a viable strategy for treatment of BRAF-mutant melanoma patients,” said lead investigator Caroline Robert, MD, PhD, Head of Dermatology at the Institute Gustave Roussy in Paris. “Trametinib provides an alternative first-line option for patients with BRAF-mutated melanoma.” Investigator-assessed median pro-

gression-free survival was significantly greater in the trametinib group: 4.8 vs 1.5 months with standard chemotherapy (P < .0001), representing a 55% risk reduction in the risk of progression. Interim overall survival was also longer in the trametinib-treated group: 81 patients (74%) were alive after 6 months of treatment vs 67 patients (56%) treated with standard chemotherapy (P = .0136). The overall confirmed response rate was 22% vs 8% for those who received chemotherapy. continued on page 6

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

At diagnosis of metastatic colorectal cancer (mCRC)

Are you getting the full picture? Name: Age: Cancer: Specialty: Biomarker Status:

George 58 mCRC Storyteller

Not an actual patient.

At diagnosis of mCRC, testing a patient’s tumors for biomarkers can help determine predictive and/or prognostic information1 Colorectal cancer is the 3rd leading cause of cancer death in men and women in the U.S.2 Understanding the patient’s biomarker profile helps define the characteristics of the patient’s disease and their overall prognosis.1 Knowing a patient’s biomarker status at diagnosis may help guide clinical decisions.3,4 Understanding the biomarker pathways involved in mCRC tumorigenesis can help inform appropriate treatment planning.3,5,6

KRAS and BRAF signaling are involved with colorectal tumorigenesis and tumor progression3 The KRAS gene may be mutated or wild-type. When KRAS is mutated, it is permanently switched on, whereas wild-type KRAS protein is activated when the EGFR is stimulated.3,5 Increased BRAF signaling may occur due to mutations in the BRAF gene.5 BRAF mutations are limited to those tumors that do not have KRAS exon 2 mutations.7 Provides information on a patient’s likelihood of response or non-response to biomarker-directed treatment1

May help define the patient’s overall prognosis irrespective of therapy1

Provides information on a patient’s likelihood of response or non-response to Approximately 2 out of every 3 patients are 1 biomarker-directed treatment 5,7 KRAS wild-type vs mutant

May help define the patient’s overall prognosis irrespective of therapy1 Approximately 5%-9% of colorectal cancers are characterized by a specific mutation in the BRAF gene7

Approximately 2 out of every 3 patients are KRAS wild-type vs mutant5,7

Testing of biomarkers at diagnosis 3,7 * of CRC treatment planning Strongly recommends KRAS genotyping tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan the treatment continuum.7 Strongly recommends KRASforgenotyping of CRC tumor tissue (either primary tumor or metastases) in all patients with mCRC at the time of stage IV disease diagnosis. Early establishment of KRAS status is appropriate in order to plan for the treatment continuum.7

T E S T

Approximately 5%-9% of colorectal cancers are by afor specific of mCRC ischaracterized important mutation in the BRAF gene7 BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7 BRAF genotyping can be considered for patients with tumors characterized by the wild-type KRAS gene. Such testing is currently optional and not a necessary part of decision making.7

T O

P L A N

EGFR = epidermal growth factor receptor. *In a CLIA-certified laboratory. References: 1. Tejpar S, Bertagnolli M, Bosman F, et al. Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into biomarker discovery. Oncologist. 2010;15:390-404. 2. American Cancer Society. Cancer Facts & Figures: 2011. http://www.cancer.org/acs/groups/content/@epidemiologysurveillance/ documents/document/acspc-029771.pdf. Accessed March 1, 2012. 3. Monzon FA, Ogino S, Hammond EH, et al. The role of KRAS mutation testing in the management of patients with metastatic colorectal cancer. Arch Pathol Lab Med. 2009;133(10):1600-1606. 4. Grossman AH, Samowitz WS. Epidermal growth factor receptor pathway mutations and colorectal cancer therapy. Arch Pathol Lab Med. 2011;135:1278-1282. 5. Krasinskas AM. EGFR signaling in colorectal carcinoma. Pathol Res Int. 2011;2011:1-6. http://www.hindawi.com/journals/pri/2011/932932/cta. Accessed January 6, 2012. 6. Linardou H, Briasoulis E, Dahabreh IJ, et al. All about KRAS for clinical oncology practice: gene profile, clinical implications and laboratory recommendations for somatic mutational testing in colorectal cancer. Cancer Treat Rev. 2011;37(3):221-233. 7. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.3.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. Accessed March 15, 2012.

The ASCO Post | JULY 15, 2012

PAGE 6

2012 ASCO Annual Meeting Landscape Changing for Metastatic Melanoma continued from page 3

METRIC enrolled 322 patients with advanced BRAF V600E/K–mutated melanoma treated with up to one prior chemotherapy regimen. Patients were randomly assigned in a 2:1 ratio to trametinib at 2 mg daily

Caroline Robert, MD, PhD

(214 patients) or standard chemotherapy with dacarbazine or paclitaxel (108 patients). Patients who progressed on chemotherapy were allowed to cross over to trametinib; about 50% crossed over. Similar to the BREAK-3 trial, crossover will compromise interpretation of overall survival in the trametinib arm. Adverse events were generally manageable. The most commonly reported (≥ 20%) adverse events in the trametinib arm included rash (57%),

diarrhea (43%), fatigue (26%), and peripheral edema (26%). Grade 3 or 4 adverse events with trametinib included skin rash (7%), chorioretinopathy (< 1%), hypertension (12%), and reduced left-ventricular ejection fraction (7%). No treatment-induced squamous cell cancers were reported. Dr. Robert said she welcomed these new drugs for melanoma. “For 50 years, we had nothing. Very recently we had two drugs on the market, an immunotherapy agent and a BRAF inhibitor; hopefully we will have others. The future will tell us how to use these drugs, and we are looking forward to studies of BRAF and MEK inhibitors.”

Preliminary Study of Combination A separate phase I/II trial3 reported at the Annual Meeting evaluated the combination of dabrafenib plus trametinib in treatment-naive patients with metastatic melanoma (see The ASCO Post, June 15, page 10). The rationale for combining these drugs is that they provide dual inhibition of the MAP kinase pathway. In this preliminary trial, the data were extremely promising for the combination, producing an overall

Targeting Metastatic Melanoma ■■ Two new oral treatment options for metastatic melanoma in phase III

development interfere with MAP kinase signaling at two different points.

■■ Dabrafenib, a BRAF inhibitor, reduced the risk of progression or death by 70% compared with standard dacarbazine.

■■ Trametinib, a MEK inhibitor, reduced the risk of progression by 50%, and also improved survival at 6 months.

■■ Dabrafenib and trametinib will be studied as combination therapy

in hopes of overcoming resistance to BRAF inhibition and improving treatment tolerability.

response of 56%. The confirmed response rate for dabrafenib at 75 mg twice daily plus trametinib at 1 mg once daily was 67%; median progression-free survival at that dose level was 8.7 months. Only 2% of patients developed squamous cell carcinoma, which is a lower rate than reported with vemurafenib. Phase III studies of the combination of dabrafenib and trametinib are ongoing.

■

Disclosure: Drs. Hauschild and Robert reported no potential conflicts of interest.

References 1. Hauschild A, Grob JJ, Demidov LV, et al: Phase III, randomized, open-label, multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) with dacarbazine (DTIC)

in patients with BRAF V600E-mutated melanoma. 2012 ASCO Annual Meeting. Abstract LBA8500. Presented June 4, 2012. 2. Robert C, Flaherty KT, Hersey P, et al: METRIC phase III study: Efficacy of trametinib, a potent and selective MEK inhibitor, in progression-free survival and overall survival compared with chemotherapy in patients with BRAF V600E/K mutant advanced or metastatic melanoma. 2012 ASCO Annual Meeting. Abstract LBA8509. Presented June 4, 2012. 3. Weber JS: Updated safety and efficacy data from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK inhibitor trametinib (GSK 1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012.

Don’t Miss These Important Reports Inside this Issue of The ASCO Post John F. Smyth, MD, on Reflections from the Old World, page 1

Ezekiel J. Emanuel, MD, PhD, on Health-care Reform Legislation page 8

Anthony L. Back, MD, on Communicating Bad News page 23

Lawrence N. Shulman, MD, on Cancer Care in Rwanda page 45

Barrie R. Cassileth, PhD, on Integrative Oncology page 62

Keith T. Flaherty, MD, on Metastatic Melanoma page 82

Visit The ASCO Post online at ASCOPost.com

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The ASCO Post | JULY 15, 2012

PAGE 8

2012 ASCO Annual Meeting Affordable Care Act continued from page 1

the Affordable Care Act is Medicaid expansion. Beginning in 2014, the legislation will expand coverage to all Americans younger than 65, up to 133% of the federal poverty level, which is an income of $29,340 or less per year. “The law also provides ‘premium credits’ for the purchase of private insurance to individuals and families earning up to 400% of the federal poverty level, which is an income of about $88,000 per year for a family of four,” Dr. Moy said. “[The Affordable Care Act] also provides dependent coverage for children up to age 26 under all individual and group policies. In short, the legislation creates national standards of uniform Medicaid eligibility for all people below the poverty level and

extends coverage for dependent adult children on their family’s policies,” Dr. Moy said. Perhaps the most popular provision for the oncology community is coverage for preexisting conditions, which will be fully implemented by 2014. “Under [the Affordable Care Act], insurance companies cannot deny coverage for people with preexisting conditions, and premiums cannot be based on gender or health status,” Dr. Moy said, She added that until the health insurances exchanges are available, uninsured Americans with preexisting conditions will be covered by a temporary high-risk pool.

ASCO Summary of Critical Provisions in the Affordable Care Act ■■ Protections for patient access to preventive cancer screening: The

Affordable Care Act includes safeguards to provide coverage of preventive cancer screening without charging copayments or coinsurance.

■■ Protections to help vulnerable patients with cancer secure and retain

access to health-care insurance: The legislation includes provisions that require insurers to allow children to remain covered under their parents’ health-care plans up until the age of 26. It also eliminates lifetime caps on insurance coverage, so patients with cancer who require repeated courses of therapy do not lose coverage due to their significant needs.

■■ Safeguards for people with cancer and other preexisting conditions: The Affordable Care Act ensures that people with preexisting conditions, such as cancer, are not excluded from enrolling in a health insurance plan.

■■ Protections for patient access to clinical trials: The law includes a

safeguard to ensure that people with cancer and other life-threatening conditions are covered under private insurance if their physicians determine that enrollment on a clinical trial is their best treatment option.

Filling the Hole Although Medicare Part D does not affect reimbursement for IV che-

motherapy, the growing number of expensive oral oncology drugs makes the

Three Experts Weigh In on the Health-care Reform Legislation

n light of the Supreme Court ruling, The ASCO Post asked three nationally regarded experts about how the Affordable Care Act will affect the practice of oncology. Ezekiel J. Emanuel, MD, PhD, Professor and Vice Provost for Global Initiatives, University of Pennsylvania: This is an overwhelmingly positive outcome. We’ve spent 2 years wondering if the Affordable Care Act would be hampered by a legal challenge, and during that time some states waited before establishing their health-care exchanges, a main component of the law. Now it’s full steam ahead; the task we now face is implementation. As far as oncology is concerned, providers are definitely going to be required to justify the value of their treatments and interventions, which should be embraced as a good thing, both for the system and our patients. After all, we pride ourselves as being a data-driven specialty, so if the data do not support an intervention, oncologists should not be doing it. We need to control costs, but you cannot turn a $2.8 trillion ship around overnight. I began campaigning for cost-effective oncology almost a decade ago; now the Affordable Care Act will help catalyze that effort. Ted Okon, Executive Director, Community Oncology Alliance (COA): We’ll begin to examine all parts of the law germane to oncology as it unfolds. There are facets of the Affordable Care Act that benefit patients with cancer. A lot of uncertainty remains, but COA remains cautiously optimistic.

Ezekiel J. Emanuel, MD, PhD

That said, there are problematic parts of the law that will definitely have a negative impact on the delivery of cancer care. Chief among them is the establishment of the independent payment advisory board (IPAB), which is a terrible piece of public policy. IPAB gives huge discretion over Medicare reimbursement to a board of 15 advisors who are not accountable to anyone but are essentially supported by the Executive Branch of the government. When certain targeted spending numbers are reached, IPAB will take a broad ax to cut provider payments. The oncology community has already been hampered by cuts to reimbursement, so IPAB could continue the assault on the community. Mathew Farber, MA, Director, Provider Economics and Public Policy, Association of Community Cancer Centers (ACCC): We’re glad that the Affordable Care Act survived the legal challenge in that many of the insurance reforms in the bill (such as the preexisting conditions section) help ensure access to

Ted Okon

Mathew Farber, MA

care for patients with cancer. But it is a massive bill, so we’re currently educating our members on what each aspect of the legislation means for their cancer care services moving forward. The big questions for ACCC are about how the Medicaid expansion is going to affect our member institutions. For instance, will some states opt out of the expansion for budgetary reasons? After all, it will have a huge price tag. So we need to see how this unfolds, and then respond with the information that helps our members care for their patients. Another issue with more Medicaid patients entering the system is reimbursement. Our members already have challenging margins, so how will they deal with more Medicaid, which pays less and takes a long time to process? Although we are optimistic about the Affordable Care Act, we need to analyze how the provisions go from paper to practice.

■

Disclosure: Dr. Emanuel, Mr. Okon, and Mr. Farber reported no potential conflicts of interest.

prescription drug program an issue of increasing importance. Prior to the Affordable Care Act (and until its provisions are fully enacted), once patients hit a preset spending limit on drugs of about $2,800, they enter a coverage gap known as the “donut hole” and are responsible for all drug costs until reaching the upper end of the donut hole—approximately $4,500—at which time they receive catastrophic coverage that pays for 95% of further medications. Dr. Moy used a case example, a 67-year-old man with metastatic renal clear-cell cancer, to illustrate the economic effect of the donut hole. “He’s on sunitinib [Sutent], which runs $4,480 per cycle, so he gets into the donut (between $2,800 and $4,500) at cycle 1 of his treatment, which costs about $18,000 for the full 6 months of therapy. After emerging, he gets the 95% catastrophic drug coverage, but while in the donut hole he spent about $5,500, which is a huge out-of-pocket expense for a senior on a fixed income,” Dr. Moy said. Dr. Moy commented that although the health-care reform legislation does not completely fix the donut hole, it helps close the out-of-pocket burden. “Every eligible senior receives a one-time tax-free $250 rebate check, but more importantly, incrementally between now and 2020, the coverage gap will be filled by subsidies from manufacturers of brand-name drugs and from the federal government. This is an extremely complex process that will require providers and payers working together to assist patients in navigating the benefit,” Dr. Moy stressed.

ASCOPost.com | JULY 15, 2012

PAGE 9

2012 ASCO Annual Meeting The Inevitable Reality Dr. Moy pointed out that the fundamental philosophy behind the implementation of the Affordable Care Act was to provide coverage for all Americans, and at the same time increase quality of care and decrease overall costs. It is a grand vision that is largely a work in progress. But one thing is certain—the way physicians get paid for delivering services is being scrutinized. “The Affordable Care Act establishes a national pilot program to encourage providers to improve coordination of care, and that’s where payment bundling comes in. Rather than the traditional fee-for-service payment model, hospitals and providers are paid a flat rate for an episode of care, such as a specific cancer diagnosis. Moreover, accountable care organizations are being set up all over the country, driving doctors together ostensibly to provide evidence-based medicine. The goal is to manage episodes of care collaboratively and reduce costs. We’ll be

The ASCO Post Wants to Hear from You

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com. Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 www.ASCOPost.com

reimbursed singly, and this is inevitable,” Dr. Moy said with emphasis.

New Foundation for Health Care “The Affordable Care Act has provided a new foundation for the entire health-care system to build on, but we in the oncology community need

to be especially aware of how this bill is going to impact the way we provide care,” Dr. Moy said. She added that the hope among oncologists is that all patients with cancer will now have access to health insurance. Moreover, she reemphasized the need for those in the oncology community to brace for what could be some

unsettling changes. “The details of implementing the Affordable Care Act are left to the discretion of the Secretary of Health and Human Services, so there will be a series of changes, both positive and negative, that we need to keep abreast of,” Dr. Moy concluded.

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Disclosure: Dr. Moy reported no potential conflicts of interest.

The ASCO Post | JULY 15, 2012

PAGE 10

2012 ASCO Annual Meeting Personalized Treatments in Non–Small Cell Lung Cancer continued from page 1

TAILOR Results

Docetaxel was superior to erlotinib (Tarceva) in prolonging progressionfree survival as second-line treatment of NSCLC patients with wild-type EGFR, according to results of the phase�� III TAILOR trial. The primary endpoint of this trial is overall survival, but survival data are not yet mature. At the ASCO Annual Meeting, Marina Chiara Garassino, MD, U.O. Oncologia Medica, A.O. Fatebenefratelli e Oftalmico, Milan, Italy, pre-

Marina Chiara Garassino, MD

sented progression-free survival, overall response, and safety data from TAILOR. “TAILOR is the only prospective head-to-head trial comparing erlotinib vs docetaxel in wild-type EGFR

NSCLC. Docetaxel significantly improved progression-free survival, response rates, and disease control rates. The reported toxicity with both drugs was as expected. KRAS was not predictive of response or progressionfree survival. TAILOR preliminary results do not support the use of erlotinib in wild-type EGFR patients with NSCLC, and survival data are awaited,” concluded Dr. Garassino. Patients enrolled in TAILOR had histologically confirmed wild-type EGFR and assessment of KRAS status, and results were cross-validated in two independent labs. All patients received previous platinum-based chemotherapy, but previous chemotherapy with taxanes and other anti-EGFR agents was excluded. The investigators randomly assigned 222 patients 1:1 to docetaxel or erlotinib. Third-line treatment was allowed at progression, but crossover to the other treatment arm was not allowed. Patients were stratified according to treatment center, recurrent NSCLC, or progressive NSCLC, and type of first-line chemotherapy.

Key Data In an intent-to-treat analysis of 219 patients at 6 months, 28.9% were free

EXPERT POINT OF VIEW: PARAMOUNT

ormal discussant Gregory Peter Kalemkerian, MD, of the University of Michigan Comprehensive Cancer Center, Ann Arbor, questioned whether all patients need maintenance therapy, since some patients on placebo lived as long as those on pemetrexed maintenance, and quality of life, as reported previously, was no better on pemetrexed than on placebo. “This doesn’t exactly arouse enthusiastic support,” he noted. “Pemetrexed is an expensive drug, at least in the United States.” Goals of maintenance therapy are to prolong survival and improve quality of life, with low cumulative toxicity and cost-effectiveness, he said. Pemetrexed improves survival, is well tolerated, has low cumulative toxicity, but may not improve quality of life. It is not known if the drug is cost-effective, he said.

Continuation Maintenance “We know that continuation maintenance therapy [the continued use of an agent given as first-line therapy after four to six cycles of initial therapy in the absence of disease progression] with pemetrexed prolongs overall survival. We know that continuation maintenance therapy with bevacizumab [Avastin] is standard of care, but we do not know if it is beneficial. There is no statistically or clinically significant survival benefit for continuation maintenance therapy with other agents or regimens,” Dr. Kalemkerian stated. He noted that maintenance therapy should be considered for patients who are symptomatic from disease and have a good performance status. But for those who are symptomatic from treatment or have a marginal performance status, a “drug holiday” with close surveillance is the most reasonable approach, with reinitiation therapy on progression of disease. Dr. Kalemkerian added that treatment strategies must be adjusted based on the patient’s status and goals. “Everyone does not need maintenance therapy. One patient received 38 cycles of placebo in this trial,” he said. “Some patients do well without maintenance therapy.”

■

Disclosure: Dr. Kalemkerian has received research funding from Lilly.

EXPERT POINT OF VIEW: TAILOR

ormal discussant of the TAILOR trial, Benjamin J. Solomon, MBBS, PhD, of the Peter MacCallum Cancer Centre, East Melbourne, Australia, noted that the study asks an important question about the benefit of an EGFR inhibitor in patients with wild-type EGFR. The progression-free survival reported in this study is consistent with other studies, he continued, suggesting the benefit of chemotherapy in wild-type EGFR patients. “The findings draw our attention to the fact that outcomes are poor with available treatments, with a median progression-free survival of 2 months,” said Dr. Solomon. “We need better treatments, but we need to use available treatments in the best way possible. Although we await the survival and quality-of-life analysis, these data suggest that outcome may be better with docetaxel than with an EGFR inhibitor in wild-type EGFR NSCLC. However, patients with wild-type EGFR are not a homogeneous population. They may have other actionable changes in their genome, such as ALK rearrangements, which may be identified through further testing.”

■

Disclosure: Dr. Solomon has been a consultant or advisor for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.

of progression in the docetaxel arm vs 16.9% in the erlotinib arm. These results held up in a multivariate analysis. No significant interaction was seen between treatment arm and KRAS status. “KRAS mutations do not seem to be predictive or prognostic in secondline therapy of NSCLC,” Dr. Garassino commented. The rate of disease control was double in the docetaxel arm, but as expected, more hematologic toxicities were reported with the chemotherapy. The rate of patients with one or more serious adverse events was similar in both arms: 14.4% in the docetaxel arm and 13.1% in the erlotinib arm.

PARAMOUNT Trial The phase III PARAMOUNT trial found that continuous maintenance therapy with pemetrexed prolonged overall survival compared with placebo in patients with advanced nonsquamous NSCLC who first received induction therapy with four cycles of pemetrexed/ cisplatin. Previous results showed improved progression-free survival with maintenance pemetrexed, and the new survival data confirm a persistent benefit with maintenance pemetrexed. “This study shows that maintenance therapy with pemetrexed offers superior overall survival compared with placebo. These final results confirm that pemetrexed/cisplatin induction followed by continuous pemetrexed further benefits patients compared with induction therapy alone, offering a change in the treatment paradigm for advanced nonsquamous NSCLC,” stated presenting author Luis PazAres, MD, University Hospital–Virgen del Rocio, Seville, Spain.

In the overall trial, 939 received induction therapy; 539 patients without disease progression were randomized 2:1 to pemetrexed plus best supportive care or placebo plus best supportive care.

Major Results At 12 months, overall survival was 58% in the pemetrexed arm vs 45% in the placebo arm; at 24 months, overall survival rates were 32% vs 21%, respectively. Median overall survival from the time of induction therapy was 16.9 vs 14 months (P = .019), respectively, representing a 22% increase in survival among those who received maintenance pemetrexed. The rate of complete or partial response was 45% at baseline. Survival did not differ for those with a complete or partial response or stable disease after induction, Dr. Paz-Ares said.

■

Disclosure: Dr. Garassino is an advisor for Eli Lilly. Dr. Paz-Ares has been a consultant or advisor for and received honoraria from Bayer, Lilly, Pfizer, and Roche.

References 1. Garassino MC, Martelli O, Bettini A, at al: TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wildtype (wt) EGFR. 2012 ASCO Annual Meeting. Abstract LBA7501. Presented June 4, 2012. 2. Paz-Ares L, De Marinis F, Dediu M, et al: PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed plus best supportive care versus placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). 2012 ASCO Annual Meeting. Abstract LBA7507. Presented June 4, 2012.

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The ASCO Post | JULY 15, 2012

PAGE 12

2012 ASCO Annual Meeting Thoracic Oncology

First-line Afatinib Superior to Standard Chemotherapy in Advanced EGFR-mutated Non–Small Cell Lung Cancer By Alice Goodman

“T

2012 ASCO Annual Meeting.1 Afatinib is an irreversible panHER (human epidermal growth factor receptor) blocker under development for NSCLC with EGFR mutations. Patients with EGFR-mutated NSCLC are commonly treated with the EGFR inhibitors erlotinib (Tarceva) and gefitinib. Neither of these drugs is FDA-approved as firstline treatment. In fact, no therapy is approved specifically for EGFR mutation–positive lung cancer. Afatinib not only blocks EGFR, but also blocks the ErbB family of receptors associated with the EGFR pathway, including HER2 and HER4. “The study, met its primary endpoint of improving progression-free survival over chemotherapy,” said principal investigator James Chih-

EXPERT POINT OF VIEW

he LUX-Lung 3 study has been much awaited. It is the first study to use cisplatin/pemetrexed [Alimta], which we now recognize as the best comparator arm. The study was positive for afatinib. While the use of maintenance pemetrexed may have dented the hazard ratio, I doubt this would have impacted on the result,” said formal discussant of this trial, Benjamin J. Solomon, MBBS, PhD, Peter MacCallum Cancer Centre, East Melbourne, Australia. “Even though the efficacy [of afatinib] comes at a cost related to toxicity, the investigators seem to have come up with ways to manage the toxicities [diarrhea, rash, stomatitis, paronychia, dry skin], because there were lower rates of discontinuation in the afatinib arm,” he noted. “Afatinib is now another proven option for EGFR-positive lung cancer patients, alongside erlotinib and gefitinib. LUX-Lung 3 can be added to the list of positive first-line studies in this population. This is the best progression-free survival data reported so far in patients with common mutations. We can’t make direct comparisons of these results with other studies because they had different comparator arms,” Dr. Solomon cautioned. LUX-Lung 7 is a planned head-to-head comparison of afatanib vs gefitinib in patients with common EGFR mutations. “As impressive as progression-free survival is with afatinib, all patients will eventually develop acquired resistance to this family of drugs. To push progression-free survival even further than 13 months, we need to find other options,” he stated. Dr. Solomon said he would be interested in the outcome with afatinib in patients with less common mutations. Preliminary data suggest that afatinib plus cetuximab (Erbitux) may overcome resistance associated with the T790M mutation in patients with NSCLC. Another emerging approach is use of third-generation mutation-specific inhibitors, Dr. Solomon said. “The next generation of EGFR inhibitors has arrived. But it is premature to say goodbye to the older generation,” he commented.

■

Disclosure: Dr. Solomon has served as consultant or advisor for AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Lilly, Pfizer, and Roche.

Afatinib in Non–Small Cell Lung Cancer ■■ Afatinib, a novel investigational oral EGFR inhibitor, extended progression

free survival vs standard chemotherapy in EGFR-mutated advanced NSCLC.

■■ Progression-free survival in patients treated with afatinib was

prolonged even more in cancers harboring the two most common EGFR mutations.

■■ Afatinib achieved clinically meaningful results in this setting, but survival data are not yet mature.

Hsin Yang, MD, PhD, National Taiwan University, Taipei, Taiwan.

More Potent Therapy “Afatinib appears to be more potent than other EGFR-directed therapies because it blocks the molecular pathways that facilitate growth of these cancers more broadly and effectively. This new oral therapy may help patients live longer with no disease progression and requires fewer office visits than standard chemotherapy,” Dr. Yang continued. This global registration study included 345 patients with NSCLC with a variety of EGFR mutations. Patients were randomized 2:1 to afatinib or standard chemotherapy with pemetrexed/cisplatin. Overall, 65% were female, 72% were East Asian, and 68% had never smoked. Median progression-free survival in the afatinib arm was 11.1 months vs 6.9 months for standard chemotherapy, representing a 42% reduced risk of progression for those treated with afatinib (P = .0004). About 90% of patients enrolled in the trial had cancers that harbored the most common EGFR mutations, deletion 19 and L858R. In the subset of patients with these two common mutations, median progression-free survival was 13.6 months on the afatinib arm vs 6.9 months on the standard chemotherapy arm, representing a 53% reduced risk of progression with afatininb (P < .0001). Overall survival results are not yet mature and will be reported sometime in the next 2 years. The most common drug-related adverse events associated with afatinib included diarrhea (95%), rash (62%), and paronychia (57%). In the chemotherapy arm, nausea (66%), decreased appetite (53%), and vomiting (32%) were the most common drug-related adverse events. Rates of discontinua-

tion due to drug-related adverse events were 7.9% in the afatinib arm and 11.7% in the chemotherapy arm. Photo by © ASCO/Todd Buchanan 2012.

irst-line therapy with the investigational oral agent afatinib improved progression-free survival compared with standard chemotherapy (pemetrexed (Alimta)/cisplatin) in patients with advanced non– small cell lung cancer (NSCLC) harboring an EGFR mutation. Afatinib improved progression-free survival by about 4 months See Page 84 in this advanced disease population, and progression-free survival benefits were almost doubled in favor of afatinib in patients with the most common EGFR mutations: deletion 19 or L858R. These results from the pivotal phase III international LUXLung 3 trial were presented at the

James Chih-Hsin Yang, MD, PhD

The randomized, open-label, phase III LUX-Lung 3 trial was conducted at 133 sites in 25 countries, and it is the largest phase III trial in the first-line setting for EGFR mutation–positive, advanced, metastatic NSCLC. LUXLung 3 was also the first trial to use pemetrexed/cisplatin as the comparator arm. At an ASCO press conference, Dr. Yang told the audience that patients in the afatinib arm had improved quality of life, with fewer lung cancer–related symptoms and a longer time to worsening of cough and shortness of breath than patients assigned to standard chemotherapy.

■

Disclosure: Dr. Yang has served as consultant or advisor for and has received honoraria from Boehringer Ingelheim and Eli Lilly. He has not received honorarium from Boehringer Ingelheim since the LUX-Lung 3 study started to enroll patients.

Reference 1. Yang J C-H, Schuler MH, Yamamoto N, et al: LUX-Lung 3: A randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as firstline treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. 2012 ASCO Annual Meeting. Abstract LBA7500. Presented June 4, 2012.

ASCOPost.com | JULY 15, 2012

PAGE 13

Announcement

2013 Certifying Examination in Pediatric Hematology-Oncology

he American Board of Pediatrics has announced that the upcoming 2013 Pediatric Hematology-Oncology Certifying Examination will be held on April 16, 2013. Registration and other information is provided below. Examination Date: April 16, 2013 Registration for first-time applicants: August 1, 2012, through October 31, 2012 Registration for reregistrants: September 13, 2012, through December 17, 2012 The final month of each registration requires payment of a late fee. All applicants must complete ap-

plications online during the registration periods. The requirements for online applications are found on the American Board of Pediatrics website: www.abp.org. Additional information including eligibility requirements is

found on the American Board of Pediatrics website. Each application will be considered individually and must be acceptable to the American Board of Pediatrics. For additional information, contact:

American Board of Pediatrics 111 Silver Cedar Court Chapel Hill, NC 27514-1513 Phone: 919-929-0461 Fax: 919-918-7114 ; 919-929-9255 Website: www.abp.org

■

FOR A DIFFERENT PERSPECTIVE IN RENAL CELL CARCINOMA, DISCOVER…

THE OTHER SIDE OF RCC

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Rights & Permissions e-mail: Permissions@harborsidepress.com

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Rates, reprints, or supplements Leslie Dubin e-mail: Leslie@harborsidepress.com Phone: 631.935.7660

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

In the United States, RCC is the 9th most common malignancy and accounts for 2% to 3% of all adult cancers.1,2 Incidence rates continue to rise; however, the reason for this increase is unknown.2 The American Cancer Society estimates that there will be 64,770 new cases and 13,570 deaths in 2012.3

Studies have demonstrated the importance of sustained drug levels; however, these levels can be compromised when toxicities lead to dose modifications, interruptions, or discontinuations.3,6,7 In the Phase III trials of targeted agents, 30% to 40% of patients required dose modifications, and in the community setting this percentage may be higher.5 Treatment modifications require significant monitoring by healthcare professionals, and may potentially compromise treatment exposure and patients’ daily living.3,6

Is good enough, enough? Today’s RCC patients are often active, with busy lifestyles and families. With a median age at diagnosis of only 64, quality of daily living on therapy is critical.1 While the introduction of targeted therapy has improved the management of advanced disease and the outlook for patients, new challenges and existing unmet needs may compromise not only patients’ everyday life, but overall outcomes.2,3

Furthermore, in addition to dose modifications deemed necessary by a physician, patients themselves may choose not to adhere to their dosing regimen due to discomfort or dissatisfaction with the toxicity of therapy, among other factors.6

There may be opportunities to improve patient care

Therapy for advanced RCC has evolved, but…

Proactive monitoring, early detection, and prompt management of side effects are important for optimal patient management. Additionally, open communication between patients and healthcare professionals can be crucial to avoid premature treatment discontinuations or adverse impacts on patients’ everyday lives.3,6

Each therapeutic class of agents is associated with distinct adverse events. Despite recent advances in treatment, side effects remain an important issue in patient management.4 Research has shown that a substantial proportion of patients—both in clinical trials and everyday clinical practice—may not receive the full dose of their therapy due to adverse event management.5,6

Go behind the scenes to learn more at www.WhyCompromiseRCC.com.

AVEO and Astellas are uncompromising in their commitment to RCC patients References: 1. Centers for Disease Control and Prevention. http://apps.nccd. cdc.gov/uscs/toptencancers.aspx. Accessed January 27, 2012. 2. National Comprehensive Cancer Network. http://www.nccn.org. Published October 18, 2011. Accessed January 27, 2012. 3. American Cancer Society. Atlanta: ACS; 2012. 4. Cowey CL, Hutson TE. Clin Adv Hematol Oncol. 2010;8(5):357-364. 5. Hudes GR, Carducci MA, Choueiri TK, et al. J Natl Compr Canc Netw. 2011;9(suppl 1):S-1-S-30. 6. Appleby L, Morrissey S, Bellmunt J, Rosenberg J. Hematol Oncol Clin N Am. 2011;25(4):893-915. 7. Rini BI. J Clin Oncol. 2009;27(19):3225-3234. 8. Ravaud A. Ann Oncol. 2009;20(suppl 1):i7-i12. 9. Houk BE, Bello CL, Poland B, Rosen LS, Demetri GD, Motzer RJ. Cancer Chemother Pharmacol. 2010;66(2):357-371. doi:10.1007/s00280-009-1170-y.

An Uncompromising Commitment to RCC

012D-073-5271

05/12

Printed in USA

The ASCO Post | JULY 15, 2012

PAGE 14

2012 ASCO Annual Meeting Survivorship

ASCO Studies Point to Risks Associated with Treating Childhood Cancers By Caroline Helwick

isks associated with being a young cancer survivor were emphasized by two studies highlighted in press briefings at the 2012 ASCO Annual Meeting. Investigators from the Children’s Oncology Group (COG) reported that adolescents and young adults treated for high-risk B-precursor acute lymphoblastic leukemia (ALL) had worse outcomes than younger children treated for the disease.1 A second study showed an increase in breast cancer among women who received low levels of radiation to the chest as children.2

younger patients (1.8%). However, postinduction remission deaths at 5 years were significantly higher among adolescents and young adults (5.5% vs 2.1%; P < .0001). Dr. Larsen said the findings might be due to differences in disease biology as well as patient-related factors. “Evolving data show that older patients with ALL are more likely to have unfavorable molecular characteristics in the leukemia cells. Also, perhaps they don’t tolerate chemotherapy as well and are given reduced doses. It’s also true that treatment protocols may differ for older pa-

Subsequent Risks in Childhood Cancer Survivors ■■ Adolescents and young adults treated for high-risk ALL had worse

outcomes than children aged 15 and younger; event-free survival and overall survival were compromised in the older age group.

■■ Women who received chest radiotherapy as children had a risk for breast cancer by age 50 comparable to BRCA1/2 mutation carriers—about 30%.

hood cancer survivors. WECARE enrolled patients with breast cancer who had survived at least 1 year after diagnosis. Among the childhood cancer survivors, breast cancer was diagnosed by age 50 in 24% overall and in 30%

More Events, Worse Survival among Adolescents and Young Adults The phase III AALL0232 study tested four treatment regimens for high-risk ALL, and those outcomes were reported last year.3 This year, the investigators reported on event-free survival and overall survival of adolescent and young adult patients (aged 16 to 30) compared to younger patients (aged 1 to 15). Historical data suggest that adolescent and young adult patients with high-risk ALL have inferior outcomes, but a direct comparison by age group, in a large enough trial, has not been available until now, said Eric Larsen, MD, of the Maine Children’s Cancer Program and Study Chair of the COG. The study included 501 adolescent and young adult patients, which made up 20% of the overall trial enrollment of 2,574 subjects. The 5-year eventSee Page 84 free survival rate was 68% in the adolescent and young adult patients compared to 80.9% in the younger patients (P < .0001), while the overall survival rate was 79.8% vs 88.4%, respectively (P < .0001). Relapses occurred in 21.3% vs 13.4%, respectively (P = .0018), mostly because the adolescents and young adults had more relapses in the bone marrow, Dr. Larsen reported. There was no significant difference in induction mortality between adolescent and young adult (2.4%) and

Eric Larsen, MD

Chaya S. Moskowitz, PhD

tients; they are not as intensive,” he noted. “Finally, there are complex social factors that may explain some of the difference, such as compliance with oral chemotherapy, which we are learning is less with older patients,” he added. “There is good evidence that poor compliance correlates with greater relapse.” As a result of this study, the COG is considering options to enhance leukemia control and also reduce the toxicity of treatment for adolescents and young adults.

Childhood Radiation Increases Breast Cancer Risk The risk of developing breast cancer after receiving radiotherapy to the chest as a child are as high as those for BRCA1 and BRCA2 mutation carriers, according to review of 1,268 cancer survivors participating in the Childhood Cancer Survivor Study (CCSS) and 4,570 female first-degree relatives of participants in the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study. CCSS is a large North American cohort study of long-term child-

Nicholas Vogelzang, MD

of Hodgkin lymphoma survivors. In comparison, among first-degree relatives of WECARE Study probands, the cumulative incidence by age 50 among BRCA1 and BRCA2 mutation carriers was 31% and 10%, respectively. In contrast to these two high-risk populations, the expected cumulative incidence in the general U.S. population is 4%. “Surprisingly, women treated with radiotherapy to the chest for Hodgkin lymphomas have a risk of breast cancer that is remarkably similar to BRCA1 mutation carriers,” said Chaya S. Moskowitz, PhD, a biostatistician at Memorial Sloan-Kettering Cancer Center, New York. Radiotherapy dose mattered, but not completely. By age 40, women treated with ≥ 20 Gy had a 12% risk, while those receiving 10 to 19 Gy had a 7% risk. “Both groups need to be followed closely,” said Dr. Moskowitz. She acknowledged that radiation doses are lower now, but the findings point to a need for caution and vigilance. “The goal is to maximize cure rates while minimizing future health problems,” she said. “For women treated with 20 Gy or more of chest radiotherapy, the COG

recommends breast cancer surveillance with annual mammograms and breast MRI starting at age 25, or 8 years after the radiation, whichever is last.” Approximately 50,000 American women received > 20 Gy as children, and another 7,000 to 9,000 were treated with lower doses, the investigators estimated. Nicholas Vogelzang, MD, of the Comprehensive Cancer Centers of Nevada, who chairs ASCO’s Cancer Communications Committee, commented, “These are striking data and warrant our careful attention, not only to improve follow-up but to improve mammographic screening of these women. We have an obligation to those many thousands of young women treated years ago, and hopefully this will increase awareness.”

■

Disclosure: Drs. Larsen, Moskowitz, and Vogelzang reported no potential conflicts of interest.

References 1. Larsen E, Raetz EA, Winick NJ, et al: Outcome in adolescent and young adult patients compared with patients treated for high-risk B precursor acute lymphoblastic leukemia: A report from the Children’s Oncology Group study AALL0232. 2012 ASCO Annual Meeting. Abstract CRA9508. Presented June 2, 2012. 2. Moskowitz CS, Chou JF, Wolden SL, et al: New insights into the risk of breast cancer in childhood cancer survivors treated with chest radiation: A report from the Childhood Cancer Survivor Study and the Women’s Environmental Cancer and Radiation Epidemiology Study. 2012 ASCO Annual Meeting. Abstract CRA9513. Presented June 4, 2012. 3. Larsen EC, Salzer WL, Devidas M, et al: Comparison of high-dose methotrexate with Capizzi methotrexate plus asparaginase in children and young adults with high-risk acute lymphoblastic leukemia: A report from the Children’s Oncology Group Study AALL0232. 2011 ASCO Annual Meeting. Abstract 3. Presented June 5, 2011.

In the treatment of myelofibrosis What does

REGULATING JAK mean for your patients?

Jakafi™ (JAK-ah-fye)—First and Only FDA-Approved Agent for MYELOFIBROSIS (MF)*

REGULATE REDUCE JAK signaling

splenomegaly and symptoms of MF

JAK2

JAK1

Jakafi

*Intermediate or high-risk MF.

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis. Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia. A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required

• The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions. Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster)

Jakafi demonstrated superior reductions in spleen volume and improvements in symptom scores at Week 241,2,a,b Percent Change in Total Symptom Score (TSS) in Individual Patients From Baseline to Week 24 or Last Observation1,a,b

Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation1,a

150

40 20 0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

100 50 0 -50

IMPROVEMENT WORSENING

Change From Baseline (%)

60 IMPROVEMENT WORSENING

Change From Baseline (%)

-100

50% Improvement Upper 50th Percentile

Placebo (n = 153)

Upper 50th Percentile

Jakafi (n = 145)

In these charts, each bar represents an individual patient’s response.

Placebo (n = 145)

Worsening of TSS is truncated at 150%.

At Week 24, significantly more patients receiving Jakafi vs placebo had — A ≥35% reduction in spleen volume (41.9% vs 0.7%, respectively; P < 0.0001)1,2,a — A ≥50% improvement in TSS (45.9% vs 5.3%, respectively; P < 0.0001)1,2,a,b Reductions in spleen volume and improvements in TSS were seen with Jakafi in both JAK2 V617F-positive patients and JAK2 V617F-negative patients, relative to placebo2

Visit www.jakafi.com/regulate

for more information on Jakafi and MF, plus valuable educational resources.

and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration]. Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by magnetic resonance imaging (MRI) or computed tomography (CT) . A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified Myelofibrosis Symptom Assessment Form (MFSAF v2.0).1,2

b Symptom

scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.1,2

References: 1. Jakafi Prescribing Information. Incyte Corporation. November 2011. 2. Data on file. Incyte Corporation.

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

JAK targeted to make a difference

NC007 JK0 BS 12P_Layout 1 11/16/11 9:16 AM Page 1

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia. A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study. Issued: November 2011 RUX-1040

ASCOPost.com | JULY 15, 2012

PAGE 19

2012 ASCO Annual Meeting Gastrointestinal Oncology

Bevacizumab beyond Progression Prolongs Survival in Metastatic Colorectal Cancer By Caroline Helwick

n a study highlighted at a press briefing during the 2012 ASCO Annual Meeting, German investigators reported that prolonging treatment with bevacizumab (Avastin) beyond disease progression extends overall survival in patients with metastatic colorectal cancer.1 Patients reSee Page 84 ceived bevacizumab plus standard second-line chemotherapy after disease progressed on bevacizumab and first-line therapy. “This is the first randomized trial to prospectively evaluate bevacizumab beyond first progression. The study confirms that continuing bevacizumab

while changing chemotherapy translates into a significant improvement in overall as well as progression-free survival in patients with metastatic colorectal cancer,” said Dirk Arnold, MD, of the University Clinic Eppendorf in Hamburg.

Study Details The randomized phase III TML 18147 trial enrolled 820 patients with metastatic colorectal cancer who had progressive disease following first-line chemotherapy with an irinotecan- or oxaliplatin-based regimen, plus bevacizumab. Upon disease progression, the patients were randomly assigned to second-line therapy with the regimen

Bevacizumab in Metastatic Colorectal Cancer ■■ The TML 18147 trial is the first randomized study to prospectively evaluate bevacizumab beyond first progression in patients with metastatic colorectal cancer.

■■ Continuing bevacizumab, while changing the chemotherapy regimen, led

to an absolute 1.4-month improvement in overall survival and a 1.6-month improvement in progression-free survival.

■■ The results were statistically significant, yet were far less impressive than

seen when bevacizumab was continued in the observational BRiTE registry.

they did not receive first, with or without concomitant bevacizumab. Median overall survival was 11.2 months with continued bevacizumab, compared with 9.8 months with chemotherapy alone, for a 19% reduction

in mortality risk (P = .0062). Median progression-free survival was 5.7 vs 4.1 months, respectively, a 32% risk reduction (P < .0001), Dr. Arnold reported. “There was no sign that the continucontinued on page 20

Other Colorectal Cancer News from ASCO

dditional noteworthy gastrointestinal cancer studies presented during oral abstract sessions at the 2012 ASCO Annual Meeting included the following trials in metastatic colorectal cancer.

Perifosine/Capecitabine Fails in Phase III Trial Adding perifosine, an oral alkylphospholipid inhibitor that targets the Akt pathway, to oral capecitabine (Xeloda) did not significantly improve overall or progression-free survival, vs capecitabine alone, in the X-PECT study.1

subset of patients with wild-type KRAS who discontinued oxaliplatin because of toxicity, the combination significantly increased progression-free survival from 6.6 weeks to 18.1 weeks (P = .003), reported Johanna C. Bendell, MD, of Sarah Cannon Research Institute, Nashville. The results contradict those from an earlier randomized phase II trial, in which patients refractory to two prior therapies had a median overall survival of 17.7 months with the combination, vs 7.6 months with capecitabine alone (P = .0052).2 The possibility was raised that the phase�� II �� population may not have been less heavily pretreated and were therefore more similar to patients who responded in the phase�� III trial. An analysis of biomarkers is underway.

Tyrosine Kinase Inhibitors

Johanna C. Bendell, MD

The phase III X-PECT trial randomly assigned 468 patients with treatmentrefractory metastatic colorectal cancer to the combination or capecitabine alone. Median overall survival was 6.4 months and 6.9 months, respectively, while progression-free survival was 10.9 weeks and 11.4 weeks. However, in a

Two other studies showed benefits for adding tyrosine kinase inhibitors to metastatic colorectal cancer regimens. In the phase�� III CORRECT trial of 760 highly refractory patients, the oral multikinase inhibitor regorafenib extended overall survival from 5.5 months with placebo to 6.6 months, a 23% reduction in risk (P = .0052).3 Coprincipal investigator Axel Grothey, MD, of the Mayo Clinic, suggested that regorafenib addresses an unmet need for patients with colorectal cancer who

exhaust all recommended treatments while still fit enough for chemotherapy. The phase III GERCOR DREAM trial evaluated the benefit of adding erlotinib (Tarceva) to bevacizumab as maintenance therapy in 700 previously untreated patients with metastatic colorectal cancer who responded to chemotherapy plus bevacizumab.4 Compared to bevacizumab alone, the combination improved median progression-free survival from 4.6 months to 5.8 months (P = .005), though diarrhea and skin toxicity were greater.

Resection of Primary Improves Outcomes In patients with metastatic colorectal cancer and unresectable metastases, resection of the primary tumor was associated with improved outcomes in a pooled analysis involving individual patient data from four first-line chemotherapy trials.5 Among 810 total patients, a multivariate analysis showed that primary tumor resection (n = 478) was an independent predictor of better overall survival (HR = 0.63; P < .0001) and better progression-free survival (HR = 0.82; P = .0007). The effect of resection was lessened in patients with higher carcinoembryonic antigen levels or a colon (vs rectal) primary tumor.

■

Disclosure: Dr. Bendell reported no potential conflicts of interest. Dr. Grothey has served as an unpaid consultant or advisor for Bayer.

References 1. Bendell JC, Ervin TJ, Senzer NN, et al: Results of the X-PECT study: A phase III randomized double-blind placebo-controlled study of perifosine plus capecitabine versus placebo plus capecitabine in patients with refractory metastatic colorectal cancer. 2012 ASCO Annual Meeting. Abstract LBA3501. Presented June 3, 2012. 2. Bendell JC, Nemunaitis J, Vukelja SJ, et al: Randomized placebo-controlled phase II trial of perifosine plus capecitabine as second- or third-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 29:4394-4400, 2011. 3. Van Cutsem E, Sobrero AF, Siena S, et al: Phase III CORRECT trial of regorafenib in metastatic colorectal cancer. 2012 ASCO Annual Meeting. Abstract 3502. Presented June 3, 2012. 4. Tournigand C, Samson B, Scheithauer W, et al: Bevacizumab with or without erlotinib as maintenance therapy, following induction first-line chemotherapy plus Bev, in patients with metastatic colorectal cancer: Efficacy and safety results of the International GERCOR DREAM phase III trial. 2012 ASCO Annual Meeting. Abstract LBA3500. Presented June 3, 2012. 5. Faron M, Bourredjem A, Pignon J, et al: Impact on survival of primary tumor resection in patients with colorectal cancer and unresectable metastasis: Pooled analysis of individual patients’ data from four randomized trials. 2012 ASCO Annual Meeting. Abstract 3507. Presented June 3, 2012.

The ASCO Post | JULY 15, 2012

PAGE 20

2012 ASCO Annual Meeting Bevacizumab in Metastatic Colorectal Cancer continued from page 19

ation of bevacizumab had an impact on further grade 3 to 5 adverse events,” he further noted. “Rates were already low and similar between the arms.” Adverse events of any grade were noted in 41% of patients receiving bevacizumab/chemotherapy, with 12% grades 3 to 5.

EXPERT POINT OF VIEW

By Axel Grothey, MD, Mayo Clinic, Rochester, Minnesota

ver the past 10 years, agents targeting the VEGF system, such as bevacizumab, have become standard components of anticancer therapy in various malignancies. Recently, it has become increasingly evident that prolonged duration of anti-VEGF therapy is needed to optimize the therapeutic effect of this class of agents.

Bevacizumab Beyond Progression

Dirk Arnold, MD

Important Concept The TML trial tested an important biologic concept for antiangiogenic drugs, showing that duration of treatment does matter. Although the current evidence is in metastatic colorectal cancer, the principle could hold true across lung cancer and breast cancer, Dr. Arnold suggested. Press briefing moderator Bruce J. Roth, MD, of Washington University in St. Louis, commented that oncologists have been trained to discontinue cytotoxic chemotherapy at the time of progression, “but the issue is more complicated for anti-

In metastatic colorectal cancer, this notion has led to the recommendation to continue anti-VEGF therapy, in particular bevacizumab, until tumor progression. In addition, preclinical findings and circumstantial evidence from observational cohort studies suggested that patients could benefit from continuation of bevacizumab beyond documented tumor progression in this malignancy. Importantly, while initial evaluations of these observational cohort studies reVEGF [vascular endothelial growth factor] therapies like bevacizumab, and this issue has been raised in other tumor types.” He explained that the mechanism of resistance to antiVEGF agents may be different, and this might explain the benefit with continued treatment.

■

ported a surprisingly large difference between the groups of patients who did or did not continue bevacizumab beyond progression, recent analysis using more sophisticated statistical methods projected a benefit for overall survival expressed as hazard ratio for bevacizumab beyond progression in the range of 0.80.1

progression, the results provide new insights into tumor biology in general and our understanding of treatment resistance in particular. The inevitable financial implications of these results aside, the data presented at ASCO Axel Grothey, MD will hopefully open the door for future innovative and optimized treatment strategies.

■

Insights in Tumor Biology

Disclosure: Dr. Grothey has served as an unpaid advisor or consultant for Bayer.

This hypothesis has now been confirmed in a prospective phase III trial, which documented a statistically significant survival benefit in patients with metastatic colorectal cancer when bevacizumab was continued from first- into second-line therapy. While the magnitude of the survival benefit observed might have disappointed some believers in the concept of bevacizumab beyond

Reference 1. Grothey A, Bekaii-Saabts, Hurwitz H, et al: Cumulative exposure to bevacixumab after progression correlates with increased survival in patients with metastatic colorectal cancer: A time-dependent analysis of the ARIES observational cohort study. European Multidisciplinary Cancer Congress. Abstract 6031. Presented September 25, 2011.

Disclosure: Dr. Arnold has served in a consulting or advisory role and has received honoraria from Amgen, Merck Serono, and Roche, and has received research funding from Roche. Dr. Roth reported no potential conflicts of interest.

Reference 1. Arnold D, Andre T. Bennouna J,

et al: Bevacizumab plus chemotherapy continued beyond first progression in patients with metastatic colorectal cancer previously treated with bevacizumab plus chemotherapy: Results of a randomized phase III intergroup study (TML study). 2012 ASCO Annual Meeting. Abstract CRA3503. Presented June 3, 2012.

EXPERT POINT OF VIEW

Alan Venook, MD

nvited discussant Alan Venook, MD, of the University of California, San Francisco, pointed out that the hazard ratio of 0.81 and the 1.4-month improvement in overall survival in the TML trial did not reach the target hazard ratio of 0.77 in the statistical design of the study. However, “it is still a positive trial,” he noted, and one that has implications for conversations with patients. “Once anti-VEGF therapy is initi-

ated, discontinuing it may lead to a small survival disadvantage,” he might tell patients with metastatic colorectal cancer. “It may be a mistake to discontinue treatment at any time, and that affects all the decisions we will make over the course of your disease.” Dr. Venook also suggested that “it may make more sense to use bevacizumab in second and subsequent lines of treatment, rather than upfront,” though he acknowledged that research is needed, with an emphasis on predictive biomarkers.

Limited Utility of Registry Studies The TML study also underscored the risk inherent in basing clinical decisions on registry data. In the BRiTE registry of almost 2,000 patients with metastatic colorectal cancer, administration of bev-

acizumab beyond progression improved median overall survival from 19.9 to 31.8 months.1 These findings precipitated the closure of SWOG 0600, which, much like the TML trial, was also evaluating continued bevacizumab, “leaving questions unanswered until today,” he said. “Though they were in the same direction, the BRiTE findings were not replicated in the TML study,” he noted, and the striking difference in outcomes “affirms the limited utility of registry studies.” He concluded that the role of bevacizumab beyond progression is still being established, but current data suggest the second-line setting is an appropriate place to use the drug. Remaining questions may be informed by the ongoing CALGB/ SWOG 80405 trial, which Dr. Venook is leading. The study is randomly as-

signing 2,334 untreated patients with metastatic colorectal cancer and wildtype KRAS to FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) or FOLFIRI (leucovorin, 5-FU, irinotecan) plus either bevacizumab or cetuximab (Erbitux) every 2 weeks. “We will have biomarker information to inform us,” he added. “Predictive biomarkers should be as high a priority as finding new drugs and indications.”

■

Disclosure: Dr. Venook receives research funding from Genentech.

Reference 1. Grothey A, Sugrue MM, Purdie DM, et al: Bevacizumab beyond first progression is associated with prolonged overall survival in metastatic colorectal cancer. Results from a large observational cohort study (BRiTE). J Clin Oncol 26:53265334, 2008.

ASCOPost.com | JULY 15, 2012

PAGE 21

Journal Spotlight Gastrointestinal Oncology

Increased Adjuvant Therapy Use and Improved Survival in Dutch Elderly Patients with Stage III Colon Cancer: A Direct Correlation? By Matthew Stenger

survival benefit of adjuvant chemotherapy has been reported for select elderly patients with stage�� III colon cancer, but many elderly patients are not candidates for or are not given adjuvant therapy due to comorbidities and fear of toxicity. In a recent Annals of Oncology article, van Steenbergen and colleagues reported findings in a Netherlands Cancer Registry study indicating increased use of adjuvant therapy and improved survival during recent years among elderly Dutch patients with stage III colon cancer.1 The authors suggested that the finding of improved survival likely reflects a contribution of inSee Page 84 creased stage migration, increased use of adjuvant therapy, and selection of fitter patients for adjuvant treatment in more recent years. The study included all (N = 8,051) patients aged ≥ 75 years with resected stage III (IIIA = T1-2, N1; IIIB = T34, N1; and IIIC = any T, N2) primary colon cancer diagnosed from 1997 to 2009 in The Netherlands. Of these patients, 46% were aged 75 to 79 years, 33% 80 to 84 years, and 22% ≥ 85 years at diagnosis. Most were women (58%), had stage IIIB disease (58%), and had moderate/well differentiated tumor grade (67%). Proportions of patients receiving adjuvant therapy and crude 5-year survival rates were compared for the periods 1997–2000 (n = 2,156), 2001–2003 (n = 1,676), 2004–2006 (n = 1,944), and 2007– 2009 (n = 2,275).

Adjuvant Therapy Use Overall, 17% of patients received adjuvant therapy. The proportion of patients receiving adjuvant therapy increased from 12% in 1997–2000, to 15% in 2001–2003, 19% in 2004– 2006, and 23% in 2007–2009 (P < .0001 for trend). The proportion of patients aged 75 to 79 years receiving adjuvant therapy doubled from 22% in 1997–2000 to 44% in 2007–2009 < .0001 for trend). Although rela(P �� tively few patients aged 80 to 84 years received adjuvant therapy, the proportion increased from 4% in the first time period to 10% in the final time period. Overall, only 1% of patients aged 85 years or older received adjuvant ther-

apy. Variations in chemotherapy use among the eight geographic regions were evident but decreased over time. After stratified analysis adjusting

for age, gender, tumor site, disease stage, tumor grade, period of diagnosis, and region, patients aged 75 to 79 years were significantly more likely to

receive adjuvant therapy when they had more advanced disease stage (odds ratio [OR] =1.4 for stage IIIC continued on page 22

Our world centers around theirs ACTION PURPOSE IMPACT

As cancer researchers, we dare to advocate uncharted paths in science and research. We engage and execute with a vision, collaborating with the oncology community to deliver personalized and measurable outcomes that improve and extend lives. We strive to advance the fight against cancer, continuously applying research to clinical practice and targeting the individual needs of people living with cancer.

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The ASCO Post | JULY 15, 2012

PAGE 22

Journal Spotlight

Adjuvant Therapy in Colorectal Cancer continued from page 21

vs stage IIIB, P < .0001) and when cancer was diagnosed more recently (OR = 1.8, P < .0001, for 2004–2006 and OR =2.8, P < .0001, for 2007– 2009 vs 1997–2000). Patients in this age group were also significantly more likely to receive therapy in two of the geographic regions. Patients ≥�� 80 years of age were significantly less likely to receive adjuvant therapy if they were female (OR = 0.7, P < .05, vs men) and significantly more likely to receive therapy when disease was more advanced (OR = 2.3, P < .0001, for IIIC vs IIIB) and was diagnosed more recently (OR = 2.0, P < .05, for 2004–2006, and OR 2.4, P < .0001, for 2007–2009 vs 1997– 2000). Patients from one geographic region were also more likely to receive adjuvant chemotherapy.

ciated with a 50% reduction in risk for death (adjusted hazard ratio [HR] = 0.5, P < .0001). Other significant predictors on multivariate analysis were age 80 to 84 years and age ≥�� 85 years (poorer survival vs age 75–79 years), disease stage IIIA (better survival vs IIIB) and stage IIIC (poorer survival vs IIIB), poor tumor grade (poorer survival vs moderate/well tumor grade), and diagnosis in any period after 1997–2000 (better survival vs diagnosis in 1997–2000). The 5-year survival rate increased from 29% in 1997–2000, to 32% in 2001–2003 (adjusted HR = 0.9, P < .05), and 35% in 2004–2006; 5-year survival could not be determined for patients diagnosed in 2007–2009, but the adjusted hazard ratio compared

■■ Adjuvant chemotherapy therapy use and 5-year survival have increased in elderly Dutch stage III colon cancer patients in recent years.

■■ Survival increased over time in multivariate survival models including and excluding adjuvant therapy, suggesting a contribution of increased stage migration to improved survival.

■■ Improved survival likely reflects a combination of stage migration,

increased use of adjuvant therapy, and increased selection of fitter patients for adjuvant therapy.

Among patients who died, colorectal cancer was the cause of death in 72% of patients who received adjuvant therapy and in 60% of those who did not. In the latter group, cardiovascular disease (10% vs 5%) and respiratory disease (3% vs 1%) were more common causes of death.

Survival of elderly patients with stage III colon cancer increased over time, most likely due to stage migration caused by better diagnosis over time and increased use of adjuvant therapy.

Improved Survival Crude 5-year survival among all patients was 33%. Five-year survival was 58% in patients receiving adjuvant therapy, compared with 28% in those not receiving adjuvant therapy (P < .0001), with survival being greater in patients aged 75 to 79 years than in patients aged ≥ 80 years, both with and without adjuvant therapy. Factors significantly associated with poorer 5-year survival in addition to greater age were male gender, proximal tumor site, more advanced disease stage, poor tumor grade, and earlier period of diagnosis. On multivariate analysis, adjuvant chemotherapy was the strongest predictor of survival after adjustment for patient and tumor factors, being asso-

Adjuvant Chemotherapy and Survival in Colon Cancer

with 1997–2000 was 0.7 (P < .0001). A multivariate survival model analysis without adjuvant chemotherapy showed similar results for the other variables, especially for period of diagnosis, with the exception of a stronger effect of age on survival. After stratification for adjuvant therapy, significant effects of both age and period of diagnosis were found both in patients receiving and in those not receiving adjuvant chemotherapy. Five-year disease-specific survival rates were 38% for patents aged 75 to 79 years, 27% for those aged 80 to 84 years, and 17% for those aged ≥ 85 years (P < .0001 for trend).

Stage Migration and Increased Adjuvant Therapy The investigators hypothesized that the improvement in survival of patients with stage III colon cancer over time is likely attributable in part to stage migration associated with improvements in evaluation of lymph nodes and imaging techniques that occurred during the study period. This effect is supported by the finding that survival improved over time in models with and without adjuvant chemotherapy. The authors also hypothesized that the reduced mortality from colon cancer in patients not receiving adjuvant thera-

py reflects avoidance of its use in patients with substantial comborbidities. They noted, “[T]his group might justifiably have not received adjuvant chemotherapy, especially since they died more often due to cardiovascular and respiratory diseases, which are frequent comorbidities in colon cancer patients.” The authors concluded, “Survival of elderly patients with stage III colon cancer increased over time, most likely due to stage migration caused by better diagnosis over time and increased use of adjuvant therapy. The marked effect of adjuvant chemotherapy on survival might be caused by selection of fitter patients without comorbidity and a good performance status, which should be investigated further.” For more on adjuvant therapy in older patients with colorectal cancer, see page 87.

■

Disclosure: The study investigators reported no potential conflicts of interest.

Reference 1. van Steenbergen LN, Lemmens VEPP, Rutten HJT, et al: Increased adjuvant treatment and improved survival in elderly stage III colon cancer patients in The Netherlands. Ann Oncol. May 4, 2012 (early release online).

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FOR PATIENTS WITH ADVANCED BCC

IS IT TIME FOR A CHANGE? The first and only FDA-approved Hedgehog pathway inhibitor

Turn the page to see more... Indication Erivedgeâ&#x201E;˘ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS See full prescribing information for complete boxed warning. Erivedge can result in embryo-fetal death or severe birth defects. Verify pregnancy status prior to initiation of Erivedge. Advise male and female patients of these risks. Advise females of the need for contraception and advise males of the potential risk of Erivedge exposure through semen. Please see additional Important Safety Information, including BOXED WARNING, on following page and Brief Summary of Prescribing Information on back.

Simulated image based on locally advanced BCC patient at Week 24. Indication Erivedge™ (vismodegib) capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.

Boxed Warning and Additional Important Safety Information • Erivedge capsule can cause fetal harm when administered to a pregnant woman based on its mechanism of action • Verify pregnancy status prior to the initiation of Erivedge. Advise male and female patients of these risks. Advise female patients of the need for contraception during and after treatment and advise male patients of the potential risk of Erivedge exposure through semen • Advise patients to contact their healthcare provider

immediately if they suspect they (or, for males, their female partner) may be pregnant • Immediately report exposure to Erivedge during pregnancy and encourage women who may have been exposed to Erivedge during pregnancy, either directly or through seminal fluid, to participate in the Erivedge pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at (888) 835-2555

Blood Donation • Advise patients not to donate blood or blood products while receiving Erivedge and for at least 7 months after the last dose of Erivedge

Nursing Mothers • Inform female patients of the potential for serious adverse reactions in nursing infants from Erivedge, taking into account the importance of the drug to the mother

TRANSFORM THE TREATMENT OF ADVANCED BCC Erivedge— a unique treatment option • Systemic therapy that targets dysregulated Hedgehog pathway signaling, a known driver of BCC1,2 • One 150-mg capsule a day until disease progression or unacceptable toxicity1 • Erivedge reduced lesions in patients with advanced BCC1 Objective response rates (ORR) by IRF from ERIVANCE1* laBCC (n=63) ORR (95% CI) Complete response

43% (n=27) (30.5-56.0) 21% (n=13)

mBCC (n=33) 30% (n=10) (15.6-48.2) 0%

Partial response

22% (n=14)

30% (n=10)

7.6 (5.7-9.7)

7.6 (5.6-NE)

Median response duration (months) (95% CI)

* Patients received at least 1 dose of Erivedge with independent pathologist-confirmed diagnosis of BCC. For laBCC, complete response was defined as objective response with no residual BCC on sampling biopsy. IRF=Independent Review Facility. CI=confidence interval. laBCC=locally advanced BCC. mBCC=metastatic BCC. NE=not estimable.

Adverse Reactions • The most common adverse reactions (≥10% were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia • In clinical trials, a total of 3 of 10 premenopausal women developed amenorrhea while receiving Erivedge • Treatment-emergent grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%) Please see Brief Summary of Prescribing Information on following page.

References: 1. Erivedge™ (vismodegib) capsule Prescribing Information. Genentech, Inc. January 2012. 2. Epstein EH. Nat Rev Cancer. 2008; 8:743-754.

Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients (cont)

MedDRA Preferred Term2 Metabolism and nutrition disorders Decreased appetite Musculoskeletal and connective tissue disorders Muscle spasms Arthralgias Nervous system disorders Dysgeusia Ageusia Skin and subcutaneous tissue disorders Alopecia

ERIVEDGE (vismodegib) capsule Initial U.S. Approval: 2012 This is a brief summary of information about ERIVEDGE. Before prescribing, please see full prescribing information. WARNING: EMBRYO-FETAL DEATH AND SEVERE BIRTH DEFECTS ERIVEDGE (vismodegib) capsule can result in embryo-fetal death or severe birth defects. ERIVEDGE is embryotoxic and teratogenic in animals. Teratogenic effects included severe midline defects, missing digits, and other irreversible malformations. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of these risks. Advise female patients of the need for contraception and advise male patients of the potential risk of ERIVEDGE exposure through semen [see Warnings and Precautions (5.1), Use in Specific Populations (8.1, 8.6)]. 1 INDICATIONS AND USAGE ERIVEDGE capsule is indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. 2 DOSAGE AND ADMINISTRATION The recommended dose of ERIVEDGE is 150 mg taken orally once daily until disease progression or until unacceptable toxicity [see Clinical Studies (14)]. ERIVEDGE may be taken with or without food. Swallow capsules whole. Do not open or crush capsules. If a dose of ERIVEDGE is missed, do not make up that dose; resume dosing with the next scheduled dose. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Death and Severe Birth Defects ERIVEDGE capsules can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Vismodegib is teratogenic, embryotoxic, and fetotoxic in rats at maternal exposures lower than the human exposures at the recommended dose of 150 mg/day. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Verify pregnancy status prior to the initiation of ERIVEDGE. Advise male and female patients of the risks of embryo-fetal death and severe birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant. Female and male patients of reproductive potential should be counseled regarding pregnancy prevention and planning. If ERIVEDGE is used during pregnancy or if a patient becomes pregnant while taking (or for a male patient, if his female partner is exposed to) ERIVEDGE, the patient should be apprised of the potential hazard to the fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Use in Specific Populations (8.1, 8.6)]. 5.2 Blood Donation Advise patients not to donate blood or blood products while receiving ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. ERIVEDGE capsule was administered as monotherapy at doses ≥ 150 mg orally daily in four open-label, uncontrolled, dose-ranging or fixed single dose clinical trials enrolling a total of 138 patients with advanced basal cell carcinoma (BCC). The median age of these patients was 61 years (range 21 to 101), 100% were White (including Hispanics), and 64% were male. The median duration of treatment was approximately 10 months (305 days; range 0.7 to 36 months); 111 patients received ERIVEDGE for 6 months or longer. The most common adverse reactions (≥ 10%) were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias, vomiting, and ageusia (Table 1). Table 1: Adverse Reactions Occurring in ≥ 10% of Advanced BCC Patients All aBCC1 Patients (N = 138) MedDRA Preferred Term2 Gastrointestinal disorders Nausea Diarrhea Constipation Vomiting General disorders and administration site conditions Fatigue Investigations Weight loss

73858ge_a.indd 3

All Grades 3 (%)

Grade 3 (%)

Grade 4 (%)

42 (30.4%) 40 (29.0%) 29 (21.0%) 19 (13.8%)

1 (0.7%) 1 (0.7%) -

55 (39.9%)

7 (5.1%)

1 (0.7%)

62 (44.9%)

10 (7.2%)

All aBCC1 Patients (N = 138) All Grades 3 Grade 3 Grade 4 (%) (%) (%)

35 (25.4%)

3 (2.2%)

99 (71.7%) 22 (15.9%)

5 (3.6%) 1 (0.7%)

76 (55.1%) 15 (10.9%)

88 (63.8%)

aBCC = Advanced Basal Cell Carcinoma. 2 MedDRA = Medical Dictionary for Regulatory Activities. 3 Grading according to NCI-CTCAE v3.0. Amenorrhea: In clinical trials, a total of 3 of 10 pre-menopausal women developed amenorrhea while receiving ERIVEDGE [see Non-Clinical Toxicology (13.1)]. Laboratory Abnormalities: Treatment-emergent Grade 3 laboratory abnormalities observed in clinical trials were hyponatremia in 6 patients (4%), hypokalemia in 2 patients (1%), and azotemia in 3 patients (2%). 1

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Vismodegib Drugs that Inhibit or Induce Drug Metabolizing Enzymes Vismodegib elimination involves multiple pathways. Vismodegib is predominantly excreted as an unchanged drug. Several minor metabolites are produced by multiple CYP enzymes. Although vismodegib is a substrate of CYP2C9 and CYP3A4 in vitro, CYP inhibition is not predicted to alter vismodegib systemic exposure since similar steady-state plasma vismodegib concentrations were observed in patients in clinical trials concomitantly treated with CYP3A4 inducers (i.e., carbamazepine, modafinil, phenobarbital) and those concomitantly treated with CYP3A4 inhibitors (i.e., erythromycin, fluconazole). Drugs that Inhibit Drug Transport Systems In vitro studies indicate that vismodegib is a substrate of the efflux transporter P-glycoprotein (P-gp). When ERIVEDGE is coadministered with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), systemic exposure of vismodegib and incidence of adverse events of ERIVEDGE may be increased. Drugs that Affect Gastric pH Drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2-receptor antagonists, and antacids) may alter the solubility of vismodegib and reduce its bioavailability. However, no formal clinical study has been conducted to evaluate the effect of gastric pH altering agents on the systemic exposure of vismodegib. Increasing the dose of ERIVEDGE when coadministered with such agents is not likely to compensate for the loss of exposure. When ERIVEDGE is coadministered with a proton pump inhibitor, H2-receptor antagonist or antacid, systemic exposure of vismodegib may be decreased and the effect on efficacy of ERIVEDGE is unknown. 7.2 Effects of Vismodegib on Other Drugs Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug is co-administered with vismodegib. In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP. Vismodegib does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D ERIVEDGE capsule can cause fetal harm when administered to a pregnant female based on its mechanism of action. Vismodegib is teratogenic in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose (estimated AUC 0-24hr steady-state exposure). In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. Fetal retardations and variations were also observed. Vismodegib is embryolethal in rats at exposures within the range achieved at the recommended human dose. If ERIVEDGE is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the embryo or fetus. Report immediately exposure to ERIVEDGE during pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may have been exposed to ERIVEDGE during pregnancy, either directly or through seminal fluid, to participate in the ERIVEDGE pregnancy pharmacovigilance program by contacting the Genentech Adverse Event Line at 1-888-835-2555 [see Boxed Warning, Warnings and Precautions (5.1)]. In an embryo-fetal developmental toxicity study, pregnant rats were administered oral vismodegib at doses of 10, 60, or 300 mg/kg/day during the period of organogenesis. Pre- and post-implantation loss were increased at doses of ≥ 60 mg/kg/day (approximately ≥ 2 times the systemic exposure (AUC) in patients at the recommended human dose), which included early resorption of 100% of the fetuses. A dose of 10 mg/kg/day (approximately 0.2 times the AUC in patients at the recommended dose) resulted in malformations (including missing and/or fused digits, open perineum and craniofacial anomalies) and retardations or variations (including dilated renal pelvis, dilated ureter, and incompletely or unossified sternal elements, centra of vertebrae, or proximal phalanges and claws). 8.3 Nursing Mothers It is not known whether vismodegib is excreted in human breast milk. Because many drugs are excreted in human milk and because

of the potential for serious adverse reactions in nursing infants from ERIVEDGE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ERIVEDGE capsule have not been established in pediatric patients. In repeat-dose toxicology studies in rats, administration of oral vismodegib resulted in toxicities in bone and teeth. Effects on bone consisted of closure of the epiphyseal growth plate when oral vismodegib was administered for 26 weeks at ≥ 50 mg/kg/day (approximately ≥ 0.4 times the systemic exposure (AUC) in patients at the recommended human dose). Abnormalities in growing incisor teeth (including degeneration/ necrosis of odontoblasts, formation of fluid-filled cysts in the dental pulp, ossification of the root canal, and hemorrhage resulting in breakage or loss of teeth) were observed after administration of oral vismodegib at ≥ 15 mg/kg/day (approximately ≥ 0.2 times the AUC in patients at the recommended human dose). 8.5 Geriatric Use Clinical studies of ERIVEDGE capsule did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. 8.6 Females of Reproductive Potential and Males ERIVEDGE capsule can cause harm to the embryo or fetus when administered during pregnancy. Counsel female and male patients regarding pregnancy prevention and planning. Advise patients to contact their healthcare provider immediately if they suspect they (or, for males, their female partner) may be pregnant [see Boxed Warning, Warnings and Precautions (5.1), Use in Specific Populations (8.1)] Female patients Determine pregnancy status within 7 days prior to initiation of treatment in females of reproductive potential. For females with a negative pregnancy test, initiate a highly effective form of contraception (failure rate of less than 1%) prior to the first dose. Continue highly effective contraception during therapy and for 7 months after the last dose of ERIVEDGE. If a patient becomes pregnant while taking ERIVEDGE, or during the 7 months after the last dose of treatment, report the pregnancy to the Genentech Adverse Event Line at 1-888-835-2555. Encourage pregnant females to participate in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. Counsel pregnant females about the teratogenic risk to the fetus. Amenorrhea has been observed in clinical trials in females of reproductive potential. Reversibility of amenorrhea is unknown [see Adverse Reactions (6), Nonclinical Toxicology (13.1)]. Male patients Male patients should use condoms with spermicide, even after a vasectomy, during sexual intercourse with female partners while being treated with ERIVEDGE capsule and for 2 months after the last dose to avoid exposing an embryo or fetus to vismodegib. 8.7 Hepatic Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with hepatic impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment The safety and effectiveness of ERIVEDGE capsule have not been established in patients with renal impairment [see Clinical Pharmacology (12.3)]. 10 OVERDOSAGE There is no information on overdosage in humans. In clinical trials, ERIVEDGE capsule was administered at 540 mg orally once daily; exposure did not increase between 150 mg and 540 mg daily. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). • Advise patients that ERIVEDGE exposure during pregnancy can cause embryo-fetal death or severe birth defects. • Instruct female patients of reproductive potential to use a highly effective form of contraception (failure rate of less than 1%) while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Instruct all male patients, even those with prior vasectomy, to use condoms with spermicide, during sexual intercourse with female partners while taking ERIVEDGE and for at least 2 months after the last dose of ERIVEDGE. • Instruct patients to immediately contact their healthcare provider if they (or, for males, their female partner) become pregnant or if pregnancy is suspected following exposure to ERIVEDGE. • Instruct patients to immediately report any pregnancy exposure to ERIVEDGE and encourage participation in the ERIVEDGE pregnancy pharmacovigilance program by calling the Genentech Adverse Event Line at 1-888-835-2555. • Inform female patients of the potential for serious adverse reactions in nursing infants from ERIVEDGE, taking into account the importance of the drug to the mother. • Advise patients not to donate blood or blood products while taking ERIVEDGE and for at least 7 months after the last dose of ERIVEDGE. • Advise patients to swallow ERIVEDGE capsules whole and not to crush or open the capsules.

ERIVEDGE™ [vismodegib] capsule Manufactured by: Patheon, Inc. Mississauga, Canada Distributed by: Genentech USA, Inc. ERIVEDGE is a registered trademark A Member of the Roche Group of Genentech, Inc. © 2012 Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 1013 5 4 9 3 HED0000832300

4/23/12 3:27 PM

ASCOPost.com | JULY 15, 2012

PAGE 23

Expert’s Corner

New Study on Communicating Bad News, from the Patient’s Perspective A Conversation with Anthony L. Back, MD By Ronald Piana fellow discussing news of cancer recurrence with a standardized patient, the participants paused the recording to comment on what they liked or disliked about the way the oncologist was communicating with the patient.

Implications of Findings

Anthony L. Back, MD

here is limited evidence in the literature about how oncologists should discuss bad or serious news with their patients. A recent study sought to understand what patients with cancer value when their doctors communicate news of recurrence.1 The ASCO Post spoke with the study’s lead author, Anthony L. Back, MD, of the Seattle Cancer Care Alliance, about how the results might affect clinical care. Dr. Back is also Affiliate Member in the Clinical Research Division at Fred Hutchinson Cancer Research Center, and Professor in the Oncology Division and Adjunct Associate Professor of Medical History and Ethics at the University of Washington School of Medicine.

Study Background What was the purpose of your study on what patients prefer when hearing about cancer recurrence? Giving serious or bad news is a fundamental communication task for oncologists. Although there are multiple recommendations about best approaches in the literature, they have not been evaluated from the patient perspective. So our study was designed to provide doctors with recommendations for communication that had been vetted by patients with cancer. How was the study designed? We recruited 23 participants who had been treated for a gastrointestinal cancer at the Seattle Cancer Care Alliance within the past 2 years. They were cancer free but had been treated recently enough to still be at risk for recurrence. While listening to audio recordings of an oncology

Did you learn anything from the study that could be used in clinical practice? Yes, there were actionable takeaway points related to what doctors should and shouldn’t do in this clinical scenario. First, doctors should communicate a sense that they understand what their patients are going through.

forth between the two functions. In fact, we had patients tell us that they want the doctor to know when to hold their hand and when to give them medical advice. We call that ability to move back and forth between recognition and guiding, “responsiveness.” Giving bad news about cancer recurrence is a high-stakes situation, and these are conversation tools to help doctors have a meaningful conversation with their patients. I think of this as a more advanced level of communication skills for oncologists who already know the basic conversation components taught in medical courses.

We’re finally beginning to accelerate the global awareness that good communication is part of good cancer care. —Anthony L. Back, MD

In the literature, there are many examples of papers stressing a need for doctors to show more empathy, but we found that patients don’t really need their doctor to share their emotions, but rather to understand what they were going through, it’s what we called “recognition”—how the oncologist responds to the gravity of the news they’re communicating. The patients also don’t want their doctor to seem overwhelmed with how bad their situation might be because of the news of recurrence. To date, most of the emphasis with regard to giving bad news is on being honest and leaving space for the patient’s emotions. However, we found that patients want to be guided through their care by the doctor’s expertise, and this is a perspective that really doesn’t appear in the literature. We call this “guiding” because patients want doctors to individualize a care plan for them, not use a standard algorithm approach. So when giving bad news, the doctor should shift between recognition and guiding. These conversations are not linear—they ebb and flow in cycles—and the doctor needs to be able to swing back and

Patient Frankness Was it difficult to get vulnerable patients with cancer to speak openly about cancer doctors? Patients with cancer are reluctant to criticize their doctors. However, one thing that enabled us to capture honest dialogue was that we had patients listening to the conversations of other patients and doctors, and because it wasn’t their doctor, there was a sort of emotional shield that fostered much franker responses. So having patients on an observational level helped us bring objective clarity to the way the conversations were critiqued.

Provisional Clinical Opinion ASCO’s recent provisional clinical opinion on palliative care stressed open and honest doctor-patient conversations. What impact do you think that guideline is having in clinical practice? ASCO’s interest in this area is tremendously powerful in setting the standard of care that people in academia and the community ought to aspire to. I think we’re seeing a turning point in awareness, and having ASCO’s growing support, as reflected by the provisional clinical opinion,

sends a strong message that palliative care is an essential component of best practices.

See Page 84

Oncotalk The audio recordings for the study were produced during an Oncotalk communication skills retreat. Please describe the purpose and function of the Oncotalk website. The Oncotalk site (www.oncotalk.info) was based on two NIH grants to advance intervention methods for improving how doctors communicate with their patients. We developed models for oncologists to help them learn and teach each other better ways of communicating with their patients in a variety of clinical scenarios. Based on the success, we’re currently working with several foundations to acquire funding so we can disseminate the Oncotalk model to a wider audience in the oncology community (via a new project called VITALtalk).2 This is one way to expand the work ASCO is doing in evidencebased training. We can help raise the bar in the palliative care field by using electronic technologies. Moreover, on the Oncotalk site there is a bank of information about enhancing communication skills, plus educational videos. We’ve also referenced our book, Mastering Communication with Seriously Ill Patients,3 which is a step-by-step manual of sorts that is written and organized in a very userfriendly format.

Improved Outcomes with Better Communication What are the most promising signs that better doctor-patient communication will become fully integrated into standard oncology practice? We now see recognition across the field that communication in difficult clinical scenarios is not something a doctor is born with; it is a learned skill that is malleable and improvable for virtually everyone. This recognition is based on data and an attitudinal change that has taken firm root in the community. The other sign is that there are continued on page 24

The ASCO Post | JULY 15, 2012

PAGE 24

Expert’s Corner

Anthony L. Back, MD continued from page 23

more and more studies producing good data linking better patient outcomes with better communication. For instance, patients who are asked what their expectations are for endof-life care are much less likely to wind up in the intensive care unit,

Richard Goldberg, MD, Gives First Moertel Lecture

ichard Goldberg, MD, Physician-in-Chief of The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, presented the first Charles G. Moertel Lecture of the Alliance for Clinical Trials in Oncology during the plenary session of the group’s recent meeting in Chicago.

Richard Goldberg, MD

This is the first annual Moertel lecture being given through the newly merged cooperative group known as the Alliance for Clinical Trials in Cancer, sponsored by the NCI. The Moertel Lecture was initiated in 1995 by the cooperative group Cancer and Leukemia Group B to honor the legacy of Dr. Moertel, one of the founding fathers of the North Central Cancer Treatment Group. Moertel, a renowned cancer researcher and former director of the Mayo Comprehensive Cancer Center, died in 1994. During his presentation titled, “Meaningful Outcomes: Lives Saved Due To Clinical Trials in Early Stage Colon Cancer,” Dr. Goldberg discussed Moertel’s work in making the first major discovery on how to increase the surgical cure rate of stage III colon cancer by adding postoperative chemotherapy, and how that initial discovery has led to further improved outcomes over 35 years of additional research.

■

their family members have less stress and regret, and the whole process is less fractured. The ripples of positive outcomes from good communication go beyond just the doctor and patient. We’re finally beginning to accelerate the global awareness that good communication is part of good cancer care.

■

Disclosure: Dr. Back reported no potential conflicts of interest.

References 1. Back AL, Trinidad SB, Hopley EK, et al: What patients value when oncologists give news of cancer recurrence: Commentary on specific moments in audio-recorded conversations. Oncologist 16:342-350, 2011.

2. Back AL, Fryer-Edwards K, Tulsky J, et al: A manifesto for VITALtalk. Available at vitaltalk.blogspot.com. Accessed May 15, 2012. 3. Back AL, Arnold R, Tulsky J: Mastering Communication with Seriously Ill Patients: Balancing Honesty with Empathy and Hope. Cambridge, UK; Cambridge University Press; 2009.

ASCOPost.com | JULY 15, 2012

PAGE 25

2012 ASCO Annual Meeting Hematology

PACE Trial Update: Ponatinib Produces High Response Rates in CML By Caroline Helwick

he third-generation tyrosine kinase inhibitor ponatinib showed robust efficacy in the 10-month followup of the phase II PACE trial (Ponatinib Ph+ALL and CML Evaluation), which

is evaluating ponatinib in treatmentrefractory chronic myeloid leukemia (CML)1 At the 2012 ASCO Annual Meeting, Jorge E. Cortes, MD, of The University of Texas MD Ander-

son Cancer Center, Houston, reported, “Responses occurred early and were durable. In chronic-phase patients, 93% are projected to remain in a molecular cytogenetic response at 1 year.”

Jorge E. Cortes, MD

Overcomes T315I mutation PACE is an open-label study that enrolled patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia who had previously been treated with, and proved resistant or intolerant to, nilotinib (Tasigna) or dasatinib (Sprycel), or who had the T315I mutation (N�� = 499). Ponatinib was designed to overcome the difficult-to-treat T315I mutation, which it showed capable of doing in this study. Chronic-phase patients have now been followed for a median of 10 months and blast-phase patients for 6 months. Molecular cytogenetic response, the primary endpoint, was achieved by 54% of chronic-phase patients, including 70% of patients with the T315I mutation and continued on page 26

Refining Tyrosine Kinase Inhibitor Treatment in CML ■■ At a median follow-up of 10

months in the PACE trial, a major cytogenetic response was achieved by 54% of chronic-phase patients, including 70% of patients with the T315I mutation and 49% of patients refractory/intolerant to dasatinib or nilotinib.

■■ Responses occurred regardless of mutation status or disease stage and they improved over time.

■■ In the 3-year update of the

DASISION trial, dasatinib produced higher rates of major molecular response than imatinib (68% vs 55%), and more patients had 4-log and 4.5-log reductions in BCR-ABL.

■■ In the 12-month follow-up

of ENESTcmr, patients not achieving a molecular response by 2 years on imatinib were twice as likely to do so if they switched to nilotinib, vs continuing on imatinib.

The ASCO Post | JULY 15, 2012

PAGE 26

2012 ASCO Annual Meeting PACE Trial Update continued from page 25

Effect of Time and Prior Treatment

49% of patients who were refractory/intolerant to dasatinib or nilotinib. In the accelerated phase, the primary endpoint of major hematologic response was achieved by 58%, including 60% refractory/intolerant and 50% with T315I mutation. In blast-phase CML, a major hematologic response was reached by 34%, 35%, and 33%, respectively. Describing the results in chronicphase CML patients in more detail, Dr. Cortes reported that “the majority of the cytogenetic responses are complete cytogenetic responses, and we also see a high rate of major molecular responses (Table 1, page 28).”

Responses improved over time. While at 3 months, 38% of all patients achieved molecular cytogenetic response, this increased to 49% at 6 months and to 53% at 9 months, and the trend was observed in all cohorts. A major molecular response was achieved by 13%, 24%, and 28% of patients at these respective time points. Some correlation was observed between number of prior treatments and response, with best responses seen in patients who had received no more than two fewer tyrosine kinase inhibitors. But even in those who received three tyrosine kinase inhibitors, rates

of complete cytogenetic response were 34% in the resistant/intolerant cohort and 48% with the T315I mutation. “These results demonstrate that ponatinib is very effective against CML in this very heavily pretreated cohort. Responses occurred regardless of mutation status or disease stage and they improved over time,” he said. A study of ponatinib as initial treatment is being initiated.

Ponatinib ‘Outpacing’ Other Agents Michael J. Mauro, MD, of Oregon Health and Science University, Portland, the invited discussant of the abstract, commented that while the data are still early, “Ponatinib in the third line is matching or

‘outpacing’ response rates we saw in the second line with nilotinib and dasatinib. Our third-line treatment See Page 84 is proving better than our second-line treatment.” Cytogenetic and molecular responses were high, irrespective of the number of prior tyrosine kinase inhibitors administered, and were consistently impressive in the less-treated T315I cohort. “But some loss of cytogenetic response was noted with increasing exposure [in this group] and in the subset of patients with T315I and additional mutations,” he said. “This may be proof continued on page 28

Updated Findings Further Define Role of Tyrosine Kinase Inhibitors in CML By Caroline Helwick

ith three available tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia (CML), attention has turned from the ability to achieve a sustained response to the possibility of “curing” patients. Updates of pivotal trials presented at ASCO may help define the role of the tyrosine kinase inhibitors in this endeavor.

DAISION 3-Year Data Reported Three-year follow-up of the phase III DASISION study was presented by Andreas Hochhaus, MD, of the Universitätsklinikum Jena in Germany.1 DASISION compared dasatinib (Sprycel) at 100�� mg/d to imatinib (Gleevec/Glivec) at 400 mg/d in 519 newly diagnosed CML patients in chronic phase. Previous analyses established dasatinib as superior, “with faster, deeper responses occurring early, at 3 months,” said Dr. Hochhaus. Major molecular responses were observed at 1 year in 46% of patients receiving dasatinib and in 23% of those receiving imatinib, while at 3 years this improved to 68% and 55%, respectively. In the updated analysis, the probability of achieving a major molecular response was 64% higher in patients receiving dasatinib (P < .0001), and this was true for all risk groups, he said. “More important is the deeper response rate—4.0-log and 4.5-log reductions in BCR-ABL,” he said. Molecular response (MR) in this setting is measured in terms of log reducSee Page 84 tion from baseline as

defined in the International Randomised in Toronto.4 “At all levels of response, Study of Interferon versus STI571 (IRIS). outcomes were twice as good with niloThus, “MR4” represents at least a 4.0-log tinib,” Dr. Lipton said. reduction in BCR-ABL from the stanThe study of 207 patients evaluated 2,3 dardized IRIS trial baseline. whether patients achieving a complete At 3 years, the MR4 was 35% with cytogenetic response, but not a molecular dasatinib vs 22% with imatinib (P = response (ie, remained BCR-ABL–posi.00635) and the MR4.5 was 22% vs 12% tive after 2 years), could achieve a com(P = .00069), replete cytogenetic spectively. “This molecular response difference is inby switching to nicreasing over time, lotinib at 400 mg and we expect widtwice daily, as oper differences after posed to continuing 4 years.” Overall on imatinib 400– survival and pro600 mg/d. gression-free surIndeed, cytogevival, however, are netic molecular renot yet different, sponse was significantly more likely with approximateamong patients ly 92% of patients At all levels of response, who switched: in each arm alive. outcomes were twice as 23.1% vs 10.7% (P “The 3-year = .02); cytogenetic follow-up of good with nilotinib. molecular responsDASISION con—Jeffrey H. Lipton, MD es were confirmed tinues to support in 12.5% vs 5.8% dasatinib at 100 mg daily as first-line treatment for new- (P = .108). He said the difference in conly diagnosed CML chronic-phase pa- firmed cytogenetic molecular responses is not statistically significant because patients,” Dr. Hochhaus concluded. tients coming off study due to adverse ENESTcmr: It Pays to Switch events were calculated as failures in the Twice as many patients achieved intent-to-treat analysis. deeper molecular responses after “But if you look only at patients switching to nilotinib (Tasigna), vs stay- achieving an evaluable response, ie, ing on imatinib, in the 12-month follow- those who are present, there is a signifiup of the ENESTcmr study (Evaluating cant difference,” he noted. Of evaluable Nilotinib Efficacy and Safety in clinical patients still on treatment, 14.9% on niTrials–complete molecular response), lotinib and 6.1% on imatinib achieved which was reported by Jeffrey H. Lip- a confirmed cytogenetic molecular reton, MD, of Princess Margaret Hospital sponse (P = .04) by 12 months.

Patients who switched also demonstrated improvements in MR4 and MR4.5. Patients switching to nilotinib had a median 0.5-log reduction in BCR-ABL from baseline, while no change was observed in patients who continued on imatinib, he added. “Deeper molecular responses on nilotinib may increase patient eligibility for future tyrosine kinase inhibitor discontinuation studies,” he said, “though it remains to be assessed whether switching results in patients being able to stop treatment.”

■

Disclosure: Dr. Lipton is on the advisory board of Novartis, Bristol-Myers Squibb, Pfizer, and Teva. He also receives research funds from Novartis and Bristol-Myers Squibb, and is a speaker for Novartis and Bristol-Myers Squibb. Dr. Hochhaus reported no potential conflicts of interest.

References 1. Hochhaus A, Shah NP, Cortes JE, et al: Dasatinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: DASISION 3-year followup. 2012 ASCO Annual Meeting. Abstract 6504. Presented June 4, 2012. 2. Hughes TP, Kaeda J, Branford S, et al: Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 349:1423-1432, 2003. 3. Cross NC, White HE, Muller MC, et al: Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. April 16, 2012 (early release online). 4. Lipton JH, Hughes TP, Leber B, et al: Switch to nilotinib versus continued imatinib in patients with chronic myeloid leukemia in chronic phase with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month follow-up. 2012 ASCO Annual Meeting. Abstract 6505. Presented June 4, 2012.

Now Enrolling

The Medical Division at Lilly Oncology is currently enrolling patients in a phase 3 trial of the VEGF receptor-2 antagonist ramucirumab (IMC-1121B)

REACH*: A Second-line Hepatocellular Carcinoma (HCC) Trial

Randomization

• H CC after progression on or intolerance to first-line sorafenib • C hild-Pugh score of <9 (Child-Pugh A or B [B7 or B8]) • A t least 1 measurable or evaluable viable lesion not previously treated with locoregional therapy

N=~544

Best supportive care + blinded ramucirumab 8 mg/kg IV infusion every 2 weeks

Best supportive care + blinded placebo 8 mg/kg IV infusion every 2 weeks

Treat until progressive disease, intolerable toxicity, noncompliance, withdrawal of consent, or investigator decision

Study Objectives Primary endpoint:

Secondary endpoints:

• Overall survival (OS)

• Progression-free survival (PFS)

• Safety profile of ramucirumab

• Best objective response rate (ORR)

• Ramucirumab serum concentrations

• Time to radiographic progression

• Pharmacodynamics of ramucirumab

• P atient-reported outcome (PRO) measures of disease-specific symptoms and health-related quality of life

• Immunogenicity of ramucirumab

For further information, please contact ImClone Systems by e-mail at ClinicalTrials@imclone.com or visit www.clinicaltrials.gov (identifier number NCT01140347). Note that, for an investigator to participate, the study must be approved by the investigator’s country competent health authority. Ramucirumab (IMC-1121B) is an investigational new drug. The safety and efficacy of ramucirumab have not been established for the use under investigation. There is no guarantee that ramucirumab will receive regulatory approval and become commercially available for the use under investigation.

* REACH: A Multicenter, Randomized, Double-blind, Phase 3 Study of Ramucirumab (IMC-1121B) Drug Product and Best Supportive Care (BSC) versus Placebo and BSC as Second-line Treatment in Patients With Hepatocellular Carcinoma Following First-line Therapy With Sorafenib

The ASCO Post | JULY 15, 2012

PAGE 28

Journal Spotlight Hematology

Prognostic Value of Integrated Cytogenetic and Mutational Risk Classification in Acute Myeloid Leukemia By Matthew Stenger

ay P. Patel, BS, and colleagues from Memorial Sloan-Kettering Cancer Center in New York recently performed mutational analysis of 18 genes in a subgroup of newly diagnosed acute myeloid leukemia (AML) patients who had been randomized to receive cytarabine plus high-dose or standard-dose daunorubicin induction therapy in the phase�� III �� ECOG E1900 trial. As reported in The New England Journal of Medicine, they identified a number of gene alterations and combinations of mutant and wild-type genes that were predictive of overall survival and incorporated these findings into a prognostic schema along with cytogenetic risk classification.1 Mutational analysis further identified alterations that were predictive of improved outcome with high-dose daunorubicin. These findings raise important issues regarding the use of more-extensive genetic profiling in AML patients prior to starting therapy.

Study Design In this study, mutational analysis of 18 genes recently identified as having recurrent somatic mutations in AML was performed in 398 patients aged ≤ 60 years from the ECOG E1900 population (test cohort). Overall, at least one somatic alteration in these genes was identified in 97.3% of patients. Univariate analysis showed that FLT3 internal tandem duplication (FLTD-ITD) mutations (P = .001),

PACE Trial Update continued from page 26

that we do want to treat earlier.” With ponatinib moving toward FDA approval, Dr. Mauro predicted how the drug might best be used. “It may be ‘built’ for T315I patients, which gives justification for mutation analysis in resistant CML to find this subset,” he said. “And its performance overall and durability of response justify approval and rapid implementation for better salvage.” Certainly for the subset of patients with evidence of early treatment resistance, ponatinib “may be the next step,” he said. Perhaps patients with T315I mutations who are resistant to imatinib (Gleevec) should be introduced earlier to the drug.

MLL partial tandem duplication (MLL-PTD) mutations (P = .009), PHF6 mutations (P = .006), and =�� .05) were asASXL1 mutations (P �� sociated with reduced overall survival, whereas CEBPA mutations (P = .05) and the core-binding-factor alterations t(8;21) and inv(16)/t(16;16) �� .001) �� were associated with im(P <�� proved overall survival. IDH2 mutations were associated with improved overall survival in the entire cohort of patients (3-year overall survival of 66%, P = .01), but the beneficial effect of these mutations was confined to patients with the IDH2 R140Q mutation. KIT mutations were associated with reduced overall survival among patients with the t(8;21) core-binding-factor alteration (P = .006) but not among those with the inv(16)/t(16;16) alteration. On multivariate analysis, with adjustment for age, white blood cell (WBC) count, transplantation status, and cytogenetic characteristics, all the associations in the univariate analyses remained significant, except for the findings for MLL-PTD, PHF6, and ASXL1 mutations.

Mutational Analysis Finds Large Risk Differences In patients with intermediaterisk AML on the basis of cytogenetic analysis, FLTD-ITD mutations were associated with reduced overall survival (P = .008), and multivariate analysis showed that “Ponatinib is revolutionizing CML and providing the remarkable ability to salvage resistant disease, especially T315I patients,” he concluded. “Its earlier use may prove even better.”

FLTD-ITD mutations were the primary predictor of outcome. It was also found that patients with NPM1 mutations and IDH1 or IDH2 mutations had significantly improved 3-year overall survival (89% vs 31%, P < .001). Patients with wild-type FLTDITD could be categorized into three risk groups with marked differences in 3-year overall survival (adjusted P < .001): those with NPM1 and IDH1 or IDH2 mutations—89% (favorable risk); those with wild-type TET2, ASXL1, PHF6, and MLL-PTD without NPM1 or IDH2 mutations—46.2% (intermediate risk); and those with TET2, ASXL1, PHF6, and MLL-PTD mutations—6.3% (high risk). After analyzing differences in overall survival according to other mutations in patients with mutant FLT3-ITD, it was found that patients could be categorized into three risk groups according to 3-year overall survival: those with trisomy 8 or TET2, DNMT3A, or MLL-PTD mutations—14.5% (high risk); those with wild-type CEBPA, TET2, DNMT3A, and MLL-PTD—35.2% (P < .001 vs high-risk group); and those with CEBPA mutations--42% (P < .001 vs highrisk group). Overall, the mutational analysis allowed patients at cytogenetically intermediate risk to be distinguished into three risk profiles—a favorable mutational risk profile, with a 3-year overall survival of 85%; intermediate mu-

See Page 84

New Prognostic Schema Changes Risk Distribution These findings permitted the investigators to develop a prognostic schema that integrated the findings from their mutational analysis with cytogenetic classification to identify three risk profiles: favorable risk profile, with median survival not reached and 3-year overall survival of 64%; intermediate risk profile, with median survival of 25.4 months and 3-year overall survival of 42%; and adverse risk profile, with median survival of 10.1 months and 3-year overall survival of 12%. This schema predicted outcome independently of age, WBC, induction dose, and transplantation status on multivariate analysis (adjusted P < .001) and was found to be accurate irrespective of type of postremission therapy (autologous or allogeneic transplantation or consolidation chemotherapy). The prognostic schema was shown to predict outcome when analyzed in an independent validation cohort of 104 patients from the ECOG E1900 trial (adjusted P < .001). The predictive value of the schema was independent of risk with

Table 1: PACE Results: Response in Chronic-phase Chronic Myeloid Leukemia Patients with Response (%)

■

Disclosure: Dr. Cortes serves in an unpaid consulting or advisory role for ARIAD, BristolMyers Squibb, ChemGenex, Novartis, and Pfizer, and has received research funding from ARIAD, Bristol-Myers Squibb, ChemGenex, Deciphera, Novartis, and Pfizer. Dr. Mauro has been consultant or advisor to and received honoraria from Bristol-Myers Squibb and Novartis.

Reference 1. Cortes JE, Kim D, Pinilla-Ibarz J, et al: PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation. 2010 ASCO Annual Meeting. Abstract 6503. Presented June 4, 2012.

tational risk profile, with a 3-year overall survival of 42%; and unfavorable mutational risk profile, with a 3-year overall survival of 13%.

Outcome

Overalld N = 267

Resistant/ Intolerant Cohort N = 203

T315I Cohort N = 64

Complete hematologic responsea

249 (93%)

191 (94%)

58 (91%)

Major cytogenetic responseb

144 (54%)

99 (49%)

45 (70%)

118 (44%)

76 (37%)

42 (66%)

79 (30%)

47 (23%)

32 (50%)

Complete cytogenetic response Major molecular responsec

Maintained or achieved during study; 103 patients had complete hematologic response at baseline. Primary endpoint. c Patients without a valid baseline major molecular response assessment, or who meet the criteria for major molecular response at baseline, counted as nonresponders. Major molecular response was assessed on the International Scale using peripheral blood. d Excludes three patients who were unassigned (post-imatinib, non-T315I) but treated. Adapted, with permission, from Cortes et al.1 a

ASCOPost.com | JULY 15, 2012

PAGE 29

Journal Spotlight

regard to treatment-related death (death within 30 days after starting treatment) or lack of response (complete remission) to induction therapy and in the combined test and validation cohorts. On the basis of cytogenetic classification alone, 19% of patients were categorized as having favorable risk (3-year overall survival of 58%), 63% as having intermediate risk (3-year overall survival of 36%), and 18% as having unfavorable risk (3-year overall survival of 11%). The integration of mutational risk into risk classification resulted in an increase in proportion of favorable risk patients to 26%, a decrease in proportion of intermediate risk patients to 35%, and an increase in proportion of unfavorable risk patients to 39% (with the respective 3-year overall survival rates noted above) compared with the cytogenetic classification alone.

Mutations Linked to Improved Survival The ECOG E1900 trial showed that induction therapy including high-dose daunorubicin improved outcome compared with standarddose daunorubicin.2 In their mutational analysis, Patel and colleagues found that high-dose daunorubicin was associated with improved survival in patients with mutant DNMTA (P = .04), but not in those with wild-type DNMTA.1 Univariate analysis also showed that high-

Risk Classification in Acute Myeloid Leukemia ■■ A mutational analysis in newly

diagnosed acute myeloid leukemia patients enrolled in a phase III clinical trial shows associations of a number of mutations with overall survival and indicates a wide variance in risk among patients with cytogenetic intermediate risk.

■■ A prognostic schema

integrating cytogenetic and mutational risk distinguishes risk groups with marked overall survival differences and results in risk reclassification for many patients.

■■ DNMT3A, NPM1, and MLL

mutations predict improved overall survival with highdose daunorubicin induction therapy.

dose daunorubicin was associated with improved survival in patients with MLL translocations (P = .01, =�� .06 with adjustment for mulbut P �� tiple testing) and NPM1 mutations (P = .01, but P = .10 with adjustment for multiple testing). Overall, high-dose daunorubicin was associated with a marked

improvement in overall survival (P = .001) in patients with DNMT3A or NPM1 mutations or MLL translocations, but not in those without these alterations. The finding was independent of age, WBC count, and status with regard to transplantation, treatment-related death, or response to chemotherapy (P = .008

for patients with mutations, P = NS for those with wild-type genes). Overall, high-dose daunorubicin was associated with greater 3-year overall survival than standard-dose daunorubicin (44% vs 25%) in patients with these alterations. For all other genotypes, 3-year overall survival continued on page 30

The ASCO Post | JULY 15, 2012

PAGE 30

Journal Spotlight

Cytogenetics of AML continued from page 29

was 35% in patients receiving highdose daunorubicin and 39% in those receiving standard-dose daunorubicin. The current evaluation for risk in AML includes assessment for FLT3, NPM1, and CEBPA alterations. In

providing context for their findings, the investigators noted, “[Our] data show that mutational analysis of a larger set of genetic alterations than that currently used in the clinic setting could be used to retrospectively classify patients with AML into more precise subgroups with favorablerisk, intermediate-risk, and unfavor-

patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% INDICATIONS AND USAGE Hispanic, 2% Black, and < 1% Asian, Native American or other. Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated malignancies receiving myelosuppressive anticancer drugs patients. associated with a clinically significant incidence of febrile Table 1. Adverse Reactions With ≥ 5% Higher Incidence neutropenia. Neulasta is not indicated for the mobilization of peripheral blood in Neulasta Patients Compared to Placebo in Study 3 progenitor cells for hematopoietic stem cell transplantation. System Organ Class Placebo Neulasta 6 mg CONTRAINDICATIONS Preferred Term (N = 461) SC on Day 2 Do not administer Neulasta to patients with a history of serious (N = 467) allergic reactions to pegfilgrastim or filgrastim. Musculoskeletal and connective tissue disorders WARNINGS AND PRECAUTIONS Bone pain 26% 31% Splenic Rupture Pain in extremity 4% 9% Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen Leukocytosis or splenic rupture in patients who report left upper abdominal In clinical studies, leukocytosis (WBC counts > 100 x 109/L) or shoulder pain after receiving Neulasta. was observed in less than 1% of 932 patients with nonmyeloid Acute Respiratory Distress Syndrome malignancies receiving Neulasta. No complications attributable Acute respiratory distress syndrome (ARDS) can occur in patients to leukocytosis were reported in clinical studies. receiving Neulasta. Evaluate patients who develop fever and Immunogenicity lung infiltrates or respiratory distress after receiving Neulasta, for As with all therapeutic proteins, there is a potential for ARDS. Discontinue Neulasta in patients with ARDS. immunogenicity. Binding antibodies to pegfilgrastim were Serious Allergic Reactions detected using a BIAcore assay. The approximate limit of Serious allergic reactions, including anaphylaxis, can occur in detection for this assay is 500 ng/mL. Pre-existing binding patients receiving Neulasta. The majority of reported events antibodies were detected in approximately 6% (51/849) occurred upon initial exposure. Allergic reactions, including of patients with metastatic breast cancer. Four of 521 anaphylaxis, can recur within days after the discontinuation of pegfilgrastim-treated subjects who were negative at baseline initial anti-allergic treatment. Permanently discontinue Neulasta developed binding antibodies to pegfilgrastim following in patients with serious allergic reactions. Do not administer treatment. None of these 4 patients had evidence of Neulasta to patients with a history of serious allergic reactions neutralizing antibodies detected using a cell-based bioassay. to pegfilgrastim or filgrastim. The detection of antibody formation is highly dependent on Use in Patients With Sickle Cell Disorders the sensitivity and specificity of the assay, and the observed Severe sickle cell crises can occur in patients with sickle cell incidence of antibody positivity in an assay may be influenced disorders receiving Neulasta. Severe and sometimes fatal sickle by several factors, including assay methodology, sample cell crises can occur in patients with sickle cell disorders handling, timing of sample collection, concomitant medications, receiving filgrastim, the parent compound of pegfilgrastim. and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence Potential for Tumor Growth Stimulatory Effects on of antibodies to other products may be misleading. Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor Postmarketing Experience through which pegfilgrastim and filgrastim act has been found The following adverse reactions have been identified during on tumor cell lines. The possibility that pegfilgrastim acts post approval use of Neulasta. Because these reactions are as a growth factor for any tumor type, including myeloid reported voluntarily from a population of uncertain size, it is not malignancies and myelodysplasia, diseases for which always possible to reliably estimate their frequency or establish pegfilgrastim is not approved, cannot be excluded. a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more ADVERSE REACTIONS of the following factors: (1) seriousness of the reaction, (2) The following serious adverse reactions are discussed in reported frequency of the reaction, or (3) strength of causal greater detail in other sections of the Brief Summary: relationship to Neulasta. • Splenic Rupture [See Warnings and Precautions] Gastro-intestinal disorders: Splenic rupture [see Warnings • Acute Respiratory Distress Syndrome [See Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis [see Warnings and Precautions] • Use in Patients with Sickle Cell Disorders [See Warnings Hypersensitivity reactions: Allergic reactions/hypersensitivity, and Precautions] including anaphylaxis, skin rash, and urticaria, generalized • Potential for Tumor Growth Stimulatory Effects on Malignant erythema and flushing [see Warnings and Precautions] Cells [See Warnings and Precautions] Respiratory, thoracic, and mediastinal disorder: ARDS The most common adverse reactions occurring in ≥ 5% of [see Warnings and Precautions] patients and with a between-group difference of ≥ 5% higher General disorders and administration site conditions: in the pegfilgrastim arm in placebo controlled clinical trials Injection site reactions are bone pain and pain in extremity. Skin and subcutaneous tissue disorders: Sweet’s syndrome, Clinical Trials Experience Cutaneous vasculitis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials DRUG INTERACTIONS of a drug cannot be directly compared with rates in the clinical No formal drug interaction studies between Neulasta and other trials of another drug and may not reflect the rates observed in drugs have been performed. Increased hematopoietic activity of the bone marrow in response to growth factor therapy may clinical practice. Neulasta clinical trials safety data are based upon 932 patients result in transiently positive bone-imaging changes. Consider these findings when interpreting bone-imaging results. receiving Neulasta in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The USE IN SPECIFIC POPULATIONS ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and Pregnancy 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy Category C tumors (n = 53) and lymphoma (n = 56) received Neulasta There are no adequate and well-controlled studies in pregnant after nonmyeloablative cytotoxic chemotherapy. Most patients women. Pegfilgrastim was embryotoxic and increased received a single 100 mcg/kg (n = 259) or a single 6 mg pregnancy loss in pregnant rabbits that received cumulative (n = 546) dose per chemotherapy cycle over 4 cycles. doses approximately 4 times the recommended human dose (based on body surface area). Signs of maternal toxicity The following adverse reaction data in Table 1 are from a randomized, double-blind, placebo-controlled study in patients occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies with metastatic or non-metastatic breast cancer receiving the potential risk to the fetus. docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegfilgrastim) injection, for subcutaneous use

able-risk profiles, with marked differences in the overall outcome. This approach could be used to identify an additional subgroup of patients who would have a mutationally defined favorable outcome with induction and consolidation therapy alone and a subgroup of patients with mutationally defined unfavorable risk

In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

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

65481-R1-V1

who would potentially be candidates for allogeneic stem-cell transplantation or participation in a clinical trial.”

Clinical Impact How might the findings of these investigators affect current practice? In an accompanying editorial, Lucy A. Godley, MD, PhD, of the University of Chicago stated “If we think about extending the findings of Patel and colleagues to clinical practice, we

Lucy A. Godley, MD, PhD

would need to know the genetic profile of patients with AML within the first few days of presentation, in order to tailor an induction regimen to the patient.”3 She noted that rapid clinical assessment is currently being used in a Cancer and Leukemia Group B study, in which patients with core-bindingfactor leukemias are being identified within 48 hours of presentation in order to test the effectiveness of adding dasatinib [Sprycel] to induction and consolidation therapy. Dr. Godley further stated, “A critical question is whether the data presented by Patel and colleagues are sufficient to justify the expansion of the number of genetic mutations being examined in patients with AML at presentation. [Their] findings challenge the field to address at what point data are compelling enough to change routine practice.”

■

Disclosure: The study authors reported no potential conflicts of interest. Dr. Godley reported an institutional contract with Celgene to provide mass spectrometry services for mouse samples.

References 1. Patel JP, Gönen M, Figueroa ME, et al: Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 366:1079-1089, 2012. 2. Fernandez HF, Sun Z, Yao X, et al: Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361:1249-1259, 2009. 3. Godley LA: Profiles in leukemia— editorial. N Engl J Med 366:1152-1153, 2012.

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PAGE 31

Issues in Oncology Prevention

After a Decade of Decline in Smoking Rates, Progress Has Stalled

IOM National Cancer Policy Forum convenes workshop to discuss the future of tobacco use By Margot J. Fromer

pproximately 20% of all Americans smoke, and 443,000 of them will die each year as a result. Tobacco use is the leading cause of preventable death in the United States and the greatest behavioral determinant of morbidity and mortality (6%–10% of U.S. health-care costs). Nearly 30% of all cancer deaths (87% of lung cancer deaths) are due to smoking, and tobacco use increases the incidence of almost all types of the disease and adversely affects treatment. Smoking had been on the wane in this country, but now the cessation rate has flattened. About 70% of smokers say they want to quit, and every year 50% try. Fewer than 2.5% succeed. Roy S. Herbst, MD, PhD, Professor of Medicine and Pharmacology, Yale Comprehensive Cancer Center, New Haven, Connecticut, made these grim observations as he opened the Institute of Medicine (IOM) National Cancer Policy Forum’s workshop, “Reducing Tobaccorelated Cancer Incidence and Mortality,” held recently in Washington, DC.

IOM Workshop: Potential Measures to Reduce Tobacco-related Illness ■■ Ban smoking in vehicles when children are passengers. ■■ Increase the number of places where smoking is prohibited—for instance, outdoor smoking restrictions, such as the one recently established in New York City parks and beaches.

■■ Ban smoking on entire college and university campuses, as done at the Graham Warren MD, PhD

pliance, decreases quality of life, and decreases survival in cancer patients. He also presented new data demonstrating that tobacco assessments and cessation are not well incorporated into federally funded research. “This significantly limits our ability to understand the true effects of smoking on cancer treatment and prevents cancer patients on clinical trials from gaining the health benefits of smoking cessation.” Terry F. Pechacek, PhD, Associate Director for Science, CDC Office on Smoking and Health, Atlanta, added that the duration of exposure to cigarette smoke is a more important risk factor than the number of cigarettes smoked. Moreover, dual tobacco use (for instance, smoking accompanied by snuff or chewing tobacco) increases risk significantly.

Society and Public Policy

Roy S. Herbst, MD, PhD

The purpose of the workshop was to explore the effects of state and federal policies on reducing tobacco use, as well as ways to encourage cessation.

Largest Contributor to Cancer Risk “Most people don’t realize that continued tobacco use by cancer patients decreases the effectiveness of cancer treatment,” said Graham Warren MD, PhD, a radiation oncologist and Director of the Tobacco Assessment and Cessation Program at Roswell Park Cancer Institute in Buffalo, NY. “The 7,000 compounds in cigarette smoke include known carcinogens that increase cancer growth, angiogenesis, metastasis, and decrease the effectiveness of chemotherapy and radiotherapy.” He cited several studies showing that smoking increases cancer treatment toxicity, decreases cancer treatment com-

“There has been a 180-degree change in social attitudes and norms about smoking,” said Kenneth E. Warner, PhD, Avedis Donabedian Distinguished University Professor of Public Health, University of Michigan School of Public Health, Ann Arbor. “Since 1964, approximately 5 million premature deaths have been averted because people have quit smoking or decided not to start. This is the greatest public health success story of the last 50 years. Nevertheless, smoking remains the greatest remaining burden of preventable illness and death.” According to Dr. Warner, there are three categories of public policy interventions:

Kenneth E. Warner, PhD

University of Michigan.

■■ Increase state cigarette excise taxes and add a federal tax. ■■ Package cigarettes in plain wrappers, as is now done in Australia. Most of the wrapper should be taken up with grimly portrayed depictions of the ravages of tobacco-induced cancer.

■■ Institute restrictions on marketing new products and cessation treatments that substitute one method of nicotine delivery for another.

■■ Give control of manufacture, supply, and sales of tobacco products to government.

■■ Prohibit possession of tobacco for people born after 2000, and eventually prohibit combusted tobacco products altogether.

■■ Require smokers to purchase a license to light up. ■■ Reduce the amount of nicotine in cigarettes to nonaddicting levels. ■■ Use only evidence-based cessation interventions and expand use of the 2008 Public Health Service guidelines for treating tobacco use.

■■ Information and education, such as Surgeon General reports, warning labels, school health information, and media antismoking campaigns ■■ Financial incentives such as tax increases: A critical factor in cigarette consumption is price; the more expensive a pack is, the less likely people are to purchase it. Low-income smokers are more responsive to price hikes than are high-income smokers, and children are two to three times more responsive than adults. ■■ Laws and regulations, such as bans on advertising, smoke-free workplaces, and sales to minors Some of these factors work better than others. For example, school health education doesn’t work well, nor do warning labels, although the proposed graphic warning labels might do better. Cessation treatment works for some people, and professional instruction and/or counseling is generally more effective than going cold turkey alone. Dr. Warner noted that the big problem with smoking now—and a major reason why the cessation rate is flat—is the possibility that a growing proportion of people who still smoke are addicted, and many do not want to quit. Up to half of current smokers have another substance abuse problem or a

mental illness comorbidity (eg, 60% of schizophrenics smoke), he pointed out.

FDA Regulatory Authority Lawrence Deyton, MD, Director of the FDA Center for Tobacco Products, said that under the Family Smoking Prevention and Tobacco Control Act, FDA now has the authority to regulate tobacco product

Lawrence Deyton, MD

manufacturing, distribution, and marketing, including conducting research, issuing health warnings, and reporting harmful levels of tobacco product constituents. There was discussion about a number of actions that the federal and state governments could potentially take to further reduce tobacco-related illness, some of which are more practical than others (see sidebar).

■

Disclosure: Drs. Herbst, Pechacek, Warren, Warner, and Deyton reported no potential conflicts of interest.

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

APPROVED FOR SUBCUTANEOUS ADMINISTRATION*

Survival never gets old VELCADE® (bortezomib) delivered >13-month overall survival advantage in combination with MP† vs MP alone for previously untreated multiple myeloma (median 56.4 vs 43.1 months‡; 60.1-month median follow-up§)

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

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

WARNINGS, PRECAUTIONS AND DRUG INTERACTIONS ▼ Peripheral neuropathy, including severe cases, may occur – manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Use caution when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Closely monitor patients with risk factors for, or existing heart disease ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

▼ Women should avoid becoming pregnant while being treated with VELCADE (bortezomib). Pregnant women should be apprised of the potential harm to the fetus ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Concomitant use of strong CYP3A4 inducers is not recommended

ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page. *The reconstituted concentration for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration for IV administration (1 mg/mL). † Melphalan+prednisone. ‡ HR=0.695 (95% CI, 0.57-0.85); p<0.05. § VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated MM. The primary endpoint was time to progression (TTP). Secondary endpoints were complete response (CR), overall response rate (ORR), progression-free survival (PFS), and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. In an updated analysis at a median follow-up of 36.7 months, the overall survival advantage was sustained despite subsequent treatments.

Living Proof

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE is contraindicated for intrathecal administration. WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs. intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 41% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of VELCADE vs. Dexamethasone following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs. dexamethasone, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%. Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients. Hepatic Impairment: Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. 3790_milpro_fa1_gry_ascopst.indd 2

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE (bortezomib) 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). In the phase 3 VELCADE subcutaneous vs. intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse events in this study were peripheral neuropathy NEC (38% vs 53%), anemia (36% vs 35%), thrombocytopenia (35% vs 36%), neutropenia (29% vs 27%), diarrhea (24% vs 36%), neuralgia (24% vs 23%), leukopenia (20% vs 22%), pyrexia (19% vs 16%), nausea (18% vs 19%), asthenia (16% vs 19%), weight decreased (15% vs 3%), constipation (14% vs 15%), back pain (14% vs 11%), fatigue (12% vs 20%), vomiting (12% vs 16%), insomnia (12% vs 11%), herpes zoster (11% vs 9%), decreased appetite (10% vs 9%), hypertension (10% vs 4%), dyspnea (7% vs 12%), pain in extremities (5% vs 11%), abdominal pain and headache (each 3% vs 11%), abdominal pain upper (2% vs 11%). The incidence of serious adverse events was similar for the subcutaneous treatment group (36%) and the intravenous treatment group (35%). The most commonly reported SAEs were pneumonia (6%) and pyrexia (3%) in the subcutaneous treatment group and pneumonia (7%), diarrhea (4%), peripheral sensory neuropathy (3%) and renal failure (3%) in the intravenous treatment group. DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information. Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2012, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA

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2012 ASCO Annual Meeting Personalized Medicine

Gene Profiling–guided Therapy May Improve Survival in Patients with Carcinoma of Unknown Primary By Matthew Stenger

olecular gene-expression profiling is an emerging technique to determine tissue of origin in patients with carcinoma of unknown primary, although the value of predictions from such profiling in improving treatment outcomes is unclear. In a prospective trial using tumor profiling results to direct site-specific therapy for patients with carcinoma of unknown primary, Frank A. Greco, MD, and colleagues at the Sarah Cannon Research Institute/ Tennessee Oncology in Nashville have found that assay-diSee Page 84 rected therapy may improve survival.1

Half of Patients Had More Responsive Tumors

stantial benefit from standard sitespecific treatment, including 27 patients with bladder cancer, 26 with colorectal cancer, 24 with non–small cell lung cancer (NSCLC), 10 each with breast cancer and ovarian cancer, 9 with kidney cancer, 4 each with prostate cancer and germ cell cancer, and 6 with other types of cancer. The 104 patients with assay diagnoses of relatively resistant tumors included 45 with biliary tract cancer, 12 with pancreas cancer, 10 with gastroesophageal cancer, 7 with liver cancer, 5 each with sarcoma and cervical cancer, and 20 with other origins of malignancy.

Overall Survival with Assay-directed Therapy

The median overall survival for all treated patients was 10.8 months. In this trial, a 92-gene real-time, reMedian overall survival for the 197 verse transcription polymerase chain patents with assay-directed treatreaction (RTment was 12.2 PCR) assay (Canmonths, vs 6.0 Patients predicted to cerTYPE ID; biomonths for 27 paTheranostics, Inc) tients receiving have more responsive was performed on empiric therapy. tumor types had longer tumor biopsies Median overall survival compared to from previously survival in the 120 untreated patients patients with asless responsive types, with carcinoma of say diagnoses of suggesting accurate unknown primary. more responsive Patients for whom tumor types was identification by the a tissue of origin 12.8 months, sigassay. was predicted and nificantly longer —Frank A. Greco, MD who were treatthan the median ment candidates overall survival were assigned of 7.4 months in standard site-specific first-line therthose with relatively resistant types apy. Between October 2008 and De(P = .027). Among subgroups of cember 2011, 289 patients were enmore responsive tumor types, merolled and 252 had successful assays dian overall survival was 30 months performed. Of these 252, 247 (98%) for ovarian cancer, 16 months for had a tissue of origin predicted, 224 NSCLC, 12 months for colorectal were eligible for treatment, and 197 and kidney cancer, and 9 months for received assay-directed treatment. pancreas cancer. Of the 224 eligible for treatment, As stated by the investigators, “This is the first prospective trial 120 (54%) had assay diagnoses of in which molecular profiling has ditumor types known to derive sub-

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Key Findings

hen asked to comment on implications of this study, lead author Frank A. Greco, MD, remarked, “The use of this gene-expression profile assay (CancerTYPE ID, bioTheranostics, Inc) on the biopsy material of patients with carcinoma of unknown primary provides a single tissue of origin diagnosis in most patients. Previous studies have validated the accuracy of molecular assay diagnoses in carcinoma of unknown primary, and this study was designed to look at the outcome or survival in patients treated with siteFrank A. Greco, MD specific therapies based on the assay diagnoses,” he said. “The overall median survival in the 197 patients was prolonged compared to large studies (100 patients or more) of empiric chemotherapy (paclitaxel/carboplatin, gemcitabine/cisplatin, or similar regimens) reported in the past 9 months or so, as well as compared to survival in 396 patients with carcinoma of unknown primary (median survival = 9.1 months) with identical prognostic features treated with empiric therapy by our same cooperative group (Sarah Cannon Research Consortium) prior to the study reported at ASCO 2012. The survival met the expectations of the study design,” he noted. “The fact that molecularly diagnosed patient groups with expected more responsive tumor types survived significantly longer than groups with assay diagnosed less responsive tumor types provides additional evidence of the usefulness of the molecular assay in carcinoma of unknown primary,” Dr. Greco continued. “These data support the use of molecular profiling in this setting when standard immunohistochemical staining patterns cannot provide a single diagnosis of the tissue or origin. The outcome overall in carcinoma of unknown primary appears improved, and for some diagnoses the survival is substantially better than the standard approach of empiric chemotherapy,” he concluded.

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Disclosure: Dr. Greco has received honoraria from bioTheranostics.

rected site-specific therapy in [patients with carcinoma of unknown primary]. Assay-directed therapy in 197 patients produced a median overall survival of 12.2 months that compares favorably with previous empiric carcinoma of unknown primary therapy…. Patients predicted to have more responsive tumor types had longer survival compared to less responsive types, suggesting accurate identification by the assay. These results strengthen the rationale for molecular profiling in

[carcinoma of unknown primary] management.”

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Disclosure: Dr. Greco has received honoraria from bioTheranostics.

Reference 1. Greco FA, Rubin MS, Boccia RV, et al: Molecular gene expression profiling to predict the tissue of origin and direct site-specific therapy in patients (pts) with carcinoma of unknown primary site (CUP): Results of a prospective Sarah Cannon Research Institute (SCRI) trial. 2012 ASCO Annual Meeting, Abstract 10530. Presented June 5, 2012.

website at ASCOPost.com

Soft Tissue Sarcoma... Most common primary sites of soft tissue sarcoma.1

HEAD AND NECK

[9%]

TRUNK

[19%] RETROPERITONEUM

[15%]

EXTREMITIES

[60%]

Raising Awareness of a Challenging Disease Soft tissue sarcomas are a heterogeneous group of more than 50 distinct histological subtypes with an estimated incidence of more than 10,000 cases per year in the United States.1 They can originate from connective tissue, including fat, muscle, nerve and nerve sheath, vasculature, and other connective tissues.1 They most commonly arise in the extremities, trunk and retroperitoneum. 1 The presentation of soft tissue sarcomas is variable, but patients often present with a painless mass that is increasing in size.2 Guidelines recommend a biopsy for diagnosis and histopathological classification of soft tissue sarcomas. The biopsy should be performed by an experienced surgeon or radiologist and assessed by a pathologist with sarcoma expertise.1 Guidelines also recommend that magnetic resonance imaging with or without computed tomography be performed for all masses with a chance of being malignant.1 1.

NCCN Guidelines速: Soft Tissue Sarcoma, V.1.2012. NCCN.org. http://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf. Accessed 05/01/2012. NCCN速 and NCCN GUIDELINES速 are trademarks owned by the National Comprehensive Cancer Network, Inc.

Ilaslan H, Schils J, Nageotte W, Lietman SA, Sundaram M. Clinical presentation and imaging of bone and soft-tissue sarcomas. Cleveland Clinic Journal of Medicine. 2010;77:S2-7.

息2012 The GlaxoSmithKline Group of Companies ONO528R0 Printed in USA. May 2012

The ASCO Post | JULY 15, 2012

PAGE 38

FDA Update

FDA Approves Cetuximab plus FOLFIRI/ Therascreen in Colorectal Cancer

he FDA has granted approval to cetuximab (Erbitux) for use in combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for firstline treatment of patients with KRAS mutation–negative (wild-type), EGFRexpressing metastatic colorectal cancer as determined by FDA-approved tests for this use. FDA also approved the TheraScreen KRAS RGQ PCR Kit (by QIAGEN) concurrently with this cetuximab approval. The approval was based on retrospective analyses in the patient subsets according to KRAS mutation status in tumor samples from patients enrolled in the CRYSTAL trial and in two supportive studies, CA225025 and EMR 62 202-047 (or OPUS trial). The addition of cetuximab to chemotherapy or best supportive care resulted in improved overall survival, progressionfree survival, and overall responses rates in the subset with KRAS wildtype tumors, whereas there was no benefit or potential harm in patients with KRAS mutant tumors. The approval of the companion diagnostic, the TheraScreen KRAS RGQ PCR Kit, provides a reliable way to identify these subsets of patients with colon cancer. This genetic assay is a real-time polymerase chain reaction assay detecting seven different mutations of the KRAS gene in a tumor specimen. The recommended dose and schedule for cetuximab is 400 mg/m2 administered intravenously as a 120-minute infusion as an initial dose, followed by 250 mg/m2 infused over 30 minutes

weekly in combination with FOLFIRI. Cetuximab administration should be completed 1 hour prior to FOLFIRI. Product labeling for cetuximab provides “limitation of use” information specifying that the drug is not indicated for treatment of KRAS mutation– positive colorectal cancer.

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Proton Therapy System Granted 510(k) Clearance

evion Medical Systems, Inc, announced that it has received FDA 510(k) clearance for its Mevion S250 Proton Therapy System. According to Mevion, the new system delivers precise, noninvasive treatment comparable to that available with larger, more complex proton therapy systems but with higher patient throughput, a significantly reduced footprint, improved reliability, and lower implementation and operational costs. This clearance enables users of the Mevion S250 to immediately treat patients upon completion of their system installation. The first installation of the Mevion S250 will soon be completed at the Kling Center for Proton Therapy at Barnes Jewish Hospital at Washington University in St. Louis, Missouri.

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Regorafenib in Metastatic Colorectal Cancer

ayer HealthCare and Onyx Pharmaceuticals announced that the FDA has granted priority review designation to Bayer HealthCare’s New Drug

Application (NDA) filed end of April 2012 for the oral multikinase inhibitor regorafenib, for the treatment of patients with metastatic colorectal cancer whose disease has progressed after approved standard therapies. Under the Prescription Drug User Fee Act (PDUFA), the FDA will complete its review within 6 months from the receipt of the NDA submission, rather than the standard 10-month review cycle. The submission was based upon data from the pivotal, global phase III CORRECT study. Regorafenib is being investigated in clinical trials for its potential to treat patients with various tumor types.

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System for Breast Cancer Surgeries Gets Positive Vote

une Medical Devices announced that an FDA Advisory Panel voted 10 to 1 in favor of Dune’s MarginProbe System for use in breast cancer surgery, as an adjunct to current standard methods of intraoperative surgical margin assessment. Dune submitted a Premarket Application (PMA) in April 2011 based on data from a 600-patient pivotal study conducted primarily in the United States. The MarginProbe System enables real time detection of cancer at or near the surface of excised tissue specimens during surgery for breast cancer. The simple and immediate assessment of the surgical margins allows surgeons to immediately excise additional tissue, significantly reducing the potential for positive margins remaining after the initial lumpectomy. The pivotal trial data shows that by

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using The MarginProbe System during the first operation, in conjunction with standard methods, surgeons will have the ability to significantly reduce the rate of positive margins following the initial surgery.

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Blood Test to Improve Prostate Cancer Detection

eckman Coulter, Inc, recently announced Premarket Approval from the FDA for the Prostate Health Index, a simple, noninvasive blood test that is 2.5 times more specific in detecting prostate cancer than prostate-specific antigen (PSA) in patients with PSA values in the 4 to 10 ng/mL range and has been shown to reduce the number of prostate biopsies. The test is indicated for use in men with a PSA in the range of 4 to 10 ng/mL. Typically, U.S. physicians recommend that men with a PSA in that range consider a prostate biopsy. However, an elevated PSA may be due to benign conditions other than cancer, which can lead to unnecessary biopsies. According to Beckman Coulter, the Prostate Health Index helps physicians distinguish prostate cancer from benign conditions. The results of a multicenter clinical study showed a 31% reduction in unnecessary biopsies with the use of the new test. Separately, results from a recent health economic study of the Prostate Health Index in the U.S. health-care system suggests the test may help reduce costs associated with prostate cancer detection. Available from Beckman Coulter in Europe since 2010, the test will be available in the United States in the third quarter of 2012 for use on the company’s Access 2 and UniCel DxI immunoassay systems.

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ASCOPost.com | JULY 15, 2012

PAGE 39

Direct from ASCO

ASCO Launches Oncology Practice Census

Survey aims to better understand how and where oncologists are working

ow many oncologists are in private practice and how many are employed by hospitals and academic medical centers in the United States? No one knows the answer for sure, but ASCO is undertaking an ambitious national effort to determine where oncologists are practicing these days.

Online Survey ASCO’s Assessment of the Evolution & Status of Oncology Practices (AESOP) task force recently created a detailed online survey in a concerted effort to obtain concrete data regarding where oncologists are currently working. The task force is working with State University of New York (SUNY) Albany’s Center for Health Workforce Studies on the project. A letter explaining the Oncology Practice Census was mailed to the practices of all ASCO members in June, as well as to oncology practices in the National Provider Identifier Registry and practices in ASCO-affiliate databases—more than 4,600 practices in all.

Anupama Kurup, MD

Ongoing Tracking The goal: to begin gathering comprehensive data to benchmark where oncologists are practicing, and to develop a system to monitor shifts and trends in the oncology care delivery system over time, said Anupama Kurup, MD, of Providence Cancer Center (Hematology & Oncology Care Clinic - West) and Co-Chair of the AESOP task force. “Anecdotally, we know many of our colleagues have been shifting away from the private practice, either affiliating loosely with an

academic medical center or hospital, or completely closing up shop to become part of a larger organization,” Dr. Kurup said. “But we don’t know how many, and it’s been happening so rapidly. ASCO felt it was important to gather data to benchmark the current medical landscape, confirm this phenomenon, and also identify underlying causes.”

Online Survey Takes 15 Minutes The Oncology Practice Census is addressed to practice managers, should take just 15 to 20 minutes to

Goal Is to Better Serve Oncologists and Patients The overall purpose of collecting data on where each oncologist is practicing is to better serve ASCO members and ultimately our members’ patients. The data also will support ASCO’s evidence-based advocacy on Capitol Hill. Said Michael Neuss, MD, Chief Medical Officer for Vanderbilt-Ingram Cancer Center and a member of ASCO’s Clinical Practice Committee who helped develop the survey, “Your practice environment determines your needs in terms of services and knowledge base. ASCO

Your practice environment determines your needs in terms of services and knowledge base. ASCO really wants to know where their members are practicing in order to best support them, and in turn, their patients. —Michael Neuss, MD

fill out online, and asks questions such as: ■■ How is your practice owned? ■■ Over the past 12 months, has your practice become affiliated with another entity, experienced layoffs for oncology physicians, and/or changed the mix of patients it treats? ■■ In the next 12 months, how likely is your practice to become affiliated with an academic medical center, a community, hospital, or another practice? To encourage practice managers to give the survey priority, ASCO is offering generous Amazon.com gift cards to the first 300 practice managers who complete the survey for their practice. The AESOP task force hopes to compile all the data in August and submit the results to be published in a peer-reviewed journal later this year. In addition, the online survey tool enables practices to update their information year-round in order to keep the database current, accurate, and relevant, said Dr. Kurup.

really wants to know where their members are practicing in order to best support them, and in turn, their patients.”

Anticipated Access Problem One concern about the migration of oncologists to urban centers is that if too many get pulled out of community-based practices where most cancer care takes place, what will become of the patients in those communities? ASCO wants to keep a close eye on this issue in order to anticipate and address potential access issues. The survey will also try to determine the reasons why oncologists are shifting the where’s and how’s of practice. Dr. Kurup said that it’s likely a combination of a number of factors: the changing of the payment model for drugs; the advent of health-care reform and the effects that has had on practitioners; the health insurance sector; the downturn in the U.S. economy; the overall effects of managed care; and the need for

Michael Neuss, MD

practices to adopt and maintain expensive electronic health records systems. But until we have the evidence-based data, we can’t be certain, she added.

Change Is Happening Fast Regular follow-up with practices will be key to a true understanding of the ever-changing landscape. “This ongoing census will enable ASCO to keep its finger on the pulse, and to better understand and communicate the effects of policy on oncologists and the way they practice,” said Dr. Kurup. One thing is certain, even without solid data yet in hand, according to Dr. Neuss: The way oncologists work is already shifting, and ASCO will need to shift its focus along with it. “Five years from now, ASCO’s offerings that support practitioners will have changed greatly,” he predicts. “Right now, ASCO is working to help people run their practices. But how many oncologists will even have an independent practice in five years is a question. If more independent oncologists become employees of larger health systems, ASCO will need to refocus its efforts to support the physicians as valued parties within the management of these organizations.” For questions about how to participate in the Oncology Practice Census or assistance in using the online data collection tool, contact Guy Forte, director of Information Management at the Center for Health Workforce Studies at (518) 4020250 or by e-mail at chws@health. state.ny.us.

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The ASCO Post | JULY 15, 2012

PAGE 40

Direct from ASCO

ASCO Bookstore Revamped

New platform is powered by Amazon

SCO has redesigned its online bookstore. Now visitors can enjoy a streamlined environment powered by Amazon, allowing them to search in just about any way they want to: newest to oldest, most popular, by disease type, by professional interest, and the list goes on. The new bookstore platform, which offers more than 200 print and online products, went live on May 8.

20% Discount for All ASCO Members

Store Credit Card Information and Addresses With the new bookstore platform, visitors can now store credit card information instead of having to type it in each time, and they can also store several shipping addresses. In addition, instead of having to abort a purchase if they suddenly have to leave the computer, visitors can save their items for later purchase if they are called away. What hasn’t changed is the vast array of products available in the ASCO bookstore. Visitors may find books that touch on cancer and practice management, as well as clinical and professional development publications.

Paying is now simpler, too. The new, enhanced checkout system allows visitors to make purchases using their existing Amazon.com login and password as well as their E-Learning Content Available traditional asco.org login and passRobert S. Miller, MD, of the word. Sidney Kimmel Comprehensive With the move to the new platCancer Center at Johns Hopkins, form, ASCO has also streamlined and Chair of the ASCO Integrated how it provides the member disMedia and Techcount. Rather nology Committhan individual Knowing that tee said, “With the cost reductions new layout of the per item, ASCO my colleagues and ASCO University is now offering peers in oncology are Bookstore, I can its membership really appreciate a standard 20% involved in reviewing the wealth and discount on all these materials gives diversity of edupurchases. Memcational products bers need only me an added sense that are available. enter their ASCO of confidence as a And it’s reassuring membership ID to know that all number or login/ purchaser. of these products username in any —Robert S. Miller, MD have gone through of several locathe ASCO review tions on the site process. Knowing that my colto obtain the discount code, which leagues and peers in oncology are they can apply at checkout.

Prostate Cancer Screening: What Patients Need to Know

Robert S. Miller, MD

involved in reviewing these materials gives me an added sense of confidence as a purchaser.” The new and improved bookstore features ASCO’s wide variety of e-

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

learning content available via ASCO University. Members can also order and download the Virtual Meeting for ASCO’s meetings that record the live sessions. Members can now see a listing of their recently viewed items, track orders in real time, and view their order history. Users can also leave reviews, feedback, and ratings. To access the new ASCO bookstore, simply go to www.asco.org/ store.

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5 most-accessed Top 10Top most-accessed articles recently published articles published in 2011 in in Journal of Clinical Oncology Journal of Clinical Oncology

What’s Hot in

JCO

JCO.org American Society of Clinical Oncology Identifies Five Key Opportunities to Improve Care and Reduce Costs: The Top Five List for Oncology

Explaining the Unexplainable: EGFR Antibodies in Colorectal Cancer

Maximizing Human Epidermal Growth Factor Receptor 2 Inhibition: A New Oncologic Paradigm in the Era of Targeted Therapy

US Food and Drug Administration Approval Overview in Metastatic Breast Cancer

irect your patients to www.cancer.net/expertsoncancernews so they can learn about ASCO’s new Provisional Clinical Opinion on PSA testing to screen for prostate cancer, including what it means for patients.

In addition, patients can find more information about prostate cancer at www.cancer.net/prostate.

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Radiotherapy in Older Women With Low-Risk Breast Cancer: Why Did Practice Not Change?

ASCOPost.com | JULY 15, 2012

PAGE 41

Direct from ASCO

YIA and CDA: Abbreviations of Great Importance to Continued Progress in Cancer Research

ehind the scenes researchers— who are well acquainted with the human cost of cancer and see the vast scientific and clinical opportunities for conquering it—are working to unlock the secrets of cancer in its many forms. Some are well established in their careers and have been conducting studies for years, while others are just starting out, full of passion and commitment to start their first project. When you are a young researcher, however, competing for grants to fund a potentially groundbreaking study can be incredibly challenging. This is where the Conquer Cancer Foundation comes in. Through its Young Investigator Awards (YIAs) and Career Development Awards (CDAs), the Foundation funds researchers early in their careers, at a time when energy and capacity for innovation outpace the years of experience needed to compete for funding.

who are seeking to answer the most compelling clinical questions, but also for people to join in its mission to build a pipeline of talent that will

enrich cancer care and research for years to come. Visit www.conquercancerfoundation.org for more information or to make a gift in support of

ambitious young researchers.

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All of your

Oncology News...

Funding Young Researchers This year the Foundation was able to support the innovative work of more than 55 promising young researchers with YIAs and CDAs totaling $4.5 million. The YIA provides $50,000 in research funding to promising physicians to support the transition from the final years of training to faculty appointment and to encourage and promote quality research in clinical oncology. Since the YIA program launched in 1984, more than $28 million has been awarded to over 700 recipients. The CDA provides $200,000 in research funding over 3 years to clinical investigators who have already received their initial faculty appointment, to establish an independent clinical cancer research program. Established in 1992, the CDA program has provided more than $36 million to over 200 recipients, helping to launch the careers of young cancer researchers around the world. As the application cycle for these awards opens on July 1, the Foundation is not only looking for applicants

...at your

Fingertips Now Available: The ASCO Post iPad App • Complete issues of The ASCO Post • Oncology News Feed – updated throughout the day • Analysis and opinions from the experts you trust

ASCOPost.com

Download The ASCO Post on iTunes

The ASCO Post | JULY 15, 2012

PAGE 42

Direct from ASCO

Sarcoma Foundation of America Teams with Conquer Cancer Foundation to Fund Potentially Life-saving Research

hen Matthew Alsante signed on to serve as Executive Director of the Sarcoma Foundation of America (SFA) 6 years ago, he had a visceral understanding of the importance of the organization’s work. Mr. Alsante had lost his father to lung cancer in 1999. “Right up until the last day of his life, if there had been one more therapy available my dad would have tried it,” he remembered. “At the Sarcoma Foundation of America, we are passionate about bringing more effective treatment options to people with sarcoma. Our collaboration with the Conquer Cancer Foundation is an important element of our strategy.”

Investing in Clinical and Translational Research The SFA was founded in 2000 by Mark Thornton, MD, PhD, Patricia Thornton, and John Brooks, MD. Since 2006, the SFA has collaborated with the Conquer Cancer Foundation to sponsor six Young Investigator Awards—the Foundation’s research grants for early-career physician scientists—

as well as two Advanced Clinical Research Awards and a Career Development Award in order to support scientists focusing on sarcoma from their fellowships all the way until they are established faculty. “We are committed to funding the very best research, and we deeply value the fact that the Con-

Sarcoma research, like all cancer research, is on the cusp of significant breakthrough…We’re driven to do all that we can to find new therapies, and we’re thrilled to be collaborating with the Conquer Cancer Foundation to do so. —Matthew Alsante

quer Cancer Foundation shares our commitment to excellence,” said Mr. Alsante. “Both organizations select grant recipients through a rigorous peer review process. By supporting the work of the Conquer Cancer Foundation, we are confident that we’re helping to focus some of the world’s sharpest teams on groundbreaking transla-

SFA-sponsored Research

tional and clinical research.” “We’re particularly excited about funding young investigators,” Mr. Alsante added. “There are so many areas that a young cancer researcher can choose to pursue, and it’s absolutely critical that we encourage and support young, bright physician-scientists who are interested in sarcoma and can con-

he Sarcoma Foundation of America has sponsored the following research projects—each selected through a rigorous peer-review process—in collaboration with the Conquer Cancer Foundation: ■■ Evaluation of the Hedgehog Signaling Pathway in the Growth of Myogenic Sarcomas ■■ Targeting the Notch Signaling Pathway: A Novel Method to Inhibit Sarcomas with Constitutive Ras Activation ■■ Improving the Detection of Osteosarcoma Tumor Margins and Metastasis Using Diagnostic Nanoparticles ■■ Identification and Characterization of Tumor Initiating Cells in Human Osteosarcoma ■■ Using Molecular Imaging to Identify Microscopic Residual Sarcoma Cells During Surgery ■■ Obstruction of Transcription at Tumorigenic Chromosomal Translocations as Therapy ■■ Examination of the Molecular and Therapeutic Effects of mTOR and PDGFRA Inhibition in Advanced Synovial Sarcoma ■■ A Phase III, Double-blind, Randomized, Placebo-controlled Trial of Sorafenib in Desmoid Tumors or Aggressive Fibromatosis (DT/DF) A Role for Injury in Sarcomagenesis

tribute to the field for many years to come.”

Targeted Research May Yield Broad-based Opportunity Sarcoma strikes only about 12,000 Americans annually, but there are upwards of 100 different subtypes of the disease, creating something of a needle-in-a-haystack scenario for researchers. Because it is so rare, sarcoma represents a relatively small slice of the global cancer research enterprise. But significant progress has been made in recent years, and Mr. Alsante believes that further exploration may lead not only to new therapies for people with sarcoma, but also to broader applications for other types of cancer. “We’ve come a long way toward understanding sarcoma,” he said. “Our hope is that, if we’re successful in targeting a specific genetic pathway to treat this specific type of cancer, we can also build on that knowledge to improve treatment for other, more common cancers.”

Cancer Research at a Tipping Point About 15% of all children with cancer—and about 1% of all adults

with cancer—have some form of sarcoma. The opportunity is great, and the need is urgent. “We feel that sarcoma research, like all cancer research, is on the cusp of significant breakthrough,” said Mr. Alsante. “We can see it. We can taste it. But it’s still frustrating. It’s still too slow. We’re driven to do all that we can to find new therapies, and we’re thrilled to be collaborating with the Conquer Cancer Foundation to do so.” “We believe that cancer research is at an exciting tipping point—a powerful nexus of opportunity for translating the dramatic discoveries of the past decade, in genomics and other areas, into new therapies,” said Nancy R. Daly, MS, MPH, Executive Director of the Conquer Cancer Foundation. “There has never been a more strategically important time for investing in cancer research.”

Nancy R. Daly, MS, MPH

“Our collaboration with the Sarcoma Foundation of America and with other organizations and individuals who share our commitment to conquering cancer through research and knowledge are a source of both strength and inspiration,” Ms. Daly continued. “Together, we will all realize the Conquer Cancer Foundation’s ultimate vision: creating a world that’s free from the fear of cancer.” To learn more about the SFA, please visit www.curesarcoma.org. To learn more about the Conquer Cancer Foundation, visit www.conquercancerfoundation.org.

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ASCOPost.com | JULY 15, 2012

PAGE 43

Oncology Worldwide Health-care Disparities

Cancer Care in Rwanda: A Model of Creative Partnerships By Ronald Piana

hile disparities in cancer care remain problematic in wealthy industrial nations like the United States, the challenges faced in poorer regions of the world are, by comparison, inestimable. Nationally regarded health-care expert Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute, is part of an ongoing initiative to bring oncology services to Rwanda, the most densely populated country in subSaharan Africa. At this year’s ASCO Annual Meeting, Dr. Shulman used his recent experience in Rwanda to illustrate the possibilities of creating a cancer care infrastructure in a lowincome country. “While it’s critical to work at the policy level, it’s equally important to demonstrate that we can build on-the-ground cancer care systems in resource-poor regions. However, many leaders in global health view this as a misguided mission, contending that we should focus our limited resources on prevention, not treating patients with cancer. I’d like to counteract that viewpoint with this presentation,” said Dr. Shulman.

dan Ministry of Health, all of which have been bolstered by the generosity of private foundations and the pharmaceutical industry. Each entity provides a vital role in bringing a continuum of cancer care and services to the country,” Dr. Shulman said. To focus their initiative, the team developed a set of principles of cancer care for several resource-challenged countries (Rwanda, Malawi, Haiti), which rest on what Dr. Shulman calls the diagonal approach. “Setting up an isolated cancer program won’t work, so we try to integrate a cancer care program within the country’s existing health-care infrastructure, using a diagonal instead of vertical approach, which will in-

Partnerships and Principles

crease chances of success,” Dr. Shulman explained. The worldwide work in HIV/ AIDS prevention and treatment has been a successful model, but Dr. Shulman noted that cancer offers different challenges. “We need to biopsy cancer patients and process the tissue in a pathology lab before we

Dr. Shulman stressed that developing strategic partnerships is key to building a cancer care infrastructure in resource-challenged countries like Rwanda (see sidebar). “We have a team from the Harvard hospitals in Boston that has worked with Partners in Health, alongside the Rwan-

Current Activities in Rwanda ■■ Dr. Shulman’s team is maintaining close collaboration with the Ministry of Health.

■■ One of the Partners in Health hospitals—Butaro Hospital—has been designated a national referral hospital for cancer.

■■ A pathology lab is being operationalized by a collaboration between Brigham and Women’s Hospital and Butaro.

■■ A major initiative to develop national cancer protocols (by disease) is in process of being approved by the Ministry.

■■ The first countrywide oncology training program for physicians and nurses was held in 2012.

can deliver surgery and chemotherapy. Currently, there’s no reliable, timely, or affordable pathology lab in Rwanda, so we ship all the specimens

There won’t be nearly enough oncologists for most of the world’s underserved cancer patients for decades to come, so if we plan to treat these people, we’ll need innovative models of care. —Lawrence N. Shulman, MD

At the 2012 ASCO Annual Meeting, Dr. Lawrence N. Shulman discussed his recent experience in Rwanda to illustrate the possibilities of creating a cancer care infrastructure in a low-income country.

back to our lab in Boston; we’ll soon have a pathology lab in Rwanda. Naturally, in order to treat our patients, we need a supply chain to provide affordable therapies, which is also part of the ongoing process,” Dr. Shulman said.

New Models Needed Dr. Shulman, who also serves as senior oncology advisor for Partners in Health, an organization that concentrates its cancer care efforts in Rwanda, Malawi, and Haiti, illustrated the scope of the challenge with a daunting statistic: Of the three countries, only Malawi has an oncologist, one to be exact. “The fact is, there won’t be nearly enough oncologists for most of the world’s underserved cancer patients for decades to come, so if we plan to treat these people, we’ll need innovative models of care,” Dr. Shulman said. He added that delivering cancer care relies on basic community supportive services. “It’s not possible to administer treatment in the absence of social support, clean water, and adequate

nutrition, so we incorporate a holistic approach into the model.” Another important principle in low-income countries is making the best use of limited resources. To that end, the team developed a Prioritization Document. “We have to decide which patients we treat and what treatments we use. These are very difficult clinical decisions, which we don’t need to make in the United States. In countries like Rwanda, value takes on a more intense meaning,” Dr. Shulman said. In prioritizing cancers to treat on a “value = benefit/cost” scale, Dr. Shulman used the example of a 4-year-old girl with Burkitt’s lymphoma, which has a high rate of cure, requires low-cost drugs and no surgery (other than biopsy) or radiation, and is associated with a very long life expectancy with minimal side effects. “This would be an example of a high-value patient. If we look at a 23-year-old man with chronic myeloid leukemia, treated with a high-cost drug, imatinib (Gleevec), and no chance of cure but potential long-term survival, this we classify as a moderately high-value patient,” Dr. Shulman explained. Although no tumor registries exist in Rwanda, Dr. Shulman commented that gastric cancer appears to be the most common malignancy in the country. He used a 60-year-old man with advanced gastric cancer and liver and lung metastases as an example of a low-value patient. “This man has no chance of long-term survival, with weeks to live, and some would argue that he should be palliated and not receive any expensive continued on page 44

The ASCO Post | JULY 15, 2012

PAGE 44

Oncology Worldwide

Cancer Care in Rwanda continued from page 43

antineoplastic agents,” Dr. Shulman said.

Making an Impact The team divided diseases up into four major categories: (1) diseases amenable to risk reduction, (2) diseases curable with early detection and treatment, including surgery, (3)�� dis�� eases curable with affordable chemotherapy, and (4) diseases palliated with systemic treatment. Fortunately, prevention efforts in Rwanda do not have to focus much attention on tobacco or alcohol control because they are simply not major issues. Cervical cancer is, however, a widespread and preventable disease. In an interview with The ASCO Post, Dr. Shulman noted that Merck had donated over 2 million doses of HPV vaccine (Gardasil) to the Rwandan effort. “But we don’t feel that prevention is a priority over treatment, as children with cancer wouldn’t be affected by a prevention strategy—they need active therapy. It should not be ‘either/ or,’ but rather, treatment strengthens efforts at prevention, as has been demonstrated with HIV.” Since many adult patients in Rwanda present with advanced disease, palliating symptoms is a major part of the prioritization strategy. During the interview, Dr. Shulman stressed, “An important component of the palliation effort will be ongoing medical education, since palliative medicine is not something that is practiced by all Rwandan doctors.”

Moving Forward Dr. Shulman commented that part of the long-term strategy is to develop

Send Us Your NEWS Write to editor@ASCOPost.com. All submissions will be considered for publication.

a research agenda and infrastructure specifically designed to address questions applicable to cancer care in challenged areas like Rwanda. “One problem is that in countries like Rwanda, we actually know very little about the incidence and specifics of cancer. That’s why we need to develop good cancer registries. Also, to have a solid grasp of

the effectiveness of our interventions, we need to conduct prospective studies and continually analyze data so as to lead iterative improvements in patient outcomes,” Dr. Shulman said. “Needless to say,” Dr. Shulman continued, “Our most valuable resource is ‘human capital,’ and in regions where there is a complete dearth of

Important Safety Information WARNINGS AND PRECAUTIONS: • Treatment with ISTODAX has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, monitor these hematological parameters during treatment with ISTODAX and modify the dose as necessary • Serious and sometimes fatal infections have been reported during treatment and within 30 days after treatment with ISTODAX and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy • Electrocardiographic (ECG) changes have been observed with ISTODAX • In patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as monitoring electrolytes and ECGs at baseline and periodically during treatment • Ensure that potassium and magnesium are within the normal range before administration of ISTODAX • Tumor lysis syndrome has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden should be closely monitored and appropriate precautions taken, and treatment should be instituted as appropriate • ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women to avoid pregnancy while receiving ISTODAX. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus (Pregnancy Category D) ADVERSE REACTIONS: Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (n=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (n=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%). Infections were the most common type of serious adverse event reported in Study 3 (n=131) and Study 4 (n=47). In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (n=131) were nausea (59%), asthenia/fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (n=47) were asthenia/fatigue (77%), nausea (75%),

oncologists, we need to train people to care for cancer patients. It must be an ongoing project, and the level of training needs to be consistent with the context of the cancer care setting.”

Success Is Incremental At the ASCO meeting, Dr. Shulman presented a slide showing the

thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

Cutaneous T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 1 (n=102) were infections (11%) and asthenia/fatigue (8%), and in Study 2 (n=83) were lymphopenia (37%), infections (33%), neutropenia (27%), leukopenia (22%), anemia (16%), asthenia/fatigue (14%), thrombocytopenia (14%), hypophosphatemia (10%), vomiting (10%), dermatitis/exfoliative dermatitis (8%), hypermagnesemia (8%), hyperuricemia (8%), hypocalcemia (6%), nausea (6%), and pruritus (6%). Infections were the most common type of serious adverse event reported in both Study 1 (n=102) and Study 2 (n=83) with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. The most common adverse reactions regardless of causality in Study 1 (n=102) were nausea (56%), asthenia/fatigue (53%), infections (46%), vomiting (34%), and anorexia (23%) and in Study 2 (n=83) were nausea (86%), asthenia/fatigue (77%), anemia (72%), thrombocytopenia (65%), ECG ST-T wave changes (63%), neutropenia (57%), lymphopenia (57%), infections (54%), anorexia (54%), vomiting (52%), hypocalcemia (52%), hyperglycemia (51%), hypoalbuminemia (48%), leukopenia (46%), dysgeusia (40%), and constipation (39%). DRUG INTERACTIONS: • ISTODAX is metabolized by CYP3A4. Avoid concomitant use with strong CYP3A4 inhibitors and potent CYP3A4 inducers if possible • Caution should also be exercised with concomitant use of moderate CYP3A4 inhibitors and P-glycoprotein (P-gp, ABCB1) inhibitors • Physicians should carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered ISTODAX and warfarin sodium derivatives USE IN SPECIFIC POPULATIONS: • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution

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

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Oncology Worldwide

banner hanging on the wall of his team’s training program: 1st National Baseline Cancer Training. At the bottom of the banner, the partners that made the mission possible are listed: The Ministry of Health; Dana-Farber Cancer Institute; GlaxoSmithKline; Brigham and Women’s Hospital; and Partners in Health.

“It was a very successful program. We had live didactic lectures and practical sessions, such as a breast-imaging workshop in which the doctors were taught ultrasound core breast biopsy, using chicken breasts with pimentostuffed olives representing the lesion. The pimento allowed the students to determine that the biopsy needle

reached the middle of the olive,” Dr. Shulman explained. The takeaway message from Dr. Shulman’s compelling presentation was that despite the many challenges, successful cancer care programs can be developed in the poorest of nations. “We need to demonstrate what works and what doesn’t as we

INDICATIONS THE FIRST AND ONLY • Treatment of peripheral T-cell lymphoma (PTCL) in patients DRUG APPROVED IN BOTH who have received at least one prior therapy PTCL AND CTCL • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy These indications are based on response rate. Clinical beneﬁt such as improvement in overall survival has not been demonstrated.

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page. Please see Brief Summary of full Prescribing Information on following pages.

integrate screening and treatment into places like Rwanda. Moreover, the efforts need to be done in parallel with the important international policy work that is currently moving the field forward,” Dr. Shulman concluded.

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Disclosure: Dr. Shulman reported no potential conflicts of interest.

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Journal Spotlight Endocrinology

Mitotane-containing Regimens Explored for a Rare Tumor By Charlotte Bath

esponse rates and progressionfree survival rates were significantly better among patients with advanced adrenocortical carcinoma receiving mitotane (Lysodren) plus EDP (etoposide, doxorubicin, and

cisplatin) than in patients receiving mitotane with streptozocin (Zanosar), according to results of a randomized, controlled, open-label, parallel-group trial. The study included 340 patients in 12 countries at 40 specialized cen-

ters for the treatment of adrenocortical carcinoma, a rare cancer with a poor prognosis and few treatment options. It was funded by the Swedish Research Council and others. “Mitotane is the only drug ap-

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8 and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and/or platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX should be handled in a manner consistent with recommended safe procedures for handling cytotoxic drugs. 5 WARNINGS AND PRECAUTIONS 5.1 Hematologic Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematological parameters should be monitored during treatment with ISTODAX, and the dose should be modified, as necessary [See Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infection Serious and sometimes fatal infections, including pneumonia and sepsis, have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment, and the risk of life threatening infections may be higher in patients with a history of extensive or intensive chemotherapy [See Adverse Reactions (6)]. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [See Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment. Potassium and magnesium should be within the normal range before administration of ISTODAX [See Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients

proved for the treatment of adrenocortical carcinoma and is used both as adjuvant therapy and for advanced disease, although its efficacy has never been shown in a randomized trial,” the investigators reported in The New Eng-

with advanced stage disease and/or high tumor burden should be closely monitored, appropriate precautions should be taken, and treatment should be instituted as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [See Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cutaneous T-Cell Lymphoma The safety of ISTODAX was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).

Common Adverse Reactions Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1. Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reaction 99 (97) 36 (35) 83 (100) 68 (82) Nausea 57 (56) 3 (3) 71 (86) 5 (6) Asthenia/Fatigue 54 (53) 8 (8) 64 (77) 12 (14) Infections 47 (46) 11 (11) 45 (54) 27 (33) Vomiting 35 (34) 1 (<1) 43 (52) 8 (10) Anorexia 23 (23) 1 (<1) 45 (54) 3 (4) Hypomagnesemia 22 (22) 1 (<1) 23 (28) 0 Diarrhea 20 (20) 1 (<1) 22 (27) 1 (1) Pyrexia 20 (20) 4 (4) 19 (23) 1 (1) Anemia 19 (19) 3 (3) 60 (72) 13 (16) Thrombocytopenia 17 (17) 0 54 (65) 12 (14) Dysgeusia 15 (15) 0 33 (40) 0 Constipation 12 (12) 2 (2) 32 (39) 1 (1) Neutropenia 11 (11) 4 (4) 47 (57) 22 (27) Hypotension 7 (7) 3 (3) 19 (23) 3 (4) Pruritus 7 (7) 0 26 (31) 5 (6) Hypokalemia 6 (6) 0 17 (20) 2 (2) Dermatitis/Exfoliative dermatitis 4 (4) 1 (<1) 22 (27) 7 (8) Hypocalcemia 4 (4) 0 43 (52) 5 (6) Leukopenia 4 (4) 0 38 (46) 18 (22) Lymphopenia 4 (4) 0 47 (57) 31 (37) Alanine aminotransferase increased 3 (3) 0 18 (22) 2 (2) Aspartate aminotransferase increased 3 (3) 0 23 (28) 3 (4) Hypoalbuminemia 3 (3) 1 (<1) 40 (48) 3 (4) Electrocardiogram ST-T wave changes 2 (2) 0 52 (63) 0 Hyperglycemia 2 (2) 2 (2) 42 (51) 1 (1) Hyponatremia 1 (<1) 1 (<1) 17 (20) 2 (2) Hypermagnesemia 0 0 22 (27) 7 (8) Hypophosphatemia 0 0 22 (27) 8 (10) Hyperuricemia 0 0 27 (33) 7 (8) Cosmos Communications 718.482.1800

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Journal Spotlight

land Journal of Medicine. “The experience with other antineoplastic drugs for the treatment of this disease is even more limited.” The current study, the First International Randomized Trial in Locally Advanced and Metastatic Adrenocortical Carcinoma Treatment (FIRMACT) is the first randomized phase III

trial in this rare tumor, and compared “the two most successful regimens in patients with advanced disease,” the investigators noted. The regimen combining EDP with mitotane had produced an objective response rate of 53% in a 28-patient study, and the regimen combining streptozocin with mitotane had produced an objective

Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%). Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome. Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

response rate of 36% in a 22-patient study.

Study Data In the FIRM-ACT trial, patients receiving first-line EDP and mitotane had a significantly higher response rate than those given first-line streptozocin plus mitotane (23.2% vs 9.2%, P <

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)]. 7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors. Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort. 7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures Cosmos Communications 718.482.1800

.001) and longer median progressionfree survival (5.0 vs 2.1 months), the researchers reported. Tumor progression was seen in 280 (92.1%) of 304 patients, the authors noted. At 12 months, 26.1% of patients who received first-line therapy including EDP were alive without disease continued on page 48

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Journal Spotlight

Mitotane for Adrenocortical Carcinoma continued from page 47

progression, compared to 7.2% who received first-line therapy including streptozocin plus mitotane. At final analysis, 232 patients (76.3%) had died, 108 in the EDP group and 124 in the streptozocin

group. The median duration of survival was 14.8 months in the EDP group and 12.0 months in the streptozocin group. “Thus, EDP plus mitotane as first-line treatment reduced the risk of death by 21%, as compared with streptozocin plus mitotane,” the researchers noted. “The efficacy of both regimens as second-line therapy was similar to

(AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin 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 ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)]. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

their efficacy as first-line therapy,” the authors stated. “Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP– mitotane group and 2.2 months in the streptozocin–mitotane group. Patients who did not receive the alternative sec-

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling. 17.1 Instructions • Nausea and Vomiting Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients. Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)]. • Low Blood Counts Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)]. • Infections Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)]. • Tumor Lysis Syndrome Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)]. • Use in Pregnancy If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling. [See Warnings and Precautions (5.5)]. • Patients should be instructed to read the patient insert carefully. Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146

ond-line therapy had better overall survival with first-line EDP plus mitotane (17.1 months) than See Page 84 with streptozocin plus mitotane (4.7 months),” the researchers wrote.

Survival Remains Dismal During first-line treatment, serious adverse events occurred among 86 patients (58.1%) in the EDP group and 62 patients (41.6%) in the streptozocin group. Bone marrow toxicity, infection, and cardiovascular or thromboembolic events were the most common serious adverse events in the EDP group. In the streptozocin group, the most common serious adverse events were gastrointestinal disorder, impaired liver function, and fatigue or general health deterioration. The authors noted that despite findings suggesting that EDP plus mitotane had superior antitumor efficacy compared to streptozocin plus mitotane, “the overall survival rates in our study remained dismal. Firstline therapy with EDP plus mitotane did not translate into a significant improvement in overall survival.” The poor overall survival rates, they added, confirm “the need for improved treatment options.”

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Reference 1. Fassnacht MF, Terzolo M, Allolio B, et al: Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 366:2189-2197, 2012.

ISTODAX® is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724

The ASCO Post

ISTBVPI.003/PPI.003 09/11

Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

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PAGE 49

Issues in Oncology Health-care Disparities

New Study Examines Racial Disparities in Breast Cancer Mortality

Black women are more likely to die from breast cancer than white women, study finds. By Jo Cavallo

ccording to the first national study looking at racial disparity in breast cancer mortality rates at the city level in the United States, societal factors—especially poverty and residential segregation—are resulting in the unnecessary deaths of five black women every day—more than 1,700 deaths a year. The study, published in a recent issue of Cancer Epidemiology,1 examined data from 2005 to 2007 on the deaths from malignant neoplasm of the breast within 25 of the largest U.S. cities culled from national death files maintained by the Centers for Disease Control

“The best estimates I’ve read suggest that about 8% to 10% of mortality differences between black and white women might be due to genetics. In our study, we found death rates for black women that are twice as high as those for white women— for example, in Memphis—which means that the black rate is 100% higher than the white rate. If you remove genetics from the equation, there is still a disparity of 90%,” said Steven Whitman, PhD, Director of the Sinai Urban Health Institute in Chicago and the lead author of the study.

New Data on Racial Disparities in Breast Cancer Mortality ■■ Recently published data on breast cancer deaths in 25 large U.S. cities

show a considerable black/white disparity in breast cancer mortality for most cities.

■■ Even accounting for the role of genetics, there are disparities between the races in breast cancer death rates for some cities.

■■ Studies of disparities are ongoing, and ASCO has launched a variety of

initiatives in efforts to close the gap in cancer care for minority patients and improve the poorer survival outcomes in these women.

and Prevention. The study findings show that 21 of 24 cities (breast cancer mortality data for Indianapolis was unavailable for the final analysis) have a black/white disparity in breast cancer mortality, with Memphis having the highest disparity and San Francisco, the lowest.

“When you look at mortality disparities in Chicago and nationwide you see that the gap opened up in the early 1990s, just when advances were being made in the early detec-

Seven Risk Factors Analyzed The study researchers analyzed seven city-level ecologic risk factors, including population size, the proportion of the population that was white, the proportion of the population that was black, median household income, proportion of the population living below the federal poverty line, the Gini Index (a measure of income inequality) and the Index of Dissimilarity (a measure of racial segregation). As a final observation, the study authors noted that while black women are diagnosed more often than white women with aggressive types of breast cancer (eg, triple-negative disease), resulting in poorer overall survival rates, that factor alone does not account for the mortality disparities among cities.

Steven Whitman, PhD

tion and treatment of breast cancer,” he said. “Between 1980 and 1990, the death rates from breast cancer in Chicago for white and black women were the same.” Because white women with breast cancer are more often able to access better health care than black women, said Dr. Whitman, the death rates for black women have remained largely unchanged over the past 3 decades, whereas the death rates for white women have decreased significantly.

Economic Obstacles to Quality Care Another study by Dr. Whitman and colleagues, published in the Journal of Women’s Health,2 analyzed data from a mammography facility survey of screening centers in Chicago. The study found that black and Hispanic women and women without private health insurance are more likely than white women and women with private insurance to have a mammogram at public rather than academic screening facilities. Academic centers have more radiologists specializing in breast imaging and use digital mammography rather than analog mammography, which may be less accurate in detecting cancers, especially in younger women and in women with dense breasts. “The quality of care that black women receive is often inferior to what white women experience. Fewer cancers are found in black women during mammography screening, treatment is started later, and it often goes uncompleted, so everything bad you can imagine is part of the phenomenon,” said Dr. Whitman. Factors such as the detection of more advanced breast cancers at the time of diagnosis and higher rates of obesity and comorbid illnesses in minority women, as well as more missed treatment appointments due to inadequate or no health insurance, a lack of a support system, job-related barriers, including limited or no sick leave, and difficulties with transportation all contribute to poorer survival outcomes among women of lower socioeconomic status. Disparities in the quality of cancer care given to black women and women of lower socioeconomic status, including reduced rates of adjuvant therapy, are also leading to lower survival rates. In a follow-up to her study on social and racial differences in adjuvant chemotherapy decisions for breast cancer, published in the Journal of Clinical Oncology,3 Jennifer J. Griggs, MD, MPH, Associate Professor in the Department of Internal Medicine and Health Management and Policy at the University of Michigan, Ann Arbor, and a member of ASCO’s Health Dis-

Jennifer J. Griggs, MD, MPH

parities Advisory Group, will further examine the association between socioeconomic status and the quality of cancer care. In two new investigations, Dr. Griggs is following more than 2,000 patients who were diagnosed with breast cancer between 1998 and 2004 to examine the type of care they received, chemotherapy regimens, and outcome. “We’re looking at every aspect of care, including tumor margins, chemotherapy doses and regimens, radiation therapy doses, and how many days of treatment patients missed. If you miss 5 or more days of radiation therapy, even if they are not consecutively missed days, the benefit of radiation may be compromised,” said Dr. Griggs.

‘Misguided Benevolence’ Certain assumptions oncologists make about different patient groups, including the patient’s likelihood to adhere to medical advice, level of social support, or ability to tolerate chemotherapy, and difficulties conveying complex information such as treatment regimens, management of side effects, and therapy goals may also be factors contributing to disparities in cancer care. “Because of the legacy of the Tuskegee syphilis experiments and other research abuses of black people, some physicians may assume that their black patients do not trust them and may bend over backwards to minimize side effects by administering lower chemotherapy doses. This behavior, which has been seen in the treatment of other complicated diseases, is what I have termed ‘misguided benevolence.’ That is, the intention is directed at helping the patient but, in fact, compromises quality of care,” said Dr. Griggs. continued on page 53

XALKORI (crizotinib) is approved for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

XALKORI, the first ALK inhibitor, offers antitumor activity in patients with locally advanced or metastatic ALK-positive NSCLC Test to find all advanced NSCLC patients appropriate for XALKORI ➤ Pretreatment testing can help guide therapeutic decisions1 ➤ An FDA-approved test should be used to determine which patients have ALK-positive NSCLC

SELECTED SAFETY INFORMATION Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis. QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.

In early-phase trials of 255 patients with ALK-positive NSCLC taking XALKORI...* EFFICACY PARAMETER

STUDY A (N=136)

STUDY B (N=119)

ORR (CR+PR)a [% (95% CI)]

50% (42%, 59%)

61% (52%, 70%)

Number of responders

Duration of responseb [median (range) weeks]

41.9 (6.1+, 42.1+)

48.1 (4.1+, 76.6+)

The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation ➤ Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia ➤ Serious adverse events in ≥2% of patients included pneumonia, dyspnea, and pulmonary embolism *XALKORI for the treatment of locally advanced or metastatic NSCLC was investigated in 2 multicenter, single-arm studies. Study A was a phase 2 trial in 136 patients; ALK-positive NSCLC was identified using the Vysis ALK Break Apart FISH Probe Kit. Study B was a phase 1 trial in 119 patients; ALK-positive NSCLC was identified using a number of local clinical trial assays. Patients enrolled in these studies had received prior systemic therapy, with the exception of 15 patients in Study B who had no prior systemic therapy for locally advanced or metastatic disease. The primary efficacy end point in both studies measured objective response rate (ORR) based on RECIST criteria; duration of response was also evaluated. a One patient was not evaluable for response in Study A; 3 patients were not evaluable for response in Study B. b Preliminary estimate using Kaplan-Meier method. +Censored values. Reference: 1. Perez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(Suppl 1):S38-S45.

Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

Take a picture with your smart phone to learn more about XALKORI

XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

IMPORTANT SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. • Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. • Neuropathy attributed to study drug was reported in 34 (13%) patients. Grade 2 motor neuropathy and grade 3 peripheral neuropathy were reported in 1 patient each. • Bradycardia was reported in 12 (5%) patients treated with XALKORI. All of these cases were grade 1 or 2 in severity. • Complex renal cysts were reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were observed in 5.2%, 0.4%, and 11.4% of patients, respectively. Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Use caution in patients with severe renal impairment or patients with end-stage renal disease.

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PAGE 53

Issues in Oncology

Racial Disparities in Breast Cancer Mortality continued from page 49

To close the quality gap in cancer care for minority patients, last year ASCO issued a policy statement, “Opportunities in the Patient Protection and Affordable Care Act to Reduce Cancer Care Disparities”

in the Journal of Clinical Oncology,4 which builds on ASCO’s policy on disparities in cancer care released in 2009. One of the recommendations was to encourage oncologists and medical facilities, including screening mammography centers, to participate in ASCO’s Quality Oncology Practice Initiative (QOPI), which

XALKORI® (crizotinib) capsules Brief Summary of Prescribing Information

CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in <1% of patients in clinical trials. Concurrent elevations in ALT >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal, with normal alkaline phosphatase, occurred in <1% of patients in clinical trials. Elevation in ALT >5 times the upper limit of normal occurred in 7% of patients in Study A and in 4% of patients in Study B. These laboratory findings were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient from Study B (<1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes of pneumonitis, and permanently discontinue XALKORI in patients diagnosed with treatment-related pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop Grade 4 QTc prolongation. Withhold XALKORI in patients who develop Grade 3 QTc prolongation until recovery to ≤ Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation, withhold XALKORI until recovery to ≤ Grade 1, then resume XALKORI at 250 mg once daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. ADVERSE REACTIONS Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). Among the 255 patients for whom data on Grade 1-4 adverse reactions are available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted >2 weeks in 13% and 19% of all patients. Dose reductions occurred in 44% and 29% of patients. The rates of treatment-related adverse events resulting in permanent discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥ 25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1), pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock, DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in ≥2% of patients included pneumonia, dyspnea, and pulmonary embolism. Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI. Table 3: Adverse Reactions in ≥ 10% of Patients with Locally Advanced or Metastatic ALK-Positive NSCLC on Studies A and B1

EYE DISORDERS

Vision Disorder2

Treatment Emergent (N=255) All Grades Grades 3/4 n (%) n (%)

Treatment Related (N=255) All Grades Grades 3/4 n (%) n (%)

163 (64%)

0 (0)

159 (62%)

0 (0)

145 (57%) 124 (49%) 116 (45%) 98 (38%) 51 (20%) 40 (16%) 27 (11%)

2 (<1%) 1 (<1%) 3 (1%) 2 (<1%) 3 (1%) 1 (<1%) 1 (<1%)

136 (53%) 109 (43%) 101 (40%) 69 (27%) 29 (11%) 20 (8%) 15 (6%)

0 0 0 1 (<1%) 0 0 1 (<1%)

97 (38%) 80 (31%) 30 (12%) 30 (12%)

2 (<1%) 6 (2%) 1 (<1%) 1 (<1%)

72 (28%) 51 (20%) 3 (1%) 2 (<1%)

0 4 (2%) 0 0

GASTROINTESTINAL DISORDERS

Nausea Diarrhea Vomiting Constipation Esophageal Disorder3 Abdominal Pain4 Stomatitis5 GENERAL DISORDERS

Edema6 Fatigue Chest Pain/Discomfort7 Fever INFECTIONS AND INFESTATIONS

Upper Respiratory Infection8 INVESTIGATIONS

Alanine Aminotransferase Increased Aspartate Aminotransferase Increased METABOLISM AND NUTRITION

Decreased Appetite MUSCULOSKELETAL

Arthralgia Back Pain

50 (20%)

1 (<1%)

4 (2%)

38 (15%) 29 (11%)

17 (7%) 7 (3%)

34 (13%) 24 (9%)

14 (5%) 5 (2%)

69 (27%)

3 (1%)

49 (19%)

29 (11%) 28 (11%)

3 (1%) 0

4 (2%) 2 (<1%)

0 0

60 (24%) 58 (23%) 34 (13%) 33 (13%)

0 1 (<1%) 1 (<1%) 0

42 (16%) 34 (13%) 10 (4%) 30 (12%)

0 1 (<1%) 0 0

NERVOUS SYSTEM DISORDERS

Dizziness9 Neuropathy10 Headache Dysgeusia PSYCHIATRIC DISORDERS

Insomnia

RESPIRATORY DISORDERS

Dyspnea Cough

SKIN DISORDERS

Rash

Study A used CTCAE v4.0, and Study B used CTCAE v3.0. Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual brightness, and visual acuity reduced. Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer, gastroesophageal reflux, odynophagia, and reflux esophagitis. 4 Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness. 5 Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain, and stomatitis. 6 Includes edema, edema localized, and peripheral edema. 7 Includes chest pain, chest discomfort, and musculoskeletal chest pain. 8 Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection. 9 Includes balance disorder, dizziness, and presyncope. 10 Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensory neuropathy. 2

INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI. DOSAGE AND ADMINISTRATION Recommended Dosing: The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy. XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. Dose Modification: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then reduce the dose of XALKORI to 200 mg taken orally twice daily. If further dose reduction is necessary, then reduce the dosage to 250 mg taken orally once daily based on individual safety and tolerability.

Adverse Event

provides tools for improving cancer care (qopi.asco.org/program). New quality measures to help eliminate disparities in patient care have recently been added to the certification process. “We’re trying to get an idea of the mix of each practice, including how many patients are on Medicare,

30 (12%)

8 (3%)

57 (22%) 54 (21%)

16 (6%) 3 (1%)

5 (2%) 9 (4%)

3 (1%) 0

41 (16%)

25 (10%)

Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia, were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks of drug administration. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%) patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were all Grade 1 or 2 in severity. Bradycardia occurred in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2 in severity. Complex renal cysts occurred in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Laboratory Abnormalities: Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 5.2%, 0.4%, and 11.4% of patients, respectively. DRUG INTERACTIONS Drugs That May Increase Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors. Drugs That May Decrease Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations. Avoid concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital phenytoin, rifabutin, rifampin, and St. John’s Wort. Drugs Whose Plasma Concentrations May Be Altered By Crizotinib: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. USE IN SPECIFIC POPULATIONS Pregnancy Category D: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies of XALKORI in pregnant women. Advise women of childbearing potential to avoid becoming pregnant while receiving XALKORI. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Nursing Mothers: It is not known whether XALKORI 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 XALKORI, consider 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 efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 10 times the AUC in adult patients at the recommended human dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatic Use: Clinical studies of XALKORI did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 136 patients in Study A, 19 (14%) were ≥65 years. Of the 119 patients in Study B, 16 (13%) were ≥65 years. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded patients with AST or ALT >2.5 x ULN, or >5 x ULN, if due to liver metastases. Patients with total bilirubin >1.5 x ULN were also excluded. Therefore, use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) and moderate renal impairment (CLcr 30 to 60 mL/min), as steady-state trough concentrations in these two groups were similar to those in patients with normal renal function (CLcr >90 mL/min) in Study B. The potential need for starting dose adjustment in patients with severe renal impairment cannot be determined, as clinical and pharmacokinetic data were available for only one patient. In addition, no data are available for patients with end-stage renal disease. Therefore, use caution in patients with severe renal impairment (CLcr <30 mL/min) or patients with end-stage renal disease. OVERDOSAGE There have been no known cases of XALKORI overdose. Treatment of overdose with XALKORI should consist of general supportive measures. There is no antidote for XALKORI. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with crizotinib have not been conducted. Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. No specific studies with crizotinib have been conducted function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (>3 times the AUC at the recommended human dose). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human daily dose on a mg/m2 basis) for 3 days. PATIENT COUNSELING INFORMATION Hepatotoxicity: Inform patients that symptoms of weakness, fatigue, anorexia, nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, and bleeding diathesis, especially in combination with fever and rash, should be reported immediately. Gastrointestinal Effects: Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received XALKORI. Supportive care for gastrointestinal adverse events requiring treatment may include standard anti-emetic and/or anti-diarrheal or laxative medications. Visual Effects: Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events. These events began most commonly during the first two weeks of treatment. Advise patients to report flashes or floaters to their physicians. Effects on Ability to Drive and Use Machines: No studies on the effect of XALKORI on the ability to drive and use machines have been performed. However, advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder, dizziness, or fatigue while taking XALKORI. Concomitant Medications: Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Instructions for Taking XALKORI: Advise patients to take XALKORI exactly as prescribed, not to change their dose or to stop taking XALKORI unless they are told to do so by their doctor. Take XALKORI with or without food. Swallow XALKORI capsules whole. Advise patients to keep XALKORI in the original container. Do not crush, dissolve, or open capsules. Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. Advise patients not to take two doses at the same time to make up for a missed dose. Pregnancy and Nursing: Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking XALKORI. Rx Only April 2012

Medicaid, or are uninsured,” said Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program at Massachusetts General Hospital in Boston and Chair of ASCO’s Health Disparities Advisory Group. “But what we are moving toward is making it feasible for more practices that care for vulnerable patients to participate in QOPI so we can ensure good quality in all practices.” ASCO is also launching a major new mentoring program as part of its Diversity in Oncology Initiative directed at medical students and residents from underrepresented minority populations to encourage them to specialize in oncology. “It’s the responsibility of organizations like ASCO to take the lead on these issues,” said Dr. Moy.

Affordable Care Act Many of the recommendations in ASCO’s policy statement are meant to build upon the provisions in the 2010 Patient Protection and Affordable Care Act for improving health care, including increasing Medicaid eligibility to reduce the number of uninsured low-income patients and to reimburse doctors who treat cancer patients on Medicaid at Medicare rates. While the Supreme Court ruled in June that the Affordable Care Act is constitutional (see pages 1, 8, and 9), it did limit the law's Medicaid provision, and it's not clear what the impact will be on these issues.

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Disclosure: Drs. Whitman, Griggs, and Moy reported no potential conflicts of interest.

References 1. Whitman S, Orsi J, Hurlbert M: The racial disparity in breast cancer mortality in the 25 largest cities in the United States. Cancer Epidemiol 36:e147-e151, 2012. 2. Rauscher GH, Allgood KL, Whitman S, et al: Unequal distribution of screening mammography services by race/ethnicity and health insurance. J Womens Health (Larchmt) 21:154-160, 2012. 3. Griggs JJ, Culakova E, Sorbero ME, et al: Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol 25:2522-2527, 2007. 4. Moy B, Polite BN, Halpern MT, et al: American Society of Clinical Oncology Policy Statement: Opportunities in the Patient Protection and Affordable Care Act to Reduce Cancer Care Disparities. J Clin Oncol 29:3816-3824, 2011.

The ASCO Post | JULY 15, 2012

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2012 ASCO Annual Meeting Tumor Biology

Alterations in PTEN Insufficient to Predict Sensitivity to Drugs Targeting PI3K/mTOR Pathway By Matthew Stenger

TEN acts as a tumor-suppressor gene through the action of its phosphatase protein product, which participates in regulation of the cell cycle to prevent too-rapid cell growth and division. Loss of PTEN function has been shown to increase PI3K/mTOR signaling, and preclinical data suggest that PTEN aberrations may be able to predict sensitivity to drugs targeting this pathway. However, Filip Janku, MD, PhD, and colleagues at The University of Texas MD Anderson Cancer Center in Houston, found that PTEN status alone did not predict response to PI3K/mTOR inhibitors in a large group of patients with diverse cancers.1 In this study, tumors from 461 patients with different cancers were scored

Filip Janku, MD, PhD

for cytoplasmic immunohistochemical expression of PTEN, and 206 of these tumors were tested for oncogenic mutations in the MAPK pathway (ie, KRAS, NRAS, and BRAF mutations). Treatment outcomes in 153 patients receiving PI3K/mTOR inhibitors were analyzed with respect to PTEN status.

PTEN Status Does Not Predict Response Of the 461 patients, 10% had negative PTEN expression (no staining), 36.5% had positive PTEN expression (intact staining), and 53.5% had reduced PTEN (reduced staining compared with stroma serving as a positive internal control). In tumor types with at least 10 patients tested, negative PTEN was found most frequently in uterine (10/33, 33%), renal (3/11, 27%), salivary gland (2/10, 20%), colorectal (15/82, 18%), breast (2/15, 13%), pancreatobiliary (3/24, 13%), and prostate cancers (2/19, 11%). Of a total of 153 patients receiving therapy with PI3K/mTOR inhibitors, partial response occurred in 17 (11%), including 2 (15%) of 13 PTEN-negative patients, 3 (6%) of 50 PTEN-pos-

itive patients, and 12 (13%) of 90 patients with reduced PTEN expression. There was no significant difference in rate of partial response between PTEN-positive patients and patients with negative or reduced PTEN expression (6% vs 14%, P = .27).

MAPK Mutations More Common with Altered PTEN While it was found that alteration of PTEN function did not predict response to treatment with PI3K/mTOR inhibitors, the investigators also found that MAPK mutations were significantly more common in patients with altered PTEN function. In particular, among the 206 patients tested, these mutations were found in 72 (50%) of 144 patients with negative or reduced PTEN expression, compared with 20 (32%) of 62 PTEN-positive patients (P = .02). The investigators thus concluded that PTEN status alone cannot be used to predict sensitivity to PI3K/ mTOR inhibitors, possibly because patients with negative or reduced PTEN expression have a greater frequency of simultaneous MAPK mutations.

Clinical Relevance In commenting on the implications of the study, Dr. Janku stated, “We believe that these findings have considerable clinical relevance. Preclinical models have demonstrated that PTEN loss can be associSee Page 84 ated with increased PI3K/AKT/mTOR signaling and sensitivity to PI3K pathway inhibitors. However, our data suggest that this effect can be compensated for by an increased rate of MAPK pathway mutations, which can ultimately lead to therapeutic resistance. This finding warrants further investigation, since many PI3K pathway inhibitors are entering the clinical arena.”

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Disclosure: Dr. Januka has received research funding from Novartis.

Reference 1. Janku F, Broaddus R, Bakkar R, et al: PTEN assessment and PI3K/mTOR inhibitors: Importance of simultaneous assessment of MAPK pathway aberrations. 2012 ASCO Annual Meeting, Abstract 10510. Presented June 5, 2012.

Two Single Nucleotide Polymorphisms Associated with Risk for Paclitaxel-related Peripheral Neuropathy By Matthew Stenger

eripheral neuropathy is the most common severe toxicity in patients receiving paclitaxel, and mutations in genes affecting drug metabolism, distribution, and elimination are likely to modulate risk for such neurotoxicity. In a recent study, Daniel Hertz, PharmD, and colleagues from the University of North Carolina at Chapel Hill identified two single nucleotide polymorphisms associated with risk of paclitaxel-associated peripheral neuropathy present in genes that have not previously been investigated in paclitaxel pharmacogenetic studies.1 The study included 412 patients with breast cancer who had received paclitaxel-containing regimens. Clinical data, inSee Page 84 cluding patient

characteristics and toxicity were collected prospectively as part of an observational registry. Blood collected at the time of the diagnosis was genotyped using a platform that interrogates nearly 2,000 known variants in genes associated with drug pharmacokinetic exposure (Affymetrix DMET Plus chip), and associations of single nucleotide polymorphisms with peripheral neuropathy of grade 2 or higher were assessed. Statistical analysis was performed for each single nucleotide polymorphism examined, with the P value for significance being set at P < .001.

Variations in ABCG1 and CYP17A1 Modulate Risk Older age and African American race may be associated with increased risk of paclitaxel-associated peripheral neuropathy, and diabe-

tes is a risk factor for neuropathy. Among the 412 patients, the median age was 50 years, 26% were African American, and 12% had preexisting diabetes. Overall, the prevalence of grade 2 or higher peripheral neuropathy was 18.5%. Among 564 single nucleotide polymorphisms interrogated, 2 were associated with peripheral neuropathy. Individuals who were homozygous for the wild-type G allele at the rs3788007 single nucleotide polymorphism in the ABCG1 transporter gene (ABCG1_43706676G>A[Intron]) had a greater than threefold increase in risk of peripheral neuropathy (odds ratio [OR] = 3.54, 95% CI = 1.77–7.72, P = .0003). Patients carrying two copies of the wild-type G allele at the rs6163 single nucleotide polymorphism in the CYP17A1 gene (CYP17A1_195G>T[S65S]) were at

Daniel Hertz, PharmD

approximately one-third of the risk of peripheral neuropathy (OR = 0.35, 95% CI = 0.18-0.66, P = .0008). Both of these genes have been found to be involved in endogenous steroid biology, which in turn is believed to be involved in the development of neuropathy. In addition, the rs6163 single nucleotide polymorphism was found to be in high linkage disequilibrium (r2 = 0.93) continued on page 55

ASCOPost.com | JULY 15, 2012

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2012 ASCO Annual Meeting Tumor Biology

Single Nucleotide Polymorphisms Predict Severe Toxicity of Adjuvant Therapy in Colorectal Cancer By Matthew Stenger

xaliplatin/fluoropyrimidine– based adjuvant therapy is of benefit in patients with resected stage II/III colon cancer, but the ability to predict risk of toxicity could improve care by permitting individualization of treatment. Ana Custodio, MD, and colleagues from GEMCAD (Grupo Español Multidisciplinario del Cancer Digestivo) recently identified several single nucleotide polymorphisms that appear to predict risk of severe toxicity in patients receiving such adjuvant therapy.1 In this study, DNA was extracted from formalin-fixed paraffin-embedded tumor samples from 379 patients with surgically treated high-risk stage II (28%) and stage III (72%) colon cancer receiving oxaliplatin and fluoropyrimidine-based adjuvant therapy (54% FOLFOX, 46% XELOX) from January 2004 to December 2008. Genotyping was performed for 35 single nucleotide polymorphisms in 18 genes known to be involved in oxaliplatin and fluoropyrimidine metabolism using MassARRAY (Sequenom, Inc) technology.

toxicities were neutropenia (15.3%), diarrhea (8.17%), and neurotoxicity (7.65%). Genotypes associated with higher risk of any grade 3/4 toxicity

were MTHFR rs1801133 C>T C/C and XRCC2 rs3218408 T>G T/T. Genotypes associated with a reduced incidence of severe toxicity

were UMPS rs3772807 G>C C/C and DPYD rs970337 G>A A/A. In addition, the DPYD rs970337 continued on page 56

Variations in Several Genes Alter Risk A total of 89 patients (23.4%) experienced at least one grade 3/4 adverse event. The most common grade 3/4

Paclitaxel-related Peripheral Neuropathy continued from page 54

with another single nucleotide polymorphism recently reported to be associated with bortezomib (Velcade)-associated peripheral neuropathy.2

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Disclosure: Dr. Hertz reported no potential conflicts of interest.

References 1. Hertz DL, EC Dees, Motsinger-Reif AA, et al: Interrogation of polymorphisms in drug metabolism or transport genes and peripheral neuropathy during paclitaxel treatment. 2012 ASCO Annual Meeting. Abstract 10515. Presented June 5, 2012. 2. Corthals SL, Kuiper R, Johnson DC, et al: Genetic factors underlying the risk of bortezomib induced peripheral neuropathy in multiple myeloma patients. Haematologica 96:1728-1732, 2011.

Unified in our uncompromising commitment to improving patient care in renal cell carcinoma For more information visit www.aveopharma.com or www.astellas.com.

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The ASCO Post | JULY 15, 2012

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2012 ASCO Annual Meeting Tumor Biology

NK Cell Signature Associated with Favorable Prognosis in Breast Cancer By Matthew Stenger

umor cell recognition by natural killer (NK) cells is mediated by the interaction of activating and inhibitory NK cell receptors with ligands expressed on the tumor cells. NK cells also express adhesion molecules that facilitate formation of the immune synapse with tumor targets. Maria Libera Ascierto (PhD student) and colleagues from the National Institutes of Health in Bethesda, Maryland, investigated whether the expression of NK-activating receptors and adhesion molecules could provide a signature to differentiate relapse and relapse-free outcomes in breast cancer.1

Relapse-free Survival Predicted Gene-expression profiling and real time, reverse transcription polymerase chain reaction screening were performed on RNA extracted from primary breast tumor See Page 84 samples obtained from patients experiencing either 5 to 9 year relapse-free survival or relapse within 1 to 6 years following initial

Single Nucleotide Polymorphisms continued from page 55

AV N AI OW LA BL E!

G>A A/A genotype was associated with a lower rate of grade 3/4 diarrhea, the ABCG2 rs3114018 A>C C/C genotype was associated with an increased rate of grade 3/4 neutropenia, and the ERCC1 rs11615

Maria Libera Ascierto

treatment. Tumors derived from patients with a favorable prognosis were characterized by increased expression of genes involved in the NK cell interaction with tumor cells and its activation signaling. In particular, upregulation of natural cytotoxicity receptors, DNAM-1 (CD226), and CD96 was observed in relapse-free patients.

Powerful Predictive Tool? As stated by the investigators, the findings indicate that expression of the NK-activating receptors and relevant adhesion molecules involved in NK cell-target interactions can predict relapse-free survival in patients with breast cancer. Together with observations in their prior studies, the findings also highlight T>C T/T genotype was associated with a lower rate of grade 3/4 neurotoxicity. Further study is warranted to determine if the identification of the single nucleotide polymorphisms that increase risk of severe toxicity with oxaliplatin/fluoropyrimidine adjuvant treatment can be translated

the effector cooperation between the innate and adaptive immune components within the tumor microenvironment. In prior studies, these investigators observed that prognostic B-cell and T-cell signatures also differentiate more favorable and poorer prognosis; these findings suggest that the presence of specific T-cell and B-cell markers identifies patients with improved prognosis. In particular, the expression of interferon-stimulated genes and immune effectors commonly observed during the inflammatory response to pathogens, as well as genes involved in B-cell development, autoimmune reactions, and the antigen presentation pathway, were exclusively upregulated in patients with longer relapse-free survival. Among the extended signatures identified, a 5-gene signature based on expression of IGKC, GBP1, STAT1, IGLL5, and OCLN that is distinct from the FDA-cleared 70-gene signature MammaPrint panel and the Oncotype DX recurrence score assay panel was found to predict relapsefree survival with greater than 85% accuracy. As stated by Dr. Ascierto, “Taken into modification of adjuvant regimens.

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Disclosure: The investigators reported no potential conflicts of interest.

Reference 1. Custodio A, Moreno J, Aparicio J, et al: Pharmacogenetic predictors of adverse events in stage II-III colon cancer (CC) pa-

together, these observations describe a cancer phenotype similar to acute inflammatory processes, characterized by the presence of innate and adaptive T cell responses that favor an immune effector mechanism capable of inducing spontaneous or treatment-related cancer regression.” She further noted, “The NK-cell parameters identified in this study, together with the prognostic B-cell and T-cell signatures previously reported by us, support an association between an ‘immune response’ signature and improved outcomes in breast cancer. This ‘immune signature’ may represent a new and powerful tool for predicting breast cancer outcome that might be easily introduced in clinical practice to join other currently used predictive parameters and markers.”

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Disclosure: Dr. Ascierto reported no potential conflicts of interest.

Reference 1. Ascierto ML, Idowu MO, Zhao Y, et al: Involvement of NK cell molecular signatures in favorable prognosis of breast cancer patients. 2012 ASCO Annual Meeting, Abstract 10565. Presented June 4, 2012.

tients treated with oxaliplatin and fluoropyrimidines-based adjuvant chemotherapy (CT): A GEMCAD study. 2012 See Page 84 ASCO Annual Meeting. Abstract 10547. Presented June 4, 2012.10547. Presented June 4, 2012.

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See Page 84

Finally in metastatic melanoma A PERSONALIZED

TREATMENT has come together

The first and only personalized treatment for unresectable or metastatic melanoma with the BRAFV600E mutation1,2

DECODE

metastatic melanoma

Indication and Usage ZELBORAF® (vemurafenib) is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. Important Safety Information Cutaneous squamous cell carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF. The incidence of cuSCC in ZELBORAF-treated patients in the Phase III study was 24%. The median time to first appearance of cuSCC was 7 to 8 weeks. Potential risk factors included age ≥65 years, prior skin cancer, and chronic sun exposure. All patients should receive a dermatologic evaluation prior to initiation of therapy, every 2 months while on therapy, and potentially for 6 months following discontinuation of ZELBORAF. Any suspicious skin lesions should be excised, evaluated, and treated as per standard of care. Hypersensitivity and Dermatologic Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe reactions may include generalized rash and erythema or hypotension. Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including 1 case of Stevens-Johnson syndrome and 1 case of toxic epidermal necrolysis in the Phase III study. ZELBORAF treatment should be permanently discontinued in patients who experience a severe hypersensitivity or dermatologic reaction. QT prolongation Exposure-dependent QT prolongation has been observed in patients treated with ZELBORAF, which may lead to an increased risk for ventricular arrhythmias, including Torsade de Pointes.

Treatment is not recommended in patients with uncorrectable electrolyte abnormalities, with long QT syndrome, or who are taking medicines known to prolong the QT interval. ECG and electrolytes should be monitored before initiating treatment with ZELBORAF and after dose modification and routinely during treatment (15 days after treatment initiation, then monthly for first 3 months of treatment and every 3 months thereafter or as clinically indicated). If the QTc exceeds 500 ms, ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities corrected, and cardiac risk factors for QT prolongation (e.g. congestive heart failure, bradyarrhythmias) controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms. Permanent discontinuation is recommended if, after correction of associated risk factors, the QTc increase meets both a value of >500 ms and >60 ms change from pre-treatment values. Liver laboratory abnormalities Liver laboratory abnormalities have occurred with ZELBORAF. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Lab abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation. Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials. While taking ZELBORAF, all patients should be advised to avoid sun exposure and, when outdoors, to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥30). For intolerable grade 2 or greater photosensitivity, dose modifications are recommended. Ophthalmologic Reactions In the Phase III study, 5 cases of uveitis were reported in patients treated with ZELBORAF.

EXTEND

survival

56% reduction in risk of death from any cause with ZELBORAF (95% CI, 0.33-0.59)

P<0.0001

OS=overall survival HR=hazard ratio CI=confidence interval * Median follow-up was 6.2 months (95% CI, 0.4-13.9 mo) for ZELBORAF patients vs 4.5 months (95% CI, <0.1-11.7 mo) for those taking dacarbazine. † There were 78 deaths and 121 deaths in the ZELBORAF and dacarbazine arms, respectively, at the time of analysis.

~4-month improvement in median progression-free survival (5.3 vs 1.6 months; HR=0.26, P<0.0001, 95% CI, 4.9-6.6 months vs 1.6-1.7 months) Significant improvement in best overall response rate (48.4% vs 5.5%; P<0.001, 95% CI, 41.6%-55.2% vs 2.8%-9.3%)3 There were 2 complete responses (1%) and 104 partial responses (PRs) (47.4%) with ZELBORAF vs 12 PRs (5.5%) with dacarbazine

0.294 inrash, alopecia, fatigue, photosensitivity The most common adverse reactions of any grade (≥30%) reported were arthralgia, reaction, nausea, pruritus, and skin papilloma; the most common (≥5%) grade 3 adverse reactions were cutaneous squamous cell carcinoma and rash

Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, 5 cases each of blurry vision and iritis and 6 cases of photophobia were reported in the Phase III study. One case of retinal vein occlusion was reported in the Phase II study. New Primary Malignant Melanoma Eight skin lesions in 7 patients were reported as new primary malignant melanoma in the Phase III study. Cases were managed with excision and patients continued treatment without dose adjustment; monitoring for skin lesions should occur as outlined above [see cuSCC]. Use in Pregnancy: Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If ZELBORAF is used during pregnancy or if the patient becomes pregnant while taking ZELBORAF, the patient should be apprised of the potential hazard to a fetus. BRAF Testing Confirmation of BRAFV600E mutation-positive melanoma as detected by an FDA-approved test is required for the selection of patients appropriate for ZELBORAF therapy. The efficacy and safety of ZELBORAF have not been studied in patients with wild-type BRAF melanoma. Most common adverse events The most common adverse reactions of any grade (≥30%) reported were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥5%) grade 3 adverse reactions were cuSCC and rash. In clinical studies, cuSCC was predefined as a grade 3 event.

Please see Brief Summary of Prescribing Information on the following page. References: 1. Smalley KS, Sondak VK. Melanoma—an unlikely poster child for personalized cancer therapy. N Engl J Med. 2010;363:876-878. 2. Flaherty KT. Next generation therapies change the landscape in melanoma. F1000 Med Reports. http://f1000.com/reports/m/3/8. Published April 1, 2011. Accessed July 14, 2011. 3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.

zelboraf.com

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2012 ASCO Annual Meeting Tumor Biology

p53 Mutation in Advanced Solid Tumors Linked to Aggressive Course By Matthew Stenger

utations in the tumor-suppressor protein p53, among the most common mutations in cancers, affect apoptosis, genomic stability, and angiogenesis. To determine the effect of p53

human melanoma tissue. The safety and efficacy of ZELBORAF have not been evaluated in patients whose melanoma tested negative by the cobas ® 4800 BRAF V600 Mutation Test. Refer to the package inserts of FDA approved test kits,for detailed information. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice. The adverse drug reactions (ADRs) described in this section were identified from Trial 1 and Trial 2 [see Clinical Studies (14)]. In Trial 1, treatment naive patients with unresectable or metastatic melanoma (n=675) were allocated to ZELBORAF 960 mg orally twice daily or to dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, (n=132) patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with ZELBORAF 960 mg orally twice daily. Adverse reactions reported in at least 10% of patients treated with ZELBORAF are presented in Table 2. The most common adverse reactions of any grade (≥ 30% in either study) reported in ZELBORAF-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies. The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the ZELBORAF arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in ZELBORAF-treated patients. The median duration of study treatment was 4.2 months for ZELBORAF and 0.8 months for dacarbazine in Trial 1, and 5.7 months for ZELBORAF in Trial 2.

tively reviewed data from 121 consecutive patients with solid tumors referred to the Center’s Clinical Center for Targeted Therapy phase I program who had been tested for p53 mutations.1

Clinically relevant adverse events reported in < 10% of patients treated with ZELBORAF in the Phase 2 and Phase 3 studies include: Skin and subcutaneous tissue disorders: palmar-plantar erythrodysaesthesia syndrome, keratosis pilaris, erythema nodosum, Stevens-Johnson syndrome Musculoskeletal and connective tissue disorders: arthritis Nervous system disorders: dizziness, neuropathy peripheral, VII th nerve paralysis Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma Infections and infestations: folliculitis Investigations: weight decreased Eye disorders: retinal vein occlusion, uveitis Vascular disorders: vasculitis Cardiac disorders: atrial fibrillation Table 3 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4. Table 3 Change From Baseline to Grade 3/4 Liver Laboratory Abnormalities* Change From Baseline to Grade 3/4 Parameter GGT AST ALT Alkaline phosphatase Bilirubin

ZELBORAF (%) 11.5 0.9 2.8 2.9 1.9

Dacarbazine (%) 8.6 0.4 1.9 0.4

* For ALT, alkaline phosphatase and bilirubin, there were no patients with a change to grade 4 in either treatment arm. 7 DRUG INTERACTIONS Table 2 Adverse Reactions Reported in ≥ 10% of Patients Treated 7.1 Effects of Vemurafenib on Drug Metabolizing Enzymes with ZELBORAF* Trial 2: Patients with Results from an in vivo drug-drug interaction study in patients with cancer Trial 1: Treatment Naive Patients Failure of at Least demonstrated that vemurafenib is a moderate CYP1A2 inhibitor, a weak One Prior Systemic CYP2D6 inhibitor and a CYP3A4 inducer [see Clinical Pharmacology (12.3)]. Concomitant use of ZELBORAF with agents with narrow therapeutic Therapy windows that are metabolized by CYP1A2, CYP2D6 and CYP3A4 is ZELBORAF Dacarbazine ZELBORAF not recommended as ZELBORAF may alter their concentrations. If n= 336 n= 287 n= 132 coadministration cannot be avoided, exercise caution and consider a ADRs All Grade Grade All Grade Grade All Grade Grade dose reduction of the concomitant CYP1A2 and CYP2D6 substrate drug. 4 4 Grades 3 4 Grades 3 Grades 3 (%) (%) (%) (%) (%) (%) (%) (%) (%) Coadministration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate) [see Clinical Pharmacology Skin and (12.3)]. Exercise caution and consider additional INR monitoring when subcutaneous ZELBORAF is used concomitantly with warfarin. tissue disorders 7.2 Drugs that Inhibit or Induce CYP3A4 Rash 37 8 2 52 7 Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, Photosensitivity 33 3 4 49 3 atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, reaction nelfinavir, voriconazole) and inducers (e.g., phenytoin, carbamazepine, Alopecia 45 <1 2 36 rifampin, rifabutin, rifapentine, phenobarbital) should be used with Pruritus 23 1 1 30 2 caution when coadministered with ZELBORAF. Hyperkeratosis 24 1 <1 28 Rash maculo8 USE IN SPECIFIC POPULATIONS 9 2 <1 21 6 papular 8.1 Pregnancy Actinic keratosis 8 3 17 Pregnancy Category D [see Warnings and Precautions (5.9)]. Dry skin 19 1 16 ZELBORAF may cause fetal harm when administered to a pregnant Rash papular 5 <1 13 woman based on its mechanism of action. Erythema 14 2 8 There are no adequate and well controlled studies in pregnant women. Musculoskeletal Women of childbearing potential and men should be advised to use and connective appropriate contraceptive measures during ZELBORAF therapy and for tissue at least 2 months after discontinuation of ZELBORAF. If this drug is used disorders during pregnancy or if the patient becomes pregnant while taking this Arthralgia 53 4 3 <1 67 8 drug, the patient should be apprised of the potential hazard to a fetus. Myalgia 13 <1 1 24 <1 8.3 Nursing Mothers Pain in extremity 18 <1 6 2 9 Musculoskeletal It is not known whether vemurafenib is excreted in human milk. Because 8 4 <1 11 pain many drugs are excreted in human milk and because of the potential for Back pain 8 <1 5 <1 11 <1 serious adverse reactions from ZELBORAF in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the General disorders drug, taking into account the importance of the drug to the mother. and administration site conditions 8.4 Pediatric Use Fatigue 38 2 33 2 54 4 Safety and efficacy in pediatric patients below the age of 18 have not Edema peripheral 17 <1 5 23 been established. Pyrexia 19 <1 9 <1 17 2 8.5 Geriatric Use Asthenia 11 <1 9 <1 2 Ninety-four (28%) of 336 patients with unresectable or metastatic Gastrointestinal melanoma treated with ZELBORAF in Trial 1 were ≥ 65 years. Elderly disorders patients (≥ 65 years) may be more likely to experience some adverse Nausea 35 2 43 2 37 2 reactions, including cutaneous squamous cell carcinoma, nausea, Diarrhea 28 <1 13 <1 29 <1 decreased appetite, peripheral edema, keratoacanthoma and atrial Vomiting 18 1 26 1 26 2 fibrillation. The effects of ZELBORAF on overall survival, progressionConstipation 12 <1 24 16 free survival and best overall response rate were similar in the elderly as Nervous system compared to younger patients. disorders 8.6 Gender Headache 23 <1 10 27 The Grade 3 adverse events reported more frequently in females than Dysgeusia 14 3 11 males were rash, arthralgia, photosensitivity and increased creatinine. Neoplasms The Grade 3 adverse events reported more frequently in males than benign, malignant females were keratoacanthoma, increased alkaline phosphatase and and unspecified increased total bilirubin. (includes cysts 8.7 Hepatic Impairment and polyps) No adjustment to the starting dose is needed for patients with Skin papilloma 21 <1 30 pre-existing mild and moderate hepatic impairment. ZELBORAF should Cutaneous SCC†# 24 22 <1 <1 24 24 Seborrheic be used with caution in patients with pre-existing severe hepatic 10 <1 1 14 keratosis impairment [see Clinical Pharmacology (12.3)]. 8.8 Renal Impairment Investigations 5 3 <1 1 Gamma15 6 4 No adjustment to the starting dose is needed for patients with glutamyltransferase pre-existing mild and moderate renal impairment. increased ZELBORAF should be used with caution in patients with pre-existing Metabolism and severe renal impairment [see Clinical Pharmacology (12.3)]. nutrition disorders 10 OVERDOSAGE Decreased appetite 18 8 <1 21 There is no specific antidote for overdosage of ZELBORAF. Patients Respiratory, who develop adverse reactions should receive appropriate symptomatic thoracic and treatment. In case of suspected overdose, ZELBORAF should be mediastinal withheld and supportive care instituted. disorders Cough Injury, poisoning and procedural complications Sunburn

*Adverse drug reactions, reported using MedDRA and graded using NCICTC-AE v 4.0 (NCI common toxicity criteria) for assessment of toxicity. † Includes both squamous cell carcinoma of the skin and keratoacanthoma. # All cases of cutaneous squamous cell carcinoma were to be reported as Grade 3 per instructions to study investigators and no dose modification or interruption was required.

Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990

Mutation Associated with Liver Metastasis, PTEN Loss Of the 121 patients, 65 (54%) had mutant p53. The presence of p53 mutations was not associated with sex or race. Metastasis to the liver occurred in 44 patients (68%) with mutant p53, compared with 26 patients (46%) with wild-type p53 (P = .0264); there was no difference in proportions of patients with metastasis to bone, lungs, brain, soft tissue, or adrenal glands according to mutant vs wild-type p53. The p53 mutation also showed a trend toward an association with loss of function of the tumor-suppressor gene PTEN, which occurred in 30% of patients with mutant p53, compared with 11% of patients with wild-type p53 (P = .053).

Bevacizumab Improves Survival in Mutant p53 Disease Among patients with p53 mutations, the best median progression-free survival prior to phase I trial entry was 10.97 months (range, 0.85–29.04 months) when the treatment regimen included bevacizumab (Avastin) and 4.37 months (range, 0.92–14.98 months) when the treatment did not include bevacizumab (P = .0046). Among patients with wild-type p53, there was no significant difference in progression-free survival between patients receiving bevacizumab-containing regimens and patients not receiving such regimens. Median overall survival from diagnosis was 7.7 years in patients with mutant p53 vs 11.8 years for those with wildtype p53 disease (P = .03). Univariate analysis of overall survival from time of diagnosis showed that mutant p53, Hispanic race (vs Caucasian), and shorter time from diagnosis to metastasis were associated with worse prognosis. As summarized by the investigators, “Tumors with p53 mutation have a more aggressive clinical behavior, metastasize more to the liver, and may have a higher rate of PTEN loss compared to tumors with wild-type p53…. In addition, antiangiogenic agents may be of therapeutic value in p53-mutated patients.” Safety:10"

ZELBORAF ® (vemurafenib) tablet, oral Initial U.S. Approval: 2011 This is a brief summary of information about ZELBORAF. Before prescribing, please refer to the full Prescribing Information. 1 INDICATIONS AND USAGE ZELBORAF ® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. Limitation of Use: ZELBORAF is not recommended for use in patients with wild-type BRAF melanoma. 5 WARNINGS AND PRECAUTIONS 5.1 Cutaneous Squamous Cell Carcinoma (cuSCC) Cases of cuSCC, including both SCCs of the skin and keratoacanthomas, have been reported in patients treated with ZELBORAF [see Adverse Reactions (6.1)]. The incidence of cuSCC in ZELBORAF-treated patients in Trial 1 was 24%. CuSCC usually occurred early in the course of treatment with a median time to the first appearance of 7 to 8 weeks. Of the patients who experienced cuSCC, approximately 33% experienced > 1 occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC in ZELBORAF clinical studies included age (≥ 65 years), prior skin cancer, and chronic sun exposure. In the clinical trials, cases of cuSCC were managed with excision, and patients were able to continue treatment without dose adjustment. It is recommended that all patients receive a dermatologic evaluation prior to initiation of therapy and every two months while on therapy. Any suspicious skin lesions should be excised, sent for dermatopathologic evaluation and treated as per standard of care. Monitoring should be considered for 6 months following discontinuation of ZELBORAF. 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with ZELBORAF and upon re-initiation of treatment. Severe hypersensitivity reactions included generalized rash and erythema or hypotension. In patients who experience a severe hypersensitivity reaction, ZELBORAF treatment should be permanently discontinued. 5.3 Dermatologic Reactions Severe dermatologic reactions have been reported in patients receiving ZELBORAF, including one case of Stevens-Johnson syndrome and one case of toxic epidermal necrolysis in Trial 1. In patients who experience a severe dermatologic reaction, ZELBORAF treatment should be permanently discontinued. 5.4 QT Prolongation Exposure-dependent QT prolongation was observed in an uncontrolled, open-label Phase 2 QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma [see Clinical Pharmacology (12.3)]. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes. Treatment with ZELBORAF is not recommended in patients with uncorrectable electrolyte abnormalities, long QT syndrome, or who are taking medicinal products known to prolong the QT interval. ECG and electrolytes, including potassium, magnesium, and calcium, should be monitored before treatment with ZELBORAF and after dose modification. Monitoring of ECGs should occur 15 days after treatment initiation and then monthly during the first 3 months of treatment, followed by every 3 months thereafter or more often as clinically indicated. Initiation of treatment with ZELBORAF is not recommended in patients with QTc > 500 ms. If during treatment the QTc exceeds 500 ms (CTC-AE ≥ Grade 3), ZELBORAF treatment should be temporarily interrupted, electrolyte abnormalities should be corrected, and cardiac risk factors for QT prolongation (e.g., congestive heart failure, bradyarrhythmias) should be controlled. Re-initiation of treatment should occur at a lower dose once the QTc decreases below 500 ms [see Dosage and Administration (2.2)]. Permanent discontinuation of ZELBORAF treatment is recommended if after correction of associated risk factors, the QTc increase meets values of both > 500 ms and > 60 ms change from pre-treatment values. 5.5 Liver Laboratory Abnormalities Liver laboratory abnormalities have occurred with ZELBORAF (Table 3) [see Adverse Reactions (6.1)]. Liver enzymes (transaminases and alkaline phosphatase) and bilirubin should be monitored before initiation of treatment and monthly during treatment, or as clinically indicated. Laboratory abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation [see Dosage and Administration (2.2)]. 5.6 Photosensitivity Mild to severe photosensitivity was reported in patients treated with ZELBORAF in clinical trials [see Adverse Reactions (6.1)]. All patients should be advised to avoid sun exposure while taking ZELBORAF. While taking the drug, patients should be advised to wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn. For intolerable grade 2 (tender erythema covering 10 - 30% body surface area) or greater photosensitivity, dose modifications are recommended [see Dosage and Administration (2.2)]. 5.7 Ophthalmologic Reactions In Trial 1, five cases of uveitis have been reported in patients treated with ZELBORAF. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Patients should be routinely monitored for signs and symptoms of uveitis. Additionally, there were five patients with blurry vision, five patients with iritis and six patients with photophobia. There was one case of retinal vein occlusion in Trial 2. 5.8 New Primary Malignant Melanoma There were eight skin lesions in seven patients reported as new primary malignant melanoma in Trial 1. Cases were managed with excision, and patients continued treatment without dose adjustment. Monitoring for skin lesions should occur as outlined above [see Warnings and Precautions (5.1)]. 5.9 Use in Pregnancy Pregnancy Category D ZELBORAF may cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. 5.10 BRAF V600E Testing Confirmation of BRAF V600E mutation-positive melanoma as detected by an FDA-approved test is required for selection of patients for ZELBORAF therapy because these are the only patients studied and for whom benefit has been shown. For patients in ZELBORAF clinical studies, including Trial 1 and Trial 2, all enrolled patients tested positive when their tumor tissue was assessed with the cobas ® 4800 BRAF V600 Mutation Test [see Clinical Studies (14)]. This test is designed to detect BRAF V600E mutations in DNA isolated from formalin-fixed, paraffin-embedded

mutation on clinical characteristics and disease and treatment outcomes, Rabih Said, MD, MPH, and colleagues from The University of Texas MD Anderson Safety:7" Cancer Center in Houston retrospec-

■

Disclosure: Dr. Said reported no potential conflicts of interest.

Reference 1. Said R, Hong DS, Wheler JJ, et al: p53 mutations in advanced cancers: Clinical characteristics and outcomes in a phase I setting. 2012 ASCO Annual Meeting. Abstract 10607. Presented June 4, 2012.

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2012 ASCO Annual Meeting Head and Neck Cancer

Cabozantinib Prolongs Progression-free Survival in Advanced Medullary Thyroid Cancer By Alice Goodman

abozantinib prolonged progression-free survival in patients with unresectable, locally advanced, or metastatic medullary thyroid cancer with documented disease progression in the phase III EXAM trial. Based on these results, Exelixis submitted a New Drug Application to the FDA in May 2012. The full data from the trial were presented at the 2012 See Page 84 ASCO Annual Meeting. Final overall survival analysis is expected in 1 to 2 years.

Key Findings Cabozantinib resulted in clinically meaningful and statistically significant prolongation of progression-free survival in this setting. The KaplanMeier estimates of the proportions of subjects alive and progression-free at 1 year are 47.3% for the cabozantinib arm and 7.2% for the placebo arm. The drug achieved durable tumor responses for a median of 14.6 months. In addition, the study demonstrated that serum calcitonin could be used as a marker of response, as serum calcitonin levels decreased with documented tumor shrinkage. “Patients with medullary thyroid cancer and their physicians face a tough

obstacle when their cancer recurs or progresses,” stated Patrick Schoffski, MD, of University Hospitals, Leuven, Belgium. “Treatment options are limited, and standard chemotherapy has shown disappointing results. The new targeted agent cabozantinib is an oral drug that inhibits genetic abnormalities associated with medullary thyroid cancer. Cabozantinib will be an important new treatment option if approved by regulatory agencies for this orphan disease.”

Study Background The study, sponsored by Exelixis, involved 90 investigators from 23 countries. Medullary thyroid cancer is a rare endocrine disease accounting for 5% to 8% of all thyroid cancers; 75% are sporadic and 25% are hereditary, Dr. Schoffski explained. Up to 65% of these sporadic cancers have somatic RET mutations, and more than 95% of the hereditary cancers have germline RET mutations. Cabozantinib is a small-molecule inhibitor of MET, VEGFR2, and RET. The drug had excellent activity in earlier trials and was granted orphan drug status by the FDA in January 2011. The phase III EXAM trial randomly assigned 330 patients with locally advanced or metastatic medullary thyroid cancer and documented disease progression within 14 months of

EXPERT POINT OF VIEW

his study follows earlier phase I and II trials showing remarkable responses in patients with advanced medullary thyroid carcinoma, some of whom had progressed on prior tyrosine kinase inhibitor therapy, explained formal discussant of this trial, Samuel A. Wells, MD, of the Center for Cancer Research at the National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Dr. Wells questioned the degree of censoring in this trial, because the numbers of patients censored Samuel A. Wells, MD did not appear to be consistent with the percentages for treatment response. He commented that he would have liked to know how many patients required dose reductions. In addition, he noted that overall survival might be confounded by patients who develop progressive disease on cabozantinib and subsequently receive another molecular targeted therapeutic once they are off the clinical trial. Approximately 45% of patients with medullary thyroid carcinoma have either somatic RET or RAS mutations, but not both together. I would like to know if the authors detected RAS mutations, and if so, did the presence of either RAS or RET mutations correlate with clinical response? Disclosure: Dr. Wells reported no potential conflicts of interest.

■

Cabozantinib in Medullary Thyroid Cancer ■■ Cabozantinib significantly prolonged progression-free survival in

medullary thyroid cancer in patients with documented disease progression at baseline.

■■ Noted as a potential marker, serum calcitonin levels decreased by a mean of 45% in patients receiving cabozantinib, and these changes correlated with tumor regression.

■■ A New Drug Application for cabozantinib was recently submitted to FDA. screening in a 2:1 ratio to cabozantinib at 140 mg/d or placebo, with treatment continued until disease progression. The planned sample size was chosen to increase power to evaluate differences in overall survival. Therefore, a relatively high degree of censoring is expected in the event-driven analysis of progression-free survival. Patients were prestratified by age (< 65 and ≥ 65) and prior exposure to tyrosine kinase inhibitors. Baseline characteristics were well balanced for demographics, gender, and performance status. Prior systemic therapy ranging from 1 to 7 previous lines per patient was administered to 37% of the cabozantinib group and 42% of the placebo group. About 20% of both groups were previously exposed to a tyrosine kinase inhibitor. Tissue samples were available for analysis, and about 50% had RET mutations in either blood or tumor.

Benefits and Toxicities EXAM met its primary endpoint. Median progression-free survival was 11.2 months for cabozantinib vs 4.2 months for placebo (P < .0001), with a 72% reduction in risk of progression favoring cabozantinib. Prespecified subgroup analysis showed superiority of cabozantinib in all subgroups, regardless of prior anticancer regimens, prior tyrosine kinase inhibitor exposure, prior radiotherapy, and presence of bone metastasis at baseline. Overall response rate was 28% with cabozantinib vs 0% for placebo < .0001). Most patients in the cabo(P �� zantinib group (94%) had some evidence of tumor regression in target lesions vs 27% of the placebo group. Common grade 3 toxicities more frequently observed in the cabozantinib arm included diarrhea, handfoot skin reactions, and fatigue. Most adverse events were grade 2. Deaths

unrelated to cancer progression were reported in 5.6% of the cabozantinib arm vs 2.8% in the placebo arm. About 2% of the deaths in the cabozantinib arm were due to causes associated with VEGF inhibition, including hemorrhage, venous thrombosis, and gastrointestinal perforation.

Patrick Schoffski, MD

Potential Biomarker Serum calcitonin levels decreased by a mean of 45% in the calcitonin arm but increased by 57% in placebo recipients. These changes correlated with tumor regression. “This study provides evidence that inhibition of RET can decrease calcitonin expression,” Dr. Schoffski said. If cabozantinib is approved for treatment of medullary thyroid cancer, it will join vandetanib (Caprelsa) as the second tyrosine kinase inhibitor to be indicated for this orphan disease. It is not clear how these agents will be sequenced.

■

Disclosure: Dr. Schoffski has received research funding from Exelixis.

Reference 1. Schoffski P, Elisei R, Müller S, et al: An international double-blind, randomized, placebo-controlled phase III (EXAM) of cabozantinib (XL184) in medullary thyroid cancer patients with documented RECIST progression at baseline. 2012 ASCO Annual Meeting. Abstract 5508. Presented June 4, 2012.

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Integrative Oncology Soy Phytoestrogens and Breast Cancer: An Enduring Dilemma By Barrie R. Cassileth, PhD, and Ian Yarett Integrative Medicine Service Memorial Sloan-Kettering Cancer Center, New York

he impact of soy consumption on breast cancer diagnosis and outcome has remained of concern to clinicians and researchers for the past 20 years. Although studied extensively in epidemiologic studies as well as lab and animal research, no medical consensus on soy’s effects has emerged. Many studies show that soy intake is associated with reduced incidence of breast cancer risk,1-3 but soy’s phytoestrogen content continues to fuel concern that it may promote tumor growth, especially in estrogen-sensitive breast cancer. This is a major issue of confusion for patients, who are exposed to conflicting media reports and marketed soy products with poorly supported health claims. Inconsistency in research findings, noncomparable study designs, and a dearth of clinical trials that assess the effect of soy on breast cancer outcome in humans have precluded the development of rigorous evidencebased guidelines to date. In this overview, we aim to summarize relevant findings and existing recommendations that may be useful to clinicians.

Estrogenic Activity of Soy Isoflavones Soy (Glycine max) is a major source of isoflavones, particularly genistein and daidzein. These compounds are structurally similar to endogenous estrogen, and may act as selective estrogen receptor modulators with the ability to stimulate or inhibit depending on factors such as isoflavone concentration and the distribution of estrogen receptor types. Isoflavones also may modulate breast carcinogenesis via nonhormonal pathways.4 Although many in vitro and preclin-

ical results suggest that soy isoflavones have antiproliferative effects,5 other studies suggest that they can promote the growth of breast cancer cells. Much of this research used isolated genistein. However, data from at least one animal study in which soy isoflavones promoted tumor growth suggests that this effect is not seen when whole soy is consumed instead of isoflavones alone.6 The effects of soy isoflavones in patients on tamoxifen therapy are similarly unclear; both synergistic and antagonistic interactions are reported.7 The exact nature and clinical implications of the estrogenic and antiestrogenic properties of isoflavones are not well understood.

Prevention To reduce the risk of breast cancer, epidemiologic evidence generally describes an inverse relationship between soy consumption and breast cancer diagnoses, although the observed degree of protective benefit varies depending on the patients studied. While some reviews and meta-analyses suggest that soy intake reduces breast cancer risk only modestly if at all,1,8 other studies have found that consumption at higher levels, such as in Asian diets, may have a more distinct protective effect.3 Asians traditionally consume a much higher concentration of isoflavones than their Western counterparts—daily consumption in Japan ranges from 26 to 54 mg, compared to 0.5 to 3 mg in the United States.9 Both dosage and timing of exposure to soy isoflavones appear relevant to their potential chemopreventive effect. Two recent meta-analyses2,3 found soy intake to be significantly associated with reduced risk of breast cancer in Asian but not Western popu-

ntegrative Oncology is guest edited by Barrie R. Cassileth, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial SloanKettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan-Kettering Cancer Center developed and maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective Barrie R. Cassileth, PhD and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 255 and growing number of entries offers health-care professional and patient versions, and entries are regularly updated with the latest research findings. lations, which may be explained by both higher soy intake among Asians and their tendency to consume soy from an early age. Several epidemiologic studies in fact suggest that diets rich in soy early in life and through puberty are associated with a decreased risk of breast cancer— and that introducing isoflavones into the diets of adult women may not have much impact on their cancer risk.10 This is generally consistent with animal studies, which suggest that soy intake is protective at specific stages of development but not at other points.11

Postdiagnosis Despite the inconsistent results of lab and animal studies and resulting concerns about whether soy might adversely affect breast cancer prognosis, there is a growing body of research in humans that supports soy consumption as safe. Three large epidemiologic studies published over the past few years, two in U.S. breast cancer survivors12,13 and one in Chinese survivors,14 found no adverse affects of soy consumption on outcome. Furthermore, they suggest that soy consumption at levels comparable to those among Asian populations does not detract from the benefits of tamoxifen therapy, and may even offer some protection against recurrence and cancer-related death. The largest of

Visit the About Herbs website at

www.mskcc.org/aboutherbs

these studies, published in the Journal of the American Medical Association in 2009, followed 5,033 breast cancer survivors for a median of 4 years.14 Based on these studies, the most recent guidelines from the American Cancer Society (ACS), released in April 2012, conclude that for breast cancer survivors, “current evidence does not suggest that consuming soy foods is likely to have adverse effects on risk of recurrence or survival.”15 It warns, however, that evidence “is more limited” with regard to isoflavone supplements. The ACS position gained further support just 1 month after its release from an even larger study of 9,514 U.S. and Chinese breast cancer survivors, which found a significantly reduced risk of cancer recurrence in patients who consumed at least 10�� mg of isoflavones (~3 g of soy protein) per day.16 The guideline does not mention a specific amount of soy that should be considered safe, unlike the previous ACS report on this topic in 2006, which specified a maximum of “three servings per day of soy foods.”17

Concluding Thoughts Despite some contradictory evidence in lab studies and animal models, a growing body of epidemiologic evidence suggests that soy food is safe

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Integrative Oncology to consume at moderate levels, and that clinicians need not advise against soy foods for breast cancer patients or survivors. Patients should avoid soy supplements, however, as these often provide very high doses of isoflavones and have not been well studied. More research and, ideally, human clinical trials, are needed to elucidate the optimal dosage and timing of exposure for maximizing the anticancer effects of soy while minimizing the risk of harm.

■

Disclosure: Dr. Cassileth and Mr. Yarett reported no potential conflicts of interest.

References 1. Trock BJ, Hilakivi-Clarke L, Clarke R: Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst 98:459-471, 2006. 2. Dong JY, Qin LQ: Soy isoflavones consumption and risk of breast cancer incidence or recurrence: A meta-analysis of prospective studies. Breast Cancer Res Treat 125:315-23, 2011. 3. Wu AH, Yu MC, Tseng CC, et al: Epidemiology of soy exposures and breast cancer risk. Br J Cancer 98:9-14, 2008. 4. Messina M, McCaskill-Stevens W, Lampe JW: Addressing the soy and breast cancer relationship: Review, commentary, and workshop proceedings. J Natl Cancer Inst 98:1275-1284, 2006. 5. Hilakivi-Clarke L, Andrade JE, Helferich W: Is soy consumption good or bad for the breast? J Nutr 140:2326S-2334S, 2010. 6. Allred CD, Allred KF, Ju YH, et al: Soy processing influences growth of estrogen-dependent breast cancer tumors. Carcinogenesis 25:1649-1657, 2004. 7. Taylor CK, Levy RM, Elliott JC, et al: The effect of genistein aglycone on cancer and cancer risk: A review of in vitro, preclinical, and clinical studies. Nutr Rev 67:398-415, 2009 8. Michels KB, Mohllajee AP, RosetBahmanyar E, et al: Diet and breast cancer: A review of the prospective observational studies. Cancer 109:2712-49, 2007 9. Nagata C: Factors to consider in the association between soy isoflavone intake and breast cancer risk. J Epidemiol 20:8389, 2010. 10. Messina M, Hilakivi-Clarke L: Early intake appears to be the key to the proposed protective effects of soy intake against breast cancer. Nutr Cancer 61:792728, 2009. 11. Warri A, Saarinen NM, Makela S, et al: The role of early life genistein exposures in modifying breast cancer risk. Br J Cancer 98:1485-1493, 2008. 12. Caan BJ, Natarajan L, Parker B, et al: Soy food consumption and breast can-

cer prognosis. Cancer Epidemiol Biomarkers Prev 20:854-858, 2011. 13. Guha N, Kwan ML, Quesenberry CP Jr, et al: Soy isoflavones and risk of cancer recurrence in a cohort of breast cancer survivors: The Life After Cancer Epidemiology study. Breast Cancer Res Treat 118:395-405, 2009. 14. Shu XO, Zheng Y, Cai H, et al: Soy

food intake and breast cancer survival. JAMA 302:2437-2443, 2009. 15. Rock CL, Doyle C, Demark-Wahnefried W, et al: Nutrition and physical activity guidelines for cancer survivors. CA Cancer J Clin. April 26, 2012 (early release online). 16. Nechuta SJ, Caan BJ, Chen WY, et al: Soy food intake after diagnosis of breast

cancer and survival: An in-depth analysis of combined evidence from cohort studies of US and Chinese women. Am J Clin Nutr 96:123-132, 2012. 17. Doyle C, Kushi LH, Byers T, et al: Nutrition and physical activity during and after cancer treatment: An American Cancer Society guide for informed choices. CA Cancer J Clin 56:323-353, 2006.

Read the Expert’s Guide to the

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

Available at:

or visit

drlacoutureskincare.com

About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

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Perspective

Reflections from the Old World continued from page 1

back in 1979. Now an Emeritus Professor, I find it fascinating to reflect on the extraordinary changes that have taken place over the past 3 decades. Here and in future columns, I will highlight areas that pose particular difficulties in modern practice in contrast to situations we dealt with in times gone by. These reflections may offer a little guidance to readers who are still in training, but we can all learn from history.

The Importance of Time Most of us from that first generation of medical oncologists in Europe did some of our training in the United States—in my case, at NCI and the University of Chicago. We have naturally maintained an interest in comparing practices and attitudes from both sides of the Atlantic. One thing that has changed significantly in both places is the use of our time spent with patients. In establishing medical oncology in Edinburgh in the early 1980s, I was fortunate to be introducing the new discipline to complement already excellent departments of surgery, radiation therapy, and pathology. What was new was to show what physicians (that is, internal medicine specialists) could add to the overall care of patients. Then, as now, surgeons and radiation oncologists were very busy with large outpatient clinics and bed occupancy pressures. One of the most valuable contributions medical oncologists could make was to spend time with the patient—time to talk, time to explain, and above all, time to listen.

Apart from the treatment of lymphomas, leukemias, and pediatric tumors, we had so little in our therapeutic armamentarium that we had to rely on the basic physician skills—taking a history, examining the patient, confirming the diagnosis, and formulating a management plan. The latter essentially focused on symptom control and, importantly, emotional support for both patients and their families.

New Priorities What I fear is that now, with the wealth of technology for achieving a more accurate diagnosis, for assigning patients to different prognostic and therapeutic subsets, and for making therapeutic choices, our time with patients is overwhelmed by the need to give out

likely prognosis, occasionally influenced by treatment, which was very often experimental and therefore associated with an uncertain outcome. We became comfortable in talking about death in all its aspects. Now, we are expected to obtain detailed family and lifestyle histories, explain the need for staging and other pathologic procedures to fully characterize the disease in an individual, to explain complex multimodality treatments, to offer likely prognosis, and much less often, to open up conversations about inevitable progression and life expectancy. Against the background of severe anxiety that most new patients express, to achieve all of this in a first consultation is virtually impossible. To make matters worse, in many institutions, fi-

Our patients need us to listen to them, to empathize in a professional way, and thereby to personalize their experience. —John F. Smyth, MD

information, leaving little time to answer questions or to just listen. Listening is the only way that you can ever really understand how an individual patient is coping with a diagnosis and its consequences. Never is this lack of time more obvious than when you first meet a patient. Whether this occurs on a hospital ward or, more usually, in a clinic, the contrast between what we set out to achieve 30 years ago and what is expected of us now is daunting. Then, our major role was to explain the cause of symptoms and outline the

nancial and other considerations mandate a fixed, almost certainly inadequate time to interview patients.

Strategies for Coping So what, if any, are the lessons, and how should we cope with this new time pressure? Clearly, if new patients require significant further workup before you can select management options, the amount of detailed information that you need to convey at the first meeting is limited and can be deferred. If the situation is more obvious to you and treatment options

are limited, then you will be expected to get through as much of the agenda as you can. In some scenarios, it may be appropriate (or essential) that you delegate areas of explanation to colleagues, especially nurses familiar with your practice. Of course, innumerable written materials are available, but these should never substitute for human conversation. The contemporary situation is often made worse when patients come armed with information they have gathered themselves, usually from the Internet. In my experience, this self-acquired information is often erroneous with regard to the specific situation, but valuable time is consumed in unpicking the patient’s anticipation of what is relevant, while trying to maintain his confidence in you as the expert and his oncologist.

Time for Listening Time is very precious. The first consultation is one of the most important occasions your patient will ever experience. It wasn’t necessarily any easier in the old days—time was on our side, but where we could listen and explain, we had less on the positive, hopeful side to convey. The challenge now is to decide how best to apportion whatever time is available while, importantly, leaving some of that time for listening. Our patients need us to listen to them, to empathize in a professional way, and thereby to personalize their experience. Finding time to explain research, which has to involve the concept of uncertainty, adds another tier to the problem of time allocation—but I will leave that for another column.

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Disclosure: Dr. Smyth reported no potential conflicts of interest.

The ASCO Post Wants to Hear from You We encourage readers to share their opinions and thoughts on issues of interest to the oncology community. Write to The ASCO Post at editor@ASCOPost.com

www.ASCOPost.com

Phone: 631.692.0800 Fax: 631.692.0805

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

FOR ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML IN CHRONIC PHASE (CP)

Choose TASIGNA first

TASIGNA provides superior MMR* rates vs imatinib at 12 months and <1% progression to AP/BC1† (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], P<0.0001)1 *Major molecular response (MMR)=≥3 logs below baseline (≤0.1% international scale [IS]).1 †

Progression to accelerated phase or blast crisis (AP/BC) includes patients with clonal evolution and CML-related death.2

INDICATION AND BOXED WARNING TASIGNA (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of TASIGNA is based on major molecular response and cytogenetic response rates. The study is ongoing and further data will be required to determine long-term outcome. WARNING: QT PROLONGATION AND SUDDEN DEATHS ■ TASIGNA prolongs the QT interval. Prior to TASIGNA administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies. Obtain ECGs to monitor the QTc at baseline, 7 days after initiation, and periodically thereafter, and follow any dose adjustments ■ Sudden deaths have been reported in patients receiving nilotinib. Do not administer TASIGNA to patients with hypokalemia, hypomagnesemia, or long QT syndrome ■ Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors ■ Patients should avoid food 2 hours before and 1 hour after taking dose Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on the following pages.

IN THE TREATMENT OF ADULT PATIENTS NEWLY DIAGNOSED WITH Ph+ CML-CP Less than 1% of TASIGNA patients progressed to AP/BC1 Progression to AP/BC at 24 months

0.7%

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17 6%

TASIGNA 300 mg bid (n=282)

Imatinib 400 mg qd (n=283)

TASIGNA

Imatinib

(n=282)

(n=283)

TASIGNA significantly improved the rate of MMR compared with imatinib at 12 months—the primary end point of the ENESTnd (44% [95% CI, 38%-50%] vs 22% [95% CI, 18%-28%], 300trial mg bid 400 P<0.0001) mg qd1

ENESTnd study design: A randomized, controlled, open-label, multicenter Phase III trial of 846 patients with newly diagnosed Ph+ CML-CP. Patients were randomized to receive either TASIGNA 400 mg bid (n=281), TASIGNA 300 mg bid (n=282), or imatinib 400 mg qd (n=283). The daily dose of imatinib could be escalated to 800 mg (400 mg bid), but no dose escalation was permitted with TASIGNA. A centralized laboratory was used for RQ-PCR testing. The primary end point was MMR at 12 months.1,2

IMPORTANT SAFETY INFORMATION ■

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Treatment with TASIGNA can cause Grade 3/4 thrombocytopenia, neutropenia, and anemia. Complete blood counts should be performed every 2 weeks for the first 2 months and then monthly thereafter

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Caution is recommended in patients with a history of pancreatitis The use of TASIGNA may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase

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TASIGNA can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia (see Boxed WARNING) ■ ■

Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080

The concomitant use of strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to, amiodarone, disopyramide, procainamide, quinidine, and sotalol) and other drugs that may prolong the QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, and pimozide) should be avoided. Grapefruit products should also be avoided The concomitant use of strong CYP3A4 inducers should be avoided (including, but not limited to, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s wort) TASIGNA must not be taken with food TASIGNA exposure is increased in patients with impaired hepatic function 3/12

AM7-1033710

TASIGNA maintained the difference in MMR rates through 24 months1,2 At 12 months

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Cases of tumor lysis syndrome have been reported in TASIGNA-treated patients with resistant or intolerant CML. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with TASIGNA The exposure of TASIGNA is reduced in patients with total gastrectomy Since the capsules contain lactose, TASIGNA is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactose-containing products, or of glucose-galactose malabsorption Women of childbearing potential should avoid becoming pregnant while taking TASIGNA and should be advised of the potential hazard to the fetus if they do. The safety and effectiveness of TASIGNA in pediatric patients have not been established

Please see Important Safety Information, including Boxed WARNING, and brief summary of Prescribing Information on adjacent pages.

At 24 months

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In newly diagnosed Ph+ CML-chronic phase, the most commonly reported nonhematologic adverse drug reactions (>10%) were rash, pruritus, headache, nausea, fatigue, and myalgia TASIGNA may need to be temporarily withheld and/or dose reduced for QT prolongation, hematologic toxicities that are not related to underlying leukemia, clinically significant moderate or severe nonhematologic toxicities, laboratory abnormalities, or concomitant use of strong CYP3A4 inhibitors References: 1. TASIGNA® (nilotinib) capsules prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2011. 2. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011;12(9):841-851.

Tasigna® (nilotinib) Capsules Initial U.S. Approval: 2007 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: QT PROLONGATION AND SUDDEN DEATHS • Tasigna prolongs the QT interval. Prior to Tasigna administration and periodically, monitor for hypokalemia or hypomagnesemia and correct deficiencies (5.2). Obtain ECGs to monitor the QTc at baseline, seven days after initiation, and periodically thereafter, and follow any dose adjustments (5.2, 5.3, 5.6, 5.12). • Sudden deaths have been reported in patients receiving nilotinib (5.3). Do not administer Tasigna to patients with hypokalemia, hypomagnesemia, or long QT syndrome (4, 5.2). • Avoid use of concomitant drugs known to prolong the QT interval and strong CYP3A4 inhibitors (5.7). • Patients should avoid food 2 hours before and 1 hour after taking dose (5.8). 1 INDICATIONS AND USAGE 1.1 Newly Diagnosed Ph+ CML-CP Tasigna (nilotinib) is indicated for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of Tasigna is based on major molecular response and cytogenetic response rates [see Clinical Studies (14.1) in the full prescribing information]. The study is ongoing and further data will be required to determine long-term outcome. 1.2 Resistant or Intolerant Ph+ CML-CP and CML-AP Tasigna is indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML) in adult patients resistant or intolerant to prior therapy that included imatinib. The effectiveness of Tasigna is based on hematologic and cytogenetic response rates [see Clinical Studies (14.2) in the full prescribing information]. 4 CONTRAINDICATIONS Do not use in patients with hypokalemia, hypomagnesemia, or long QT syndrome [see Boxed Warning]. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with Tasigna can cause Grade 3/4 thrombocytopenia, neutropenia and anemia. Perform complete blood counts every two weeks for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Tasigna temporarily or dose reduction [see Dosage and Administration (2.2) in the full prescribing information]. 5.2 QT Prolongation Tasigna has been shown to prolong cardiac ventricular repolarization as measured by the QT interval on the surface ECG in a concentration-dependent manner [see Adverse Reactions (6.1), Clinical Pharmacology (12.4) in the full prescribing information]. Prolongation of the QT interval can result in a type of ventricular tachycardia called torsade de pointes, which may result in syncope, seizure, and/or death. ECGs should be performed at baseline, seven days after initiation, periodically as clinically indicated and following dose adjustments [see Warnings and Precautions (5.12)]. Tasigna should not be used in patients who have hypokalemia, hypomagnesemia or long QT syndrome. Hypokalemia or hypomagnesemia must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. Significant prolongation of the QT interval may occur when Tasigna is inappropriately taken with food and/or strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT. Therefore, co-administration with food must be avoided and concomitant use with strong CYP3A4 inhibitors and/or medicinal products with a known potential to prolong QT should be avoided [see Warnings and Precautions (5.7, 5.8)]. The presence of hypokalemia and hypomagnesemia may further enhance this effect [see Warnings and Precautions (5.6, 5.12)]. 5.3 Sudden Deaths Sudden deaths have been reported in patients with CML treated with nilotinib in clinical studies (n= 5,661; 0.3%). The relative early occurrence of some of these deaths relative to the initiation of nilotinib suggests the possibility that ventricular repolarization abnormalities may have contributed to their occurrence. 5.4 Elevated Serum Lipase The use of Tasigna can cause increases in serum lipase. Caution is recommended in patients with a previous history of pancreatitis. If lipase elevations are accompanied by abdominal symptoms, interrupt dosing and consider appropriate diagnostics to exclude pancreatitis. Test serum lipase levels monthly or as clinically indicated. 5.5 Hepatotoxicity The use of Tasigna may result in elevations in bilirubin, AST/ALT, and alkaline phosphatase. Hepatic function tests should be checked monthly or as clinically indicated [see Warnings and Precautions (5.12)]. 5.6 Electrolyte Abnormalities The use of Tasigna can cause hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia. Electrolyte abnormalities must be corrected prior to initiating Tasigna and these electrolytes should be monitored periodically during therapy [see Warnings and Precautions (5.12)]. 5.7 Drug Interactions The administration of Tasigna with agents that are strong CYP3A4 inhibitors or anti-arrhythmic drugs (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) and other drugs that may prolong QT interval (including, but not limited to chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin and pimozide) should be avoided. Should treatment with any of these agents be required, it is recommended that therapy with Tasigna be interrupted. If interruption of treatment with Tasigna is not possible, patients who require treatment with a drug that prolongs QT or strongly inhibits CYP3A4 should be closely monitored for prolongation of the QT interval [see Boxed Warning, Dosage and Administration (2.2), Drug Interactions (7.2) in the full prescribing information]. 5.8 Food Effects The bioavailability of nilotinib is increased with food. Tasigna must not be taken with food. No food should be taken at least 2 hours before and at least one hour after the dose is taken. Grapefruit products and other foods that are known to inhibit CYP3A4 should be avoided [see Boxed Warning, Drug Interactions (7.2) and Clinical Pharmacology (12.3) in the full prescribing information]. 5.9 Hepatic Impairment Nilotinib exposure is increased in patients with impaired hepatic function. A lower starting dose is recommended for patients with mild to severe hepatic impairment (at baseline) and QT interval should be monitored closely [see Dosage and Administration (2.2) and Use in Specific Populations (8.7) in the full prescribing information]. 5.10 Tumor Lysis Syndrome Cases of tumor lysis syndrome have been reported in Tasigna treated patients with resistant or intolerant CML. Malignant disease progression, high WBC counts and/or dehydration were present in the majority of these cases. Due to potential for tumor lysis syndrome, maintain adequate hydration and correct uric acid levels prior to initiating therapy with Tasigna. 5.11 Total Gastrectomy The exposure of nilotinib is reduced in patients with total gastrectomy. More frequent follow-up of these patients should be considered. Dose increase or alternative therapy may be considered in patients with total gastrectomy [see Clinical Pharmacology 12.3) in the full prescribing information]. 5.12 Lactose Since the capsules contain lactose, Tasigna is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency with a severe degree of intolerance to lactosecontaining products or of glucose-galactose malabsorption.

5.13 Monitoring Laboratory Tests Complete blood counts should be performed every two weeks for the first two months and then monthly thereafter. Chemistry panels, including the lipid profile, should be checked periodically. ECGs should be obtained at baseline, seven days after initiation and periodically thereafter, as well as following dose adjustments [see Warnings and Precautions (5.2)]. Laboratory monitoring for patients receiving Tasigna may need to be performed more or less frequently at the physician’s discretion. 5.14 Use in Pregnancy There are no adequate and well controlled studies of Tasigna in pregnant women. However, Tasigna may cause fetal harm when administered to a pregnant woman. Nilotinib caused embryo-fetal toxicities in animals at maternal exposures that were lower than the expected human exposure at the recommended doses of nilotinib. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should avoid becoming pregnant while taking Tasigna [see Use in Specific Populations (8.1) in the full prescribing information]. 6 ADVERSE REACTIONS The following serious adverse reactions can occur with Tasigna and are discussed in greater detail in other sections of the package insert [see Boxed Warning, Warnings and Precautions (5)]. Myelosuppression [see Warnings and Precautions (5.1)] QT prolongation [see Boxed Warning, Warnings and Precautions (5.2)] Sudden deaths [see Boxed Warning, Warnings and Precautions (5.3)] Elevated serum lipase [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Electrolyte abnormalities [see Boxed Warning, Warnings and Precautions (5.6)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Newly diagnosed Ph+ CML-CP The data below reflect exposure to Tasigna from a randomized trial in newly diagnosed patients with Ph+ CML in chronic phase treated at the recommended dose of 300 mg twice daily (n=279). The median time on treatment in the nilotinib 300 mg twice daily group was 25 months (range 0.1 – 35.4 months). The median actual dose intensity was 594 mg/day in the nilotinib 300 mg twice daily group. The most common (>10%) non-hematologic adverse drug reactions were rash, pruritus, headache, nausea, fatigue and myalgia. Upper abdominal pain, alopecia, constipation, diarrhea, dry skin, muscle spasms, arthralgia, abdominal pain, peripheral edema, vomiting and asthenia were observed less commonly (≤10% and >5%) and have been of mild to moderate severity, manageable and generally did not require dose reduction. Pleural and pericardial effusions occurred in 1% of patients. Gastrointestinal hemorrhage was reported in 2.5% of patients. Increase in QTcF >60 msec from baseline was observed in 1 patient (0.4%) in the 300 mg twice daily treatment group. No patient had an absolute QTcF of >500 msec while on study drug. The most common hematologic adverse drug reactions (all grades) were myelosuppression including: thrombocytopenia (17%), neutropenia (15%) and anemia (7%). See Table 7 for Grade 3/4 laboratory abnormalities. Discontinuation due to adverse events regardless of causality was observed in 9% of patients. Resistant or intolerant Ph+ CML-CP and CML-AP In the single open-label multicenter clinical trial, a total of 458 patients with Ph+ CML-CP and CML-AP resistant to or intolerant to at least one prior therapy including imatinib were treated (CML-CP=321; CML-AP=137) at the recommended dose of 400 mg twice daily. The median duration of exposure in days for CML-CP and CML-AP patients is 561 (range 1-1096) and 264 (range 2-1160), respectively. The median dose intensity for patients with CML-CP and CML-AP is 789 mg/day (range 151–1110) and 780 mg/day (range 150-1149), respectively and corresponded to the planned 400 mg twice daily dosing. The median cumulative duration in days of dose interruptions for the CML-CP patients was 20 (range 1-345), and the median duration in days of dose interruptions for the CML-AP patients was 23 (range 1–234). In patients with CML-CP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus, nausea, fatigue, headache, constipation, diarrhea, vomiting and myalgia. The common serious drug-related adverse reactions (≥1% and <10%) were thrombocytopenia, neutropenia and anemia. In patients with CML-AP, the most commonly reported non-hematologic adverse drug reactions (≥10%) were rash, pruritus and fatigue. The common serious adverse drug reactions (≥1% and <10%) were thrombocytopenia, neutropenia, febrile neutropenia, pneumonia, leukopenia, intracranial hemorrhage, elevated lipase and pyrexia. Sudden deaths and QT prolongation were reported. The maximum mean QTcF change from baseline at steady-state was 10 msec. Increase in QTcF >60 msec from baseline was observed in 4.1% of the patients and QTcF of >500 msec was observed in 4 patients (<1%) [see Boxed Warning, Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.4) in the full prescribing information]. Discontinuation due to drug-related adverse reactions was observed in 16% of CML-CP and 10% of CML-AP patients. Most Frequently Reported Adverse Reactions Tables 5 and 6 show the percentage of patients experiencing non-hematologic adverse drug reactions (excluding laboratory abnormalities) regardless of relationship to study drug. Adverse reactions reported in greater than 10% of patients who received at least one dose of Tasigna are listed. Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Skin and subcutaneous Rash 37 18 <1 2 tissue disorders Pruritus 20 7 <1 0 Alopecia 11 6 0 0 Periorbital edema <1 15 0 0 Gastrointestinal Nausea 20 39 1 1 disorders Constipation 17 6 0 0 Diarrhea 14 40 <1 2 Vomiting 11 24 0 <1 Abdominal pain upper 15 11 <1 <1 Abdominal pain 14 10 1 0 (continued)

Table 5: Most Frequently Reported Non-hematologic Adverse Reactions (Regardless of Relationship to Study Drug) in Patients with Newly Diagnosed Ph+ CML-CP (≥10% in Tasigna 300 mg twice daily or Imatinib 400 mg once daily groups)a Patients with Newly Diagnosed Ph+ CML-CP TASIGNA Imatinib TASIGNA Imatinib 300 mg 400 mg 300 mg 400 mg twice daily once daily twice daily once daily N=279 N=280 N=279 N=280 Body System and Preferred Term All Grades (%) CTC Gradesb 3 / 4 (%) Nervous system Headache 30 18 3 <1 disorders General disorders Fatigue 21 16 1 1 and administration Pyrexia 11 12 <1 0 site conditions Asthenia 11 10 <1 0 Edema, peripheral 8 18 0 0 Face edema <1 11 0 <1 Musculoskeletal and Myalgia 14 18 <1 0 connective tissue Arthralgia 17 13 <1 <1 disorders Muscle spasms 11 31 0 <1 Pain in extremity 11 13 <1 <1 Back pain 14 11 <1 1 Respiratory, thoracic Cough 14 9 0 0 and mediastinal disorders Infections and Nasopharyngitis 22 17 0 0 infestations Upper respiratory tract infection 14 10 <1 0 Eye disorders Eyelid edema 1 16 0 <1 aExcluding laboratory abnormalities bNCI Common Terminology Criteria for Adverse Events, Version 3.0 Table 6: Most Frequently Reported Non-hematologic Adverse Reactions in Patients with Resistant or Intolerant Ph+ CML Receiving Tasigna 400 mg Twice Daily (Regardless of Relationship to Study Drug) (≥10% in any Group)a CML-CP CML-AP N=321 N=137 All CTC All CTC Grades Gradesb Grades Gradesb Body System and Preferred Term (%) 3 / 4 (%) (%) 3 / 4 (%) Skin and subcutaneous Rash 36 2 29 0 tissue disorders Pruritus 32 <1 20 0 Night sweat 12 <1 27 0 Alopecia 11 0 12 0 Gastrointestinal Nausea 37 1 22 <1 disorders Constipation 26 <1 19 0 Diarrhea 28 3 24 2 Vomiting 29 <1 13 0 Abdominal pain 15 2 16 3 Abdominal pain upper 14 <1 12 <1 Dyspepsia 10 <1 4 0 Nervous system Headache 35 2 20 1 disorders General disorders and administration site conditions

Fatigue Pyrexia Asthenia Edema, peripheral Myalgia

32 22 16 15 19

3 <1 0 <1 2

23 28 14 12 16

<1 2 1 0 <1

Musculoskeletal and connective tissue disorders

Arthralgia Muscle spasms Bone pain Pain in extremity Back pain Musculoskeletal pain

26 13 14 20 17 11

2 <1 <1 2 2 <1

16 15 15 18 15 12

0 0 2 1 <1 1

Respiratory, thoracic and mediastinal disorders

Cough Dyspnea Oropharyngeal pain

27 15 11

<1 2 0

18 9 7

0 2 0

Infections and infestations

Nasopharyngitis Upper respiratory tract infection

Metabolism and nutritional disorders

Anorexia

Psychiatric disorders

Insomnia

Vascular disorders

Hypertension

aExcluding bNCI

laboratory abnormalities Common Terminology Criteria for Adverse Events, Version 3.0

Laboratory Abnormalities Table 7 shows the percentage of patients experiencing treatment-emergent Grade 3/4 laboratory abnormalities in patients who received at least one dose of Tasigna.

Table 7: Percent Incidence of Clinically Relevant Grade 3/4* Laboratory Abnormalities Patient Population Resistant or Intolerant Ph+ Newly Diagnosed Ph+ CML-CP

Hematologic Parameters Thrombocytopenia Neutropenia Anemia Biochemistry Parameters Elevated lipase Hyperglycemia Hypophosphatemia Elevated bilirubin (total) Elevated SGPT (ALT) Hyperkalemia Hyponatremia Hypokalemia Elevated SGOT (AST) Decreased albumin Hypocalcemia Elevated alkaline phosphatase Elevated creatinine

CML-CP

CML-AP

TASIGNA 300 mg twice daily N=279 (%)

Imatinib 400 mg once daily N=280 (%)

TASIGNA 400 mg twice daily N=321 (%)

TASIGNA 400 mg twice daily N=137 (%)

10 12 4

9 21 5

301 312 11

423 424 27

7 6 5 4 4 2 1 <1 1 0 <1

3 0 8 <1 3 1 <1 2 1 0 0

18 12 17 7 4 6 7 2 3 4 2

18 6 15 9 4 4 7 9 2 3 5

0 0

<1 <1

1 <1

*NCI Common Terminology Criteria for Adverse Events, version 3.0 1CML-CP: Thrombocytopenia: 12% were grade 3, 18% were grade 4 2CML-CP: Neutropenia: 16% were grade 3, 15% were grade 4 3CML-AP: Thrombocytopenia: 11% were grade 3, 32% were grade 4 4CML-AP: Neutropenia: 16% were grade 3, 26% were grade 4 6.2 Additional Data from Clinical Trials The following adverse drug reactions were reported in patients in the Tasigna clinical studies at the recommended doses. These adverse drug reactions are ranked under a heading of frequency, the most frequent first using the following convention: common (≥1% and <10%), uncommon (≥0.1% and <1%), and unknown frequency (single events). For adverse drug reactions listed under “Investigations”, very common events (≥10%), which were not included in Tables 5 and 6, are also reported. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Infections and Infestations: Common: folliculitis. Uncommon: upper respiratory tract infection (including nasopharyngitis, pharyngitis, rhinitis), pneumonia, bronchitis, urinary tract infection, candidiasis (including oral candidiasis), gastroenteritis. Unknown frequency: sepsis, subcutaneous abscess, anal abscess, furuncle, tinea pedis. Neoplasms Benign, Malignant and Unspecified: Common: Skin papilloma. Unknown frequency: oral papilloma. Blood and Lymphatic System Disorders: Common: febrile neutropenia, pancytopenia, lymphopenia. Unknown frequency: thrombocythaemia, leukocytosis, eosinophilia. Immune System Disorders: Unknown frequency: hypersensitivity. Endocrine Disorders: Uncommon: hyperthyroidism, hypothyroidism. Unknown frequency: hyperparathyroidism secondary, thyroiditis. Metabolism and Nutrition Disorders: Common: electrolyte imbalance (including hypomagnesemia, hyperkalemia, hypokalemia, hyponatremia, hypocalcemia, hypophosphatemia, hypercalcemia, hyperphosphatemia), diabetes mellitus, hyperglycemia, hypercholesterolemia, hyperlipidemia, decreased appetite. Uncommon: dehydration, increased appetite. Unknown frequency: hyperuricemia, gout, hypoglycemia, dyslipidemia. Psychiatric Disorders: Common: depression, insomnia, anxiety. Unknown frequency: disorientation, confusional state, amnesia, dysphoria. Nervous System Disorders: Common: dizziness, peripheral neuropathy, hypoesthesia, paresthesia. Uncommon: intracranial hemorrhage, migraine, loss of consciousness (including syncope), tremor, disturbance in attention, hyperesthesia. Unknown frequency: brain edema, optic neuritis, lethargy, dysesthesia, restless legs syndrome. Eye Disorders: Common: eye hemorrhage, periorbital edema, eye pruritus, conjunctivitis, dry eye. Uncommon: vision impairment, vision blurred, visual acuity reduced, photopsia, hyperemia (scleral, conjunctival, ocular), eye irritation. Unknown frequency: papilloedema, diplopia, photophobia, eye swelling, blepharitis, eye pain, chorioretinopathy, conjunctival hemorrhage, conjunctivitis allergic, ocular surface disease. Ear and Labyrinth Disorders: Common: vertigo. Unknown frequency: hearing impaired, ear pain, tinnitus. Cardiac Disorders: Common: angina pectoris, arrhythmia (including atrioventricular block, cardiac flutter, extrasystoles, atrial fibrillation, tachycardia, bradycardia), palpitations, electrocardiogram QT prolonged. Uncommon: cardiac failure, pericardial effusion, coronary artery disease, cyanosis, cardiac murmur. Unknown frequency: myocardial infarction, ventricular dysfunction, pericarditis, ejection fraction decrease. Vascular Disorders: Common: hypertension, flushing. Uncommon: hypertensive crisis, peripheral arterial occlusive disease, hematoma. Unknown frequency: shock hemorrhagic, hypotension, thrombosis. Respiratory, Thoracic and Mediastinal Disorders: Common: dyspnea, dyspnea exertional, epistaxis, cough, dysphonia. Uncommon: pulmonary edema, pleural effusion, interstitial lung disease, pleuritic pain, pleurisy, pharyngolaryngeal pain, throat irritation. Unknown frequency: pulmonary hypertension, wheezing.

Gastrointestinal Disorders: Common: pancreatitis, abdominal discomfort, abdominal distension, dyspepsia, dysgeusia, flatulence. Uncommon: gastrointestinal hemorrhage, melena, mouth ulceration, gastroesophageal reflux, stomatitis, esophageal pain, dry mouth. Unknown frequency: gastrointestinal ulcer perforation, retroperitoneal hemorrhage, hematemesis, gastric ulcer, esophagitis ulcerative, subileus, gastritis, enterocolitis, hemorrhoids, hiatus hernia, rectal hemorrhage, gingivitis. Hepatobiliary Disorders: Common: hepatic function abnormal. Uncommon: hepatotoxicity, hepatitis, jaundice. Unknown frequency: cholestasis, hepatomegaly. Skin and Subcutaneous Tissue Disorders: Common: night sweats, eczema, urticaria, erythema, hyperhidrosis, contusion, acne, dermatitis (including allergic and acneiform), dry skin. Uncommon: exfoliative rash, drug eruption, pain of skin, ecchymosis, swelling of face. Unknown frequency: erythema multiforme, erythema nodosum, skin ulcer, palmar-plantar erythrodysesthesia syndrome, petechiae, photosensitivity, blister, dermal cyst, sebaceous hyperplasia, skin atrophy, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy. Musculoskeletal and Connective Tissue Disorders: Common: bone pain, musculoskeletal chest pain, musculoskeletal pain, flank pain. Uncommon: musculoskeletal stiffness, muscular weakness, joint swelling. Unknown frequency: arthritis. Renal and Urinary Disorders: Common: pollakiuria. Uncommon: dysuria, micturition urgency, nocturia. Unknown frequency: renal failure, hematuria, urinary incontinence, chromaturia. Reproductive System and Breast Disorders: Uncommon: breast pain, gynecomastia, erectile dysfunction. Unknown frequency: breast induration, menorrhagia, nipple swelling. General Disorders and Administration Site Conditions: Common: pyrexia, chest pain (including noncardiac chest pain), pain (including neck pain and back pain), chest discomfort, malaise. Uncommon: face edema, gravitational edema, influenza-like illness, chills, feeling body temperature change (including feeling hot, feeling cold). Unknown frequency: localized edema.

Investigations: Common: hemoglobin decreased, blood amylase increased, gamma-glutamyltransferase increased, blood creatinine phosphokinase increased, blood alkaline phosphatase increased, weight decreased, weight increased. Uncommon: blood lactate dehydrogenase increased, blood urea increased. Unknown frequency: troponin increased, blood bilirubin unconjugated increased, blood insulin increased, lipoprotein increased (including very low density and high density), blood parathyroid hormone increased. 10 OVERDOSAGE Overdose with nilotinib has been reported, where an unspecified number of Tasigna capsules were ingested in combination with alcohol and other drugs. Events included neutropenia, vomiting, and drowsiness. In the event of overdose, the patient should be observed and appropriate supportive treatment given. Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ÂŠ Novartis T2011-126 November 2011

ASCOPost.com | JULY 15, 2012

PAGE 71

Journal Spotlight Supportive Care

Early Access to Palliative/Supportive Care vs Usual Care Improves Pain Management By Matthew Stenger

any cancer patients remain undertreated for pain despite availability of guidelines and educational efforts to improve pain treatment. In a recent Annals of Oncology article, Bandieri and colleagues from the Italian Epidemiologia Clinico-Assistenziale del Dolore in Ospedale (ECAD-O) group report a significant improvement in pain treatment in patients given access to an early palliative/supportive intervention compared with patients receiving usual care from a primary specialist.1

Study Details This ECAD-O survey was a crosssectional observational study involving 1,450 cancer patients seen in 32 Italian hospitals from 2007 to 2010. Among these, 602 patients constituted a standard care group treated in accordance with standard clinical practice by primary specialists who oversaw primary disease assessment and treatment and supportive/palliative care needs. A total of 848 patients in the early palliative/supportive care group were seen at the Oncology and Palliative Care Unit of the Local Health Unit in Modena, where an integrative early palliative/supportive care approach been established. Patients receiving early palliative/ supportive care met a trained team including 2 physicians, 2 nurses, a psychologist, and volunteers soon after diagnosis of cancer and received supportive care from the team concurrently with primary oncology care provided by their oncologist. The team followed each patient on a regular basis (eg, at every scheduled visit or every 3 to 4 weeks) in conjunction with the primary oncologist, and the team and oncologists met weekly to discuss patient issues. Pain intensity during the previous 24 hours was assessed by a numeric scale during an interview with a pharmacist not directly involved with patients’ care. Data on type of analgesic drug prescribed and administered within the previous 24 hours for each patient was collected from medical records. Patients in both groups had a median age of 65 years. More patients in the early palliative/supportive care group were male (59% vs 52%, P = .010) and had metastatic disease (89% vs 71%, P < .001). All patients in the early palliative/ supportive care group were recruited

from oncology wards, whereas 43% of patients in the standard care group were from nononcology (internal medicine) wards. More than 90% of all patients were receiving analgesic treatment around the clock, but the proportion of patients receiving analgesia on an asneeded basis was greater in the standard care group (4.0% vs 0.1%).

Palliative/Supportive Care and Pain Management ■■ In an Italian study of 1,450 patients with cancer, more standard care

patients received nonopioids and weak opioids, and more early palliative/ supportive care patients received strong opioids, primarily morphine.

■■ Significantly more early palliative/supportive care patients had no pain, and significantly fewer had severe pain.

■■ On multivariate analysis, early palliative/supportive care was associated with a 31% reduction in risk for severe pain.

Opioid Use Nonopioid use (9.5% vs 2.0%, P < .001) and weak opioid use (27.7% vs 18.4%, P < .001) were significantly more common in standard care patients, whereas strong opioid use (62.8% vs 79.6%, P < .001) was significantly less common. Among 378 standard care patients and 675 early palliative/supportive care patients receiving strong opioids, transdermal fentanyl (Duragesic) use was significantly more common in standard care patients (40.8% vs 6.7%, P < .001), whereas morphine use (25.1% vs 53.6%,

male gender (25% risk reduction, RR = 0.75, P = .002, vs female gender), and age (RR = 0.99, P = .016); factors not significantly associated with severe pain were hospital ward (oncology vs nononcology), metastatic disease, and type of analgesic therapy (weak or strong opioids vs nonopioids). On multivariate analysis, only early palliative/supportive care (31% risk reduction, RR = 0.69, P = .045) and male gender (24% risk reduction, RR = 0.76, P = .003) were independent predictors of reduced

The most striking finding from our study is that the risk of severe pain is remarkably reduced when an integrated care model is used compared with a model of routine care based on primary specialist alone. However, it is clear that the control rate of cancer pain needs to be improved. P < .001) and oxycodone use (20.1% vs 34.2%, P < .001) were significantly less common. Use of ‘other’ strong opioids was more common in the standard care group (14.0% vs 5.5%, P < .001).

Pain Control Assessment of pain intensity during the previous 24 hours showed that significantly more early palliative/supportive care patients reported no pain (27.1% vs 16.9%, P < .001) and mild pain (32.9% vs 23.7%, P < .001) and significantly fewer patients receiving early palliative/supportive care reported moderate pain (22.6% vs 27.9%, P = .022) and severe pain (17.3% vs 31.4%, P < .001). On univariate analysis, factors significantly associated with risk of severe pain were early palliative/supportive care (31% reduction in risk, relative risk [RR] = 0.69, P = .037, vs standard care),

risk for severe pain after adjustment for the other variables. The authors note that their findings indicate that current recommendations regarding analgesia in cancer patients appear not to be rigorously followed in standard care. For moderate to severe pain, oral formulations, and particularly oral morphine, continue to be recommended. Nonopioids or weak opioids were more frequently used in standard care patients compared with early palliative/supportive care patients in this study, and the most frequently used strong opioid in standard care patients was transdermal fentanyl, a drug infrequently used in the early palliative/supportive care group.

Study Ramifications The authors also note that palliative medicine has largely focused on end-oflife care, with few patients gaining early

access to such care. In this regard, they point out that a recent randomized controlled trial showed that patients with advanced non–small cell lung cancer and access to a specialist palliative care team had reduced depression, improved quality of life, and improved survival compared with patients receiving usual care alone.2 The current observational study both confirms that an early palliative/ supportive care approach can be integrated into hospital oncology practice and suggests that it can improve pain treatment. A randomized controlled trial is needed to confirm the findings regarding improved treatment of pain. The investigators concluded, “Clearly, the most striking finding from our study is that the risk of severe pain is remarkably reduced when an integrated care model is used compared with a model of routine care based on primary specialist alone. However, it is clear that the control rate of cancer pain needs to be improved: despite the integrated care model, an unacceptable high percentage (17%) of patients still [suffer] with severe intensity. Thus, both pharmacological (such as therapy for breakthrough cancer pain) and nonpharmacological (such as psychosocial and spiritual) interventions should be considered and become the object of extensive research in the near future….”

■

Disclosure: The authors of this article published in Annals of Oncology reported no potential conflicts of interest.

References 1. Bandieri E, Sichetti D, Romero M, et al: Impact of early access to a palliative/supportive care intervention on pain management in patients with cancer. Ann Oncol. May 6, 2012 (early release online). 2. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 363:733-742, 2010.

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Patient’s Corner

My Breast Cancer Had Been Coming for Years

Since my diagnosis, my perspective on life has changed. I’m not so afraid anymore. By Sheri Kay, as told to Jo Cavallo for the test results, I wasn’t surprised when he said that the test was positive. I think I knew for years that this day would come, but I was scared.

Living as a Cancer Survivor

Sheri Kay

’ve never had a normal mammogram screening. There was always something suspicious the test picked up: macrocalcifications in one breast 1 year and a cyst in the other breast the next year. Over a period of 3 years, I had six tissue biopsies, all benign for cancer. So when I flunked another mammogram screening 2 years ago, I thought, “It’s no big deal, this cyst will be benign, too.” However, all the false alarms had been taking their toll. Several years earlier, when my surgeon told me that the tissue he removed from my right breast had looked so suspicious he was surprised when the biopsy report came back negative, I became so alarmed we started exploring the possibility of a prophylactic bilateral mastectomy. This time the questionable-looking cyst was in my left breast. I had a tissue biopsy of the tumor and then left for a planned dental mission trip to Guatemala. When I called my husband

I was diagnosed with stage II, grade 3, invasive ductal carcinoma, and I knew immediately that I was going to be aggressive about conquering this cancer. I decided on a contralateral prophylactic mastectomy. Because the cancer had spread to my lymph nodes, I also had to have four rounds of a combination regimen of doxorubicin and cyclophosphamide, plus four rounds

a recurrence. I almost wish that the BRCA tests were positive because at least I would have an answer as to why I got cancer. I’m on tamoxifen now, I’ve modified my diet, and I’m trying to reduce the stress in my life, but I don’t know if all that will be enough to stave off a recurrence. It’s not something I worry about every day, but the possibility never leaves my consciousness.

Life Lessons Learned Cancer changed my life in ways I never expected. When I was a little girl, my grandfather was a cantor. I

The more conversations patients can have with their oncologists, the more empowered and less victimized they’ll feel. —Sheri Kay

of paclitaxel. Having to go through the chemotherapy was devastating for me. Although my oncologist now considers me in permanent remission, I don’t really believe it. I hear stories from other survivors about their breast cancer recurrence, and I know the statistics. I don’t know why I got breast cancer—there’s no family history of the disease and I tested negative for the BRCA1 and BRCA2 genes—so I don’t really know what I can do to prevent

was raised singing in his synagogue, but the experience was always terrifying. In my professional life as a dental practice coach, I frequently have to speak in front of large audiences, and before I was diagnosed with breast cancer, I would get very nervous before each presentation. Having cancer has taken away the intensity of these events. Now I sing with abandon during religious services, and public speaking is no longer so fearful. My

perspective since my diagnosis has gotten much clearer, and nothing seems so frightening to me anymore. I also recently published a book about my cancer experience called Hineni: Here I Am (see www.sherikay. com for more information), which I give away to cancer centers, support groups, and people I hear about who are going through tough times. It’s my way of paying it forward for all the help I received while I was going through treatment.

Participating in Treatment Decisions I’m especially appreciative to all my doctors who gave me a voice and allowed me to participate in my treatment decisions. Having that sense of control made me feel in partnership with my medical team. I never felt like anything was being done to me, but rather, that decisions were being made based on mutual agreement. I came armed with information about my treatment options when I met with my surgeon, so it was easy for us to engage in a conversation about the most effective course of treatment. The more conversations patients can have with their oncologists, the more empowered and less victimized they’ll feel.

■

Sheri Kay is the Chief Operating Officer and Lead Practice Coach for ACT Dental Practice Coaching in Amherst, Ohio. Tumor Biology

Identification of Novel Mechanism for Suppression of Antitumor Immunity By Matthew Stenger

he efficacy of cancer immunotherapy has been limited, likely reflecting in large part the incomplete understanding of the complex interactions between tumors and the immune microenvironment. A study presented at the 2012 ASCO Annual Meeting helps clarify some of these interactions.

Changes in Tumor Microenvironment Brent A. Hanks, MD, PhD, and colleagues at Duke University Medical Center in Durham, North Carolina, have found that progression in several types of tumors is accompanied by

downregulation of expression of the type III transforming growth factor β (TGFβ) receptor TβRIII; the receptor is shed from the cell surface to form soluble TβRIII (sTβRIII), which is capable of sequestering TGFβ. These investigators have now shown that the loss of TβRIII expression is associated with a reduction in tumor infiltrating CD8-positive T cells and an increase in regulatory T cells in the tumor microenvironment in both breast cancer and melanoma tumor models.1 The data imply that these changes correlate with suppression of tumor antigenspecific T-cell responses and more rapid disease progression.

Synergy of TGFβ Inhibition and HER2/neu Vaccine These changes have been shown to be associated with increased TGFβ signaling within the immune compartment of the tumor microenvironment, resulting in increased expression of indoleamine 2,3-dioxygenase immunoregulatory enzyme by local plasmacytoid dendritic cells and regulatory Tcell–recruiting CCL22 chemokine by local myeloid dendritic cells. Microarray analysis has indicated that the associated changes in gene expression also occur in human breast cancers. Consistent with these findings, Dr. Hanks and colleagues have shown that inhibi-

tion of TGFβ synergistically enhances the antitumor effect of a HER2/neu vaccine in a breast See Page 84 cancer model; further, they have found that plasma levels of sTβRIII are correlated with clinical response and overall survival in stage III melanoma patients. The investigators stated, “We have elucidated a novel mechanism that tumors utilize to suppress the generation of antitumor immunity by establishing a link between the loss of an endogenous suppressor of tumor metastasis, TβRIII, and the generation of

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2012 ASCO Annual Meeting an immunotolerant tumor microenvironment.”

Additional Studies When asked to comment on the implications of these findings, Dr. Hanks stated, “I would emphasize that additional studies still need to be completed to determine the significance of this immune evasion mechanism in human tissues. However, we are encouraged that we are seeing very similar results in both breast cancer and melanoma tumor models. This mechanism links intrinsic changes in the genetic makeup of the tumor with an altered dendritic cell phenotype that effectively dampens the generation of targeted antitumor immunity.”

He continued, “The data strongly suggest that combining a TGF-beta inhibitor with another immunotherapy approach has significant potential. As a result, we are pursuing additional preclinical studies to better optimize this strategy for future early phase clinical trials. Further, since the process we have identified involves a

soluble protein, measuring this protein in patient plasma may enable us to better understand the immunology of the tumor microenvironment. Additional work investigating the usefulness of sTβRIII as a clinical biomarker is ongoing.”

■

Disclosure: Dr. Hanks potential conflicts of interest.

reported

Reference 1. Hanks BA, Holtzhausen A, Gimpel P, et al: Effect of the loss of the type III TGFβ receptor during tumor progression on tumor microenvironment: Preclinical development of TGFβ inhibition and TGFβ-related biomarkers to enhance immunotherapy efficacy. 2012 ASCO Annual Meeting. Abstract 10563. Presented June 4, 2012.

AMG 386: Phase III Clinical Trials in Ovarian Cancer

Trials Now Enrolling

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TRINOVA-1: A Phase 3, Randomized, Double-Blind Trial of Weekly Paclitaxel Plus AMG 386 or Placebo in Women With Recurrent Partially Platinum Sensitive or Resistant, Epithelial Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

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For Additional Informat Information on: • Amgen Call Center: (866) 57-AMGEN • www w.Amgen .AmgenT Trials.com T rials.com (20101129) • www.ClinicalTrials.gov Trials.gov T rials.gov (NCT01493505)

The ASCO Post | JULY 15, 2012

PAGE 74

In the Clinic

Pazopanib: New Drug for Advanced Soft-tissue Sarcoma In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

Indication

n April 2012, pazopanib (Votrient) was approved for the treatment of patients with advanced soft-tissue sarcoma who have received prior chemotherapy.1,2 The efficacy of pazopanib for the treatment of patients with adipocytic soft-tissue sarcoma or gastrointestinal stromal tumors has not been demonstrated. Pazopanib has a prior indication in the treatment of advanced renal cell carcinoma.

OF NOTE Pazopanib targets VEGF receptors, which are expressed in many types of soft-tissue sarcoma, and PDGF receptors, which are also believed to be involved in soft-tissue sarcoma angiogenesis. Approval in advanced soft-tissue sarcoma was based on a multicenter trial in which 369 patients with metastatic softtissue sarcoma who had received prior chemotherapy including an anthracycline were randomly assigned (2:1) to receive double-blind oral pazopanib at 800 mg once daily (n = 246) or placebo (n = 123).2 Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Patients had a median age of 55 years, 59% were female, 72% were Caucasian, and 56% had received two or more prior systemic therapies. The proportions of patients in the three prespecified histologic subgroups of leiomyosarcoma, synovial sarcoma, and other soft-tissue sarcomas were 43%, 10%, and 47%, respectively. Median treatment durations were 4.5 months in the pazopanib group and 1.9 in the placebo group. Median progression-free survival—the primary endpoint of the trial—was 4.6 months in the pazopanib group vs 1.6 months in the placebo group, representing a significant 65% reduction in risk of progression with pazopanib (HR = 0.35, 95% CI = 0.26–0.48, P < .001). In the three histologic subgroups, risk

of progression was significantly reduced with pazopanib by 63% (HR = 0.37, 95% CI = 0.23–0.60) among patients with leiomyosarcoma, 57% (HR = 0.43, 95% CI = 0.19–0.98) among patients with synovial sarcoma, and 61% (HR = 0.39, 95% CI = 0.25–0.60) among patients with other soft-tissue sarcomas. These improvements were consistent with the progression-free survival improvement observed with pazopanib treatment in the overall population. The objective response rate was 4% for patients receiving pazopanib and 0% in the placebo group. Median overall survival was nonsignificantly increased in the pazopanib group (12.6 vs 10.7 months, HR = 0.87, 95% CI =0.67–1.12).

How It Works Pazopanib is an antiangiogenic multi– tyrosine kinase inhibitor that targets vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor (PDGF) receptors, and c-kit, among other receptors.2,3 VEGF is expressed in many types of soft-tissue sarcoma, with increased expression being associated with higher malignancy grade and poorer metastasis-free and overall survival in localized disease. VEGF blood levels are elevated in patients with soft-tissue sarcoma compared with controls and are correlated with histologic grade of the primary tumor. PDGF is also believed to be involved in soft-tissue sarcoma angiogenesis.

How It Is Given Pazopanib is given at 800 mg once daily without food, at least 1 hour be-

OF NOTE Pazopanib carries a boxed warning for hepatotoxicity. Severe, even fatal, hepatotoxicity has been observed in clinical trials. Hepatic function must be assessed prior to starting treatment and monitored regularly during treatment. fore or 2 hours after a meal. Tablets should not be crushed. The dose should not exceed 800 mg. Dose changes should be performed in 200-mg steps based on individual tolerability. Alternatives to pazopanib should be considered in patients with moderate hepatic impairment; in these patients,

Pazopanib in Soft-tissue Sarcoma ■■ Previously approved in advanced renal cell carcinoma, pazopanib is an

oral multikinase inhibitor that has been newly approved for the treatment of patients with advanced soft-tissue sarcoma who have received prior chemotherapy.

■■ Pazopanib is given at 800 mg once daily without food, at least 1 hour

before or 2 hours after a meal. The dose should not exceed 800 mg, and dose changes based on tolerability should be performed in 200-mg steps.

pazopanib should be started at 200 mg/d. Pazopanib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. Concomitant use of strong CYP3A4 inhibitors (for example, protease inhibitors [ritonavir, idinavir], some macrolide antibiotics [clarithromycin], and some antifungals [ketoconazole, itraconazole]) increases pazopanib concentrations and should be avoided. If use of a strong CYP3A4 inhibitor is warranted, the pazopanib dose should be reduced to 400 mg. Further dose reductions may be needed if adverse effects occur during therapy. Strong CYP3A4 inducers may decrease pazopanib concentrations and should be avoided. Pazopanib should not be used in patients who cannot avoid chronic use of strong CYP3A4 inducers.

Safety Profile The most common (≥ 20%) adverse reactions (any grade) in patients with soft-tissue sarcoma in the randomized, double-blind trial were fatigue (65% vs 48% in placebo group), diarrhea (59% vs 15%), nausea (56% vs 22%), weight loss (48% vs 15%), hypertension (42% vs 6%), decreased appetite (40% vs 19%), hair color changes (39% vs 2%), vomiting (33% vs 11%), tumor pain (29% vs 21%), dysgeusia (28% vs 3%), headache (23% vs 8%), musculoskeletal pain (23% vs 20%), myalgia (23% vs 9%), gastrointestinal pain (23% vs 9%), and dyspnea (20% vs 17%).2 Grade 4 adverse events were infrequent. The most common grade 3 adverse events in pazopanib patients were fatigue (13%, 1% grade 4), tumor pain (8%; 7% grade 3 and 2% grade 4 in the placebo group), hypertension (7%), and decreased appetite (6%). Other significant adverse events reported in pazopanib-treated patients included hepatic toxicity, arterial and

venous thrombotic events, hemorrhage, gastrointestinal perforation and fistula formation, pneumothorax, and left ventricular dysfunction. The most common laboratory abnormalities (all grades) in pazopanib recipients were increased AST (51%), increased ALT (46%), increased glucose (45%), leukopenia (44%), and lymphocytopenia (43%). Other abnormalities that occurred in > 15% of pazopanib-treated patients and with at least 5% greater frequency than in the placebo group were (in order of decreasing frequency) thrombocytopenia, decreased albumin, neutropenia, decreased alkaline phosphatase, decreased sodium, increased total bilirubin, and increased potassium. The most frequent grade 3/4 abnormalities in pazopanib patients were lymphocytopenia (10%/0%), increased AST (8%/2%), and increased ALT (5%/3%). Pazopanib carries a boxed warning for hepatotoxicity. Severe hepatotoxicity, including fatal hepatotoxicity, has been observed in clinical trials. Hepatic function must be assessed prior to starting treatment and monitored regularly during treatment, and evidence of hepatic toxicity requires dose reduction, interruption, or dis-

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www. fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088). provided online, or by telephone (1-800-FDA-1088).

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In the Clinic

continuation. Pazopanib also carries warnings/precautions for QT prolongation and torsades de pointes, cardiac dysfunction, hemorrhagic events, arterial thrombotic events, venous thromboembolic events, gastrointestinal perforation and fistula, reversible posterior leukoencephalopathy syndrome, hypertension, wound

Jesus San Miguel Receives José Carreras Award

esús San Miguel, MD, Professor of Medicine (Hematology), Head of the Hematology Department at the University Hospital of Salamanca, and Director of the Biomedical Research Institute of Salamanca, Spain, was awarded the José Carreras Lecture at the 17th Congress of the European Hematology Association (EHA) held recently in Amsterdam. He presented his lecture during the meeting’s opening ceremony.

healing, hypothyroidism, proteinuria, infection, and increased toxicity with other cancer therapy. Pazopanib may cause fetal harm. Interruption of pazopanib treatment is recommended in patients undergoing surgery.

■

References 1. U.S. Food and Drug Administration:

Hematology/oncology (cancer) approvals & safety notifications. Pazopanib. http:// www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm302090.htm. 2. VOTRIENT (pazopanib) tablets, prescribing information. GlaxoSmithKline, April 2012. http://www. accessdata.fda.gov/drugsatfda_docs/ label/2012/022465s-010S-012lbl.pdf.

3. Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: A phase II study from the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC study 62043). J Clin Oncol 27:3126-3132, 2009.

Join ASCO and experience the value of a global oncology community

Every Oncology Professional, Everywhere, Should be an ASCO Member ASCO’s diverse network of more than 30,000 oncology professionals, encompassing all oncology subspecialties, allows members to grow from the professional and personal expertise of their colleagues worldwide and across disciplines.

Valuable ASCO Member Benefits Jesús San Miguel, MD 2008_Practic alTips_COVER _design-r4.q xd:2008

PracticalTip s-color_desi gns

Seminal Contributions A leader in the area of multiple myeloma, Dr. San Miguel has made seminal contributions to myeloma cell biology. These included studies of the diagnostic and prognostic roles of immunophenotyping, morphology, and molecular genetics together with investigation of disease evolution and the significance of minimal residual disease. In addition, in the area of therapeutics he has made major contributions to pivotal preclinical and clinical studies of new antimyeloma drugs including proteasome inhibitors and chromatin-modifying agents. Dr. San Miguel has provided international leadership through the generation of numerous guidelines on diagnosis, classification, and treatment and was responsible for the creation of the International Staging System for multiple myeloma.

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2012 Oncology Meetings July Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma 13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com 5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.org

ICC World Cancer Congress 2012 August 27–30 • Montreal, Quebec For more information: www.worldcancercongress.org

September Health Effects of Chernobyl Catastrophe: A Quarter of a Century September 1-2 • Kiev, Ukraine For more information: www.nbscience.com/20.html Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org

11th International Congress on the Future of Breast Cancer July 26-28 • Coronado, California For more information: http://cancerlearning.onclive.com

August Best of ASCO® Boston August 3-4 • Boston, Massachusetts For more information: http://boa2012.asco.org Best of ASCO® San Diego August 10-11 • San Diego, California For more information: http://boa2012.asco.org 10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

8th International Jordan Oncology Society Conference September 6-8 • Amman, Jordan For more information: http://jo-events.com/jos-conference 9th Asia Pacific Musculoskeletal Tumor Society Meeting September 6-9 • Kuala Lumpur, Malaysia For more information: apmsts2012.com 17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/conference/17th_ ICCN 2nd World Congress on Cancer Science & Therapy September 10-12 * San Antonio, Texas For more information: www.omicsonline.org/ cancerscience2012

Australian and New Zealand Children's Haematology/Oncology Group Annual Scientific Meeting August 24-26 • Surfers Paradise, Queensland, Australia For more information: www.anzchog2012.org

8th International Conference of the International Mesothelioma Interest Group September 11-14 • Boston, Massachusetts For more information: www.imig2012.org

9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com British Association for Cancer Research: Chasing Cancer Stem-like Cells September 12 • Harrogate, North Yorkshire, United Kingdom For more information: www.bacr.org.uk 2012 Breast Cancer Symposium September 13-15 • San Francisco, California For more information: http://breastcasym.org Modern Principles of Treatment of Neurooncology Diseases: Prospects for Functional Neurosurgery September 15-16 • Yalta, Ukraine For more information: http://nbscience.com 1st Multidisciplinary Symposium: Molecular Oncology: From Laboratory Bench to Medicine September 17-22 • Kyiv, Ukraine For more information: http://rmd.org.ua/en Cancer Vaccines: Advances in Design, Therapy and Efficacy September 19-20 • London, United Kingdom For more information: www.smi-online.co.uk/events 32nd Congress of the European Society of Clinical Oncology September 19-21 • Valencia, Spain For more information: www.ecco-org.eu Congress of Oncologists September 20-22 • Sudak, Ukraine For more information: http://nbscience.com/congress-ofoncologists 8th Annual Symposium on Controversies and Clinical Challenges in Myeloma, Lymphoma, and Leukemia September 21-23 • Pasadena, California For more information: http://cancerlearning.onclive.com

Molecular Diagnostics World Congress September 25-26 • San Diego, California For more information: http://selectbiosciences.com/ conferences 1st Malaysian Proteomics Conference September 26-27 • Penang, Malaysia For more information: www.informm.usm.my/mpc2012 Sydney Cancer Conference September 27-28 • Sydney, Australia For more information: sydney.edu.au/cancer-research/ SCC2012 European Conference of Oncology Pharmacy September 27-29 • Budapest, Hungary For more information: www.ecco-org. eu/home/conferences 37th ESMO Congress September 28-October 2 • Vienna, Austria For more information: www.esmo.org

October 2nd Annual Next Generation Sequencing Asia Congress October 1-2 • Singapore For more information: www. discoveryontarget.com/HDACInhibitors 6th Next-Generation Histone Deacetylase Inhibitors October 1-2 • Boston, Massachusetts For more information: www. discoveryontarget.com/HDACInhibitors Targeting the Ubiquitin Pathway: Discovery and Development of Novel Inhibitors October 1-2 • Boston, Massachusetts For more information: www. discoveryontarget.com/UbiquitinPathway 27th Annual Critical Issues in Tumor Microenvironment, Angiogenesis, and Metastasis October 1-4 • Cambridge, Massachusetts For more information: http://steele.mgh.harvard.edu continued on page 81

XGEVA速 (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA速 is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. Please see the following pages for Important Safety Information.

GEVA®, THE FIRST AND ONLY RANK LIGAND INHIBITOR TO PREVENT SREs

INDICATION XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

IMPORTANT SAFETY INFORMATION Hypocalcemia

• Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

• XGEVA® can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA® treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when XGEVA® is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

Osteonecrosis of the Jaw (ONJ)

www.XGEVA.com

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ.

SUPERIORITY XGEVA® delayed the median time to first SRE by 8.2 months in a prespecified integrated analysis across 3 head-to-head studies vs zoledronic acid1,2

PERCENTAGE OF PATIENTS WITHOUT SRE

Time to first SRE, evaluated in more than 5,600 patients2 XGEVA® 120 mg Q4W (n = 2,862) zoledronic acid 4 mg Q4W (n = 2,861)

100 90

8.2 month delay in time to first SRE

80 70 60 50

Median time: 19.4 months

40 30

17%

Median time: 27.7 months

20 10

RISK REDUCTION

HR = 0.83 (95% CI: 0.76–0.90) P < 0.0001†

0 0

Reduction in risk of ﬁrst SRE in 3 individual studies • Breast cancer: 18% vs zoledronic acid (P = 0.010, superiority)1 • Prostate cancer: 18% vs zoledronic acid (P = 0.008, superiority)1 • Other solid tumors* or multiple myeloma: 16% vs zoledronic acid (P < 0.001, noninferiority; P = 0.060, NS for superiority)1 – Subanalysis of other solid tumors*: 19% vs zoledronic acid (P = 0.034, superiority)2 – XGEVA® is not indicated for the prevention of SREs in patients with multiple myeloma *Excluding breast and prostate cancer. † P value for superiority.

STUDY MONTH

Data from three international, phase 3, randomized, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid for the prevention of skeletal-related events in patients with bone metastases from advanced breast cancer (N = 2,046), castration-resistant prostate cancer (N = 1,901), and solid tumors (other than breast or prostate) or multiple myeloma (N = 1,776). Zoledronic acid 4 mg was administered as an IV infusion over a minimum of 15 minutes, once every 4 weeks, in accordance with prescribing information. XGEVA® was administered subcutaneously 120 mg, once every 4 weeks. The primary endpoint was time to first SRE (noninferiority), and the secondary endpoints were time to first SRE (superiority) and time to first and subsequent SREs (superiority). SREs are defined as: radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1

NO DOSE ADJUSTMENTS

PRECISE ACTION

SUBCUTANEOUS INJECTION

XGEVA® is not cleared by the kidneys and does not require dose adjustments, regardless of renal function2-5

XGEVA® acts precisely to bind to RANK Ligand, a key mediator of bone resorption, to inhibit osteoclast activity1

XGEVA® is administered once every 4 weeks as a single, 120 mg subcutaneous injection1

Administer calcium and vitamin D as necessary to prevent or treat hypocalcemia.2 • Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. • Patients who are suspected of having or who develop ONJ while on XGEVA® should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Pregnancy • Women should be advised not to become pregnant when taking XGEVA®. If the patient is pregnant or becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia. During post approval use, severe symptomatic hypocalcemia, including fatal cases has been identiﬁed. Please see brief summary of Prescribing Information on the following page.

T:9.5â&#x20AC;?

Brief Summary: Consult package insert for complete Prescribing Information

Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletalrelated events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletalrelated events in patients with multiple myeloma (see Clinical Trials [14] in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25Â°C/77Â°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Hypocalcemia. Xgeva can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Adverse Reactions and Patient Counseling Information [17] in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/ min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis.

Xgeva n = 2841 %

Zoledronic Acid n = 2836 %

GASTROINTESTINAL Nausea Diarrhea

31 20

32 19

GENERAL Fatigue/ Asthenia

INVESTIGATIONS )ZQPDBMDFNJBb )ZQPQIPTQIBUFNJBb

18 32

9 20

NEUROLOGICAL )FBEBDIF

RESPIRATORY Dyspnea Cough

21 15

18 15

Body System

Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and beneďŹ ts in continuing or discontinuing treatment with Xgeva. Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a â&#x20AC;&#x153;knockout mouseâ&#x20AC;?). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other ďŹ ndings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology [13.2] in full Prescribing Information).

Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (â&#x2030;¤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal NBNNBSZ HMBOE MFBEJOH UP JNQBJSFE MBDUBUJPO QPTUQBSUVN )PXFWFS JO DZOPNPMHVT monkeys treated with denosumab throughout pregnancy, maternal mammary gland Severe Mineral/Electrolyte Abnormalities development was normal, with no impaired lactation. Mammary gland histopathology t 4FWFSF IZQPDBMDFNJB DPSSFDUFE TFSVN DBMDJVN MFTT UIBO NH E- PS MFTT UIBO at 6 months of age was normal in female offspring exposed to denosumab in utero; 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients however, development and lactation have not been fully evaluated (see Nonclinical treated with zoledronic acid. Of patients who experienced severe hypocalcemia, Toxicology [13.2] in Full Prescribing Information). 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in SpeciďŹ c Populations). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients t 4FWFSF IZQPQIPTQIBUFNJB TFSVN QIPTQIPSVT MFTT UIBO NH E- PS MFTT UIBO of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain treated with zoledronic acid. osteoprotegerin bound to Fc (OPG-Fc) at doses â&#x2030;¤ 10 mg/kg was associated with inhibition or slow healing of the mouth or jaw after dental surgery may also be manifestations of of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses ONJ. In clinical trials, in patients with osseous metastasis, 2.2% of patients receiving Osteonecrosis of the Jaw Xgeva developed ONJ after a median exposure of 13 doses; of these patients, 79% had In the primary treatment phases of Trials 1, 2, and 3, ONJ was conďŹ rmed in 1.8% of patients 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of a history of tooth extraction, poor oral hygiene, or use of a dental appliance (see Adverse in the Xgeva group and 1.3% of patients in the zoledronic acid group (see Warnings and 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal Reactions). In a clinical trial conducted in patients with prostate cancer at high risk for Precautions). When events occurring during an extended treatment phase of approximately growth plates, considered to be consistent with the pharmacological activity of denosumab. osseous metastasis, a condition for which denosumab is not approved, 5.4% of patients 4 months in each trial are included, the incidence of conďŹ rmed ONJ was 2.2% in patients Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence developed ONJ after a median exposure of 20 doses. Perform an oral examination and who received Xgeva. The median time to ONJ was 14 months (range: 4 â&#x20AC;&#x201C; 25). of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Postmarketing Experience. Because postmarketing reactions are reported voluntarily recovered once exposure was ceased following birth; however, axillary and inguinal lymph Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who from a population of uncertain size, it is not always possible to reliably estimate their nodes remained absent 6 months post-birth (see Use in Pregnancy). develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these frequency or establish a causal relationship to drug exposure. Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were patients, extensive dental surgery to treat ONJ may exacerbate the condition. The following adverse reactions have been identiďŹ ed during post approval use of Xgeva: 65 years of age or older. No overall differences in safety or efďŹ cacy were observed between these patients and younger patients. PREGNANCY: Xgeva can cause fetal harm when administered to a pregnant woman. t )ZQPDBMDFNJB Severe symptomatic hypocalcemia, including fatal cases. Based on ďŹ ndings in animals, Xgeva is expected to result in adverse reproductive effects. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Renal Impairment. In a trial of 55 patients without cancer and with varying degrees In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of renal function who received a single dose of 60 mg denosumab, patients with a stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, of patients with osseous metastases treated with denosumab doses ranging creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of abnormal bone growth and decreased neonatal growth (see Use in SpeciďŹ c Populations). from 30 â&#x20AC;&#x201C; 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive severe hypocalcemia with denosumab compared to patients with normal renal function. There are no adequate and well controlled studies with Xgeva in pregnant women. for binding antibodies. No patient with positive binding antibodies tested positive for The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 Women should be advised not to become pregnant when taking Xgeva. If this drug is neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/ used during pregnancy, or if the patient becomes pregnant while taking this drug, the biological assay. There was no evidence of altered pharmacokinetic proďŹ le, toxicity min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical patient should be apprised of the potential hazard to the fetus. proďŹ le, or clinical response associated with binding antibody development. The incidence Pharmacology [12.3] in full Prescribing Information). ADVERSE REACTIONS: The following adverse reactions are discussed below and of antibody formation is highly dependent on the sensitivity and speciďŹ city of the assay. OVERDOSAGE: There is no experience with overdosage of Xgeva. Additionally, the observed incidence of a positive antibody (including neutralizing elsewhere in the labeling: antibody) test result may be inďŹ&#x201A;uenced by several factors, including assay methodology, HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. t )ZQPDBMDFNJB (see Warnings and Precautions) sample handling, timing of sample collection, concomitant medications, and underlying Store Xgeva in a refrigerator at 2Â°C to 8Â°C (36Â°F to 46Â°F) in the original carton. Do not t 0TUFPOFDSPTJT PG UIF +BX (see Warnings and Precautions) disease. For these reasons, comparison of antibodies to denosumab with the incidence freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25Â°C/77Â°F or direct light and must be used within 14 days. Discard Xgeva if not The most common adverse reactions in patients receiving Xgeva (per-patient incidence of antibodies to other products may be misleading. used within the 14 days. Do not use Xgeva after the expiry date printed on the label. greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. (see Table 1). The most common serious adverse reaction in patients receiving Xgeva Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva administered in combination with standard anticancer treatment. Serum denosumab PATIENT COUNSELING INFORMATION: were osteonecrosis and hypocalcemia. concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/ Advise patients to contact a healthcare professional for any of the following: Clinical Trials Experience. Because clinical trials are conducted under widely varying Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar t Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Warnings and Precautions and Adverse Reactions) conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly in patients with and without prior intravenous bisphosphonate therapy. There was no compared to rates in other clinical trials and may not reďŹ&#x201A;ect the rates observed in practice. evidence that various anticancer treatments affected denosumab systemic exposure t 4ZNQUPNT PG 0/+ JODMVEJOH QBJO OVNCOFTT TXFMMJOH PG PS ESBJOBHF GSPN UIF KBX mouth, or teeth (see Warnings and Precautions and Adverse Reactions) The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months (see Clinical Trials [14] in full Prescribing Information) in which a total of 2841 patients were not altered by concomitant chemotherapy and/or hormone therapy. The median t 1FSTJTUFOU QBJO PS TMPX IFBMJOH PG UIF NPVUI PS KBX BGUFS EFOUBM TVSHFSZ (see Warnings and Precautions) with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology [12.2] t 1SFHOBODZ PS OVSTJOH (see Warnings and Precautions and Use in SpeciďŹ c Populations) and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a in full Prescribing Information). Advise patients of the need for: subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid t 1SPQFS PSBM IZHJFOF BOE SPVUJOF EFOUBM DBSF every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) USE IN SPECIFIC POPULATIONS: from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva t *OGPSNJOH UIFJS EFOUJTU UIBU UIFZ BSF SFDFJWJOH 9HFWB Patients who had received IV bisphosphonates were excluded, as were patients with prior can cause fetal harm when administered to a pregnant woman based on ďŹ ndings in t "WPJEJOH JOWBTJWF EFOUBM QSPDFEVSFT EVSJOH USFBUNFOU XJUI 9HFWB history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased Advise patients that denosumab is also marketed as ProliaÂŽ. Patients should inform surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, their healthcare provider if they are taking Prolia. the study, serum chemistries including calcium and phosphorus were monitored every abnormal bone growth and decreased neonatal growth. There are no adequate and Amgen Manufacturing Limited, a subsidiary of Amgen Inc. 4 weeks. Calcium and vitamin D supplementation was recommended but not required. well-controlled studies with Xgeva in pregnant women. Women should be advised not One Amgen Center Drive The median duration of exposure to Xgeva was 12 months (range: 0.1 â&#x20AC;&#x201C; 41) and median to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the Thousand Oaks, California 91320-1799 duration on-study was 13 months (range: 0.1 â&#x20AC;&#x201C; 41). Of patients who received Xgeva, patient becomes pregnant while taking this drug, the patient should be apprised of the XFSF GFNBMF &JHIUZ mWF QFSDFOU XFSF 8IJUF )JTQBOJD -BUJOP "TJBO BOE potential hazard to the fetus. Women who become pregnant during Xgeva treatment ÂŠ2012 Amgen Inc. 3% Black. The median age was 63 years (range: 18 â&#x20AC;&#x201C; 93). Seventy-ďŹ ve percent of patients are encouraged to enroll in Amgenâ&#x20AC;&#x2122;s Pregnancy Surveillance Program. Patients or their All rights reserved. Printed in USA. physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. who received Xgeva received concomitant chemotherapy. Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: t "U MFBTU HSFBUFS JODJEFODF JO 9HFWB USFBUFE QBUJFOUT PS t #FUXFFO HSPVQ EJGGFSFODF FJUIFS EJSFDUJPO PG MFTT UIBO BOE NPSF UIBO greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 â&#x20AC;&#x201C; 8.5 mg/dL (2.075 â&#x20AC;&#x201C; 2.125 mmol/L) for calcium and 2.2 â&#x20AC;&#x201C; 2.8 mg/dL (0.71 â&#x20AC;&#x201C; 0.9 mmol/L) for phosphorus] a

DOUS2X0307_T_4Pg Tabloid_Update_Q2_2012_BS_r7.indd 1

6/19/12 10:48 AM

T:13â&#x20AC;?

REFERENCES: 1. XGEVAÂŽ (denosumab) prescribing information, Amgen. 2. Data on ďŹ le, Amgen. 3. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066. 4. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653. 5. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507.

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2012 Oncology Meetings continued from page 76

Functional Genomics Screening Strategies October 2-3 • Boston, Massachusetts For more information: www. discoveryontarget.com/RNAiScreens-Functional-Genomics ACCC National Oncology Conference October 3-6 • San Antonio, Texas For more information: http://accc-cancer.org American Society of Head and Neck Radiology 46th Annual Meeting October 3-7 • Miami Beach, Florida For more information: www.ashnr.org 14th Annual Lynn Sage Breast Cancer Symposium October 4-7 • Chicago, Illinois For more information: www.lynnsagebreastcancer 44th Congress of the International Society of Paediatric Oncology October 5-8 • London, United Kingdom For more information: www.siop2012.org

32nd Annual Oncology Nurses Symposium October 7-10 • San Diego, California For more information: www.scripps.org Oncology Clinical Development Congress October 10-11 • Manchester, Cheshire, United Kingdom For more information: www.oncologyclinicaldevelopmentcongress.com

Current Approaches to Diagnosis and Treatment of Non-Hodgkin's Lymphoma October 18-19 • Kiev, Ukraine For more information: nbscience. com/current-approaches-todiagnosis-and-treatment-of-nonhodgkins-lymphoma Western Neuroradiological Society 44th Annual Meeting October 18-21 • Sedona, Arizona For more information: www.wnrs.org American College of Gastroenterology Annual Scientific Meeting October 19-24 • Las Vegas, Nevada For more information: http://gi.org Sydney International Breast Cancer Congress October 23-26 • Sydney, Australia For more information: www.sydneybreastcancer2012.com Society for Immunotherapy of Cancer Workshop--Focus on the Target: The Tumor Microenvironment October 24-25 • North Bethesda, Maryland For more information: www.sitcancer. org/meetings/am12/workshop12 Society for Immunotherapy of Cancer: Primer on Tumor Immunology and Cancer Immunotherapy October 25 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/primer 12th Meeting of the International Society of Geriatric Oncology October 25-27 • Manchester, UK For more information: www.siog.org

Optimization Methods for Radiation Diagnosis in Oncology October 27-28 • Odessa, Ukraine For more information: nbscience. com/optimization-methods-forradiation-diagnosis-in-oncology 3rd International Conference on Stem Cells and Cancer October 27-30 • New Delhi, Delhi, India For more information: www.iscc.in IASLC 15th World Conference on Lung Cancer October 27-31 • Sydney, Australia For more information: www.2013worldlungcancer.org ASTRO’s 54th Annual Meeting October 28-31 • Boston, Massachusetts For more information: www.astro.org

November 2012 AICR Annual Research Conference on Food, Nutrition, Physical Activity and Cancer November 1–2 • Washington, DC For more information: www.aicr.org/research/conference 8th Annual Multidisciplinary Symposium on Head and Neck Cancer November 3 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

3rd International Breast Cancer Prevention Symposium October 10-12 • Lafayette, Indiana For more information: www.purdue.edu/breastcancer

9th Annual School of Breast Oncology October 25-28 • Atlanta, Georgia For more information: http://cancerlearning.onclive.com

24th EORTC-NCI-AACR Symposium in Molecular Targets and Cancer Therapeutics November 6-9 • Dublin, Ireland For more information: www.ecco-org.edu

14th Biennial Meeting of the International Gynecologic Cancer Society October 13-16 • Vancouver, Canada For more information: www2.kenes. com/igcs2012/Pages/home.aspx

Society for Immunotherapy of Cancer 27th Annual Meeting October 26-28 • North Bethesda, Maryland For more information: www.sitcancer. org/2012/annualmeeting

Chemotherapy Foundation Symposium XXX November 6-10 • New York, New York For more information: http://chemotherapyfoundation symposium.org

7th Annual New York Lung Cancer Symposium November 10 • New York, New York For more information: http://cancerlearning.onclive.com AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics November 12-16 • San Francisco, California For more information: www.aacr.org Society for Neuro-Oncology Annual Meeting November 15-18 • Washington, DC For more information: www.soc-neuro-onc.org 17th Annual Perspectives in Thoracic Oncology November 16-17 • New York, New York For more information: www.imedex.com RSNA Annual Meeting November 25-30 • Chicago, Illinois For more information: rsna2012.rsna.org/ 5th Asia Pacific Lung Cancer Conference November 26-28 • Fukuoka, Japan For more information: nsaijo@med.kindai.ac.jp ASCO's Quality Care Symposium November 30-December 1 • San Diego, California For more information: quality2012.asco.org

December 35th Annual San Antonio Breast Cancer Symposium December 4-8 • San Antonio, Texas For more information: www.sabcs.org

2012 ASH Annual Meeting December 8-11 • Atlanta, Georgia For more information: www.hematology.org

The ASCO Post | JULY 15, 2012

PAGE 82

In the News Dermatologic Oncology

MEK Inhibitor Reduces Progression of BRAF-mutated Melanoma and Might also Benefit Others By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit. This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

he MEK inhibitor trametinib improved progression-free and overall survival compared to chemotherapy in a phase III trial including 322 patients who had metastatic melanoma with a BRAF V600E or V600K mutation. Findings from this study were published in The New England Journal of Medicine1 and presented at the 2012 ASCO Annual Meeting (see page 3). These data and findings from other studies showing improved survival in patients receiving BRAF inhibitors, or BRAF and MEK inhibitors combined, position these targeted therapies as first-line treatment for patients with BRAF-mutated melanoma.

Reduced Role of Chemotherapy The lead author of the trametinib trial, Keith T. Flaherty, MD, explained in an interview with The ASCO Post that it “was the last trial to be done before BRAF inhibitors were widely available, certainly before their approval.” (Trial participants were screened between December 2010 and July 2011; vemurafenib [Zelboraf], so far the only BRAF inhibitor to receive FDA approval, was approved in August 2011.) “Now we are well into an era where both physicians and patients would look at chemotherapy as our least attractive option,” said Dr. Flaherty, who is Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School in Boston. BRAF mutations, most commonly V600E and V600K, have been identified in approximately 50% of patients with advanced melanoma. “Even for those who lack the mutation, we would still opt for immunotherapy with ipilimumab (Yervoy) or, in some cases, even interleukin-2 (Proleukin), albeit for a smaller number of people. But

we would still favor that over chemotherapy, generally speaking,” Dr. Flaherty said. “The role of chemotherapy is now in patients with fairly symptomatic, burdensome, metastatic disease when they first walk in the door for treatment, who don’t have a BRAF mutation and might not have time to respond to the immune therapies, which can take a while to kick in. In those cases, chemotherapy is still offered as a sort of temporizing measure.” Data from the trametinib study was also presented at the ASCO Annual Meeting by Caroline Robert, MD, PhD, Head of Dermatology at the Institut Gustave Roussy in Paris. Dr. Robert and Dr. Flaherty contributed equally to the New England Journal ar-

ticle. Major publications including The New York Times, The Wall Street Journal, and The Boston Globe, also reported results of the study.

‘We Knew They Were Coming’ Patients were randomly assigned in a 2:1 ratio to reKeith T. Flaherty, MD Caroline Robert, MD, PhD ceive either trametinib once daily or intravenous chemotherapy, group, despite crossover, which was consisting of either dacarbazine or papermitted for patients in the chemoclitaxel every 3 weeks. Median protherapy group experiencing disease gression-free survival was 4.8 months progression. with trametinib vs 1.5 months with Although 51 of 108 patients on the chemotherapy. At 6 months, overall chemotherapy arm crossed over to trasurvival was 81% in the trametinib metinib therapy, the investigators nevcontinued on page 84 group vs 67% in the chemotherapy

Expect Questions from Your Patients

romising results announced at the recent ASCO Annual Meeting from studies with BRAF and MEK inhibitors have made headlines, but only one of these agents—the BRAF inhibitor vemurafenib (Zelboraf)— has been approved by the FDA. The others are still investigational. Patients interested in gaining access to these drugs through clinical trials should be aware of clinical evidence suggesting that patients may develop resistance to BRAF inhibitors and that BRAF and MEK inhibitors used singly or together have adverse effects.

Secondary Squamous Cell Carcinoma The use of BRAF inhibitors in patients with advanced melanoma has been associated with secondary squamous cell carcinoma. “There are no documented cases yet of another cancer, but we are obviously keeping our eyes open to that as we treat patients,” noted Keith T. Flaherty, MD, Director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School in Boston. In the metastatic setting, this is not a concern. “These patients are dealing with a life-threatening circumstance, and the possibility of other tumors

forming beyond these skin tumors is not a reason to not offer the therapy,” Dr. Flaherty said. “In the adjuvant setting, the stakes are a little different. If there is any protumor effect happening in a subgroup of patients on these trials who aren’t destined to have their melanoma show up again, there’s a harm there that obviously causes us to have much greater concern. The FDA and practitioners are in high surveillance mode on that topic,” Dr. Flaherty noted. “The MEK inhibitor doesn’t raise that concern,” he added. Adverse effects of the MEK inhibitor trametinib, as reported in phase III trials, are mainly skin rash, diarrhea, edema, hypertension, fatigue, and chorioretinopathy. These are clinical class effects that can be expected of all MEK inhibitors, according to Dr. Flaherty.

Fever and Chills from Combined Use In a phase I/II trial combining the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib, the rate of fever of any grade in the phase I group was 52%. Focusing on the group that received full doses of both drugs, 58% of patients had fever, but only 8% were grade 3. Similarly, in the overall phase I group, 38% of patients had chills of any grade (37% of the patients receiving

full doses of both drugs), and 1% of patients had grade 3 chills. For the phase III trials, efforts are being made to increase awareness and early recognition of these effects, while instructing patients on how to manage them, Dr. Flaherty said. “It is fairly clear that it you intervene quickly, even with Tylenol, you can help prevent that sort of escalation. If Tylenol won’t handle it, then you quickly start holding the doses,” he added, and the fever will resolve fairly rapidly. “When we were first working with the combination, we didn’t know to expect this as such a frequent or bothersome issue, so patients were continuing dosing and we’d hear about it after they had been dealing with it for several days,” Dr. Flaherty said. “But a much more proactive stance evolved as that trial continued.” In a few patients with recurring fever despite dose interruptions, lowdose prednisone was successfully used to stop the fever. “But we are a little cautious in these patients about just using steroids,” Dr. Flaherty said, “because we feel like that could potentially compromise treatment outcomes. We like to hold that in reserve.” The phase III trial, he noted, includes “a much more well-fleshed-out algorithm” for managing fever and chills.

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Stimulating Possibilities

The potential of Dendritic Cell Mediated Immunotherapy (DCMI) in advanced NSCLC BINDS

PROPOSED MECHANISM OF ACTION: Orally administered DCMIs are thought to bind in the gut epithelium and interact with dendritic cells in the gut wall 1,2

STIMULATES

Binding produces an immunostimulatory cytokine cascade in the gut, stimulating the migration and maturation of tumor antigen-presenting dendritic cells2,3

ACTIVATES Matured dendritic cells present tumorassociated antigens to T lymphocytes and activate them2,3

INFILTRATES These effector T lymphocytes then make their way to distal tumors, where they infiltrate and inhibit tumor growth2,3

There is an unmet need for treatments in advanced NSCLC that work in a broad range of patients, regardless of tumor histology or mutation status.4 Agennix is investigating a novel oral DCMI in advanced NSCLC. Learn more at www.discoverDCMI.com

DCMI References: 1. Suzuki YA et al. Biochem. 2001;40:15771-15779. 2. Spadaro M et al. Cancer Res. 2007;67:6425-6432. 3. Varadhachary A et al. Int J Cancer. 2004;111:398-403. 4. Kelly RJ, Giaccone G. Expert Opin Biol Ther. 2010;10:1379-1386.

The ASCO Post | JULY 15, 2012

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In the News

MEK Inhibitor continued from page 82

ertheless observed a 46% reduction in the risk of death among patients receiving trametinib. “It is possible that the between-group difference in overall survival might have been even more significant in the absence of crossover,” they wrote. This study began while ipilimumab and vemurafenib were still investigational, and progression-free survival was chosen as the primary endpoint out of concern that postprotocol therapy with either of those drugs could confound results for overall survival. “We knew they were coming,” Dr. Flaherty said. “I was heavily involved in all phases of the vemurafenib trials, and we knew full well in designing this trial that it was just a matter of months before vemurafenib was going to be available—first through expanded access and then approval, meaning that in the lifespan of a trial like this, as you are following patients over 1 or 2 years, nearly all patients would eventually be able to get a BRAF inhibitor. That’s good for the patients; it’s just bad for the overall survival endpoint, because at some point that would influence the outcome of the trial.” Progression-free survival, however, is a “within-the-trial See Page 84 issue,” Dr. Flaherty noted. “Patients usually don’t seek other therapy until their disease gets worse, in which case the progression-free survival couldn’t possibly be altered.” He added that the FDA and European regulatory authorities “agreed that was a reasonable justification for designing the trial the way we did.” A final overall analysis is planned when 80% of randomly assigned pa-

tients have died or otherwise been lost to follow-up, “We haven’t even crossed the 40% mark,” Dr. Flaherty said. “When we do the final analysis, we will also be accounting for what other therapies they got, and we obviously expect that to influence the outcome.”

Combining BRAF and MEK Inhibitors The overall response rate for patients receiving trametinib was 22%, compared to 48% in a randomized

BRAF mutation and that the progression-free survival increased to 10.8 months among patients receiving the highest study doses of both drugs—2 mg of trametinib once a day and 150 mg of dabrafenib twice a day. That full-dose combination will be tested against single-agent BRAF inhibitors in two different phase III trials. “That is the only combination going forward at this time because it looks to be the most effective and it is also per-

A future trial would likely test the question of which is the best approach—starting with a MEK inhibitor vs starting with a BRAF inhibitor vs starting with both. —Keith T. Flaherty, MD

phase III trial with vemurafenib. “Although the response rate associated with trametinib appears to be inferior to that with vemurafenib, the two agents appear to provide similar improvements in progression-free and overall survival, as compared with chemotherapy,” according to the trametinib trial report. A direct comparison of trametinib and vemurafenib would be needed to definitively determine whether one is superior to the other, but currently there is less interest in head-to-head comparisons than in combining BRAF and MEK inhibitors to treat melanoma, Dr. Flaherty noted. A phase I/II trial combining BRAF and MEK inhibitors was presented at the ASCO Annual Meeting2 and reported in a previous issue of The ASCO Post.3 The study found that trametinib combined with the BRAF inhibitor dabrafenib produced median progression-free survival of 7.4 months among patients with advanced melanoma and the V600E

Using QR Codes The QR (Quick Response) codes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. These barcodes can be read by any mobile device with a camera, QR code–reading software, and internet access. Some devices come with the software preinstalled; if not, visit your device’s application store (such as the iTunes Store or the Android Market) and download the software of your choice.

fectly safe to give the two together,” Dr. Flaherty stated. One trial based mainly in the United States will compare the combination to dabrafenib, and another more global trial will compare the combination to vemurafenib. Both trials are for patients with advanced or metastatic melanoma, but Dr. Flaherty said that adjuvant trials are expected to launch in 2012. Based on emerging evidence, Dr. Flaherty said “it would look like the combination is working better than either agent does alone.” If that is borne out by the phase III trials, “a future trial would likely test the question of which is the best approach—starting with a MEK inhibitor vs starting with a BRAF inhibitor vs starting with both—understanding that people who get only a BRAF or MEK inhibitor could then receive the other agent as a backup approach.”

Broader Application Near the end of the trametinib study report, the authors state, “Selec-

tive BRAF inhibitors appear to be relevant only in the treatment of BRAFmutated cancers, whereas extensive preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.” Those cancers include melanomas without an identified BRAF mutation as well as some other common cancers. About 25% of all cancers have RAS mutations, and “some subset of that 25% is sensitive, meaning will respond with tumor shrinkage that is clear and objective, to a MEK inhibitor,” Dr. Flaherty explained. “The big ticket items are pancreatic cancer, where 90% to 95% have KRAS mutations; colon cancer, where about 40% have KRAS mutations; and lung cancer, about 30%. These are common cancers, and those percentages equate to huge numbers of patients.” In addition, “some patients with neither a BRAF or a RAS mutation have responded to MEK inhibitors in trials,” Dr. Flaherty noted.

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Disclosure: Dr. Flaherty served as a consultant to GlaxoSmithKline.

References 1. Flaherty KT, Robert C, Hersey P, et al: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. June 4, 2012 (early release online). 2. Weber JS, Flaherty KT, Infante JR, et al: Updated safety and efficacy results from a phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. 2012 ASCO Annual Meeting. Abstract 8510. Presented June 4, 2012. 3. Helwick C: Dual BRAF and MEK inhibition is active in advanced melanoma. The ASCO Post. June 15, 2012.

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Position your device in front of the code so that it fills about half your screen.

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ASCOPost.com | JULY 15, 2012

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Lab Notes

Ongoing Molecular Research in the Science of Oncology OUTCOME PREDICTORS Pretreatment Tumor Hypoxia Predicts Biochemical Failure after Radiotherapy for Prostate Cancer Hypoxia often occurs early in solid tumor development as a result of imbalances between oxygen supply and consumption and may lead to genetic and molecular signaling that influences the biology and clinical behavior of tumors and response to treatment. Milosevic and colleagues from Princess Margaret Hospital and Ontario Cancer Institute in Toronto recently showed that hypoxia is an independent predictor of biochemical recurrence of prostate cancer after radiotherapy alone or together with neoadjuvant and concurrent hormonal therapy.

diate-risk prostate cancer and provide a rationale for studying the combination of radiotherapy with new hypoxia-targeted treatment approaches. As stated by the investigators, “New treatment approaches for high-risk patients with hypoxic tumors might consist of

further radiation dose-escalation, the use of hypoxic cell sensitizers or cytotoxins in combination with radiotherapy, or molecular therapeutic strategies that either alter the balance between oxygen supply and consumption or exploit the molecular consequences of

hypoxia to enhance radiation response, tumor control, and patient survival.”

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Milosevic M, et al: Clin Cancer Res 18:2108-2114, 2012.

Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.

Navigate the New ASCOPost.com Most Read See which articles are most popular on ASCOPost.com.

Early Failure Preferentially Predicted In this study, direct oxygen measurements were made prior to treatment in 247 patients with clinically localized prostate cancer who were followed for over 6 years. When added to a baseline clinical model consisting of Gleason score and prostate-specific antigen level, hypoxia was an independent predictor of early biochemical relapse-free survival. Its effect as a predictor was even more pronounced when analysis was limited to 142 patients with bulk tumor at the oxygen measurement site. As noted by the investigators, this finding contributes to other emerging evidence “indicating that early biologic and clinical behavior [of the tumor] is determined by the dominant focus of disease in the prostate gland and less so by secondary more indolent foci.” On univariate analysis, the effect of hypoxia on biochemical relapse-free survival was greatest earlier in follow-up and diminished with increasing time. Patients with hypoxic tumors were more likely than those with well-oxygenated tumors to develop biochemical failure within the first 48 months of completing treatment but not at longer durations after the end of treatment. Hypoxia was the only factor predictive of local recurrence in 70 patients who had biopsies conducted during followup, with the effect again being greatest early after completing treatment. These findings support the hypothesis that hypoxia influences clinical outcome after radiotherapy in interme-

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In the Literature

Emerging Clinical Data on Cancer Management GASTROINTESTINAL CANCER Screening Should Begin Early for Survivors of Childhood Cancer Survivors of childhood cancer, particularly those treated for childhood Hodgkin lymphoma or Wilms tumor with abdominal radiation, procarbazine (Matulane), and platinum chemotherapy, are at an increased risk of developing gastrointestinal subsequent malignant neoplasms, according to a retrospective cohort study among 14,358 survivors. “These findings suggest that surveillance of at-risk childhood cancer survivors should begin at a younger age than that recommended for the general population,” the study authors stated in the Annals of Internal Medicine. The Childhood Cancer Survivor Study includes patients at 26 centers in the United States and Canada diagnosed with leukemia, central nervous system cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, neuroblastoma, soft-tissue sarcoma, Wilms tumor, or bone cancer. The patients were diagnosed when they were younger than 21 and survived 5 or more years after the initial diagnosis. The increased risk for gastrointestinal cancer occurred as soon as 5.5 years after the diagnosis of childhood cancer. The study is ongoing, and the authors stated that they ex-

pect the incidence of gastrointestinal subsequent malignant neoplasms to continue to increase as the cohort ages. In a cohort of 14,337 childhood cancer survivors, 802 subsequent malignant neoplasms were identified in 732 individuals. Of that group, 45 (5.6%) gastrointestinal cancers were identified (in 45 patients) at a median follow-up of 22.8 years after primary diagnosis. The median age at diagnosis of gastrointestinal subsequent malignant neoplasms was 33.5 years. The risk for developing a gastrointestinal cancer was 4.6-fold higher in childhood cancer survivors than in the general population, the researchers reported.

Subsequent Tumor Sites According to the investigators, the most frequent site of a subsequent neoplasm was the colon, followed by the rectum or anus. Of the 45 identified gastrointestinal subsequent malignant neoplasms, 25 (56%) were adenocarcinomas. Of those 45 patients, 23 (51%) had died, 15 (65%) of the subsequent malignant neoplasms. While the researchers anticipated that “survivors treated with abdominal radiation would be at greatest risk for gastrointestinal cancer,” they reported that 13 of the 45 subsequent malignant neoplasms occurred outside of the radiation field or in survi-

vors who did not receive radiotherapy as part of their primary treatment. In addition, procarbazine and platinum drugs were independently associated with a greater risk for subsequent cancers in the radiation field, suggesting that these agents may “potentiate the carcinogenic effects of radiation,” the authors noted. “Because cure of the primary childhood cancer is a priority, we do not advocate for modification of the current treatment protocols used for childhood cancer to decrease the long-term risk for gastrointestinal [subsequent malignant neoplasms]. However, pediatric oncologists strive to reduce or eliminate late toxicity without affecting the probability of cure; therefore, the necessity of such therapies as radiation is under constant scrutiny. Our observations should enable researchers and clinicians to better identify survivors at highest risk for gastrointestinal [subsequent malignant neoplasms], potentially facilitating the implementation of better surveillance in clinical practice,” the authors concluded. The Children’s Oncology Group currently recommends that “survivors exposed to more than 30 Gy of abdominal radiation have colonoscopy at a minimum of every 5 years, beginning 10 years after radiation or at age 35 years, whichever is later,” the authors added. “If the findings of this study are confirmed, physicians should also consider chemotherapy exposures when determining the indications for early colorectal cancer surveillance in childhood cancer survivors.” Henderson TO, et al: Ann Intern Med 156:757-766, 2012.

COLON CANCER Adjuvant Chemotherapy May Confer Survival Benefit in Patients Older than 75 with Stage III Disease

Because few people over 75 participate in clinical trials, it is unknown whether adjuvant chemotherapy could benefit this population. Faced with this gap in clinical trial evidence, researchers reviewed data from 5,489 patients ≥ 75 years with stage�� III colon cancer. The review suggests that patients over age 75 with surgically resected colon cancer may have a survival benefit from chemotherapy similar to that

previously demonstrated for younger patients in randomized and observational studies. The results were published in the Journal of Clinical Oncology. “From the perspective of a practicing clinician, these results suggest that consideration of adjuvant systemic therapy is absolutely warranted for patients older than 75 years,” the authors concluded. “Of the 141,000 people diagnosed with colorectal cancer in the United States in 2011, 40% will be 75 years of age or older. Patients older than 75 years also account for half of colorectal cancer deaths. Despite this disproportionate burden, older patients are underrepresented in clinical trials of colorectal cancer chemotherapy,” the researchers noted.

Study Design “To shed light on actual practice patterns and outcomes, we evaluated the effectiveness of any adjuvant chemotherapy for patients older than 75 years with stage III colon cancer and whether the addition of oxaliplatin provides additional survival benefit,” the researchers explained. Demographic, stage, treatment, and survival information were obtained from four data sets: SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, the National Comprehensive Cancer Network Outcomes (NCCN) Database, and the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS). The use of chemotherapy after resection of stage III cancer differed among cohorts, ranging from 42% in the SEER-Medicare group to 75% in the NCCN group. “As expected, the use of both any chemotherapy and oxaliplatin-containing regimens dropped off quickly with advancing age,” the investigators reported. Chemotherapy-treated patients had much better survival than those not receiving chemotherapy after resection of stage III colon cancer. “Oxaliplatin offers no more than a small, incremental benefit,” the researchers added. A critical, unanswered question is how adjuvant therapy affects quality of life. For more information on adjuvant therapy in older patients with colorectal cancer, see page 21.

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Sanoff HK, et al: J Clin Oncol, June 4, 2012 (early release online).

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates: Taking targeted therapy to the next level ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic agent. ADCs are designed to deliver potent anticancer agents to tumors in a targeted manner to limit systemic exposure.1-5

Monoclonal antibody

Stable linker

Cytotoxic agent

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer effects1,3,6-8

designed to allow an ADC to remain inactive while in circulation1,2,7-9

incorporated into an ADC, may be up to 1000-fold more potent than currently used chemotherapies7

These investigational ADCs have multiple proposed mechanisms of action, including antibody-mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic agent.6

Visit www.ResearchADCs.com to learn more References:

1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol. 2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Ghose T, Blair AH. Antibody-linked cytotoxic agents in the treatment of cancer: current status and future prospects. J Natl Cancer Inst. 1978;61:657-676. 6. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 9. Sanderson RJ, Hering MA, James SF, et al. In vivo drug-linker stability of an anti-CD30 dipeptidelinked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.