TAP Vol 3 Issue 7 by Harborside Press LLC

FDA Update 17

VOLUME 3, ISSUE 7

| R&D at Pharma 26 | Gastrointestinal Stromal Tumors 31 | Cervical Cancer Screening Guidelines 37

MAY 1, 2012

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

Gastrointestinal Oncology

Novel Multikinase Inhibitor Improves Survival in Metastatic Colorectal Cancer

ASCOPost.com

Caveat Oncologist: Counterfeit Pharmaceuticals

By Caroline Helwick

he novel tyrosine kinase inhibitor regorafenib, given as a single agent to patients with treatment-refractory metastatic colorectal cancer, significantly improved overall survival and delayed disease progression in an international phase III trial preAxel Grothey, MD sented at the 2012 Gastrointestinal Cancers Symposium.1 “Regorafenib is the first small-molecule kinase inhibitor showing proof of efficacy in colorectal cancer, and identifies itself as a potential new standard of care” in metastatic patients who have progressed on other treatments, said lead investigator Axel Grothey, MD, of the Mayo Clinic, Rochester, Minnesota. Regorafenib is an oral multikinase inhibitor of a broad range of angiogenic, oncogenic, and stromal ki-

nases. It has been shown that several compensatory pathways are activated during therapy with bevacizumab (Avastin) and FOLFIRI (leucovorin, fluorouracil, irinotecan).2 According to Dr. Grothey, this provides a rationale for using a multitargeted agent following progression.

By Charles L. Bennett, MD, PhD, MPP, Zaina P. Qureshi, PhD, MPH, and Oliver Sartor, MD

See Page 42

CORRECT Trial Dr. Grothey presented the results of the global ORRECT trial, which enrolled 760 patients from 105 C centers, randomly assigning them 2:1 to best supportive care plus either regorafenib (160 mg/d for 3 weeks on, 1 week off) or placebo. The primary endpoint was overall survival. Sixty percent of the patients had received at least four prior treatment regimens, which had to include a fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and if continued on page 6

Issues in Oncology

Defining Meaningful Benefit: The Debate Continues in Bevacizumab’s Wake A Conversation with Harold J. Burstein, MD, PhD

n 2002, Tim F., a 17-year-old liver transplant patient, received 40,000 units of erythropoietin weekly, beginning immediately after his transplantation procedure.1 His family had purchased the product from the local CVS Pharmacy, upon his discharge from a Manhattan hospital. After each injection, Tim experienced severe muscle cramps and abdominal pains, which tremendously alarmed his parents. His nurse became aware of an FDA Public Health Advisory warning of instances of counterfeit erythropoietin. She inspected the vials of erythropoietin, noting several misprints on the label. She reported these concerns to the transcontinued on page 9

Dr. Bennett and Dr. Qureshi are with South Carolina College of Pharmacy, Columbia and Charleston, South Carolina, and Arnold School of Public Health of the University of South Carolina, Columbia, South Carolina; Dr. Bennett is also with Hollings Cancer Center, Charleston, South Carolina; Dr. Sartor is with Tulane College of Medicine and the Tulane Cancer Center, New Orleans.

By Ronald Piana

he events surrounding the labeling of bevacizumab (Avastin) have been well covered since last November when the FDA withdrew the drug’s accelerated approval as a treatment for metastatic breast cancer. However, the controversy initiated a debate over the value of endpoints in clinical trials in advanced cancer that remains unresolved.

The ASCO Post recently spoke with Harold J. Burstein, MD, PhD, Associate Professor of Medicine, Harvard Medical School, and a medical oncologist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, about some of the unsettled issues surrounding the bevacizumab story.

Adequate Endpoints

Throughout the medical system, there is a sense that we are going to have to start looking at how health-care dollars are being spent relative to cost and benefit. — Harold J. Burstein, MD, PhD

Did the bevacizumab trials and ensuing revocation of its indication in metastatic breast cancer give us a better understanding of endpoints that will help inform future trials? The bevacizumab trials and subsequent analyses clearly underscored the

MORE IN THIS ISSUE Oncology Meetings Coverage National Comprehensive Cancer Network Annual Meeting �� 3 2012 Gastrointestinal Cancers Symposium �� 6–8 Letter to the Editor �� 2 Kenneth C. Anderson, MD, on Multiple Myeloma �� 4 Direct from ASCO �� 18

continued on page 12

A Harborside Press® Publication

The ASCO Post | MAY 1, 2012

PAGE 2

Letter to the Editor Opinion

Patient Protection and Affordable Care Act Reconsidered Editorial Board James O. Armitage, MD Editor-in-Chief Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

ASSOCIATE EDITORS

William T. McGivney, PhD Philadelphia, Pennsylvania

Joseph S. Bailes, MD Texas Oncology

James L. Mulshine, MD Rush University Medical Center

Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute 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 Michael P. Link, MD Stanford University Medical Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 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 Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

read with interest the front-page interview of Dr. Ezekiel Emanuel by Jo Cavallo in the December 15, 2011, issue of The ASCO Post. Dr. Emanuel may have had some of the most prestigious positions in all of medicine, but his opinion of the Affordable Care Act is completely misguided. This legislation represents government control of the health-care market—one-sixth of the U.S. economy—and is a disaster for America. The only resulting reduction in health-care costs will be through government rationing. Congressman Paul Ryan has a much better plan: The tax deduction available to employers for health insurance premiums for their employees needs to be made available to all. And health insurance needs to be available across state lines to encourage competition. Donald Trump states he can only get 1 bid on health insurance for his employees,

The ASCO Post Wants to Hear from You

but he would like 20. He says this kind of competition alone would reduce costs to the point where helping poor patients would not be an issue. Indiana Governor Mitch Daniels has used health savings accounts for government employees, and his state has demonstrated how costs can be reduced. Since people are using their own money with health See Page 42 savings accounts, they are more discriminating as to how it is spent. Patients have to be paying enough of the bill to be adequately concerned to even ask three key questions: First, do I really need this test? Second, how will it affect my care? Third, where can I get it the cheapest? —Calvin J. Dykstra, MD Medical Oncologist Spring Lake, Michigan

■

The Editors 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

Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France

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.

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

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Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

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.

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

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.

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

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Correspondence: Address general inquiries to Harborside Press®, 37 Main Street, Cold Spring Harbor, NY 11724. Phone: 631.692.0800; Fax: 631.692.0805. Address editorial correspondence to James O. Armitage, MD, Editor-in-Chief, c/o Cara Glynn, phone: 631.935.7654; e-mail: cara@harborsidepress.com. Advertising: For information on advertising rates, reprints, or supplements, contact Leslie Dubin, phone: 631.935.7660; e-mail: leslie@harborsidepress.com. Notice to Advertisers: Advertiser and advertising agency recognize and accept that the following language appears within the publication: “All statements, including product claims, are those of the person or organization making the statement or claim. Neither the publisher nor ASCO adopts any such statement or claim as its own, and any such statement or claim does not necessarily reflect the opinion of the publisher or ASCO.” Advertiser and advertising agency accept and assume liability for all content (including text, representations, illustrations, opinions, and facts) of advertisements printed, and also assume responsibility for any claims made against the publisher or ASCO arising from or related to such advertisements. In the event that legal action or a claim is made against the publisher or ASCO arising from or related to such advertisements, advertiser and advertising agency agree to fully defend, indemnify, and hold harmless the publisher and ASCO, and to pay any judgment, expenses, and legal fees incurred by the publisher and by ASCO as a result of said legal action or claim. The publisher reserves the right to reject any advertising that it believes is not in keeping with the publication’s standards. The publisher is not liable for delays in delivery and/or non-delivery in the event of Act of God, action by any government or quasi-governmental entity, fire, flood, insurrection, riot, explosion, embargo, strikes (whether legal or illegal), labor or material shortage, transportation interruption of any kind, work slow-down, or any condition beyond the control of the publisher affecting production or delivery in any manner.

ASCOPost.com | MAY 1, 2012

PAGE 3

News National Comprehensive Cancer Network

NCCN Clinical Practice Guidelines:

Important Updates for 2012 By Caroline Helwick

he National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology have become the most widely used guidelines in oncology practice. The Guidelines cover 97% of all patients with cancer and are continually updated by expert panels. The 2012 Guidelines include some completely new recommendations with regard to screening for lung cancer, treating adolescents and young adults, and managing acute lymphoblastic leukemia. The following is a synopsis of these and other updates and key points made by Panel representatives at the NCCN 17th Annual Conference.

Lung Cancer Screening “Screening with low-dose chest computed tomography conclusively reduces mortality from lung cancer in high-risk patients.” —Douglas E. Wood, MD, University of Washington/Seattle Cancer Care Alliance, Seattle

■■ NCCN established a new Lung Cancer Screening Panel. ■■ The Panel recommends low-dose helical CT screening of persons at risk for lung cancer. ■■ The recommendations are largely based on results from the National Lung Screening Trial, which showed a 20% relative risk reduction in mortality with screening. ■■ The cost-effectiveness of routine screening still needs to be established. ■■ The NCCN Guidelines: (1) describe the risk factors for lung cancer (2) recommend criteria for selecting high-risk persons for screening (3) provide recommendations for evaluation and follow-up of nodules found during screening (4) discuss the accuracy of lowdose chest CT screening protocols and imaging modalities (5) discuss the benefits and risks of screening

Non–Small Cell Lung Cancer “We need close collaboration among all providers, and the pathologist has a role at all levels. The more involved the pathologist, the greater the likelihood that you will come up with the right answers.” —Richard T. Cheney, MD, Roswell Park Cancer Institute, Buffalo, New York

■■ The Principles of Pathologic Review and Principles of Radiation Therapy were extensively revised in the Guidelines, to reflect the growing role of pathology and molecular profiling in the management of non–small cell lung cancer. ■■ The adenocarcinoma classification was updated to include and define adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma, and invasive adenocarcinoma variants. The use of the term “bronchioloalveolar” was eliminated. ■■ Molecularly targeted agents are not recommended for adjuvant therapy, but their importance in advanced disease is growing. ■■ Crizotinib (Xalkori) was added as a systemic therapy option for patients with advanced or metastatic disease and ALK mutations.

Acute Lymphoblastic Leukemia “On the pediatric side, there has been a significant advance in cure rates for acute lymphoblastic leukemia (ALL) over the past decades, yet the story has not been near as rosy on the adult side.” —Patrick A. Brown, MD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore

■■ The NCCN introduced new guidelines for ALL. ■■ Two main features that distinguish the different treatment paradigms in ALL are the primacy of Philadelphia chromosome (Ph) status and age. ■■ The NCCN Guidelines recom-

mend the incorporation of tyrosine kinase inhibitors for Ph+ ALL, as virtually every study has shown improved outcomes. ■■ The NCCN Guidelines recommend the use of risk stratification in ALL (including minimal residual disease testing).

Breast Cancer

Melanoma “We are moving away from the concept that the patient with earlystage disease should routinely get a battery of tests.” —Benjamin O. Anderson, MD, University of Washington/ Seattle Cancer Care Alliance, Seattle

“BRAF is drawing the most attention recently because about half of patients with metastatic melanoma will have a mutation in BRAF, usually V600E. Some degree of tumor shrinkage with vemurafenib (Zelboraf) was achieved by 80% of these patients.” —John A. Thompson, MD, University of Washington/Seattle Cancer Care Alliance, Seattle

■■ Ipilimumab (Yervoy) and vemurafenib were added to the Guidelines as category 1 options (based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate) for first-line systemic treatment of advanced or metastatic melanoma. ■■ Ipilimumab may be associated with a delayed response and potentially prolonged survival, whereas vemurafenib is indicated for patients who have the BRAF mutation. ■■ Patients with metastatic melanoma should be screened for the BRAF mutation. ■■ For clinical stage IIA melanoma, in the absence of specific signs and symptoms, routine imaging and screening blood work are not recommended.

■■ Routine systemic staging is not indicated for early breast cancer (clinical stages 0, 1, or 2) in the absence of signs or symptoms of possible metastatic disease. ■■ The use of fluoride PET/CT to identify bone lesions is an addition to the Guidelines; FDG PET/CT remains optional. ■■ Patients fitting the American College of Surgeons Oncology Group (ACOSOG) Z0011 enrollment criteria may forgo complete axillary lymph node dissection despite the potential for See Page 42 residual nodal disease: T1-T2 clinically node-negative disease with only one or two involved sentinel lymph nodes who are undergoing breast-conserving surgery and whole-breast radiation. ■■ Recurrent tumors should be retested for estrogen receptor, progesterone receptor, and HER2 status. ■■ Guidelines for monitoring metastatic disease were updated. ■■ The Panel noted that addition of everolimus (Afinitor) to exemestane in endocrine-sensitive advanced disease may be effective, but this is not a recommendation. continued on page 13

The ASCO Post | MAY 1, 2012

PAGE 4

Expert’s Corner Hematology

Novel Agents and Genomic Sequencing Show Promise in Improving Multiple Myeloma Management A Conversation with Kenneth C. Anderson, MD By Jo Cavallo

Kenneth C. Anderson, MD

or over 30 years, Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute in Boston, has focused his translational research on B-cell malignancies, especially multiple myeloma. Multiple myeloma is the second most common blood cancer in the United States, and although the disease remains incurable, the past decade has seen dramatic progress in more effective treatments, increasing median survival from just 3 years to 7 years and beyond. At last year’s Annual Meeting, ASCO presented Dr. Anderson with its 2011 David A. Karnofsky Memorial Award in recognition of his outstanding achievements in cancer research and patient care and for his pioneering work in novel, biologically based therapies for multiple myeloma. The ASCO Post talked with Dr. Anderson about the advancements that have been made in more effective treatments for multiple myeloma and how sequencing the genome in patients with multiple myeloma is revealing the mutational events that lead to development of this cancer.

Role of Novel Agents For nearly 40 years, from the 1960s until 2000, treatment for multiple myeloma was limited to chemotherapy

agents such as melphalan and stem cell transplantation, and median survival was stalled at under 3 years. Today median survival is 7 years. How has so much progress been made in just the past decade? I think there was an appreciation that novel agents, such as the proteasome inhibitor bortezomib (Velcade) or the immunomodulatory drugs thalidomide (Thalomid) and lenalidomide (Revlimid), could overcome resistance to conventional therapies in preclinical models. And those observations rapidly translated from the bench to clinical trials in relapsed/refractory myeloma, to earlier in the disease course, and most recently as initial treatment. Now, all patients with newly diagnosed myeloma receive these novel agents. Are these novel agents replacing autologous stem cell transplantation as standard of care in the front-line setting? And what is the role now of stem cell transplantation in myeloma treatment?

ezomib, lenalidomide, and dexamethasone. What quickly ensued was the use of that combination as initial therapy in myeloma, which achieved unprecedented results: 100% of patients responded—74% with very good partial responses or better and 52% with complete or near complete responses. As a consequence of those findings, we have launched a large ongoing clinical trial with our colleagues in the United States and France called the IFM-DFCI study, which is enrolling 1,000 newly diagnosed myeloma patients. All study patients receive bortezomib/lenalidomide/dexamethsone combination therapy and then have autologous peripheral blood stem cells harvested. Half the patients go on to get high-dose therapy and a stem cell transplant, and half do not. Both arms of the study will include lenalidomide as maintenance therapy. This is the first time that a study is asking whether patients who are likely to have significant responses to combination targeted therapies receive ad-

The upfront use of novel targeted combination therapies, with or without a transplant in the appropriate populations, coupled with the use of novel agents in the maintenance setting, has clearly extended progression-free and overall survival. The development of proteasome inhibitors, such as bortezomib, and immunomodulatory drugs, particularly lenalidomide, and their independent approval in the treatment of myeloma have altered the transplant paradigm. Preclinical models suggested that combining bortezomib, lenalidomide, and dexamethasone triggered synergistic myeloma killing. Clinical trials derived from these findings showed that 58% of patients whose myeloma was refractory to bortezomib or lenalidomide alone responded to the combination of bort-

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

ditional benefit from stem cell transplant. Already we know that the use of novel therapies such as lenalidomide as consolidation for transplant and for maintenance after transplant has improved progression-free and overall survival in some studies.

Myeloma as Chronic Disease? The second-generation proteosome inhibitors and immunomodulatory agents are showing promising results in studies for patients with relapsed/refractory disease. Is myeloma being converted from a fatal disease to a chronic illness?

Although we have had remarkable progress in the past decade, I think the best is yet to come. We now have the next generation of proteasome inhibitors, including the intravenous chymotryptic inhibitor carfilzomib and the oral proteasome chymotryptic inhibitors, including MLN-9708 and ONX-0192. There is also the broader inhibitor of the proteasome called marizomib (NPI-0052), which targets chymotryptic, tryptic, and caspase-like activities of the proteasome. Carfilzomib is furthest along in development and has shown remarkable activity even in patients with far advanced relapsed/refractory myeloma, with a very favorable side-effect profile. Based on early studies, the oral proteasome inhibitors MLN-9708 and marizomib are also looking very promising. In terms of second-generation immunomodulatory drugs, multicenter studies of pomalidomide have shown remarkable activity in relapsed/refractory myeloma, achieving 30% to 40% durable responses in myeloma that is resistant to bortezomib and lenalidomide. There is also a series of new targeted therapies and combination therapies in clinical trials that hold even greater promise. The upfront use of novel targeted combination therapies, with or without a transplant in the appropriate populations, coupled with the use of novel agents in the maintenance setting, has clearly extended progression-free and overall survival in many patients. Indeed, for many patients, myeloma is now a chronic disease.

Genomic Sequencing What is the sequencing of the genomes of myeloma patients showing about the diversity of the disease, and how will the findings influence the direction of research? The first genomic sequencing of human myeloma is a major advance. 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.

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E A R S UR VIVAL R ATE I S 17 % F O R PATIENTS W ITH M E TA S TATIC S OF T TIS S UE SA RC OMA , YE T SI G N IF ICANT THER APEUTIC A D VA N CE MENTS AR E LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Merck Oncology

The ASCO Post | MAY 1, 2012

PAGE 6

News

Novel Multikinase Inhibitor continued from page 1

KRAS wild-type, cetuximab (Erbitux) or panitumumab (Vectibix). “Regorafenib was tested in a setting [treatment-refractory] that many companies shy away from in drug development. There is no standard salvage therapy, although many patients long retain good performance status. There is a high unmet clinical need for active salvage therapy for this population,” he emphasized.

At the second interim data analysis, the median overall survival was 6.4 months in the regorafenib arm and 5.0 months in the placebo arm, for a hazard ratio of 0.77 (95% CI = 0.64–0.94, P = .0052). “The P value is highly significant,” Dr. Grothey emphasized. “For patients who are running out of treatment options, who have a very poor prognosis, this added 1.4 months of benefit, a 29% improvement in survival.”

Since the prespecified overall survival efficacy boundary was crossed, the Data Monitoring Committee recommended the study be unblinded and patients be allowed to cross over to regorafenib.

Disease Progression Median progression-free survival was 1.9 months for regorafenib and 1.7 months for placebo, for a hazard ratio of 0.49 (95% CI = 0.42–0.58, P < .000001). He noted that the 0.2

EXPERT POINT OF VIEW

“I certainly hope it will be approved,” he said in an interview. “Many of my patients run out of effective options for treatment long before they are ready to make a transition to supportive care alone.” Richard Goldberg, MD Herbert Hurwitz, MD Dr. Goldberg observed that the maghe results of the CORRECT trial nitude of benefit is similar to what created some degree of “buzz” was initially observed with cetuxat the 2012 Gastrointestinal Cancers imab (Erbitux) and panitumumab Symposium, with experts predicting (Vectibix) prior to the identification that regorafenib will become FDA- of KRAS as a biomarker. Finding such approved and have strong clinical a biomarker for multikinase inhibiutility. While numerically, the benefit tors such as regorafenib will be imappeared small, “There is a real dif- portant, he noted. ference with this drug,” maintained Richard Goldberg, MD, of Ohio Search for New Therapies Herbert Hurwitz, MD, of Duke State University Medical Center, Columbus, who chaired the meeting’s Cancer Institute in Durham, North Carolina, the invited discussant steering committee.

Kenneth C. Anderson, MD continued from page 4

Unlike other cancers where there is a hallmark genomic abnormality, such as BCR-ABL rearrangement in chronic myelogenous leukemia, there isn’t a predominant mutation found in the majority of patients with myeloma. What genomic researchers found was both very exciting and very consistent with what we know about the biology of multiple myeloma. In particular, there were mutations in pathways of protein homeostasis, consistent with very high levels of protein production and responses to proteasome inhibitors in myeloma. The investigators found mutations in nuclear factor–kappaB, which is an important transcriptional regulator in multiple myeloma implicated in tumor cell growth, interaction with the bone

marrow, and production of cytokines. Mutations in interferon regulatory factor 4 and Blimp-1, which are required for normal B-cell differentiation to plasma cells, are again consistent with B- and plasma-cell biology. They also found mutations in histone methyltransferases, which is again consistent with prior observations, including MMSET in the t4;14 translocation subset of multiple myeloma. A surprising finding in patients’ tumor cells was the BRAF V600E mutations that have been found in malignant melanoma. In the case of the V600E mutation there may be really short-term implications because there are already drugs, such as vemurafenib (Zelboraf), that are being used in melanoma that could now be examined and tested for efficacy in the 4% of patients who have that le-

of Dr. Goldberg's presentation, said that the findings “credential” vascular endothelial growth factor (VEGF) as a useful target in colorectal cancer, but suggested that researchers “move beyond” VEGF and epidermal growth factor receptor in their search for new therapeutic options. “Why did this drug work?” he asked. One reason may lie in the pharmacokinetics. While regorafenib and sorafenib (Nexavar) are “close cousins,” the M5 metabolite of regorafenib has a prolonged halflife (about 3 days), which may allow for target coverage during the week in which patients are off the drug. Also helping to show a treatment effect was the “clean design” of the study—single agent, no crossover, he added. “This is the first study that is a clean, randomized, monotherapy comparison to best supportive care,

sion in myeloma. So this genomic study has shown that mutations are found in patients with multiple myeloma and that the disease is genetically heterogeneous.

Genetic Profiling Will genomic tumor typing be available to all myeloma patients in the near future? Genomic profiling is moving very rapidly from research to the clinical realm. The cost is coming down very quickly and the ability to carry out the assays at a clinical level is also rapidly progressing. I do think that there will be genetic profiling of patients, which will consist of an integrated characterization of their DNA with copy number analysis, RNA with microarray profiling, and microRNA profiling with mutation analyses.

months difference does not reflect the full benefit of regorafenib. “The median difference of only 0.2 months demonstrates that medians are not the best way to show efficacy. The curves, on the other hand, separate nicely,” Dr. Grothey said. “The main emphasis,” he added, “is that the drug delayed disease progression. While response rates were low in both arms (1.6% with continued on page 7

and I applaud the investigators for this,” he said.

Further Investigation Like Dr. Goldberg, Dr. Hurwitz maintained that the overall and progression-free survival benefits were “clinically meaningful for many patients,” though he believes toxicity, especially hand-foot reactions, could be a concern for some. “This merits further investigation since these reactions can affect quality of life and occasionally lead to discontinuations.” While regorafenib is a strong candidate for regulatory approval, he said, it is important to determine the drug’s value in patients with poor performance status (who were not included in CORRECT), and its activity when given on a weekly, continuous basis.

■

Disclosure: Dr. Goldberg has received research support (which goes to Ohio State University) from Bayer. Dr. Hurwitz reported no potential conflicts of interest.

It will be a multilayered integrated profile of patients’ tumor cells not only at the time of diagnosis but also at the time of disease relapse, because we and others have shown that the genetic profile—in terms of DNA, RNA, microRNA, and mutations—does change as the patient’s disease progresses. We have had great progress in myeloma in the past 5 years, the result of cutting-edge genomics and benchto-bedside drug development collaboration between academic centers, biotech and pharmaceutical companies, regulatory agencies, and funding and research support agencies, such as the NCI, as well as patients and patient foundations. The best is yet to come.

■

Disclosure: Dr. Anderson is on the advisory board for Millennium Takeda.

ASCOPost.com | MAY 1, 2012

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News

Novel Multikinase Inhibitor continued from page 6

regorafenib and 0.4% with placebo), regorafenib produced a much higher rate of disease control (44% vs 15%), he pointed out. “This drove the efficacy of the drug,” Dr. Grothey maintained. “I personally have treated 35 patients within the trial. I have had one patient on the drug for almost 12 months, with excellent performance status, and virtually no side effects after dose-adjustment,” he offered. The most frequent grade 3 or higher adverse events with regorafenib were hand-foot skin reaction (17%) and fatigue (15%). No new or unexpected safety signals, above and beyond what has been seen with other multikinase inhibitors, were observed.

nase inhibitors [such as regorafenib] in later lines of therapy,” he suggested. Phase II studies evaluating regorafenib in combination with standard chemotherapy backbones are planned, “moving the drug into earlier lines of therapy,” he said, but it remains to be seen whether the combination will be as beneficial as the single agent, he added.

■

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

References 1. Grothey A, Sobrero A, Siena S, et al: Results of a phase III randomized, double-blind, placebo-controlled, multicenter trial (CORRECT) of regorafenib plus best supportive care versus placebo plus BSC in patients with metastatic colorectal cancer who have pro-

Small Molecules in Colorectal Cancer Dr. Grothey acknowledged that, up to now, small-molecule tyrosine kinase inhibitors have not made an impact in colorectal cancer. “So far, in drug development, sorafenib (Nexavar), cediranib, and PTZ/ZK, which were all added to first-line or second-line chemotherapy, have not produced the desired result,” he said in a press briefing. Regorafenib, on the other hand, was evaluated as a single agent, which Dr. Grothey credits with providing the treatment effect.

Regorafenib in Colorectal Cancer ■■ Regorafenib is a multitargeted tyrosine kinase inhibitor.

■■ The global phase III CORRECT

trial met its primary endpoint, improved overall survival, for regorafenib as a single agent, vs best supportive care, in patients with heavily pretreated metastatic colorectal cancer.

■■ Survival was improved by 1.4 months (6.4 vs 5.0 months), which reflected a 23% reduction in risk of death.

Other pathways can contribute to prostate cancer promotion.5

“I think regorafenib can produce an effect because we used it as a single agent and not with chemotherapy, and in a patient population that had gone through many lines of treatment. We know that tumors change over time, and activate multiple pathways and resistance mechanisms. It could be that we need more promiscuous multiki-

References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008; 68(11):4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68 (15):6407-6415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5): 2815-2825. 4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 2/12 08ADA10011R1

gressed after standard therapies. 2012 Gastrointestinal Cancers Symposium. Abstract LBA385. Presented January 21, 2012. 2. Kopetz S, Hoff PM, Morris JS, et al: Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: Efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol 28:453-459, 2010.

The ASCO Post | MAY 1, 2012

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News Gastrointestinal Oncology

ColoPrint Gene Assay Can Guide Treatment Decisions in Stage II Colon Cancer By Caroline Helwick

oloPrint, an 18-gene expression profile assay for patients with early-stage colon cancer, accurately stratifies patients by recurrence risk and identifies a subset who can be adequately treated by surgery alone, investigators reported at the 2012 Gastrointestinal Cancers Symposium.1

Josep Tabernero, MD

According to lead investigator Josep Tabernero, MD, of Vall d’Hebron University Hospital in Barcelona, Spain ColoPrint was more powerful than clinical factors recommended by ASCO for selecting highrisk stage II patients, which include T4 tumors, perforation, fewer than 12 lymph nodes assessed, and high-grade histology.

Development and Validation There is a need for a means of accurately predicting which patients with

stage II colon cancer need adjuvant chemotherapy, due to their risk of relapse and metastasis. Since the clinical factors that often guide treatment decisions are not particularly accurate, many patients are unnecessarily treated, he said. ColoPrint was developed using gene-expression data from whole-genome microarrays and was validated in independent patient cohorts from five European hospitals. Fresh frozen tissues, clinical parameters, microsatellite instability status, and follow-up data for patients were available. Analyses were performed on 320 patients with stage II colon cancer followed for a median of 70 months. By microarray technology and tumor classification methods, researchers identified a subset of 18 genes that proved to be predictive for the risk of recurrence of stage II and III colon cancer. Using this, they developed a prognostic profile, ie, a classifier of risk, and independently validated it. In the clinical validation study, ColoPrint classified 209 patients—over 65% of the total—as having a low risk for disease recurrence. Their 3-year relapse-free survival was 91%, Dr. Tabernero reported. In contrast, 111 patients, about 35%, were classified as being at high

ColoPrint Assay in Stage II Colon Cancer ■■ The ColoPrint assay was developed using gene-expression data from

whole-genome microarrays and was validated in independent patient cohorts from five European hospitals.

■■ ColoPrint classified 65% of patients with stage II colon cancer as having a low risk for disease recurrence: Their 3-year risk of relapse was 9%.

■■ ColoPrint classified 35% as having high risk for recurrence; their 3-year risk of relapse was 26%.

■■ The assay is undergoing further validation studies.

Visit

EXPERT POINT OF VIEW

xel Grothey, MD, of the Mayo Clinic, Rochester, Minnesota, told The ASCO Post that he finds the data “intriguing” and that the study exemplifies the value of developing molecular signatures for use in colon cancer. “It identifies patients with an excellent prognosis, who perhaps should not be further treated,” he said. While the Oncotype DX Colon Cancer Assay also claims to do the same, ColoPrint “spreads out the prognostic groups a little further,” he noted, assigning just two risk groups (low, high) rather than three (low, intermediate, high). “The risk separation is larger than we see with Oncotype DX,” he noted. But the Oncotype DX Recurrence Score has been evaluated in a much larger series of patients, he acknowledged. In addition, the need for fresh frozen tissue with ColoPrint could be a drawback, he added. “But, there was a time [in patients with breast cancer] when estrogen and progesterone receptor status was done on fresh frozen tissue, so if we become convinced that this is the right way to go, we could probably adapt,” he added.

■

Disclosure: The Mayo Clinic received research funding for this study and honoraria for Dr. Grothey’s consulting activities from Bayer.

risk, and their 3-year relapse-free survival was 74% (P = .001). The 5-year relapse-free survival rates were 88% vs 71%, respectively. By hazard ratio, the high-risk patients had almost a threefold increased risk of relapse, vs the low-risk patients.

Further Analysis Microsatellite instability status and the number of assessed lymph nodes were the only significant clinical parameters that stood out in the univariate analysis. Parameters from the ASCO recommendations for the identification of high-risk patients (T4, perforation, less than 12 nodes assessed, and/ or high grade) were not significant, and no clinical parameter added power to the ColoPrint classification in the multivariate analysis, he reported. “Clinical risk factors distinguish the risk groups, but they are not sufficient,” Dr. Tabernero said. “The ColoPrint is better at identifying high-risk

patients than any clinical factor alone. It complements clinical and pathologic factors, for making better treatment decisions.” ColoPrint is developed by Agendia, Inc, which also markets the MammaPrint assay in breast cancer. In the United States, ColoPrint is currently in the fiSee Page 42 nal stage of validation, and evaluation is ongoing in the PARSC clinical trial.

■

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

Reference 1. Tabernero J, Moreno V, Rosenberg R, et al: Clinical and technical validation of a genomic classifier (ColoPrint) for predicting outcome of stage II colon cancer patients. 2012 Gastrointestinal Cancers Symposium. Abstract 384. Presented January 21, 2012.

website at ASCOPost.com

ASCOPost.com | MAY 1, 2012

PAGE 9

Perspective

Caveat Oncologist continued from page 1

plant surgeon, who in turn contacted the manufacturer. Tim had indeed received counterfeit erythropoietin. Counterfeit pharmaceuticals are an increasingly important safety concern. An ideal target for counterfeiting is high-cost, parentally administered medications packaged in vials.2 Three of the most prominent drug counterfeiting episodes in recent years have involved hematology/oncology products. While most reports on counterfeit drugs implicate Asia as the weak link in a complex international supply chain, seSee Page 42 curity breaches have also occurred in the United States.

cals. Reviewing experiences with prior counterfeit pharmaceutical episodes, such as the case with Tim F. discussed above, may serve to increase awareness of this concern. Clinicians should consider the possibility that counterfeit product has been used when evaluating patients who experience unexplained acute toxicity or

loss of efficacy. Attention must be paid to this growing public health threat. See our report on page 10 for more about experiences involving counterfeit drugs and this very real issue in hematology and oncology practice today.

■

Disclosure: Drs. Bennett, Qureshi, and Sartor reported no potential conflicts of interest.

‘Fake Fakes’ and ‘Real Fakes’ Counterfeit drugs come in two varieties. “Fake fakes” are pharmaceutical packages that differ from what is stated on the affixed label, including having smaller amounts of active ingredient, wrong ingredients, or no active ingredient at all. “Real fakes” contain the expected active ingredients, but have not been made by indicated manufacturers, or the vials may have counterfeit labels or fake expiration dates. Clinicians rarely suspect that patients receive counterfeit pharmaceuti-

The ASCO Post

@ASCOPost References: 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61(7):2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Yu S-Q, Lai K-P, Xia S-J, Chang H-C, Chang C, Yeh S. The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer. Asian J Androl. 2009;11(1):39-48. 4. Corey E, Quinn JE, Buhler KR, et al. LuCaP 35: a new model of prostate cancer progression to androgen independence. Prostate. 2003;55(4):239-246. 5. Loberg RD, St. John LN, Day LL, Neeley CK, Pienta KJ. Development of the VCaP androgen-independent model of prostate cancer. Urol Oncol. 2006;24(2):161-168.

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 2/12 08ADA10027R2

References 1. Qureshi ZP, Norris LB, Sartor O, et al: Caveat oncologist: Clinical findings and consequences of distributing counterfeit erythropoietin in the United States. J Oncol Pract 8:84-90, 2012. 2. Rudolf PM, Bernstein IB: Counterfeit drugs. N Engl J Med 350:1384-1386, 2004.

The ASCO Post | MAY 1, 2012

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Issues in Oncology

Clinical Findings and Consequences of Distributing Counterfeit Drugs for Hematology and Oncology By Charles L. Bennett, MD, PhD, MPP, Zaina P. Qureshi, PhD, MPH, and Oliver Sartor, MD

s introduced in our report on page 1 of this issue, counterfeit pharmaceuticals are an increasingly important safety concern, and three of the most prominent drug-counterfeiting episodes in recent years have involved hematology/oncology products.

Counterfeit Erythropoietin Helen B., a 61-year-old woman with recurrent breast cancer, received erythropoietin, 40,000 units weekly for 8 weeks, which was initiated to treat chemotherapy-induced anemia.1 Despite the erythropoietin therapy, her anemia became more severe. Her nurse had recently read a Dear Healthcare Professional letter, describing 40,000-unit vials of counterfeit erythropoietin confiscated from several regional distributors. The nurse noted that the lot number on the patient’s vial was the same as the lot number reported in the Letter, and typing imperfections matched those also described in the Warning Letter. Shortly thereafter, the patient’s breast cancer became more aggressive, and she died from the disease. Testing by the manufacturer revealed that the vials contained 2,000 units of erythropoietin instead of the purported 40,000 units—so-called “uplabeled” vials. Subsequent investigation revealed that 110,000 vials of uplabeled erythropoietin had been distributed throughout the United States (Fig. 1). Criminal investigations revealed that the uplabeled erythropoietin had been sourced from a small pharmacy in Miami Beach. Counterfeiters had replaced “2,000-unit” vial labels with counterfeit “40,000-unit” vial labels and then sold relabeled product to wholesalers throughout the country. These wholesalers sold the product to other wholesalers, who sold it to Dr. Bennett and Dr. Qureshi are with South Carolina College of Pharmacy, Columbia and Charleston, South Carolina, and Arnold School of Public Health of the University of South Carolina, Columbia, South Carolina; Dr. Bennett is also with Hollings Cancer Center, Charleston, South Carolina; Dr. Sartor is with Tulane College of Medicine and the Tulane Cancer Center, New Orleans.

Charles L. Bennett MD, PhD, MPP

Zaina P. Qureshi, PhD, MPH

national pharmaceutical distributors, who sold it to pharmacies nationwide. Counterfeit labels were identified by their lot numbers and printing mistakes. Of note, the FDA received reports of only 6 of an estimated 20,000 or more patients who may have received uplabeled erythropoietin.

Counterfeit Heparin In 2008, the FDA received reports of 81 deaths and 785 severe allergic reactions among renal dialysis patients shortly after undergoing a hemodialysis session. An additional 68 deaths following dialysis procedures were reported in countries outside the United States during the same period. Initial concerns Probable sales

Amgen drug maker 2,000 U/mL

Manufacturer Cardinal 8,931 boxes 2,000 U/mL

National wholesaler

Unknown sources and sales Confirmed sales

AmerisourceBergen 3,363 boxes 2,000 U/mL

J&M Pharmacare FL pharmacy bought 12,294 boxes 2,000 U/mL

Pharmacy

Armando Rodriguez FL go-between 12,294 boxes 2,000 U/mL

Gray market Silvino Morales relabeled vials

Playpen South FL strip club Nick Just/Paul Perito

Tradewinds Trading TX wholesaler 135 boxes Lot 2970 Rebel Dist CA wholesaler

Grapevine Trading OH wholesaler

Ivan Villarchao FL 45 boxes Lot 2970

Optia Medical Mark Novosel UT shell co. 45 boxes Lot 2970

AD Pharmaceutical FL wholesaler 2 boxes Lot 2970

Armin Medical NH wholesaler 129 boxes Lot 2970

Jemco Medical FL wholesaler 16 boxes Lot 2970

Double J unlicensed FL wholesaler

Medix Intl, Carlos Luis, TX shell co. 180 boxes Lot 2970

Express Rx, Eddie Mor, TX shell co. 180 boxes Lot 2970

AmeRx Susan Cavalieri FL wholesaler 182 boxes Lot 2970

Dialysist West AZ wholesaler 1,056 boxes, Lot 2970

YW Consultants unlicensed FL wholesaler

Premier Medical Group GA shell co. 460 boxes Lot 1091 812 boxes Lot 2970

CSG TN wholesaler 812 boxes Lot 2970

CSG TN wholesaler 460 boxes Lot 1091

Dialysist West AZ wholesaler 461 boxes, Lot 1091

National wholesaler

AmerisourceBergen KY distribution center 1,517 boxes

Pharmacy

CVS, NY

Patient

Printer in Hialeah, FL made counterfeit labels

Jose Grillo alleged FL counterfeiter 2,000 U/mL à40,000 U/mL

Coastal Medical VA wholesaler 135 boxes Lot 2970

Regional wholesaler

Oliver Sartor, MD

Patient

Fig. 1: Reconstruction of the route traversed by counterfeit erythropoietin. Figure from Dangerous Doses by Katherine Eban. Copyright © 2005 by Katherine Eban. Reprinted by permission of Houghton Mifflin Harcourt Publishing Company. All rights reserved.

about these reactions had been reported by dialysis workers at a pediatric clinic in Missouri. Following initiation of a dialysis session, facial edema, tachycardia, hypotension, urticaria, and nausea had developed in eight children undergoing hemodialysis. Case-finding by the Centers for Disease Control and Prevention identified similar clusters in other states, including patients undergoing photopheresis or treatment for cardiac conditions. A common feature was receipt of heparin produced by Baxter Healthcare.2 In January 2008, nine lots of vials of heparin manufactured by Baxter were voluntarily recalled. A more extensive recall of heparin products occurred in February 2008. Although initial evaluation failed to identify any impurity, subsequent evaluation revealed that the heparin was contaminated with oversulfated chondroitin sulfate. Additional investigations indicated that contaminated heparin had been distributed in Australia, Canada, China, Denmark, France, Germany, Italy, Japan, the Netherlands, New Zealand, and the United States from product made using active pharmaceutical ingredient obtained from 14 Chinese suppliers. Investigation revealed that a large percentage of the heparin supplied by Baxter (the supplier of 50% of the domestic heparin supply at that time) was contaminated with oversulfated chondroitin sulfate. Contaminated product was produced from active ingredient supplied by companies (“consolidators”) that processed heparin from pig intestines in small unregulated workshops in China. The other major supplier of heparin produced heparin from pig intestines provided by farmers whose work sites had been evaluated for quality by the manufacturer. After contamination of the Baxter product was discovered, FDA assisted the other supplier in becoming the sole supplier of domestic heparin. This case readily underlines the difficulty in regulating pharmaceutical manufacturing in a global marketplace.

Counterfeit Bevacizumab In 2010, bevacizumab (Avastin) was administered intravitreally at Shanghai Number 1 Hospital to 116 patients for treatment of macular degeneration.3 Three vials of bevacizumab were the source of product for the patients.

ASCOPost.com | MAY 1, 2012

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Issues in Oncology

Testing by the manufacturer and an independent laboratory in Shanghai confirmed that the vials did not See Page 42 contain active pharmaceutical ingredient. In 2012, FDA was alerted by foreign regulatory agencies that additional vials of counterfeit bevacizumab had been identified. Following up on this report, FDA identified 16 medical practices in California, 2 in Texas, and 1 in Chicago that had purchased 167 vials of counterfeit bevacizumab. Fortunately, there was no evidence that counterfeit products had been administered to patients. FDA and regulatory authorities in Europe hypothesized that counterfeit bevacizumab originated in China or India and was sold to pharmaceutical wholesalers in Turkey and Syria, then to a wholesaler in Egypt, and then on to a Swiss wholesaler. A Danish wholesaler purchased counterfeit vials from the Swiss wholesaler and shipped the product to a British wholesaler. A Canadian Internet pharmaceutical distributor (CanadaDrugs.com) purchased the counterfeit vials and sold these products to wholesalers in Tennessee and Montana—who, in turn, sold the product to the practices in California, Texas, and Chicago. Counterfeit labels contained misprints of vial lot numbers (not matching the lot numbers on the box) and included the Roche logo (rather than the Genentech logo).

ingredients originates from foreign suppliers—the FDA is devoting more resources to inspecting foreign pharmaceutical manufacturers. Clinicians should consider the possibility that counterfeit product has been used when evaluating patients who experience unexplained acute toxicity or loss

of efficacy. Attention must be paid to this growing public health threat.

■

Disclosure: Drs. Bennett, Qureshi, and Sartor reported no potential conflicts of interest.

References 1. Eban K: Dangerous doses: How counterfeiters are contaminating America’s

Looking Forward The travel history of pharmaceuticals provided to patients in the United States can be remarkably complex. Regulatory agencies, policymakers, manufacturers, wholesalers, and pharmacies are adopting new strategies to ensure the safety of the supply chain. Most importantly—given that 80% of domestic active pharmaceutical

Reporting Counterfeit Drugs If you have any information on suspect counterfeit drug products: • Call FDA’s Office of Criminal Investigations at 800-551-3989, or • Visit the FDA's Office of Criminal Investigation's website (www.accessdata.fda.gov/scripts/ email/oc/oci/contact.cfm), or

References : 1. Pienta KJ, Bradley D. Mechanisms underlying the development of androgenindependent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671. 2. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454. 3. Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med. 2004;10(1):33-39.

• E-mail DrugSupplyChainIntegrity@ fda.hhs.gov

Janssen Biotech, Inc. © Janssen Biotech, Inc. 2012 2/12 08A11024R3

drug supply. New York, Harcourt Inc, 2005. 2. Blossom D, Kallen A, Patel P, et al: Outbreak of adverse reactions associated with contaminated heparin. N Engl J Med 359:2674-2684, 2008. 3. Sun X, Xu X, Xhang X: Counterfeit bevacizumab and enopthalmitis. N Engl J Med 365:378-379, 2011.

The ASCO Post | MAY 1, 2012

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Issues in Oncology

Meaningful Benefit continued from page 1

concept that survival is a very important endpoint in cancer clinical trials. However, I do not believe that the bevacizumab issue resolved the important question that remains in breast can36 ASCO Ad_v8_Layout 1 4/18/12 12:54 PM Page 1 cer studies: What magnitude of ben-

efit would be required (and in which specific line of therapy) to determine whether progression-free survival is an adequate endpoint in breast cancer?

Accelerated Approval The accelerated approval system is seen, especially by the lay public, as a nec-

essary vehicle to rapidly bring lifesaving drugs to patients. Has the system suffered a credibility crisis? No, in fact, I think the credibility of the accelerated approval system will be strengthened by the controversy surrounding the bevacizumab issue, largely because of comments

IMMUNO-ONCOLOGY: AN EVOLVING APPROACH TO CANCER CARE

Saturday, June 2, 2012 7:30 PM - 9:30 PM Great Lakes Ballroom The Westin Michigan Avenue Chicago 909 North Michigan Avenue Chicago, Illinois

Learning Objectives Upon completion of this activity, participants should be better able to: • Enhance knowledge on the biological foundations of immunooncology approaches to the treatment of cancer • Describe the roles, targets, and mechanisms of action of novel and emerging immuno-oncologic agents • Evaluate new safety and efficacy data on recently approved and emerging immuno-oncologic agents across tumor types • Identify unique patterns of clinical response in patients treated with immuno-oncologic agents • Monitor and manage immune-related adverse effects associated with immuno-oncologic agents • Describe how new immuno-oncologic agents are being integrated into existing treatment evidence-based guidelines

Agenda

Target Audience This activity is designed to meet the educational needs of oncologists and other healthcare professionals involved in cancer care.

Purpose The goal for this activity is to keep healthcare professionals involved in cancer care informed on rapidly evolving immunologic treatment approaches and their clinical applications.

Activity Overview Our immuno-oncology expert faculty panel will provide an update on the important clinical advances regarding immunotherapies. Didactic sessions will review the rationale for targeting immune modulatory pathways in different tumor types (including melanoma, prostate cancer, lung cancer, and renal cell carcinoma) and will discuss safety and efficacy of recently approved and emerging immunologic agents, clinical experience with approved agents, the latest data from ongoing trials and the management of immune-related adverse events. Case studies will stimulate interactive discussion of real-world treatment scenarios, expert clinical experience, and challenges faced in the incorporation of novel and emerging immunotherapies in clinical practice. This satellite symposium will be supported by the SeamlessCMETM technology which enhances the learning experience by providing participants with the opportunity to view the presentation, respond to questions, and to pose real-time questions, comments, or personal experiences to the faculty via provided iPad devices (or on your own personal device).

Jointly sponsored by:

7:30 - 7:35 pm Welcome and Activity Overview 7:35 - 7:50 pm Immuno-Oncology: Understanding Biological Foundations of the Immune System in Cancer 7:50 - 8:10 pm Melanoma: A Classic Tumor Model for Immunotherapy 8:10 - 8:25 pm The Evolving Role of Immunotherapy for Prostate Cancer 8:25 - 8:40 pm The Emerging Role of Immunotherapy for Lung Cancer 8:40 - 8:55 pm Emerging Immunotherapies for Renal Cell Carcinoma 8:55 - 9:15 pm Interactive Case Studies: Applying Current Immunotherapies Into Practice 9:15 - 9:25 pm Expert Panel Perspectives: Placing Current and Emerging Immunotherapies in Clinical Context 9:25 - 9:30 pm Q&A and Activity Conclusion

Chairperson Thomas F. Gajewski, MD, PhD The University of Chicago Medicine Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Postgraduate Institute for Medicine and the Institute for Medical Education & Research. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation The Postgraduate Institute for Medicine designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ASCO Disclaimer Not an official event of the 2012 ASCO Annual Meeting. Not sponsored or endorsed by ASCO or the Conquer Cancer Foundation. There is no fee for participating in this educational activity.

To register please go to www.IMERonline.com/immuno_oncology

In partnership with: Jointly sponsored by:

that arose from a comprehensive 2009 Government Accountability Office (GAO) report that addressed the value of the accelerated approval program.1 One recommendation was that the FDA Commissioner should clarify the conditions under which the agency would exercise its authority to expedite the withdrawal of drugs that are approved based on surrogate endpoints under the accelerated approval process, if sponsors either fail to complete required confirmatory studies with due diligence, or if studies are completed but fail to demonstrate the clinical effectiveness of the drugs. Bevacizumab is an example of what this GAO mandate was striving to accomplish. The subsequent confirmatory trials—AVADO and RIBBON-1— did not demonstrate a benefit on par with the original E2100 study. In response, FDA applied its authority and revoked the approval, which is what the GAO report encouraged. So, I think the bevacizumab episode actually gives more backbone to the requirements that follow an accelerated approval, which strengthens the whole scientific and drug regulatory process.

Associated Guidelines and Coverage Has the guideline system used for coverage decisions been challenged by FDA’s revocation? The data that have emerged in the years following the original bevacizumab trial have eroded the sense that this drug is a major advancement in the treatment of breast cancer. In response to those data, my understanding is that the utilization of bevacizumab for breast cancer has sharply declined. That response by clinicians across the country has more to do with the data than the FDA decision, because this usage trend was beginning before the agency took the formal action to withdraw the drug’s indication. It is also likely that anytime there is uncertainty about a drug’s coverage status, the utilization of that treatment will decline. Moreover, whether thirdparty payers will continue to support use of a drug that has specifically had approval withdrawn by the FDA remains to be seen.

The Cost Issue Although the regulatory bodies do not use cost as an instrument in their decision-making, is it realistic to believe continued on page 13

This activity is supported by an independent educational grant from Bristol-Myers Squibb Company.

ASCOPost.com | MAY 1, 2012

PAGE 13

News

NCCN Guidelines continued from page 3

■■ The Panel noted that evidence supports the addition of everolimus to exemestane in women who fulfill the criteria for the BOLERO-2 trial (endocrine-sensitive, previously treated advanced disease) but this is not a recommendation.

Non-Hodgkin Lymphoma

the patient is asymptomatic, observation until disease progression or occurrence of symptoms is reasonable. ■■ In symptomatic patients with T-PLL, alemtuzumab (Campath) is the treatment of choice for previously untreated disease. ■■ Testing for MYC positivity is advised for all diffuse large B-cell and related lymphomas, due to the poor prognostic impact related to this finding.

Adolescent and Young Adult Oncology

guidelines, not treatment guidelines. ■■ The new Panel was instituted in light of the limited progress that has been made in managing cancer in this age group. ■■ Reasons for poor outcomes in AYAs include low participation in clinical trials, unaddressed psychosocial issues, poor treatment adherence, and lack of a consistent treatment approach.

—Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago

■■ New Guidelines for the rare but aggressive disorder of mature T cells known as T-cell prolymphocytic leukemia (T-PLL) were introduced. ■■ The treatment pathway centers on the presence or absence of symptoms. If

Meaningful Benefit continued from page 12

that given the untenable rise in healthcare expenditures that cost can be left out of the equation? Current law prevents cost from being a consideration in the FDA approval process or for Medicare and Medicaid coverage decisions. Approval and coverage is based solely on a drug’s safety and efficacy. Other countries, by mandate, do include cost analyses in their drug regulatory decision-making procedure. Everyone wants newer, better treatments for cancer. Innovation is expensive, and companies that invest in research and development to promote innovation that brings important new drugs to patients deserve the appropriate rewards of the marketplace. However, we as a medical community do not ask rigorously enough what cancer drugs should cost and what

“Compared with younger and older patients, there has been dismal progress in treating adolescents and young adults with cancer.” —Peter F. Coccia, MD, University of Nebraska Eppley Cancer Center at the Nebraska Medical Center, Omaha

■■ In 2012, the NCCN established new Guidelines for adolescents and young adults; they are supportive care clinical return they should deliver for that cost. Throughout the medical system, there is a sense that we are going to have to start looking at how healthcare dollars are being spent relative to cost and benefit. The discussion about bevacizumab in breast cancer highlighted the fact that we do not have a solid enough process in the medical community for evaluating a drug before it goes to market.

Closing Thoughts As a breast cancer specialist, do you have any last thoughts on what we’ve learned from the bevacizumab experience? There is still tremendous innovation in the field of breast cancer, and the good news is that there are many exciting drugs in the pipeline. We have a growing understanding of tumor biology, and we are still going

Renal Cell Carcinoma

Hodgkin Lymphoma “Stanford V is an acceptable regimen, particularly for patients who may have some underlying cardiac disease.” —Leo I. Gordon, MD, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago

“Most patients with T-cell prolymphocytic leukemia are symptomatic with fairly aggressive disease and need treatment.”

vention is appropriate). ■■ The NCCN does not recommend routine PET surveillance after treatment of early disease unless relapse is suspected, nor bone marrow biopsy for favorable disease.

■■ As initial treatment for favorable stage IA or IIA Hodgkin lymphoma, the Panel gave category 1 recommendations to both the ABVD regimen (doxorubicin, bleomycin, vinblastine, dacarbazine) and Stanford V regimen (doxorubicin, vinblastine, mechlorethamine [Mustargen], etoposide, bleomycin, vincristine, prednisone), given along with involved-field radiotherapy. ■■ Use of the ABVD regimen alone for stage IIA disease carries a category 2B recommendation (ie, based upon lower-level evidence, there is NCCN consensus that the interto see progress in breast cancer in spite of the controversy surrounding bevacizumab. But it is important to note that the final word on bevacizumab isn’t out yet. Results from studies in the adjuvant setting and more research in the metastatic setting are yet to be seen. At the same time, I think the bevacizumab experience emphasizes some real challenges for regulators, researchers, and clinicians to identify the most important endpoints for clinical trials. Also, how much data are required for decision-making, and what clinical benefits should we insist upon from a regulator’s perspective, taking into consideration the clinical and patient perspectives, which add another layer of value to the process. And last, as a community, what cost should we bear relative to the clinical benefits of the treatments we provide to society.

“I have yet to see, in other solid tumors, the approval of seven drugs in just 6 or so years, as we have seen in renal cell carcinoma.” —Toni K. Choueiri, MD, Dana-Farber/ Brigham and Women’s Cancer Center, Boston

■■ Axitinib (Inlyta), a multi–tyrosine kinase inhibitor, was added to the NCCN Guidelines as a second-line option for advanced renal cell carcinoma. ■■ Cytoreductive nephrectomy remains beneficial in the era of targeted agents.

■

See page 17 for conflict of interest disclosures.

The bevacizumab debate poses all these questions but fails to answer all but one: Is bevacizumab going to be part of current breast cancer treatment? The answer seems to be no. As we move forward into an era when more drugs become available for more types of cancers, we will face more of these difficult questions, not fewer. Over the past decades, we have seen tremendous success in breast cancer survival rates, and the best is yet to come.

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

Reference 1. U.S. Government Accountability Office: New drug approval: FDA needs to enhance its oversight of drugs approved on the basis of surrogate endpoints. September 2009. Available at http://www. gao.gov/new.items/d09866.pdf. Accessed March 12, 2012.

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.

CRI00334/CRI445700

Printed in USA/April 2012

ASCOPost.com | MAY 1, 2012

PAGE 17

FDA Update

FDA Approves Investigational New Drug Application for Clinical Testing of Oncology Drug Candidate ME-344

arshall Edwards, Inc, an oncology company focused on the clinical development of novel therapeutics targeting cancer metabolism,

announced that it has received approval from the FDA of its Investigational New Drug (IND) application for ME344, the Company’s lead mitochon-

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

drial inhibitor. The Company is in the process of initiating a phase I clinical trial of intravenous ME-344 in patients with solid refractory tumors.

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

The phase I clinical trial of ME344 is being conducted in collaboration with the Sarah Cannon Research Institute. The open-label, dose-escalation trial will evaluate the safety and tolerability of intravenous ME-344 in patients with refractory solid tumors. In addition, the trial is designed to characterize its pharmacokinetic profile and describe any preliminary clinical antitumor activity observed. Patients will be administered intravenous infusions of ME344 once weekly for three weeks and, after safety assessment, may continue weekly dosing if a clinical benefit is determined. The trial is expected to enroll up to 24 patients at three sites. Additional information regarding the trial, including enrollment criteria and site information, is available on the National Institutes of Health clinical trials database at www.clinicaltrials.gov. ME-344 is the Marshall Edwards’ lead mitochondrial inhibitor and an active metabolite of NV-128, a first-generation compound. In preclinical studies, ME-344 has demonstrated far superior antitumor activity against a broad range of human cancer cell lines compared to NV128, including breast, colorectal, and ovarian cancers.

■

NCCN Guidelines continued from page 13 Disclosure: Comprehensive disclosure information relevant to the complete NCCN Clinical Practice Guidelines is available at nccn. org. The following NCCN panel members reported no potential conflicts of interest with the manufacturer(s) of product(s) mentioned in this report: Drs. Douglas E. Wood, Patrick A. Brown, Peter F. Coccia, Leo I. Gordon, John A. Thompson, Benjamin O. Anderson. Other NCCN panel members reported potential conflicts of interest as follows: Dr. Richard T. Cheney serves on an expert panel for OptumHealth to evaluate Centers of Excellence. Dr. Toni K. Choueiri serves on advisory boards for Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer/Onyx, See Page 42 and Aveo Pharmaceuticals.

The ASCO Post | MAY 1, 2012

PAGE 18

Direct from ASCO

JCO Presents New Training Seminar for Authors

ournal of Clinical Oncology (JCO) recently launched a training seminar for potential authors, entitled, “Publishing Your Research: A Seminar From the Editors of JCO.” The first seminar was held in January prior to the 2012 Gastrointestinal Cancers Symposium in San Francisco. Daniel G. Haller, MD, Editor-in-Chief Emeritus, presented the seminar to a group of 16 visiting oncologists from Japan.

Seminar Topics JCO developed the seminar to help meet the need that medical researchers have to promptly write up the results of new studies and publish their work. Attendees learn how to identify the appropriate target jour-

nals for submissions, meet journal submission requirements, assess and ensure the quality of manuscripts, and navigate the peer-review process. Because many journals follow the guidelines established by the International Committee of Medical Journal Editors, the seminar combines these criteria along with instruction based on JCO’s guidelines. Seminar topics include: ■■ Determining authorship and creating the author list ■■ Writing key sections of an original report ■■ Reviewing statistical guidelines ■■ Understanding why manuscripts may be rejected ■■ Responding to decision letters

ASCO Guidelines Support Weightbased Chemotherapy Dosing

he American Society of Clinical Oncology supports research showing that it’s safe and effective for people with cancer— especially those who are obese—to receive higher chemotherapy doses

based not on estimates but on their actual weight. Direct your patients to ASCO’s guidelines on weightbased dosing. Find information for patients on more than 20 ASCO guidelines at www.cancer.net/whattoknow.

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■■ Following common publishing ethical practice

Ethical Practice in Publishing As Dr. Haller explained, ethical practice in publishing is one of the most important topics covered: “As medical journalism has evolved, unfortunately issues of fraud, plagiary, and conflict of interest have been more apparent and publicized both in medical journals and the lay press. Whenever I speak of these issues, I always ask the audience whether they ever had formal training in such authorship issues; the resounding answer is ‘no.’ We

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

hope that raising these issues with prospective authors will reduce the incidence of such infractions.” JCO anticipates that the knowledge that authors gain in the seminar will translate into better-prepared manuscripts and will enhance the authors’ likelihood for article acceptance by JCO or other medical journals. Organizations interested in hosting the seminar may contact the ASCO Licensing, Rights, and Permissions Office at 571-483-1714 or licensing@ asco.org for more information.

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

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I nhibiting Angiogenesis in Breast Cancer: The Beginning of the End or the End of the Beginning?

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PAGE 19

Direct from ASCO

Constructing a Top Five List in Oncology

ASCO identifies five key opportunities to improve quality and value of patient care

he American Society of Clinical Oncology has joined the American Board of Internal Medicine (ABIM) Foundation and eight other medical specialty societies to take a collective stand in improving patient care and addressing rising health-care costs. As part of the ABIM Foundation’s Choosing Wisely® campaign, ASCO, backed by the expertise of more than 30,000 member oncologists, has developed a “Top Five” list of tests and procedures in oncology whose frequent use should be questioned because they do not add clinical value. The list identifies practices that are expensive, widely employed, and not supported by clinical evidence. When used unnecessarily, these procedures may contribute to increasing costs without improving outcomes for patients. In many cases, they may actually do more harm than good, by leading to unnecessary procedures, misdiagnosis, and anxiety among patients.

Culture of Self-examination “As oncologists, it is our personal and professional responsibility both to provide the highest quality of care to our patients and to help rein in the rising costs of cancer care,” said Michael P. Link, MD, President of ASCO. “We hope that ASCO’s participation in this campaign helps to create a culture of self-examination in our field, so that every intervention our patients receive provides meaningful benefit.”

Lowell E. Schnipper, MD

the rising cost of cancer care. Selections were based on a comprehensive review of published studies and current guidelines from ASCO and other organizations. The final list also reflects input from more than 200 oncologists, including the society’s Clinical Practice Committee, the leadership of the state/regional oncology societies, as well as other leading oncologists and patient advocates.

When treatment is no longer likely to work, our chief responsibility as physicians is to help our patients live in comfort and dignity. — Michael P. Link, MD

“By working together to reduce the overuse of these procedures, the oncology field can help improve the care of our patients, while achieving substantial cost savings,” said Lowell E. Schnipper, MD, Chair of ASCO’s Cost of Care Task Force. “This list will help oncologists and their patients make more informed decisions about their care.”

The development of the list for oncology was led by ASCO’s Cost of Care Task Force, a multidisciplinary group of expert oncologists committed to addressing the underlying issues contributing to

bility as physicians is to help our patients live in comfort and dignity,” Dr. Link said. “Oncologists should not feel compelled to provide an intervention when there is no evidence that it will result in meaningful benefit to the patient, especially if it might limit their quality of life.”

ASCO’s Top Five list makes the following recommendations:

2. Do not use PET, CT, and radionuclide bone scans in the staging of early breast cancer that is at low risk of spreading.

1. For patients with advanced solid-tumor cancers who are unlikely to benefit, avoid unnecessary anticancer therapy and focus on symptom relief and palliative care instead. Overtreatment near the end of life is common. Data have shown that a significant number of cancer patients received chemotherapy in their last 2 weeks of life. Such treatment does little to improve

3. Do not use PET, CT, and radionuclide bone scans in the staging of early prostate cancer at low risk of spreading. For patients with these earlystage cancers, use of expensive PET, CT, or radionuclide bone scans to search for further spread has not been shown to improve detection of metastatic disease or result in greater survival. These tests are also known to increase the risk

The Recommendations

Michael P. Link, MD

survival or quality of life. It has the unintended consequence of increasing costs. It may also delay patients’ access to supportive care that could maximize their comfort at this extremely difficult moment. ASCO recommends eliminating treatment that is unlikely to be effective in patients who meet all of the following criteria: those with low performance status (3 or 4); who have not benefited from prior standard therapy; who have no further standard treatment options for their disease; and who are not eligible for a clinical trial. For these patients, emphasis should be placed on palliative and supportive care, which evidence has shown can increase quality of life and, in some cases, increase survival. “When treatment is no longer likely to work, our chief responsi-

of misdiagnosis, which can lead to unnecessary invasive procedures and overtreatment or incorrect treatment. ASCO recommends against the use of these imaging modalities for patients with newly identified ductal carcinoma in situ (DCIS) or stage I or II breast cancer, as well as newly diagnosed low-grade prostate cancer that is unlikely to have macrometastases. 4. For individuals who have completed curative breast cancer treatment and have no symptoms of cancer recurrence, routine blood tests for certain biomarkers (eg, CEA, CA 15-3, CA 2729) and advanced imaging tests (PET, CT, and radionuclide bone scans) should not be used to screen for cancer recurrences. Although these types of tests have been shown to have clinical value for certain cancers, such as colorectal cancer, for women with breast cancer that has been treated with curative intent, these tests have not been shown to improve survival. Moreover, false-positive results can lead to invasive procedures, overtreatment, and misdiagnosis that can severely impact an individual’s quality of life. ASCO guidelines continue to emphasize that routine physical exams and mammography are safe and effective for detecting recurrences. 5. Avoid administering white cell–stimulating factors to patients undergoing chemotherapy who have less than a 20% risk for febrile neutropenia. ASCO guidelines recommend these treatments only when the risk of febrile neutropenia from chemotherapy is greater than 20% and effective alternative therapies are unavailable. However, research shows that use varies widely across the United States, and that many low-risk patients receive the drugs. “There is growing evidence that these drugs are overused, likely costing the U.S. health system tens of millions of dollars. Myeloid growth factors have been continued on page 20

The ASCO Post | MAY 1, 2012

PAGE 20

Direct from ASCO

Top Five List continued from page 19

proven essential in the delivery of dose-dense chemotherapy for [estrogen receptor (ER)]-negative, node-positive women with breast cancer.1 Yet this regimen has dem-

onstrated minimal benefit for the ER-positive patient over standard regimens with lower risk of [febrile neutropenia].2,3 In spite of this evidence, dose-dense chemotherapy remains a widely accepted and recommended standard for all women

with breast cancer in the adjuvant setting,” Dr. Schnipper said. ASCO recognizes that there are exceptions to this recommendation, such as for patients at higher risk for chemotherapy-related febrile neutropenia because of other complica-

Experience our world at ASCO Booth 10115

tions including age, medical history, or disease characteristics.

Implementation in Practice Over the coming months, ASCO will work with its members and other partners in the cancer community to help implement these recommendations in practice. ASCO is developing additional tools and publications for physicians, together with new resources to help patients have informed discussions with their physicians.

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References 1. Citron ML, Berry DA, Hudis C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C99741/ CALGB trial 9741. J Clin Oncol 21:1431-1439, 2003. 2. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:16581667, 2006. 3. Bonilla L, Ben-Ahron I, Vidal L, et al: Dose dense chemotherapy in nonmetastatic breast cancer: A systemic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845-1854, 2010. Originally printed in ASCO Connection. © American Society of Clinical Oncology. “Constructing a Top-Five List in Oncology.” ASCO Connection, May 2012: 36-37. All rights reserved.

Our world centers around theirs ACTION PURPOSE IMPACT

For more information on ASCO’s cost of cancer care efforts and the Choosing Wisely campaign, visit asco.org/TopFive.

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.

This is our pledge. This is GSK Oncology. Learn more at the new GSKoncology.com

04/12

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Direct from ASCO

Institute of Medicine Report on Omics-based Testing Bolsters ASCO’s Blueprint for Transforming Cancer Research

recent report by the Institute of Medicine (IOM) addresses elements that ASCO has stated are necessary for transforming the therapeutic development and clinical trial processes. In March, the IOM released the report “Evolution of Translational Omics: Lessons Learned and the Path Forward,” which includes recommendations for using test models based on “omics” technologies to predict clinical outcomes, and ways to ensure adoption and adherence to the evaluation process. The IOM uses “omics” to characterize global sets of biologic molecules such as DNA, RNA, proteins, and metabolites.

Many of the IOM report’s recommendations align with those in “Accelerating Progress Against Cancer: ASCO’s Blueprint for Transforming Clinical and Translational Research.” Released in November 2011, the Blueprint lays out ASCO’s vision and path for transforming clinical and translational research to deliver more effective and personalized cancer therapies faster. Validated omics-based tests are a fundamental tool for cancer biology discovery and application of molecularly targeted therapies. Their creation and continued development will accelerate realization of the Blueprint.

Oversight of Diagnostic Tests Both the Blueprint and the IOM report call for a strategy to create a clear pathway for regulatory review and oversight of diagnostic tests that relate to use of biomarkers and therapies. The IOM report further details that recommendation, stating that the FDA should “develop and finalize a risk-based guidance or a regulation on: 1. Bringing omics-based tests to the FDA for review 2. Oversight of laboratory-based tests” The Blueprint and the IOM report also include recommendations on promoting greater interdisciplin-

ary collaboration in therapeutic development and clinical research, as well as biospecimen collection, storage, and analysis. ASCO will be holding a session on the IOM report at its 2012 Annual Meeting, taking place June 1-5 in Chicago. The session will be held on June 1 at 1:00 PM and will be chaired by Daniel F. Hayes, MD, who also served on the committee that developed the report. For additional information on the Blueprint, please go to www. asco.org/blueprint.

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The Conquer Cancer Foundation. Our name says a little. Our mission says a lot: Conquering cancer worldwide by funding breakthrough research and sharing cutting-edge knowledge. We are the go-to organization in supporting the world’s preeminent cancer specialists, so one day we can live in a world free from the fear of cancer. To get to know us better now and be a part of our ambitious future, visit ConquerCancerFoundation.org.

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The ASCO Post | MAY 1, 2012

PAGE 22

Lab Notes

Ongoing Molecular Research in the Science of Oncology TARGETED THERAPY PEDF Has Cytotoxic Effect on Breast Cancer Cells and Neuron-protective Effect The cytokine pigment epithelium– derived factor (PEDF) is downregulated in brain metastases of breast cancer by approximately 14-fold compared with primary breast tumors, suggesting that promoting its expression might inhibit metastatic spread. Normal breast epithelial cells express high levels of PEDF; loss of expression of PEDF from these cells is correlated with cancer progression, and level of expression is inversely related to survival in breast cancer. PEDF was discovered as a secreted factor from human retinal pigment epithelial cells that showed potent neuronal differentiation activity. It has a broad expression pattern, with high levels also being found in brain and blood. A number of studies have shown that PEDF has a striking ability to protect neurons from a variety of insults, and it has been implicated as a regulatory factor in numerous processes, including lipid metabolism, stem cell renewal, modulation of inflammatory response, antiangiogenesis, and tumor suppression.

New Pharmacologic Targets In a recent study, Fitzgerald and colleagues from the National Institutes of Health, Bethesda, Maryland, showed that treatment with PEDF exerted tumor-suppressive and neuroprotective effects in experimental brain metastases. Growth of braintropic human (231-BR) and mouse (4T1-BR5) breast cancer cells was suppressed in vitro by treatment with PEDF. Expression of PEDF by breast cancer cells (induced via transduction with a human PEDF transgene) rapidly inhibited proliferation and activated apoptosis of breast cancer cells in the mouse brain. The suppressive effects of PEDF were rapid and independent of antiangiogenic effects. Further, PEDF had a prosurvival effect on neurons that shielded the brain from tumorinduced damage, as indicated by a relative 3.5-fold reduction in the number of dying neurons adjacent to tumors expressing PEDF. As stated by the investigators, “[Our findings] prompt the exciting hypothesis that PEDF can prevent

some of the neuronal and cognitive sequelae associated with the development of brain metastases, both by tumor-suppressive and neuroprotective effects…. Differential expression of [PEDF] receptors on neuronal, endo-

thelial, and cancer cells may provide a partial explanation for the differential effects on these cell populations. Identification of which of these PEDF receptors are present on cancer cells, as well as further elucidation of signal-

ing downstream of PEDF, could lead to the identification of new pharmacologic targets for both anti-cancer and neuronal survival therapies.” Fitzgerald DP, et al: Cancer Res 72:144153, 2012.

TREANDA® is her chemo.

This is her therapy.

ASCOPost.com | MAY 1, 2012

PAGE 23

Lab Notes

Targeting Human Endogenous Retrovirus K Envelope Protein Inhibits Breast Cancer Growth

ily shows conservation of apparently intact retroviral genes and is transcriptionally active in several human cancer tissues and tumor cell lines. Full-length HERV-K transcripts have been shown to be expressed in human breast cancer, and the envelope (env) protein of the HERV-K family is commonly expressed on the surface of breast cancer cells.

The human genome contains a large variety of endogenous retroviral sequences (approximately 8% of the genome). Although most of these are highly defective, the human endogenous retrovirus type K (HERV-K) fam-

Novel Immunotherapy In a recent study, Wang-Johanning and colleagues from The University of Texas MD Anderson Cancer Center, Houston, assessed the effects of targeting HERV-K env with anti-HERV-K env monoclonal antibodies in malignant breast cancer cell lines and in mice bearing xenografts tumors. In

Single-agent TREANDA tripled median PFS in patients with CLL*

Survival distribution function

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

• TREANDA was generally well tolerated in the pivotal phase 3 trial

6 months median PFS

P<.0001

• The most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150)

HR†=0.27 (95% CI‡: 0.17, 0.43)

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. CI=confidence interval.

‡

Single-agent TREANDA produced a 74% ORR§ in patients with indolent B-cell NHL that had progressed ORR§: INDOLENT B-CELL NON-HODGKIN’S LYMPHOMA (NHL) THAT HAS PROGRESSED

57%

PR (n=57)

17%

CR/CRu (n=17)

74%

Total ORR

(95% CI: 64.3, 82.3)

• TREANDA was evaluated in a single-arm pivotal study of 100 patients with indolent B-cell NHL that had progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Patients were scheduled to receive TREANDA 120 mg/m2 on Days 1 and 2 of a 21-day treatment cycle, up to 8 cycles • TREANDA was generally well tolerated in 2 single-arm studies of patients with indolent B-cell NHL that had progressed (N=176)

100

Patients responding (%) Overall response rate (ORR) was defined as a best response of a complete response (CR), unconfirmed complete response (CRu), or partial response (PR) during the study (ORR=CR+CRu+PR). Independent Review Committee assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.

• The most common non-hematologic adverse reactions (frequency ≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%), and pyrexia (34%) (N=176). The most common hematologic abnormalities (frequency ≥15%) were lymphopenia (99%), leukopenia (94%), anemia (88%), neutropenia (86%), and thrombocytopenia (86%)

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established. TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen. Selected Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. Women should be advised to avoid becoming pregnant while using TREANDA l

Discover the elements of efficacy and safety LEARN MORE AT TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Oncology

this study, the expression of HERV-K env protein in malignant breast cancer cell lines was substantially higher than that in nonmalignant breast cells. Several anti-HERV-K-specific monoclonal antibodies inhibited growth and induced apoptosis of breast cancer cells in vitro. Mice treated with anti-HERV-K ancontinued on page 24

The ASCO Post | MAY 1, 2012

PAGE 24

Lab Notes

Ongoing Molecular Research continued from page 23

tibody had significantly reduced growth of tumors (eg, mean size 475 vs 1,448 mm3 for tumors from malignant cell line MDA-MB-231, P < .001) compared with mice receiving control immunoglobulin. Expression of a number of proteins involved in apoptosis signaling pathways

was increased in vitro in malignant breast cancer cells treated with monoclonal antibodies compared with those treated with control immunoglobulin. In a study in 223 primary human breast tumors, 148 (66%) exhibited HERV-K expression, with HERV-K– positive tumors being associated with a significantly higher rate of lymph

node metastasis compared with HERVK-negative tumors (43% vs 23%, P = .003). As stated by the investigators, these findings suggest that “monoclonal antibodies against HERV-K env protein show potential as novel immunotherapeutic agents for breast cancer therapy.”

Wang-Johanning F, et al: J Natl Cancer Inst 104:189-210, 2012.

Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0

Bone Morphogenesis Protein 4 Pathway as Treatment Target in Hepatocellular Carcinoma Bone morphogenesis protein 4 (BMP4), which belongs to the transforming growth factor (TGF)-β family, is a multifunctional cytokine that is known to be involved in human carcinogenesis. The cytokine exerts its effects through

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality Hemoglobin Decreased Platelets Decreased Leukocytes Decreased Lymphocytes Decreased Neutrophils Decreased

TREANDA (N=150) All Grades Grade 3/4 n (%) n (%) 134 (89) 20 (13) 116 (77) 16 (11) 92 (61) 42 (28) 102 (68) 70 (47) 113 (75) 65 (43)

Chlorambucil (N=141) All Grades Grade 3/4 n (%) n (%) 115 (82) 12 (9) 110 (78) 14 (10) 26 (18) 4 (3) 27 (19) 6 (4) 86 (61) 30 (21)

In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two singlearm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Preferred term Total number of patients with at least 1 adverse reaction Cardiac disorders Tachycardia Gastrointestinal disorders Nausea Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia Gastroesophageal reflux disease Dry mouth Abdominal pain upper Abdominal distension General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain

Number (%) of patients* All Grades Grade 3/4 176 (100) 94 (53) 13 (7)

132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 18 (10) 15 (9) 8 (5) 8 (5)

7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 0 1 (<1) 0 0

101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5)

19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0

ASCOPost.com | MAY 1, 2012

PAGE 25

Lab Notes

pathways dependent on and independent of SMAD proteins, which are the intracellular effectors of TGF-β signaling. In a study evaluating the potential role of BMP4 in hepatocellular carcinoma, Chiu and colleagues from National Sun Yat-Sen University in Kaohsiung, Taiwan, showed that BMP4 and the BMP4 receptor BMPR1A are

overexpressed in a majority of primary hepatocellular carcinomas, that BMP4 promotes the growth and migration of hepatocellular carcinoma cell lines in vitro, and that BMP4 can induce hepatocellular carcinoma cyclin-dependent kinase (CDK)1 and cyclin B1 upregulation to accelerate cell-cycle progression. Induction of hepatocellular carci-

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients All Grades Grade 3/4 99 94 94 56 88 11 86 60 86 25

Hematology Variable Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased

noma cell proliferation was independent of the SMAD signaling pathway, as evidenced by upregulation of CDK1 and cyclin B1 expression with BMP4 treatment despite Smad4 knockdown of hepatocellular carcinoma cell lines. Induction of CDK1 and cyclin B1 mRNA and protein was dependent on the activation of MEK (MAPK/ERK)

TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/ mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. PostMarketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 50

DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

Manufactured by: Pharmachemie B.V. The Netherlands

Manufactured for: Cephalon, Inc. Frazer, PA 19355

TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2011 Cephalon, Inc., or its affiliates. TRE-2263 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

signaling. Xenograft studies confirmed that the BMPR1A-knockdown cells were significantly less tumorigenic than control cells. The investigators stated, “BMP4 signaling pathways may have potential as new therapeutic targets in [hepatocellular carcinoma] treatment.”

Chiu C-Y, et al: Mol Cancer Res 10:415427, 2012.

NOVEL MECHANISMS SMAC Mimetics Induce Proinflammatory Cancer Cell Death and Adaptive Antitumor Immune Response SMAC/DIABLO (second mitochondria-derived activator of caspase/ direct inhibitor of apoptosis-binding protein with low pI) is a proapoptotic mitochondrial protein that is released in response to various apoptotic stimuli. Molecular mimetics of SMAC are being investigated for use in cancer treatment, but their activities in vivo have not been fully characterized. In a recent study, Emeagi and colleagues from Vrije Universiteit Brussel, Belgium, showed that SMAC mimetics induce cancer cell death via a proinflammatory effect that is accompanied by an adaptive antitumor immune response. Transduction with lentiviral vectors encoding a cytosolic form of a SMAC mimetic (LV-tSMAC) resulted in apoptosis of cancer cells of different histologic origins, and treatment of tumor-bearing mice with the SMAC mimetic resulted in induction of apoptosis, activation of antitumor immunity, and prolonged survival.

Immune Response The antitumor immune response included increased levels of tumor-infiltrating lymphocytes with low expression of PD-1 (an inhibitory molecule on activated T cells that plays a role in regulating immune response), high lytic capacity, and high levels of the proinflammatory cytokine interferon-γ. Levels of regulatory T cells were reduced in vivo, activation of tumor-specific cytotoxic T cells was observed in vivo, and activation of tumor-specific T cells by dendritic cells isolated from tumor-draining lymph nodes was observed in vitro. As stated by the investigators, “Our findings suggest that SMAC mimetics can elicit a proinflammatory cell death that is sufficient to activate adaptive antitumor immune responses in cancer.”

■

Emeagi PU, et al: Cancer Res 72:13421352, 2012.

The ASCO Post | MAY 1, 2012

PAGE 26

Expert’s Corner Drug Development

Changing the Course of Human Health through Bold Pursuits in Science A Conversation with Jean Pierre Bizzari, MD By Ronald Piana mide—we’ve seen survival for patients with these diseases move from a few years to 10 years, which was unheard of 15 years ago. We are taking our success stories in immunomodulation and epigenetics, and applying these concepts to other blood cancers such as non-Hodgkin lymphoma and chronic lymphocytic leukemia. To put these advances into the pipeline, we currently have more than 30 ongoing phase III trials. Jean Pierre Bizzari, MD

he synergy between industry, academic research, and regulatory bodies will play an increasingly important role in ensuring the future of a robust cancer drug pipeline. To gain insight on oncologic development trends, The ASCO Post recently spoke with Jean Pierre Bizzari, MD, Head of Global Clinical Oncology/ Hematology for Celgene Corporation, a multinational biopharmaceutical company.

Bench to Bedside Please describe the research and development process in the oncology sector. At Celgene, the R&D mission begins and ends with the patient. To that end, our focus is on getting a deeper understanding of tumor biology and employing a translational approach to move that information from “bench to bedside,” in order to improve the specificity of therapies. Much of our research is in biomarker development, which is the driving factor in targeted therapies. Two areas of particular interest to Celgene are immunomodulatory therapy, where we’ve developed thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide, and the exciting new field of epigenetics, with azacitidine (Vidaza) and romidepsin (Istodax). Moreover, our R&D efforts are centered on the emerging trend of turning cancer into a chronic disease. This effort mirrors some of the success we’ve had in difficult-to-treat blood cancers like myelodysplastic syndromes and particularly multiple myeloma. Through the use of novel therapies including lenalidomide and pomalido-

Smaller Patient Populations Please discuss the future of Pharma in this emerging era of personalized medicine and targeted therapies, and how you plan to address the smaller markets in which these agents will be used. There is no choice but to find scientific- and market-driven ways to adapt to the challenging but exciting new markets that are embracing the rapid advances in biology, genomics, and

In non–small cell lung cancer, we found a biomarker called SPARC (secreted protein acidic and rich in cysteine), and we are currently trying to determine if this marker predicts a positive outcome when patients are given albumin-bound paclitaxel (Abraxane). Along with the changing market structure, developing smaller and more targeted therapies will present global opportunities that will enable health-care providers to deliver the right drug to the right patient at the right time, so that patients live longer and better lives.

New Endpoints and Trial Structures We’ve seen growing interest in looking at new ways to structure clinical trials, in an effort to have a more robust drug pipeline. What part can Pharma play in this evolution? A primary thrust in ensuring that

Developing smaller and more targeted therapies will present global opportunities that will enable health-care providers to deliver the right drug to the right patient at the right time. —Jean Pierre Bizzari, MD

proteomics. In short, the markets are increasingly being based on patientand disease-specific needs. Celgene is already in clinical trials with innovative approaches to address that changing landscape. For example, lenalidomide therapy in myelodysplastic syndromes is associated with a successful pharmacogenomic approach to identifying deletion 5q abnormalities in patients who, based on clinical evidence, will receive the maximum benefit. Furthermore, in diffuse large B-cell lymphoma—which affects a rather small patient population—we found that lenalidomide is more active in a subgroup with non–germinal center B cell–like disease (about half of that population). Being able to identify and deliver maximum clinical benefit to those patients is a major breakthrough.

we advance targeted agents is having productive discussions with the regulatory bodies about defining and developing new endpoints. Naturally, overall survival is the most meaningful clinical endpoint, but waiting from clinical trial randomization until death from any cause represents a protracted time lag that delays the process. In order to leverage the emerging biologics, we need to focus on new trial structures such as adaptive design, in which the investigators frequently analyze the data to make necessary clinical adjustments and give the study a better chance of success. Given the small populations of oncology trials (compared to cardiovascular trials, which can have accrual of up to 25,000 patients), this is a significant need. The other component that we feel

will help move promising agents from phase II to phase III is the use of biomarkers, not only for greater efficacy but also to increase safety and avoid adverse events that might take patients off trial. In this exciting new era of medical innovation, we need to increase access to these powerful new therapies that may help patients live longer and better lives. Therefore, collaboration among the biopharmaceutical industry, government, patient advocates, and cooperative groups, here and abroad, is key to our mission to improve the lives of patients worldwide.

Closing Thoughts Any last thoughts about career in oncology? I began my career in oncology 30 years ago in France. I came to the United States and continued my work with many esteemed researchers. Looking back, those past 30 years show a remarkable path of advances that have saved countless lives. I lost my father to colon cancer, and at the time he was battling the disease there was only one drug option. Now, in diseases like colon or breast cancers, we have five lines of active therapies. The key to this incredible 3 decades of progress has come largely from an ongoing cycle of innovation, driving scientific discoveries in the laboratory and delivering medically meaningful therapies to patients in need through rigorous clinical trials. At Celgene, we believe that of all the critical trends that will advance the course of human health, innovation will be the most important. Innovation is the key to improving quality of life and reducing health-care costs. We continue to combine our scientific resources with an optimistic and energetic approach toward building and expanding on existing collaborations with other industries and government institutions, in an effort to bring promising disease-altering therapies to patients with cancer.

■

Disclosure: Dr. Bizzari is Executive Vice President of Celgene, on the scientific board of Transgene, and on the scientific board of the French National Cancer Institute.

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® (denosumab) 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

• 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.

Hypocalcemia

Osteonecrosis of the Jaw (ONJ)

• XGEVA® can cause severe hypocalcemia. Correct preexisting 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. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

• Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA® (denosumab), 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.

www.XGEVA.com

SUPERIORITY XGEVA® (denosumab) 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*/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. Adverse Reactions • The most common adverse reactions in patients receiving XGEVA® were fatigue/asthenia, hypophosphatemia, and nausea.

• The most common serious adverse reaction in patients receiving XGEVA® was dyspnea. • The most common adverse reactions resulting in discontinuation of XGEVA® were osteonecrosis and hypocalcemia. Please see brief summary of Prescribing Information on the following page.

ASCOPost.com | MAY 1, 2012

PAGE 31

In the Clinic

Using Imatinib for Adjuvant Treatment after Resection of Kit (CD117)-positive Gastrointestinal Stromal Tumors By Matthew Stenger

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 January 2012, imatinib mesylate (Gleevec) was granted regular approval for use in adult patients as adjuvant treatment following complete gross resection of Kit (CD117)-positive gastrointestinal stromal tumors (GIST).1 Imatinib had received accelerated approval in this indication in 2008. Labeling for this indication has been updated with results of a phase III trial showing that recurrence-free and overall survival were improved by continuing adjuvant imatinib therapy to 36 months compared with 12 months. Imatinib has prior indications in Philadelphia chromosome–positive chronic myeloid leukemia, myelodysplastic/myeloproliferative diseases, aggressive systemic mastocytosis, hypereosinophilic syndrome/chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, and Kit-positive unresectable/metastatic malignant GIST. In a phase III open-label trial,2 397 patients undergoing surgical resection of Kit-positive GIST were randomized to receive 12 (n = 199) or 36 (n = 198) months of imatinib at 400 mg/d. Patients had to have a tumor diameter > 5 cm and mitotic count > 5/50 high-

OF NOTE By inhibiting the tyrosine kinase receptor c-Kit, imatinib inhibits proliferation and induces apoptosis in GIST cells that express an activating c-Kit mutation.

Visit

power fields, tumor diameter > 10 cm and any mitotic count, or tumor of any size with mitotic count > 10/50 highpowerfields, or a tumor ruptured into the peritoneal cavity. Patients had a median age of 61 years. Median follow up durations were 42 months for patients without a relapse event and 48 months for patients still living. Relapse events occurred in 42% of patients in the 12-month arm and 25% of patients in the 36-month arm, representing a significant 54% reduction in risk of relapse with 36-month treatment (HR = 0.46, P < .0001). Death occurred in 13% of patients in the 12-month arm vs 6% of patients in the 36-month arm, representing a significant 55% reduction in risk for death with 36-month treatment (HR = 0.45, P = .0187).

OF NOTE Imatinib labeling has been updated with results of a phase III trial in GIST showing that survival was improved by continuing adjuvant imatinib therapy to 36 (vs 12) months.

How It Works Imatinib inhibits receptor tyrosine kinases for bcr-abl, platelet-derived growth factor, and stem cell factor (c-Kit). Thus, imatinib inhibits proliferation and induces apoptosis in GIST cells that express an activating c-Kit mutation.

How It Is Given As adjuvant treatment following complete gross resection of GIST, imatinib is dosed at 400 mg once daily, with treatment for 3 years recommended. The optimal duration of imatinib treatment in this setting is not known. Imatinib should be taken with food and a large glass of water to avoid gastrointestinal irritation. Imatinib is metabolized by the CYP3A4 isoenzyme.

Adjuvant Imatinib after Resection of Kit-positive GIST ■■ Imatinib (Gleevec) has received regular approval for use in adults as

adjuvant treatment following complete gross resection of Kit-positive gastrointestinal stromal tumors, an indication for which the drug was granted accelerated approval in 2008.

■■ For the new indication, imatinib is dosed at 400 mg once daily;

recommended treatment duration is 3 years, but the optimal treatment duration is unknown.

Since significant reductions in imatinib concentration may occur when imatinib is administered concomitantly with strong CYP3A4 inducers (for example, many anticonvulsants, barbiturates, and St. John's Wort), such agents should be avoided. If concomitant use of a strong CYP3A4 inducer is necessary, the dosage of imatinib should be increased by at least 50% and clinical response should be carefully monitored. Dosage adjustments are required in patients with moderate renal impairment.

Safety Profile In the trial described above, the most common adverse events were similar to those observed in other imatinib trials and included edema, nausea, vomiting, muscle cramps, bone or muscle pain, diarrhea, rash, fatigue, and abdominal pain. Discontinuation of imatinib therapy due to adverse events occurred in 8% and 14% of patients in the 12- and 36-month arms, respectively. In a prior adjuvant GIST trial, treatment was discontinued for adverse events in 17% of imatinib patients and 3% of placebo patients, with edema, gastrointestinal disturbances (nausea, vomiting, abdominal distention, and diarrhea), fatigue, low hemoglobin, and rash being the most frequently reported adverse events at the time of discontinuation. In adjuvant trials, adverse events of grade 3 or higher observed in imatinib recipients included increased alanine

aminotransferase (3% vs 0% for placebo), increased aspartate aminotransferase (2% vs 0%), decreased neutrophil count (3% vs 1%), and decreased hemoglobin (1% vs 0%) among laboratory abnormalities. Clinical adverse events included abdominal pain (3% vs 1%), diarrhea (3% vs 1%), rash (3% vs 0%), fatigue (2% vs 1%), nausea (2% vs 1%), vomiting (2% vs 1%), and periorbital edema (1% vs 0%).

■

References 1. U.S. Food and Drug Administration: Imatinib mesylate tablets. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289789.htm. Accessed March 23, 2012. 2. GLEEVEC (imatinib mesylate) tablets prescribing information. Novartis Pharmaceuticals Corporation, January 2012. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2012/021588s035lbl.pdf. Accessed March 23, 2012.

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 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).

website at ASCOPost.com

The ASCO Post | MAY 1, 2012

PAGE 32

2012 Oncology Meetings May 4th IMPAKT Breast Cancer Conference May 3-5 • Brussels, Belgium For more information: www.esmo.org ONS 37th Annual Congress May 3-6 • New Orleans, Louisiana For more information: www.ons.org

ASCO Annual Meeting June 1-5 • Chicago, Illinois For more information: chicago2012.asco.org Cambridge Healthtech Institute’s 10th Annual Meeting: Next-Gen Kinase Inhibitors June 4-6 • Cambridge, Massachusetts For more information: www.healthtech.com ASHP 2012 Summer Meeting June 9-13 • Baltimore, Maryland For more information: www.ashpmedia.org

State of the Art Techniques in IMRT, IGRT, SBRT, Proton and Brachytherapy May 4-6 • Las Vegas, Nevada For more information: www.astro.org Current Strategies in the Treatment of Multiple Myeloma, Lymphoma and Leukemia May 12 • Dallas, Texas For more information: www.cancernetus.com Accelerating Anticancer Agent Development and Validation Workshop May 16-18 • Bethesda, Maryland For more information: www.acceleratingworkshop.org AUA Annual Meeting May 19-23 • Atlanta, Georgia For more information: www.aua2012.org Keystone Symposia: The Role of Inflammation during Carcinogenesis May 20-25 • Dublin, Ireland For more information: www.keystonesymposia.org

June Society for Immunotherapy of Cancer Primer on Tumor Immunology and Cancer Immunotherapy™ From Biology to Treatment June 1 • Chicago, Illinois For more information: www.sitcancer. org/meetings/primer12/06/

Apoptosis and Cancer June 14-15 • Cambridge, United Kingdom For more information: www.abcam.com Melanocytes and Melanoma: From Basic Science to Clinical Applications June 18-20 • Malmö, Sweden For more information: www.melanoma2012.org 4th Molecular Diagnostics for Cancer Drug Development June 25-28 • Boston, Massachusetts For more information: http://moleculardiagnostics-cancer.com

13th International Lung Cancer Congress July 19-22 • Huntington Beach, California For more information: http://cancerlearning.onclive.com

July Best of ASCO® Chicago July 12-13 • Chicago, Illinois For more information: http://boa2012.asco.org Pan Pacific Lymphoma Conference July 17-20 • Lahaina, Maui, Hawaii For more information: unmc.edu/panpacificlymphoma

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

5th Latin American Lung Cancer Conference July 25-27 • Rio De Janeiro, Brazil For more information: www.lalca2012.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

Cancer Vaccines & Active Immunotherapeutics: 3rd Annual Summit June 26-28 • Boston, Massachusetts For more information: http://cancervaccines-meeting.com MASCC/ISOO International Symposium on Supportive Care in Cancer June 28–30 • New York, New York For more information: www.kenes.com/mascc

10th International Congress on Targeted Therapies in Cancer August 10-12 • Washington, DC For more information: http://cancerlearning.onclive.com

September Multidisciplinary Symposium in Thoracic Oncology September 6-8 • Chicago, Illinois For more information: http://thoracicsymposium.org 17th International Conference on Cancer Nursing September 9–13 • Prague, Czech Republic For more information: www.isncc.org/conference/17th_ICCN 9th International Symposium on Melanoma and Other Cutaneous Malignancies September 12 • Chicago, Illinois For more information: http://cancerlearning.onclive.com

Pan Pacific

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Conference Directors James James O. O. Armitage, Armitage, MD MD

Joe Joe Shapiro Shapiro Professor Professor of of Medicine Medicine Division Division of of Oncology Oncology and and Hematology Hematology Department of Internal Medicine Department of Internal Medicine University University of of Nebraska Nebraska Medical Medical Center Center

Julie Julie M. M. Vose, Vose, MD, MD, MBA MBA

Chief, Chief, Division Division of of Oncology Oncology and and Hematology Hematology Neumann Neumann M. M. and and Mildred Mildred E. E. Harris Harris Professor Professor Department Department of of Internal Internal Medicine Medicine University University of of Nebraska Nebraska Medical Medical Center Center

CALL CALL FOR FOR ABSTRACTS: ABSTRACTS: April April 16, 16, 2012 2012

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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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Leadership

Dr. Ronald D. Alvarez Elected 44th President of the Society of Gynecologic Oncology

onald D. Alvarez, MD, Professor and Director of the Division of Gynecologic Oncology at the University of Alabama at Birmingham, was elected the 44th President of the

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.

ary times and our members need to be prepared for the changes coming with health-care reform,” states Dr. Alvarez. “Our members need to feel empowered to be the best providers of high-

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

Ronald D. Alvarez, MD

quality, cost-effective prevention and treatment to women at risk for or diagnosed with gynecologic cancer.” Dr. Alvarez received his MD degree from Louisiana State University Medical Center. His postgraduate training included a residency in Obstetrics and Gynecology and fellowship in Gynecologic Oncology, both completed at University of Alabama. After completing his training, he remained on the faculty of the University of Alabama Department of Obstetrics and Gynecology, where he currently serves as Director of the Division of Gynecologic Oncology and Vice-Chairman of the Department of Obstetrics and Gynecology; he also holds the Ellen Gregg Shook Culverhouse Chair. His long-term research interests have included the development of novel therapeutics for ovarian cancer and new screening and prevention strategies for cervical cancer. 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

Society of Gynecologic Oncology at the society’s 43rd Annual Meeting on Women’s Cancer held March 24-27, 2012, in Austin, Texas. Safety:7" “We are in the midst of evolution-

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*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

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PAGE 37

In the News Gynecologic Oncology

New Guidelines Recommend Less Frequent Screening for Cervical Cancer, but That Doesn’t Mean Screening Is Less Important 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.

n March 2012, the U.S. Preventive Services Task Force (USPSTF) released updated recommendations about cervical cancer screening. The guideline revisions chiefly entail lengthening the intervals between cervical cancer screening tests to every

“Just because we have lengthened the interval does not mean that this is not an important test to have. We strongly encourage women to continue to be screened at the appropriate interval and not to think this means that they can ignore this problem,” Michael L. LeFevre, MD, MSPH, Co-Vice Chair of the U.S. Preventive Services Task Force, stated in an interview with The ASCO Post. “The major reason for cervical cancer in the United States today is not a failure of screening; it is a failure to be screened and get appropriate follow-up,” Dr. LeFevre added. “At least half of the cases of invasive cervical cancer in the United States occur because women have not been screened or have not had adequate follow-up to a positive test.” Dr. LeFevre is Professor and Vice Chair in the Department of Family and Community Medicine at the University of Missouri School of Medicine, Columbia.

Annual Pap: A ‘Thing of the Past’ Michael L. LeFevre, MD, MSPH

3 years for women aged 21 to 65 who are screened with cytology, or every 5 years for women aged 30 to 65 who are screened with a combination of cytology and human papillomavirus (HPV) testing, and waiting until a woman is 21 to start screening, regardless of sexual history. Reduced frequency of screening tests, however, does not equate with reduced importance.

The demise of the annual Papanicolaou test after decades as a trusted early detection strategy was mentioned in news reports about the updated cervical cancer screening guidelines. “The annual Pap smear, a cornerstone of women’s health for at least 60 years, is now officially a thing of the past, as new national guidelines recommend cervical cancer screening no more often than every 3 years,” reported The New York Times.2 In a statement announcing the updated guidelines, USPSTF Chair Virginia Moyer, MD, MPH, Professor

Women Who Received HPV Vaccine Still Need Cervical Cancer Screening

he updated cervical cancer screening guidelines from the the U.S. Preventive Services Task Force (USPSTF) note that women who receive the HPV vaccine still need to be screened for cervical cancer because the vaccine does not protect against all strains of HPV that can cause cervical cancer. “The reality is that we just don’t have any idea what the effect of the HPV vaccine is going to be, on either precancerous cervical lesions or cervical cancer itself,” according to Michael L. LeFevre, MD, MSPH, Co-Vice Chair of the USPSTF. “We don’t know the length of immunity,” Dr. LeFevre continued. “We just don’t have 15- or 20-year follow-up on the vaccine,” Dr. LeFevre said. “I think the important thing is that people may think, ‘I had the HPV vaccine, I don’t need to worry about being screened for cervical cancer,’ but that’s not true. This is a very important public health message for us to get out. It may be true 20 years from now, but right now it is not.”

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Could HPV Testing Be Used Alone?

“I

n the United States, there are no recommendations currently for HPV screening alone as a primary screening test for cervical cancer,” Michael L. LeFevre, MD, MSPH, Co-Vice Chair of the U.S. Preventive Services Task Force (USPSTF) told The ASCO Post. “Cytology picks up very few cases of precancerous lesions that are not found with HPV screening. So it is kind of a fail-safe,” Dr. LeFevre said. Both tests can be done at the same time using the same sample. “There is limited evidence on the benefits and harms of HPV testing alone as a screening strategy,” the USPSTF noted in its updated guidelines on cervical cancer screening. “An emerging chain of evidence suggests that HPV testing followed by cytology in women with positive HPV test results may also be a reasonable screening strategy. Ongoing studies, such as the HPV Testing for Cervical Cancer Screening (HPV FOCAL) trial, which compares HPV with cytology triage to cytology with HPV triage of test results interpreted as atypical squamous cells of undetermined significance, should provide relevant direct evidence on HPV testing that applies to current U.S. practice.” Dr. LeFevre remarked, “We look forward to the results of the FOCAL trial, which is going on in Canada. For right now, we don’t recommend HPV testing alone. We recommend co-testing with cytology and HPV as a way to lengthen the interval between the screenings.” Other promising data may emerge from the Population Based Screening Study Amsterdam (POBASCAM) trial in the Netherlands, which also used HPV testing as the primary screening tool and cytology for those who tested positive for HPV. “We might learn more in about 3 to 4 years about other strategies that might cause even less trouble for women who are getting screened and yet could be just as safe,” Dr. LeFevre said.

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of Pediatrics at Baylor College of Medicine in Houston, commented, “This is good news for women because evidence shows that an annual Pap smear is not necessary to prevent deaths from cervical cancer. Screening every 3 years starting at age 21 saves the same number of lives as annual screening, but with half the number of colposcopies and fewer false-positive tests,” she noted. “Many individuals and clinicians have used the annual [Pap] smear screening visit as an opportunity to discuss other health problems and preventive measures,” the Task Force noted in its report. New opportunities for these discussions may need to be created to supplement those that already exist, such as other screening examinations recommended by the USPSTF, which have varying intervals, or annual or periodic checkups, Dr. LeFevre said. “In the primary care community, we know that if we only tie preventive services to an annual checkup, we will fail to get the necessary services to people because not everybody comes in for that. As a health system, we have to try to achieve the necessary preventive services at a variety of intervals, and we have

to capitalize on periodic health exams as well as visits for other reasons to make sure that happens. We don’t want to discourage people from enSee Page 42 gaging in necessary health services just because they don’t need a Pap smear,” he continued.

HPV Infections Can Clear by Themselves “It is well established that HPV infection is associated with nearly all cases of cervical cancer,” the guidelines note, but many HPV infections clear by themselves and do not lead to cervical cancer. “There is nothing that we can do to make it go away. A woman’s own body takes care of it and rids her of the HPV infection,” Dr. LeFevre noted. “We recommend against using HPV as a screen for cervical cancer or precancerous lesions for women under 30 because the prevalence of HPV in that age range is still fairly high and most of those cases are going to go away by themselves. So we would be detecting a lot of HPV that doesn’t need to be decontinued on page 39

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PAGE 39

In the News

Less Frequent Screening for Cervical Cancer continued from page 37

tected.” In women over age 30, however, HPV “is decreased in incidence, and we are picking up enough infections that are going to persist rather than go away spontaneously,” Dr. LeFevre explained. “That’s the point at which HPV testing may be helpful.” In addition, HPV testing is more sensitive but less specific than cytology, leading to more false-positives.

Harms of Screening and Treatment Screening with cervical cytology or HPV testing and treatment of screening-detected disease can lead to harm, according to the updated guidelines. “Abnormal test results can lead to more frequent testing and invasive diagnos-

tic procedures, such as colposcopy and cervical biopsy. Evidence from randomized, controlled trials and observational studies indicates that harms from these diagnostic procedures include vaginal bleeding, pain, infection, and failure to

“Summary evidence from observational studies indicates that some treatments for precancerous lesions (such as cold-knife conization and loop excision) are associated with adverse pregnancy outcomes, such as preterm

clinically important over a woman’s lifetime; identification and treatment of these lesions constitute overdiagnosis. It is difficult to estimate the precise magnitude of overdiagnosis associated with any screening or treatment strategy, but it is of concern because it confers no benefit and leads to unnecessary surveillance, diagnostic tests, and treatments with the associated harms.” According to Dr. LeFevre, “The more you screen, the more likely it is that you are going to detect abnormalities of the cervix that even in the absence of treatment would go away by themselves.” He estimated that 90% of women with acute HPV infection “will clear that infection within 2 years.” Even among those who don’t clear the infection within 2 years but go on to develop cervical intraepithelial neoplasia (CIN)

The more you screen, the more likely it is that you are going to detect abnormalities of the cervix that even in the absence of treatment would go away by themselves. —Michael L. LeFevre, MD, MSPH

diagnose (due to inadequate sampling). Abnormal screening test results are also associated with mild psychological harms; short-term increases in anxiety, distress, and concern about health have been reported with cytology and HPV testing,” the Task Force stated.

delivery, that can lead to low birthweight in infants and perinatal death,” the Task Force continued. “Evidence is convincing that many precancerous cervical lesions will regress and that other lesions are so indolent and slowgrowing that they will not become

continued on page 40

Expect Questions from Your Patients: Cervical Cancer Screening Guidelines

hanges in the cervical cancer screening guidelines, as recommended by the U.S. Preventive Services Task Force (USPSTF), mainly concern longer intervals between screening tests and recommended ages when women should start and stop being screened. USPSTF Co-Vice Chair Michael L. LeFevre, MD, MSPH, addressed some of the questions that patients might have about the revised guidelines. Do the cervical cancer screening guidelines apply to all women? No. In general, the guidelines apply to women who have a cervix, regardless of sexual history, and are aged 21 to 65, although as noted below, in some cases screening may continue past age 65. The new guidelines reaffirm recommendations from the previous guidelines, published in 2003, “against screening in adequately screened women older than age 65 years and in women who have had a total hysterectomy with removal of the cervix.” The new recommendation statement “does not apply to women who have received a diagnosis of a high-grade precancerous cervical lesion or cervical cancer, women with in utero exposure to diethylstilbestrol, or women who are immunocompromised (such as those who are HIV-positive).” When should screening start? The USPSTF recommends screening for cervical cancer in women starting at age 21, regardless of sexual history, but

against screening in younger women “because the evidence shows no net benefit.” When should screening stop? Women who have been adequately screened for cervical cancer can stop screening at age 65. The guidelines point out that the American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology “define adequate prior screening as three consecutive negative cytology results or two consecutive negative HPV results within 10 years before cessation of screening, with the most recent test occurring within 5 years.” Screening may be indicated in older women who have never been screened for cervical cancer or inadequately screened. In addition, “certain considerations may support screening in women older than age 65 years who are otherwise considered [to be at] high risk (such as women with a highgrade precancerous lesion or cervical cancer, women with in utero exposure to diethylstilbestrol, or women who are immunocompromised),” the Task Force noted. “Women choosing co-testing to increase their screening interval (and potentially decrease testing) should be aware that positive screening results are more likely with HPV-based strategies than with cytology alone and that some women may require prolonged surveil-

lance with additional frequent testing if they have persistently positive HPV results,” according to the guidelines. “Because HPV test results may be positive among women who would otherwise be advised to end screening at age 65 years on the basis of previously normal cytology results alone, the likelihood of continued testing may increase with HPV testing. The percentage of U.S. women undergoing co-testing who will have a normal cytology test result and a positive HPV test result (and who will therefore require additional testing) ranges from 11% among women age 30 to 34 years to 2.6% among women age 60 to 65 years.” What if the results of screening tests are positive? Before answering this question, Dr. LeFevre stressed that these comments go beyond the scope of the Task Force recommendations and are based on recommendations from the ACS and the ASCCP. “The current standard of care for women who have, on cytology, atypical squamous cells of undetermined significance (ASCUS) is to do an HPV test and if the HPV test is positive, to go to colposcopy,” Dr. LeFevre said. “But if their HPV test is negative, they should have more intense screening, typically coming back at 6 months and 1 year.” Changes in the ACS/ASCPP guidelines now call for women who have ASCUS but who are HPV negative to continue with rou-

tine screening. “You’re treated as normal basically because your chances of having something bad are really no greater than somebody who had a normal Pap smear and a negative HPV. So in the context of a negative HPV, both ASCUS and normal cytology would be treated the same. That’s new. That’s not in the Task Force, but it is in the ACS guideline,” Dr. LeFevre said. He added that the ACS guidelines also advise against colposcopy for women over 30 who have a normal cytology and are HPV-positive, recommending instead one of two options. One option would be retesting in a year and, if negative, then returning to routine screening. “So you have to be positive 2 years in a row for HPV to go to colposcopy if your cytology is normal,” he noted. “The other option would be to have specific genotype testing for HPV, and if you are positive for HPV 16 or 18, to go straight to colposcopy.” The genotype testing “is a step beyond the usual HPV screening,” Dr. LeFevre said, and would involve “taking another sample from the cervix.” He added that genotype testing is not widely available, although the new recommendation may mean that more centers may start to offer it. “But right now the strategy for many women will be to wait a year, repeat the test, and only if you are positive 2 years in a row, to go to colposcopy.”

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The ASCO Post | MAY 1, 2012

PAGE 40

In the News

Less Frequent Screening for Cervical Cancer continued from page 39

grade 2 or 3, “a significant percentage of those will go away also,” Dr. LeFevre said. “It is standard practice in the United States, certainly at the CIN2 level, to go ahead and treat to prevent further

progression. So we end up treating people whose conditions would have gone away without treatment. The treatment of CIN2+ has been associated in some circumstances with pregnancy complications. It is not the screening test itself; it is the treatment for cervical changes,” Dr. LeFevre explained.

In a key statement from its recommendations, the Task Force noted, “Maintaining the comparability of the benefits and harms of co-testing and cytology alone demands that patients, clinicians, and health-care organizations adhere to currently recommended screening intervals, protocols for repeat

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testing, cytologic thresholds for further diagnostic testing (that is, colposcopy) and treatments, and extended surveillance as recommended by current American Cancer Society/American Society for Colposcopy and Cervical Pathology/ American Society for Clinical Pathology (ACS/ASCCP/ASCP) guidelines.”

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

References 1. Moyer VA, on behalf of the U.S. Preventive Services Task Force: Screening for Cervical Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. March 14, 2012 (early release online). 2. Parker-Pope T: New guidelines advise less frequent Pap smears. New York Times, March 14, 2012.

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PAGE 41

Patient’s Corner Gastrointestinal Oncology

Quality of Life Is What’s Most Important to Me By Connie Thoelen, as told to Jo Cavallo

or me, getting a cancer diagnosis has been more annoying than frightening. Mainly, I’m annoyed at myself for not taking care of an anal skin tag sooner. (I’d had it since birth.) The growth hadn’t been a problem until I got pregnant with my first child and it became temporarily engorged with blood. During each of my next two pregnancies, the skin tag became progressively problematic, changing in appearance and becoming hard to the touch.

colostomy would only have to be in place temporarily, I refused to have any part of it. Even though I understood the

B:8.375”

seriousness of my situation, I made T:7.63” the decision to take a chance that S:6.875” my cancer hadn’t spread beyond the lymph nodes excised during surgery.

And I’m grateful that my doctors respected my wishes and didn’t pressure me into acquiescing to more continued on page 42

Having cancer has taught me to not put off things that need attention. —Connie Thoelen

After giving birth to my third child, my gynecologist recommended that I have it removed, but I was too embarrassed to have the procedure and I didn’t think the skin tag presented any real threat to my health. Over the next few years, however, the growth became more uncomfortable and I began to feel more and more fatigued, although I never related being tired to the tumor.

Clinical Course In 2003, when I finally saw my primary care physician about the problem, he promptly sent me to a colorectal surgeon to have the growth removed. By then the tumor was 5 cm long and extended back to my vaginal wall. A biopsy of the tumor showed that I had stage IV anal cancer and that it had spread to my lymph nodes. My oncologist recommended that a colostomy be done so he could remove the entire tumor. Although there was a possibility the

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PAGE 42

Patient’s Corner

Quality of Life

Life Lessons

continued from page 41

Although the treatments affected my digestive and bowel systems and threw me into early menopause, I’ve been fortunate that over the past 9 years, my follow-up biopsies have been clear and there is no sign of cancer recurrence. However, what I knew from

aggressive therapy. Instead, I had three cycles of continuous-infusion fluorouracil for 5 days each cycle, followed by 62 doses of radiation therapy, which eliminated the remaining tumor.

the beginning—and I feel the same way now—is that if my cancer had been more widespread, requiring more aggressive and radical treatment, even though it might have potentially given me a few more years, I wouldn’t have agreed to it if that meant sacrificing my quality of life. At the time of my diag-

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nosis, I had three small children and a young husband, and I didn’t want to put them through what could have been years of seeing me suffer from this disease. When I got my cancer diagnosis, I didn’t feel angry or ask, “Why me?” I didn’t fear death or worry about making the crucial decisions regarding my treatment. I didn’t go through any of that emotional upheaval. But what having cancer has taught me is to not put off things that need attention. My doctor told me that if I had waited 6 more months before seeking treatment, instead of getting well, I would have been preparing my family for my death. And that was an eye-opener for me, because life would have dramatically changed for everyone. I’m glad my family was spared that pain.

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Connie Thoelen lives in Mahwah, New Jersey.

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PAGE 43

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Nearly 800,000 Lung Cancer Deaths Averted during 1975–2000 Due to Decline in Smoking Rates The cumulative impact of changes in smoking behavior that started in the mid-1950s averted approximately 795,851 U.S. lung cancer deaths, 552,574 among men and 243,277 among women from 1975 to 2000, according to a report in the Journal of the National Cancer Institute. The researchers also estimated that more than 1.6 million lung cancer deaths among men and more than 880,000 among women might have been averted if all smokers had quit in response to the Surgeon General’s first Report on Smoking and Health issued in 1964. A consortium of six universities and research centers developed independent models to estimate the impact of tobacco control policies on lung cancer mortality. “The models explicitly consider factors associated with the risk of smoking, including the number of cigarettes smoked per day, the age of initiation, and the number of years quit,” the investigators stated. “The prevalence of smoking and lung cancer deaths under three scenarios were considered: actual tobacco control, based on historical changes in smoking rates; no tobacco control, based on predicted smoking rates if tobacco control had not been enacted; and complete to-

bacco control, which considers what might have happened if all smoking ceased in 1965,” the authors explained. “The models yielded a range of results for the numbers of lung cancer deaths among the three smoking scenarios, but the estimates of the fraction of lung cancer deaths averted were reasonably consistent across models,” the authors noted.

Take-home Message “The main message of these analyses is clear. Tobacco control strategies implemented mid-century have averted hundreds of thousands of lung cancer deaths in the United States during the period 1975 to 2000, but these are only approximately 30% of the lung cancer deaths that could have been averted had all cigarette smoking ended in 1965,” the investigators stated. They attributed this to several factors: lag time between the Surgeon General’s Report and the time it took for smoking rates to decline; smokers’ risk of lung cancer remaining elevated for years after they quit; and “a sizable fraction of the population” who continued to smoke. “Clearly, further reductions in smoking rates will be required to reduce lung cancer incidence and mortality rates substantially,” the authors concluded. “The recently reported 20% reduction in lung cancer mortality as a result of early detection using lowdose spiral CT suggests that screening of high-risk individuals may play

a role in reducing mortality from this disease. Because risk of lung cancer remains elevated for a long time among smokers who quit, effective screening techniques may have a role in reducing lung cancer mortality among ex-smokers. However, continued implementation of evidence-based tobacco control policies, programs, and services remains the most promising approach to reducing the burden of lung cancer.” Moolgavkar SH, et al: J Natl Cancer Instit 104:541-548, 2012.

COLON CANCER Adding Cetuximab to Adjuvant Therapy with Modified FOLFOX6 Does Not Improve Survival Adding cetuximab (Erbitux) to adjuvant treatment with mFOLFOX6, the modified sixth version of FOLFOX (leucovorin, fluorouracil, oxaliplatin) did not improve disease-free survival among patients with resected stage III colon cancer, even those with wildtype KRAS, according to a phase III study in the Journal of the American Medical Association. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab in patients with wild-type KRAS, and 67.1% vs 65% in patients with mutated KRAS, with no evidence of benefit in any individual subgroup. Neither time to recurrence nor overall survival was significantly different between treatment groups. A total of 2,686 patients comprised the analysis cohort (1,863 patients with wild-type KRAS, 717 patients with mutated KRAS, and 106 patients with indeterminate KRAS). The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. “Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%) and failure to complete 12 cycles (33% vs 23%) were significantly higher with cetuximab,” the researchers reported. “Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older.” The authors noted that cetuximab has provided additional benefit above that derived from chemotherapy in the metastatic setting, but that benefit was limited to patients expressing the

wild-type form of the KRAS gene as opposed to those with the mutated form of KRAS. The reasons for the lack of benefit of mFOLFOX6 with cetuximab in the adjuvant setting remain unclear. “New approaches are needed to identify drugs that may be of benefit in adjuvant therapy, because as shown in our trial promising activity in the metastatic setting did not translate into adjuvant therapy benefit and underscores the importance of performing clinical trials,” the researchers concluded.

Practical Implications This theme was echoed in an accompanying editorial by Neil H. Segal, MD, PhD, and Leonard B. Saltz, MD, of Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York. “The inescapable conclusion is that efficacy in the metastatic setting does not reliably predict efficacy in the adjuvant setting,” Drs. Segal and Saltz stated. “The role of adjuvant chemotherapy does not involve treating the tumor that the surgeon has removed, but rather attempts to eradicate whatever occult micrometastatic disease may still be present after surgery. If there are no micrometastases, surgery is curative and adjuvant chemotherapy is unnecessary. If micrometastases are present, the long-term health of the patient will depend on whether the chemotherapy can destroy all remaining micrometastases,” they commented. “The practical implications of the observation that the mechanism by which chemotherapies kill tumor cells in the macrometastatic setting must differ in some fundamental way from how these agents kill tumor cells in the micrometastatic setting are that activity in the macrometastatic setting cannot be used as a surrogate for activity in the adjuvant setting,” they continued. “However, it should not be assumed that agents that are ineffective in the macrometastatic setting will not be active in the adjuvant setting (this may be particularly true of immunomodulating agents). For now, the only way to determine if an approach is useful in the adjuvant setting is by obtaining reliable results from rigorously conducted clinical trials.

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Alberts SR, et al: JAMA 307:13831393, 2012. Segal NH, Saltz LB: JAMA 307:14311432, 2012.

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